bluuebunny/crossref_metadata_2025_split huggingface dataset:
An open-label phase II study of sorafenib and dacarbazine as first-line therapy in patients with advanced melanoma
Authors: Eisen T. , Marais R. , Affolter A. , Lorigan P. , Ottensmeier C. , Robert C. , Corrie P. , Chevreau C. , Erlandsson F. , Gore M. 
Published: March 2020

8529 Background: Sorafenib (SOR) exerts anti-tumor and anti-angiogenic effects via inhibition of VEGFR-1,-2,-3, PDGFR-a, -β and Raf. In a phase I, study SOR + dacarbazine (DTIC) as first-line therapy for advanced melanoma patients (pts) was well-tolerated and had activity. Methods: In this multicenter, phase II, open-label, uncontrolled, 2-stage study, eligibility criteria included: measurable disease by RECIST, ECOG performance status 0 or 1, no prior chemotherapy. Prior immunotherapy was allowed. Planned sample size was 82 pts based on a Simon 2-stage optimal design. Pts were treated with oral SOR 400 mg bid daily combined with repeated 21-day cycles of iv DTIC 1,000 mg/m2 given on day 1 of each cycle until occurrence of progressive disease or intolerable toxicity. The primary endpoint was overall tumor response rate using RECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and toxicity. Results: 30 and 53 pts were treated in Stages I and II, respectively. Baseline characteristics were as follows: median age 56 yrs; 60% male, 34% ECOG 1, 80% AJCC Stage IV M1c; 31% elevated LDH. Eight (10%) pts had partial responses, 34 (41%) had stable disease, 32 (39%) had progressive disease and 9 (11%) were not evaluable. The median PFS was 14 wks (95% CI 12, 19; 28% censored). PFS rates at 3 & 6 mos were 56% (45%, 67%; 13% censored) and 33% (22%, 45%; 24% censored), respectively. Median OS was 41 wks (28, 59, 63% censored). Grade 3/4 drug-related adverse events included: neutrophils 33%, platelets 22%, hand-foot skin reaction 8%, fatigue 7% and abdominal pain 6%. 1 patient had febrile neutropenia. To correlate treatment response with mutational status, melanoma samples from 20 pts were analyzed for mutations in B-RAF (exon 15) and PI3Kinase (exons 9 & 20). 3 of 20 samples had V600E mutations in B- RAF; no PI3Kinase alterations were detected. Conclusions: Addition of SOR to DTIC was well-tolerated and resulted in encouraging PFS and OS rates in this poor prognostic cohort of patients. The data are promising as compared with published results of DTIC alone in metastatic melanoma (RR 7.5%, PFS 6 wks; Bedikian et al. 2006). A recently completed randomized Phase II trial will provide additional information on the efficacy of this combination regimen. [Table: see text]
VEGF serum levels during bevacizumab plus paclitaxel combination in metastatic melanoma
Authors: Viteri S. , Diaz-Lagares A. , González A. , Martin Algarra S. , Redondo P. , Espinos J. , González Cao M. 
Published: March 2020

8534 Background: Angiogenesis has an important role in melanoma progression. A prognostic value has been suggested for serum VEGF in melanoma. The novel agent bevacizumab (Bev) has demonstrated in combination with chemotherapy high activity in other tumors. We studied the combination of weekly paclitaxel (TXL) and bevacizumab (Bev) in previously treated metastatic melanoma patients (pts) and analyzed serum VEGF levels before and during treatment. Methods: TXL 70 mg/m2 weekly and Bev 10 mg/kg biweekly during 5 consecutive weeks every six weeks. VEGF levels pre-treatment and at response evaluation were analyzed with enzyme-linked immunoassays. Results: 13 pts have been treated: male/female: 4/9, median age: 45 (29–71), median PS ECOG: 2 (0–3), stage distribution M1b/ M1c: 2/11, high LDH levels: 8 pts. Median number of previous lines: 3 (1–6). Hematological toxicity: G III lymphopenia in 6 pts, G III leucopenia in 2 pts, G III thrombocytopenia in 1 pt and G I anemia in 3 pts. Non-hematological toxicities: alopecia in 7 pts, diarrhea G I in 4 pts, epistaxis G I in 8 pts. Response (and time to progression, months [m]): 2/12 PR (6 m and 4 m), 1/12 MR (6 m), 7/12 SD (7+ m, 7 m, 4 m, 4+ m, 3 m, 3 m, 3+ m), 2/12 PD. Responses were seen in soft tissue, lung and brain metastases. Overall survival at 12 months was 43.3%. Pre-treatment serum levels were high in five patients and they became negative at response evaluation (1 pt achieved MR, 3 pts SD and 1 pt PD). Unexpectedly patients with high pre-treatment VEGF levels had long survival: 4/5 patients remain alive and 2 pts have survived over one year: 12+ m, 12+ m, 5 m, 3+ m, 3.5+ m.VEGF was undetectable pre-treatment and at response evaluation in 7 pts, only 2/7 pts remained alive: 15+ m, 8 m, 7.5 m, 7 m, 6.8+ m, 3 m, 2.6 m. Conclusions: The combination of Bev and weekly TXL is active in melanoma and it has a good tolerance profile. Serum VEGF could be a good marker in this setting. Further research is needed to confirm these results. No significant financial relationships to disclose.
Shedding of distinct cryptic epitope (HU177) in sera of melanoma patients
Authors: Zakrzewski J. , Ng B. , Warycha M. , Christos P. , Shapiro R. , Berman R. , Pavlick A. , Liebes L. , Brooks P. , Osman I. 
Published: March 2020

