bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidating distinct tumorigenic pathways in nodular versus superficial spreading melanoma.
Authors: Farhadian Joshua Andrew , O'Reilly Kathryn E. , Vega-Saenz de Miera Eleazar , Ye Fei , Zavadil Jiri , Taunton Jack , Zhang David Y. , Osman Iman
Published: March 2020

8544

Background: Superficial spreading melanoma (SSM) and nodular melanoma (NM), which account for 70% and 20% of all melanoma diagnoses respectively, are believed to represent sequential phases of linear progression from radial to vertical growth. Recent evidence from several groups including ours challenges this linear progression model and suggests that SSM and NM are biologically distinct. In this study, we focused on identifying tumorigenic pathways that are differentially activated in melanoma subtypes and that can be therapeutically exploited. Methods: We performed Protein Pathway Array on SSM/radial growth phase (RGP) and NM/vertical growth phase (VGP) primary melanoma cell lines to determine expression levels of 141 tumorigenic proteins/phospho-proteins. Differential protein expression was determined using the Pavlidis Template Matching algorithm in TIGR Multi Experiment Viewer. Differentially expressed proteins were validated in an expanded panel of RGP, VGP, and metastatic melanoma cell lines using western blot. Constitutively active, overexpressed proteins in VGP melanoma were down-regulated in cell lines using several small molecule inhibitors and the effects on proliferation and migration were assessed. Results: 17 (12%) proteins/phospho-proteins are significantly overexpressed in VGP versus RGP melanoma (p<0.05). Western blot confirmed the results of 5 proteins/phospho-proteins. Each of those 5 was equally overexpressed in VGP and metastatic melanoma cell lines. Phospho-p90 ribosomal s6 kinase (RSK) was prioritized for functional studies based on its role in both the MAPK and AKT signaling cascades, two tumorigenic pathways often dysregulated in melanoma. Constitutive phosphorylation of p90 RSK in VGP, but not RGP melanoma was observed in response to serum starvation. Small molecule inhibition of phospho-p90 RSK attenuated proliferation and migration (p<0.05) in VGP melanoma. Conclusions: Data demonstrate discrete tumorigenic pathways are activated in nodular versus superficial spreading melanoma and suggest that phospho-p90 RSK might be a viable target against nodular melanoma.
Serum IL-6 as a prognostic biomarker in patients with stage IIB-III melanoma.
Authors: Hoejberg Lise , Bastholt Lars , Johansen Julia S. , Christensen Ib Jarle , Krogh Merete , Fode Kirsten , Schmidt Henrik
Published: March 2020

8545

Background: Interleukin (IL)-6 is an immunomodulatory cytokine produced by cancer cells and different immune cells. The specific function of IL-6 in cancer is unknown. Serum IL-6 is elevated in patients with different types of cancer. Elevated serum concentration of IL-6 is related to short survival in patients with stage IV melanoma. Methods: IL-6 was measured by ELISA (R&D) in pretreatment serum samples from 435 patients with stage IIB-III melanoma (151 women and 284 men, median age 51 years, range 18-77). After surgery patients were treated in a randomized study (The Nordic IFN trial) with either adjuvant interferon for 1 or 2 years, or observation. Results: Median serum concentration of IL-6 after surgery and before treatment was 1.8 ng/l, range 0.23-24 ng/l. Patients with serum IL-6 above the median had shorter overall survival (OS) compared to patients with serum IL-6 below the median (p=0.004). Median OS was 4.5 years in patients with serum IL-6 above the median (95% confidence interval (CI): 3.05-7.60). In patients with serum IL-6 below the median, median OS was not reached at the last survival-update. Multivariate Cox analysis including serum IL-6, ulceration in primary melanoma, LDH, white blood cells, lymph node metastases and Breslow thickness of primary melanoma showed that only serum IL-6 (hazard ratio (HR) = 1.48, 95% confidence interval (CI) : 1.13-1.94, p=0.004) was an independent prognostic factor for OS. In subgroup analysis of the control group and the two treatment groups, serum IL-6 demonstrated a negative prognostic impact in the control group (HR = 1.62, 95% CI: 1.02-2.57, p=0.04) and in the group treated with 2 years interferon HR = 1.69, 95% CI: 1.06-2.7, p=0.03). In the group treated with 1 year interferon this negative impact was not significant (HR = 1.15, 95% CI: 0.71-1.85, p=0.58). An interaction between IL-6 and treatment arm was not significant (p=0.45), suggesting that the negative prognostic effect of elevated pretreatment serum IL-6 is independent of treatment. Conclusions: Serum IL-6 above the median is an independent prognostic biomarker of short OS in patients operated for stage IIB-III melanoma.
Phase II study of the anti-ganglioside GD3 mouse/human chimeric antibody KW2871 combined with high dose interferon-a2b in patients with metastatic melanoma.
Authors: Moschos Stergios J. , Tarhini Ahmad A. , Gajewski Thomas , Scott Andrew Mark , Lin Yan , Shipe-Spotloe Janice , Deblasio Weiping Xu , Sander Cindy , Matijevich Karen , Smyth Fiona Elizabeth , Liu Zhanqi , Hoffman Eric W. , Venhaus Ralph Rudolph , Pan Linda S. , Tran Sinhan , Fiore James , Kirkwood John M.
Published: March 2020

8547

Background: Immunotherapy has demonstrated notable effects in metastatic melanoma (MM) with durable responses achieved by high-dose IL-2 and IFNα2b, leading to approval of these therapies for treatment of melanoma. However, complete responses occur in only a minority of patients. KW2871 is a chimeric monoclonal antibody (mAb) targeting the GD3 ganglioside with demonstrated antitumor activity and enhancement of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). IFNα2b has potent immunoregulatory, anti-proliferative, differentiation-inducing, pro-apoptotic, and anti-angiogenic properties against a variety of malignancies including melanoma. Combining high dose IFNα2b (HDI) + KW2871 was hypothesized to have synergistic anti-tumor activity due to (1) the ability of HDI to enhance KW2871 induced ADCC in vitro (Liu, Cancer Immun 2002); (2) improved mAb targeting due to increased GD3 expression and induced inflammatory cytokines (TNF-α, IL-4 and IFN-γ) (Hoon, Cancer Res, 1991); (3) increased tumor-infiltrating immune cells (Kirkwood, Cancer 2002; Moschos, J Clin Oncol 2006). Methods: This is an open label, dose-escalation, phase II study of KW2871 plus HDI in patients with measurable MM. Primary objectives are progression-free survival (PFS) and safety. Secondary objectives include assessment for tumor response by RECIST, ADCC, CDC, pharmacokinetics, human antichimeric antibodies (HACA), tumor-infiltrating immune cells, biomarkers and OS. Patients with measurable disease by RECIST, stable brain metastases, and performance status ECOG 0 or 1 are eligible. Patients with severe comorbidities or autoimmune disease or prior exposure to anti-GD3 antibodies are excluded. Sequential enrollment to cohorts of KW2871 at 5, 10 , 20 mg/m2 IV every 2 week in combination with HDI 20 MU/m2 IV once daily x 5 Days for 4 weeks, then 10 MU/m2 SC three times weekly until disease progression. Results: To date, Cohort 1 (5 mg/m2 KW2871) and Cohort 2 (10 mg/m2 KW2871) have been completed safely. Cohort 3 (20 mg/m2 KW2871) has enrolled of 18 of 27 planned patients. Conclusions: Will be presented at study completion.
Correlations of molecular alterations in clinical stage III cutaneous melanoma with clinical-pathological features and patients outcome.
Authors: Rutkowski Piotr , Jurkowska Monika , Gos Aleksandra , Tysarowski Andrzej , Michej Wanda , Switaj Tomasz , Dziewirski Wirginiusz , Zdzienicki Marcin , Falkowski Slawomir , Olszewski Wlodzimierz Tadeusz , Siedlecki Janusz A
Published: March 2020

8548

Background: To evaluate frequency and type of oncogenic BRAF/NRAS mutations in cutaneous melanoma with clinically detected nodal metastases (stage IIIB,C) in relation to clinicopathologic features and outcome. Methods: We analyzed 221 patients after therapeutic lymphadenectomy-LND (1995-2010) not treated with tyrosine kinase inhibitors and performed molecular characterization of nodal metastases in terms of BRAF/NRAS genes (analyzed by sequencing of respective coding sequences). Median follow-up time was 53 months. Results: BRAF mutations were detected in 139 (63%) cases (127–V600E, 8–V600K, 4-others), mutually exclusive NRAS mutations in 35(15.8%) cases (mainly Q61R and Q61K). BRAF mutation presence correlated with patients' younger age(median 52 vs 60 years for BRAF+ vs. BRAF-, p<0.05), metastases in axillary basin (p<0.05) and less involved nodes (median 3 vs. 4; p<0.05). 5-year overall survival (OS) was 35% and 45% (calculated from date of LND and primary tumor excision, respectively); 5-year recurrence-free survival RFS (from LND) – 29%. We have not found correlation between mutational status and RFS or OS (calculated from date of LND and primary tumor excision) – for BRAF mutated-melanomas prognosis was the same as wild-type melanoma patients(p=0.26) with even trend for better OS for non-V600E mutants. Negative prognostic factors (in univariate and multivariate analysis) for OS and RFS were: male gender (p<0.01), metastatic lymph nodes>1 (p<0.001), nodal metastases extracapsular extension (p<0.001). The interval from diagnosis of first-ever melanoma to regional nodal metastasis (median-10 months) was not significantly different between BRAF-mutant and BRAF wild-type patients (p=0.29). Conclusions: BRAF/NRAS mutational status is not prognostic marker in stage III melanoma patients with macroscopic nodal involvement, what may have implication for potential adjuvant therapy. BRAF status had no impact on disease-free interval from diagnosis of primary melanoma to nodal metastases. Our first-ever comprehensive molecular analysis of clinical stage III melanomas revealed that BRAF-mutants show characteristic clinicopathologic features.
Patterns of progression in patients (pts) with V600 BRAF-mutated melanoma metastatic to the brain treated with dabrafenib (GSK2118436).
Authors: Azer Mary W. F. , Menzies Alexander M. , Haydu Lauren , Kefford Richard , Long Georgina V.
Published: March 2020

8558

Background: Dabrafenib has shown efficacy in pts with previously untreated brain metastases (BM) but most will progress. We report the pattern of disease progression (PD) in pts with either previously treated (surgery (Sx), SRS, WBRT) or untreated BM on dabrafenib. Methods: Clinicopathologic parameters were collected on 23 pts enrolled in the brain cohort of the BRF112680 phase I and BRF113929 phase II BM study of dabrafenib at Westmead Hospital between Sept 2009 and June 2011. Pts with RECIST PD but ongoing clinical benefit were allowed to continue dabrafenib. Results: 12 pts (52%) had previously untreated BM and 11 (48%) were previously treated with evidence of progression prior to dabrafenib. Median OS from study entry (8.4 mo, 95% CI 5.0-11.8), diagnosis of first BM (11.0 mo, 95% CI 9.1-13.0), and stage IV diagnosis (17.5 mo, 95% CI 12.1-23.0) were not different between the two groups. Similarly, PFS did not differ between groups. Of the 19 pts who had RECIST PD at datacut, 13 pts had intracranial (IC) PD with no pts progressing in new brain lesions alone (see table). At IC PD, 3/13 underwent SRS/Sx, 5/13 WBRT and 5/13 had no salvage local therapy to BM. 8 pts continued dabrafenib beyond IC PD, median 36 days; range 28-273. All measures of baseline disease burden correlated with worse OS; elevated LDH (HR 1.003, 95% CI 1.0-1.007, P=0.044), increased number (no.) metastatic sites (HR 1.32, 95% CI 0.97-1.81, P=0.08), increased no. of IC lesions (HR 1.04, 95%CI 1.00-1.09, P=0.04), increased no. extracranial (EC) lesions (HR 1.07, 95%CI 1.02-1.12, P<0.01) and increased RECIST sum of diameters (SoD) (HR 1.012, 95% CI 1.003-1.021, P=0.007). High baseline SoD was the only factor that predicted worse RECIST response. Conclusions: Clinical benefit from dabrafenib does not appear to be influenced by prior local therapies to BM. There was no dominant pattern of progression in pts with BM on dabrafenib, but PD due to new lesions alone is rare. Pts with IC PD may benefit from salvage local therapy and continued dabrafenib. [Table: see text]
MAGE-A3 expression in patients screened for the DERMA trial: A phase III trial testing MAGE-A3 immunotherapeutic in the adjuvant setting for stage IIIB-C-Tx melanoma.
Authors: Thompson John F , Santinami Mario , Jouary Thomas , Levchenko Eugeny , Smithers Bernard Mark , Mortier Laurent , Grob Jean Jacques , Trefzer Uwe , Gutzmer Ralf , Jamoul Corinne , Peeters Olivier , Dreno Brigitte , Kirkwood John M.
Published: March 2020

8559

Background: Administration of MAGE-A3 immunotherapeutic involves the active immunization of patients (pts) with tumors expressing the MAGE-A3 protein. This new investigational approach has been previously assessed in two phase II trials, one in pts with metastatic melanoma (NCT00086866) and another in pts with completely resected non-small cell lung cancer (NCT00290355). Based on the positive responses observed in both studies, a randomized phase III placebo controlled trial assessing MAGE-A3 immunotherapeutic as adjuvant treatment in pts with resected, regionally advanced melanoma (stage IIIB-C-Tx AJCC/UICC 2010) is currently ongoing (DERMA Phase III trial, NCT00796445). Methods: Formalin-fixed, paraffin-embedded tumor tissues were prepared from surgically removed metastatic lymph nodes and tested for MAGE-A3 expression by qRT-PCR. Other baseline patient and tumor characteristics were collected during screening to further investigate factors that could potentially influence MAGE-A3 expression. Results: Between Dec 1, 2008 and Oct 25, 2011, 3917 pts were screened. Of the 3,183 valid samples (excluding the 513 inconclusive tests [66% for poor quality, 27% out-of range, 7% miscellaneous]) and the 221 missing samples, 2,092 (65.7%) were positive for MAGE-A3 expression. In these stage III melanoma pts, no difference in MAGE-A3 expression levels were identified with regard to (1) disease stage - IIIB (62.6%), IIIC (66.5%) and IIITx (66.2%); (2) gender - male (64.2%), female (68.1%); (3) age group - 18 to 39 years (63.2%), 40 to 49 years (65.3%), 50 to 59 years (66.8%), 60 to 69 years (68.1%) and 70 years and over (63.4%) and (4) region: Europe (66.1%), North America (63.0%) and rest of the world including Argentina, Brazil, Australia, Mexico, Taiwan, Japan, Korea (67.9%). Conclusions: Expression of the MAGE-A3 gene in the DERMA trial population (stage IIIB-IIIC-IIITx) was 66%. It was not correlated with age, gender, disease stage or geographic region. This expression frequency is consistent with published data in metastatic melanoma (Van den Eynde, 1997; Vourc’h-Jourdain et al, 2009) and has potentially important clinical implications.
Association of the activation of the mTOR pathway with prognosis in Chinese melanoma patients.
Authors: Kong Yan , Si Lu , Xu Xiao wei , Flaherty Keith T. , Chi Zhi Hong , Cui Chuan Liang , Sheng Xi Nan , Dai Jie , Liang Long , Zhang Qian Nan , Guo Jun
Published: March 2020

8561

Background: mTOR is a ubiquitously expressed protein kinase and a validated target in the treatment of cancer. However, the characterization of mTOR pathway in Asian melanoma populations has not been reported. Methods: This study involved primary tumor samples from 173 melanoma patients (79 acral melanomas, 57 mucosal melanomas, 17 melanomas on skin with chronic sun-induced damage, 20 melanomas on skin without chronic sun-induced damage) in Peking University Cancer Hospital & Institute. Clinical data were collected. Immunohistochemistry assays using antibodies against pmTOR, pS6RP, p4E-BP1 and pAKT were performed on formalin-fixed, paraffin-embedded specimens. Somatic mutations within the hotspot regions of frequently mutated genes in mTOR pathway (AKT1, TSC1, PI3K genes, etc) were analyzed by PCR amplification and Sanger sequencing. Results: Among the 173 samples, 26% of the cases (45/173) demonstrated positive staining with pmTOR. Expression of pS6RP was observed in 37% (64/173) of cases. Expression of p4E-BP1 was observed in 27% (46/173) of cases. pAKT was expressed by 22% (38/173) of cases. Somatic mutations in examined genes were detected. The median survival time for patients with expression of pmTOR was significantly shorter than patients with absence of pmTOR expression (25.3 vs 62.9 months, P =0.048). In addition, statistical differences were found for ulceration rates between melanomas with or without pS6RP (64.1%vs 35.9%, P= 0.049). Moreover, the median survival time for mucosal melanoma patients with pAKT expression was significantly shorter than for patients with absence of pAKT expression (20.4 vs 52.1 months, P =0.022). Conclusions: These data demonstrate that activation of the mTOR signaling pathway carries prognostic significance in Asia patients with melanoma. Targeted therapies to mTOR pathway may offer a therapeutic benefit for these melanoma patients.
Percutaneous hepatic perfusion (PHP or ChemoSat) with melphalan versus best alternative care (BAC) in patients (pts) with hepatic metastases from melanoma: A post hoc analysis of PHP-randomized versus BAC-to-PHP crossover versus BAC-only pts.
Authors: Alexander H. Richard ,   on behalf of the CS-PHP Investigators
Published: March 2020

8570

Background: PHP (Chemosat, Delcath Systems Inc, New York, NY) allows repeated delivery of high dose chemotherapy to the liver while limiting unwanted systemic exposure by extracorporeal filtration of hepatic venous blood. A prospective randomized multicenter study compared melphalan PHP versus BAC in pts with unresectable hepatic metastases from ocular or cutaneous melanoma and showed a highly significant advantage for PHP in terms of the primary endpoint, hepatic PFS, and multiple secondary endpoints. We present an exploratory post-hoc analysis of pts assigned to BAC who crossed over to PHP after disease progression (BAC-to-PHP crossover) versus those who did not (BAC-only) versus PHP-randomized pts. Methods: 93 pts were randomized to PHP (n=44) or BAC (n=49). In the BAC group, crossover to PHP with melphalan was permitted after hepatic disease progression. Up to 6 PHP treatments with melphalan 3.0 mg/kg ideal body weight were given every 4–8 weeks. Results: In the BAC group, 28 of 49 pts crossed over to PHP. Updated efficacy findings (investigator) as of 31 March 2011 are shown in the table. Independent Review Committee results were similar to investigator-assessed efficacy. Safety in BAC-to-PHP crossover pts was similar to that seen in PHP-randomized pts. The most common toxicities in BAC-to-PHP crossover pts were hematological: peri-procedural thrombocytopenia (71%) and anemia (57%), and melphalan-related neutropenia (82%) and thrombocytopenia (79%). Conclusions: Efficacy of melphalan PHP in BAC-to-PHP crossover pts was consistent with that seen in PHP-randomized pts with hepatic metastases from melanoma. Crossover from BAC to PHP after hepatic disease progression led to a median 11-month survival advantage vs BAC alone. [Table: see text]
Evaluation of chemokine-ligand pathways in pretreatment tumor biopsies as predictive biomarker of response to adoptive therapy in metastatic melanoma patients.
Authors: Bedognetti Davide , Tomei Sara , Spivey Tara L , De Giorgi Valeria , Ascierto Maria Libera , Wang Ena , Dudley Mark E. , Uccellini Lorenzo , Sertoli Mario Roberto , Marincola Francesco , Rosenberg Steven A.
Published: March 2020

8576

Background: Adoptive therapy with tumor infiltrating lymphocytes (TILs) induces objective responses (OR) in approximately 50% of patients with metastatic melanoma. The recruitment of TILs through CXCR3/CCR5-ligand chemokines is believed critical for immune-mediated rejection. Here, we investigated the predictive role of a gene-signature based on CXCR3/CCR5-ligand chemokine transcripts in pre-treatment melanoma biopsies, its biological role and its relation with CCR5-Δ32 polymorphism, which encodes a protein not expressed on cell surface. Methods: Expression of CXCR3/CXCR3-ligand transcripts (i.e CXCL9, 10, 11) and CCR5/CCR5-ligand transcripts (i.e. CCL3, 4, 5) were assessed in 113 pre-treatment tumor biopsies from patients enrolled in adoptive therapy trials: 24 patients achieved a complete remission (CR), 34 a partial remission (PR), and 55 did not respond (NR). Copy number variation and gene expression profile of these target genes were assessed in 15 biopsy-derived cell lines. CCR5-Δ32 was assessed by sequencing germinal DNA. Results: CXCL9, 10 and 11 and CCL5 clustered together and were selected for hierarchical clustering analysis based on the mean-centered gene expression values. A signature characterized by the over-expression of these genes was associated with the likelihood to achieve a clinical response (OR rate: PR+CR: 65% vs 38%, High vs Low, respectively, P=0.015). Neither correlation between the copy number variation and the gene-expression of the corresponding genes, nor correlation between the transcripts of the investigated genes between tumor biopsies and the matched cell lines was detected. Transcript expression of the target genes did not differ between CCR5-Δ32 (n =20) and wild type patients (n=93). Conclusions: Coordinate over-expression of CXCR3/CCR5 ligands in pre-treatment tumor samples was associated with responsiveness to treatment. However, the lack of correlation between in vivo and ex vivo data suggest the inflammatory status characterized by the up-regulation of these inflammatory chemokine genes is an in vivo multifactorial phenomenon.
Rapid rational drug targeting of Merkel cell polyomavirus (MCV)-positive Merkel cell carcinoma (MCC) using the survivin inhibitor YM155.
Authors: Arora Reety , Shuda Masahiro , Guastafierro Anna , Toptan Tuna , Tolstov Yanis , Normolle Daniel Paul , Vollmer Laura , Vogt Andreas , Domling Alexander , Brodsky Jeffrey , Chang Yuan , Moore Patrick S.
Published: March 2020

8577

Background: MCC is an aggressive, chemoresistant skin cancer causing more deaths each year than chronic myelogenous leukemia. We discovered a new virus, Merkel cell polyomavirus (MCV), clonally integrated into ~80% of primary and metastatic MCC in 2008. To find therapeutic targets for this cancer, we examined cellular genes perturbed by MCV infection. Methods: Digital transcriptome subtraction was used to discover MCV and also to reveal survivin gene (BIRC5) upregulation in virus-positive tumors. MCV T antigen knockdown studies in seven MCC lines and large T (LT) transduction into BJ fibroblasts were used to confirm this. Drug screening was performed in vitro using Cell-Titer Glo assays in a two stage analysis. In vivo screening used an MKL-1 (MCV+) MCC NOD-SCIDg mouse xenograft model with a single three-week treatment round. Results: MCV large T oncoprotein induces survivin transcription through retinoblastoma protein sequestration by the LT LXCXE motif. MCV T antigen knockdown results in nonapoptotic MCC cell death and loss of survivin expression. YM155, a phase II survivin transcription inhibitor, causes MCV+ MCC cell necroptosis associated with autophagy at 1-12 nM EC50. Of 1359 other drugs from LOPAC and NCI Oncology Set II libraries, only bortezomib had in vitro potency comparable to YM155. In MKL-1 xenograft studies, mice were treated with saline, bortezomib or YM155 for three weeks using standard dosings. Bortezomib did not significantly improve mouse survival (33%) over saline (24%) during treatment. In contrast, all YM155-treated mice survived (100%, p<0.001) the 3 week treatment period. Tumors resumed growth once YM155 treatment was stopped suggesting that YM155 is cytostatic in vivo rather than cytotoxic. Conclusions: Survivin expression is induced by MCV LT and is critical to MCV+ MCC survival. A survivin inhibitor, YM155 was nontoxic to mice and cytostatic for MCV+ MCC xenografts. Using genomic technologies, in less than four years, the primary viral cause for most MCC was discovered, new diagnostic tests developed and a promising rational drug candidate identified. A cooperative group trial (E1611) for YM155 and bortezomib in MCC patients is currently planned.
A clinical and translational phase II trial of sequential axitinib and carboplatin/paclitaxel in advanced melanoma.
Authors: Algazi Alain Patrick , Cha Edward , Pampaloni Miguel H , Behr Spencer , Cortez Brandon , Quiroz Anteo , Coakley Fergus V. , Liu Songling , Daud Adil
Published: March 2020

8580

Background: Several clinical trials adding VEGF signaling inhibitors to chemotherapy have not demonstrated any benefit over chemotherapy alone in advanced melanoma potentially due to decreased tumor cell proliferation induced by VEGF blockade. We tested the hypothesis that sequential administration of axitinib followed by carboplatin and paclitaxel may be more effective than chemotherapy alone in metastatic melanoma. Methods: We conducted a prospective phase II trial of this combination in previously treated metastatic melanoma patients. Patients had an ECOG PS 0-1, and normal organ function. Axitinib 5 mg PO bid was taken on days 1 through 14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg/m2) was administered on day 1 starting with cycle 2. FLT-PET scans were performed on 6 patients to assess tumor cell proliferation on days 1, 14, 17, and 20 of cycle 1. Results: Treatment has been well tolerated. The most common grade 3 AEs have been neutropenia, hypertension, and gastrointestinal events. Grade 4 non-hematologic AEs have not been observed. 4 of 5 patients completing FLT-PET scans to date showed increases (23% to 92%) in SUV values during the axitinib holiday. The fifth patient had a single, minimally FLT avid lesion at baseline (SUV=1.9). In 30 evaluable patients, there have been 4 confirmed PRs, 2 unconfirmed PRs, and 3 patients with 28.6, 29.3, and 29.5% decreases in tumor size by RECIST. Overall, 19 patients have had SD and 5 have had PD as the best response. With a median follow-up of 8.3 months and 17 patients still active, the median PFS is 6.9 months, and 23 patients (77%) are still alive. 26 of 30 evaluable patients have been wild type for BRAF-V600E/K mutations. Conclusions: Axitinib followed by carboplatin and paclitaxel has been well tolerated and effective in a largely BRAF wild-type metastatic melanoma population. Given the urgent need for effective therapies in this population, this regimen warrants phase III testing.
The impact of immune status on clinical outcomes in patients with Merkel cell carcinoma.
Authors: Donovan Sean , Weaver Amy , Otley Clark , Joseph Richard Wayne
Published: March 2020

8590

Background: Merkel Cell Carcinoma (MCC) is an aggressive cutaneous malignancy of neuroendocrine origin associated with immunosuppression presumably through infection with Merkel Cell Polyomavirus present in >80% of patients (pts). The impact of immune status on clinical outcomes in pts with MCC is unknown. The primary objective of this study was to compare clinical characteristics and outcomes of pts with MCC who are immunosuppressed (ISP) versus non-immunosuppressed (non-ISP). Methods: We performed a retrospective chart review on pts with MCC diagnosed at the Mayo Clinic between 1981 and 2009. A dermatopathologist confirmed all cases. ISP was defined as pts diagnosed with chronic lymphocytic leukemia, HIV, solid organ transplant recipients, or chronic immunosuppressive medication. The association between ISP status and overall survival was summarized using the hazard ratio (HR) and 95% confidence interval (CI) estimated from a Cox regression model. Results: Of the 268 pts identified and included in the study, 38 (14%) were ISP. We found no differences in age, tumor size, tumor location, stage of disease, or recurrence rate in ISP vs Non-ISP. Among pts who had Stage 3-4 disease, there was no difference in the size of the primary between groups. Among pts with Stage 1-2 disease, ISP status was not significantly associated with poorer survival (HR 1.5, 95% CI 0.7-3.3). However, among pts with Stage 3-4 disease, ISP pts had significantly poorer survival compared to non-ISP pts (HR 2.7, 95% CI 1.2 - 6.2). Conclusions: Baseline clinical characteristics of pts with MCC do not differ based on immunosuppression, and outcomes do not differ in pts in regards to immunosuppression in early stage MCC (Stage 1-2). However, in pts with Stage III-IV MCC, ISP pts have a worse clinical outcome suggesting that metastatic MCC either behaves more aggressively in ISP pts either through intrinsic differences in the biology of the tumor or improved immune evasion in ISP pts. These results should be cautiously interpreted given the small number (n=12) of immunosuppressed pts with advanced stage MCC. The authors will update their data with an additional 58 patients by the date of presentation.
A video decision support tool for CPR in advanced cancer: A randomized controlled trial.
Authors: Volandes Angelo E. , Paasche-Orlow Michael , El-Jawahri Areej , Mitchell Susan L. , Kemeny Margaret , Hartshorn Kevan L. , Jackson Vicki A. , Barry Michael J , Davis Aretha Delight , Lopez Lenny , Walker-Corkery Elizabeth , Chang Yuchiao , Epstein Andrew S. , Bulone Linda , Misra Sumathi , Peachey Matt , Noy Ariela , Levin Tomer , Eichler April F. , Temel Jennifer S.
Published: March 2020

9004

Background: End-of-life decision-making is important to patients, including whether or not to attempt cardiopulmonary resuscitation (CPR). Doctors often rely solely on verbal descriptions to communicate information regarding CPR. Video decision support tools have the potential to improve patients’ understanding of CPR by providing visual images of what this intervention entails. The objective of this study was to examine the effect of a CPR video among patients with advanced cancer on their preferences and knowledge of CPR. Methods: A randomized controlled trial of 150 subjects with diverse advanced cancers (< 1-year prognosis) recruited from 4 cancer centers in the United States. Subjects were randomized to either a verbal narrative describing CPR, or to a video with verbal narrative. The video depicts CPR and reviews the success rate in advanced cancer. Study endpoints were subjects’ CPR preferences, knowledge of CPR (knowledge scores ranged from 0-4, higher score indicating more knowledge), and perceived value of the video. Chi-square tests were used to compare the distributions of categorical outcomes and two-sample t-tests were used to compare the means between the two groups. Results: A total of 150 subjects were randomized to a verbal narrative (n=80) or video with verbal narrative (n=70). Mean age was 62, 49% were women, 47% White, 34% Black, and 47% had lung or colon cancer. Among subjects receiving the verbal narrative, 38 (47.5%) preferred to have CPR attempted; 41 (51.2%) chose not to have CPR; and 1 (1.3%) was uncertain. In the video group, 14 (20%) preferred to have CPR attempted; 55 (78.6%) chose not to have CPR; and 1 (1.4%) was uncertain (P<0.001). The mean knowledge score was higher in the video group than in the verbal group (3.3 vs. 2.6 respectively; P<0.001). Of the subjects who viewed the video, 94.1% stated they were comfortable watching the video, 97.1% found the video helpful, and 100% would recommend the video. Conclusions: Compared to subjects who only heard a verbal description, subjects with advanced cancer who viewed a CPR video were more likely to prefer not having CPR, and were more knowledgeable about CPR. The majority of subjects found the video helpful, comfortable to view, and would recommend it to others.
Physical activity participation and functional limitations in geriatric cancer survivors.
Authors: Sprod Lisa , Mohile Supriya Gupta , Fan Lin , Janelsins Michelle Christine , Peppone Luke Joseph , Chandwani Kavita Dayal , Morrow Gary R. , Mustian Karen Michelle
Published: March 2020

9009

Background: Functional limitations (FL) increase with age, as does cancer incidence. Treatments for cancer may exacerbate age-related FL. Physical activity (PA) reduces the risk of recurrence of some cancers and may improve survival. FL may reduce PA participation in geriatric cancer survivors (>65 yrs.) which could increase the risk of recurrence and reduce survival. This investigation describes and compares patterns of PA and FL in geriatric cancer survivors versus those without a cancer history. Methods: Using a national sample of community-dwelling elders (> 65 yrs.) from the 2003 Medicare Current Beneficiary Survey (N=14,887), we characterized the differences between cancer survivors and those without a cancer history in FL, current amount of PA, and current amount of PA compared to PA one year prior. Respondents rated FL on a 1-5 scale (1=no difficulty, 5=can’t do): stooping, crouching, or kneeling (stoop), carrying objects up to 10 lbs (lift), extending arms above shoulder level (reach), grasping small objects (grasp), and walking ¼ of a mile (walk). Frequency of walking for a least 10 minutes (1-5 rating scale; 1=daily, 5=never), weekly participation in PA, exercise, or sports (yes/no), and time spent doing moderate or vigorous PA (hrs/wk) were reported. Multivariate logistic regression was used to determine associations. Results: Of the 14,887 participants, 2,603 (6%) reported a history of cancer. Compared to those without a cancer history, a greater proportion of cancer survivors reported having difficulty or being unable to stoop, lift, reach, grasp or walk (all p<0.01). Cancer survivors who had more FL were less likely to engage in PA (all p<0.01). Cancer survivors reported a lower frequency of walking at least 10 minutes at a time (p<0.01). Cancer survivors were more likely to decrease PA from the previous year (p<0.01) and spent less time doing moderate (p=0.01) or vigorous activity (p<0.01) than those without a cancer history. Conclusions: Older cancer survivors engage in less PA and are at greater risk of FL than those without a history of cancer. This may lead to reduced independence, a greater risk of cancer recurrence, and reduced survival. Therefore, PA interventions are important in this population.
Correlation of short telomeres (ST) with vulnerability, toxicity, and early death in elderly AOC patients receiving carboplatin: A multicenter GINECO trial.
Authors: Falandry Claire , Horard Béatrice , Alexandre Jerome , Deplanque Gael , Cojocarasu Oana , Salvat Jacques , Legouffe Eric , Cretin Jacques , Meunier Jérome , Maraval-Gaget Raymonde , Micheau-Bonnier Douglas , Gilson Eric , Freyer Gilles
Published: March 2020

9011

Background: Age induces a progressive decline in the functional reserve and interferes with cancer treatments. As aging is heterogeneous, this decline has to be assessed individually. Telomere attrition leads to tissue senescence. We tested the hypothesis that telomere lenght (TL) could predict pts vulnerability and outcome during cancer treatment. Methods: This study was performed in the “Elderly women” GINECO trial designed to evaluate the impact of geriatric covariates on survival in AOC pts over 70 receiving 6 courses of carboplatin. TL was estimated in duplicate using standard Terminal Restriction Fragment analysis from peripheral blood cells at inclusion and tested for its correlation with geriatric covariates and pts outcomes (TC and tolerance, overall survival: OS). Results: TL (in base pair) was estimated for 109/111 pts (median 5997; extremes [4517-8333]). No significant correlation was found with any pts characteristics. With a cutoff of 5770 bp, TL discriminated two groups with significantly different Treatment Completion (TC) rates: 0.80 (95CI[0.71-0.89]) and 0.59 (95CI[0.41-0.76]), OR=2.8, p=0.02 for long telomere (LT) and short telomere groups, respectively . ST pts were at higher risk of severe adverse events (SAE, OR=2.7; p<0.02) and tended to have more unplanned hospital admissions (OR=2.1; p<0.08). Considering OS, after adjustment on FIGO stage, TL shorter than the median was a nearly significant risk factor of premature death (HR=1.57; p=0.06. Finally, we addressed if TL correlated with our previously validated geriatric vulnerability score (GVS)c including ADL score<6, IADL score<25, albuminemia<35g/l, lymphopenia<1G/L, HADS score£15 as risk factors of poorer survival. Despite no significant correlation with any of these factors, GVS³3) and ST tended to be correlated (OR=2.1; p=0.08). Conclusions: This exploratory study identifies TL as predictive factor of decreased TC, SAE risk, unplanned hospital admissions and OS after adjustment on FIGO stage.
SWOG S0715: Randomized placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy.
Authors: Hershman Dawn L. , Unger Joseph M , Crew Katherine D. , Moinpour Carol , Minasian Lori M. , Hansen Lisa , Lew Danika , OKane Patricia , Wade James Lloyd , Wong Siu-Fun , Hortobagyi Gabriel N. , Meyskens Frank L. , Albain Kathy S.
Published: March 2020

9018

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect of taxanes that leads to suboptimal treatment and diminished quality of life. Acetyl-L-Carnitine (ALC) is a natural compound involved in tubulin acetylation and neuronal protection. Pre-clinical and phase II studies suggest ALC may be effective for the prevention and treatment of CIPN. Methods: A randomized, double-blind, multi-center, phase III trial comparing ALC (1000 mg TID) vs placebo for 24 wks in women with stage I-III breast cancer undergoing adjuvant taxane therapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale (low score = worse NTX) at 12 wks. Secondary objectives included change at 24 wks, change in the Trial Outcome Index (TOI), fatigue (FACIT Fatigue) and NTX grade. Patients were stratified by planned treatment, and age (<60, ≥60). Results: 409 patients were evaluable (208 ALC, 201 placebo). No imbalances were observed by age, ethnicity, race, planned taxane treatment, performance status, or stage. The mean FACT-NTX score was 5.2 points lower at 12 wks on ALC and 4.5 points lower on placebo. In a linear regression adjusting for baseline score, planned treatment and age, wk 12 scores were 0.9 points lower on ALC than placebo (95% CI: -2.2 to 0.4, p=.17). At 24 wks, the mean observed FACT-NTX score was lower for ALC (5.3 vs. 3.6). In the multivariate model, wk 24 scores were 1.8 points lower on ALC (95% CI: -3.2 to -0.4, p=.01), representing more self-reported NTX. Grade 3/4 NTX was more frequent in the ALC arm (p=.04). Also at 24 wks, 38% on ALC had >5 point decrease score compared to 28% on placebo (OR=1.57, p=.05), and FACT-TOI scores were 3.5 points lower on ALC (95% CI: -6.5 to -0.4, p=.03). No differences between arms were observed for the FACIT-Fatigue scale or for other toxicities. Conclusions: There is no evidence that ALC has a positive impact on CIPN at 12 wks. However, ALC increases CIPN by 24 wks. Correlative studies are ongoing to explain this unexpected finding. Patients should be discouraged from using ALC and other supplements without proven efficacy.
Phase Ib, multicenter, single-blinded, placebo-controlled, sequential dose-escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer (LAHNC) receiving induction chemotherapy (ICT).
Authors: Limaye Sewanti Atul , Sonis Stephen T. , Cilli Fiona , Colevas A. Dimitrios , Brennan Michael , Hu Kenneth , Haddad Robert I. , Murphy Barbara A.
Published: March 2020

9024

Background: Oral mucositis (OM) is a significant toxicity of ICT in LAHNC. AG013, a mouth rinse composed of a recombinant Lactococcus lactis (sAGX0085) engineered to secrete human Trefoil Factor 1 (hTFF1) and deficient in the gene encoding thymidylate synthase, was investigated in patients receiving ICT (cisplatin, 5-fluorouracil +/-docetaxel:PF+/-T). TFFs have wound-healing properties and are protective of mucosal tissues. Methods: To evaluate the safety, tolerability, PK profile and efficacy of AG013 in attenuating ICT-associated OM, 52 patients (pts) with newly diagnosed LAHNC receiving ICT (24TPF, 1PF) were screened in ICT cycle (Cy) 1 for symptomatic OM (SOM). 25 pts who developed SOM in Cy1 were enrolled into 3 successive groups of at least 7 pts each in the active phase and randomly assigned at the Baseline visit (d1 of ICT Cy2) in a 5:2 ratio to receive AG013 or placebo during ICT Cy2. Dose was escalated in successive groups from 1 x/day (qd) to 3 x/day (tid) and to 6 x/day, resulting in doses of 2 x 1011, 6 x 1011, and 1.2 x 1012 colony-forming units (CFU)/day respectively. Pts were assessed daily from Cy 2 d1 to d14 for OM using WHO criteria. Safety endpoints and PK (mucosal, salivary and blood samples) were assessed. Results: AG013-sAGX0085 could not be detected in blood. Recovered oral live bacterial levels were high immediately after dosing, decreased by 90 minutes post dose, and undetectable at study end. No differences in hTFF1 serum levels were seen. Pts in the placebo group had ulcerative OM (UOM) on nearly 60% of the days vs. 35-40% days in the AG013 group. 29 % pts who received AG013 had 0 or 1 day of UOM vs. at least 2 days of UOM in the placebo group. Pts who received AG013 on any dosing schedule had a lower % of days with OM, fewer unplanned office and emergency room visits compared to pts who received placebo. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement. Conclusions: Topical administration of AG013 appears safe, well tolerated and effective in reducing the severity and course of OM in patients receiving ICT for HNC.
Effect of chemotherapy and psychosocial distress parameters on perceived cognitive disturbances in Asian breast cancer patients.
Authors: Cheung Yin Ting , Ham Guo Maung Shwe , Chui Wai Keung , Dent Rebecca Alexandra , Yap Yoon Sim , Lo Soo Kien , Ng Raymond C.H. , Chan Alexandre
Published: March 2020

9041

Background: A qualitative study has revealed that Asian breast cancer patients attributed their post-chemotherapy cognitive disturbances to psychosocial distress. To validate this claim, we aim to examine perceived cognitive disturbances, anxiety and quality of life (QoL) in Asian breast cancer patients and to identify clinical and psychosocial factors associated with perceived cognitive disturbances. Methods: A prospective, observational study was held at the largest cancer center in Singapore. Chemotherapy (CT) and non-chemotherapy (non-CT) receiving breast cancer patients completed self- reported questionnaires to assess the following domains: patients’ perceived impact of chemotherapy on cognitive disturbances (FACT-Cog), health-related QoL (EORTC QLQ-C30) and anxiety (Beck Anxiety Inventory). Multiple regression was conducted to delineate factors associated with perceived cognitive impairment. Results: A total of 166 (1:1 CT/non-CT) patients were recruited (age: 54.1±10.2 years; 78.9% Chinese; 53.6% post-menopausal). Most of the CT patients received anthracycline-based chemotherapy (93.1%) and anti-hormonal therapy (69.4%). Comparing to non-CT patients, CT patients experienced more fatigue (QLQ-C30 fatigue scores: 22.2 vs 33.3 points; p=0.005), more significant anxiety (8.6% vs 21.9%; p=0.002), and more cognitive disturbances (FACT-Cog scores: 110 vs 124 points; p<0.0001). Regression model identified chemotherapy, anti-hormonal therapy, emotional functioning and global health status to be strongly associated with cognitive disturbances in Asian breast cancer patients. The interacting effect between anxiety and fatigue, comparing to fatigue alone, was more associated with cognitive disturbances (β=-0.212; p=0.032 vs β=-0.07; p=0.25, respectively). Conclusions: This is the first study to demonstrate that Asian breast cancer patients experiencing both fatigue and anxiety are more predisposed to cognitive disturbances. Post-chemotherapy cognitive changes are observed in our patients, and our results suggest that psychosocial factors are impactful to identify cancer patients who are more susceptible to cognitive disturbances.
Patient-related factors influencing time between first signs of breast cancer (BC) and appointment for medical visit (AMV): An international survey.
Authors: Jassem Jacek , Bacanu Florin , Eglitis Janis , Mardiak Jozef , Pienkowski Tadeusz , Kahan Zsuzsanna , Ozmen Vahit , Drobniene Monika , Vrbanec Damir , Semiglazova Tatyana , Stamatovic Ljiljana , Timcheva Constanta , Vasovic Suzana , Zaborek Piotr
Published: March 2020

9046

Background: Reducing diagnostic delays may improve treatment outcomes in BC. We investigated in various countries patient-related factors influencing time to seeking medical advice for signs of BC. Methods: A total of 4,816 female BC patients from 10 countries were surveyed using a uniform questionnaire translated into local languages. Time between first patient-detected signs of BC and AMV was measured using categorized time scales. Out of 14 original items on a multiple scale measuring BC-related attitudes and behaviors, 5 factors were extracted and used for further analysis: distrust in medical system and success of therapy, disregard of signs, fear of BC, practicing regular breast self-examination and support from friends and family. Results: In the subset of 2,870 patients with self-detected BC who provided complete answers to relevant variables, the mean time to AMV varied in particular countries from 3.4 to 6.2 weeks (grand mean of 4.7 weeks), with 39% of cases with a delay of >4 weeks. Overall, patient attributes that significantly influenced time to AMV were: distrust (p<1E-36), disregard (p=1.26E-30), fear (p=2.65E-16), self-examination (p=1.31E-21), place of living (p=3.5E-3) and education (p=2.73E-3). Multilevel analysis indicated that significant differences among particular countries were only due to slopes of distrust and disregard included in general regression model. The model enhanced with the two abovementioned random effects provided significant improvement in predicting time to AMV. Re-estimation of the model based solely on data from individual countries produced 10 significant equations with varied coefficients for distrust and disregard (see table). Conclusions: Patient-related factors contribute considerably to delay in the diagnosis of BC. Differences between particular countries call for country-specific approaches. [Table: see text]