8550 Background: Our preclinical data suggest that a newly identified cryptic epitope HU177 within collagen regulates endothelial and tumor cell adhesion in-vitro and angiogenesis and tumor growth in-vivo. We investigated whether 1) HU177 shedding can be measured in melanoma patients’ sera, and 2) if HU177 concentration correlates with clinicopathological features, recurrence and survival. Methods: Sera from 291 melanoma patients (primary Stage I, n=140; II n=41; III n=29; recurrent/metastatic n=81) and 30 normal volunteers prospectively enrolled at the NYU School of Medicine were analyzed for HU177 epitope concentration (ng/ml) by ELISA. Microtiter plates were incubated overnight with monoclonal antibody (anti-HU177 epitope). Patients’ sera and standards (denatured type-IV collagen) were added in duplicate followed by dilutions of biotinylated anti-collagen type IV polyclonal and HRP-labeled anti-biotin antibodies with multiple washes after each incubation. Absorbance was monitored at 400 nm. Results: The mean concentration of anti-HU177 epitope was 5.8 ng/ml (range 0.1 to 139.8). Normal volunteers were 1.6±0.3 (mean ± SEM). A significant correlation was observed between HU177 concentration and tumor thickness in patients who presented with primary melanoma (=1.00 mm, n=113, 3.8±0.4; 1.01–3.99 mm, n=72, 8.9 ±2.1; =4.00 mm, n=22, 10.3±2.2; P=0.003 by ANOVA test) and nodular melanoma histological subtype (nodular, n=47, 10.5±3.1; superficial spreading, n=95, 4.4±0.5; others, n=68, 6.0±2.1; P=0.02, ANOVA). Multivariate analysis confirmed the independent correlation between higher HU177 concentration and nodular subtype after controlling for tumor thickness (P=0.04). Primary patients with ulcerated melanomas and those who developed recurrences both showed higher HU177 epitope levels, however, the difference was not significant (P>0.05). Conclusions: This is the first study on HU177 epitope shedding in melanoma patients. Data demonstrate the clinical feasibility of HU177 testing in melanoma patients’ sera and suggest that HU177 epitope shedding correlates with thicker primary melanomas. Longer follow-up is required to better define the prognostic value of HU177 epitope shedding in melanoma patients. [Table: see text]
Phase II trial of tanespimycin (KOS-953), a heat shock protein-90 (Hsp90) inhibitor in patients with metastatic melanoma
Authors: Kefford R. , Millward M. , Hersey P. , Brady B. , Graham M. , Johnson R. G. , Hannah A. L. 
Published: March 2020

8558 Background: Tanespimycin binds to and inhibits the activity of Heat Shock Protein 90 (Hsp90). Hsp90 inhibition results in the degradation of a variety of RAF family proteins, including mutant BRAF. As the majority of melanomas have activation of the BRAF-MAPK pathway, we postulate that tanespimycin will interrupt the MAPK pathway and may lead to clinically significant anti-melanoma effects. Methods: This is a multi-center two-stage Simon design study; continuation to the second stage required at least 1 pt with progression free survival (PFS) of at least 24 weeks (the primary endpoint of this trial). Eligibility: pts with stage M1 melanoma, measurable/unresectable disease, up to 1 prior chemotherapy treatment for metastatic disease and ECOG PS 0 or 1. Tanespimycin (275 mg/m2 IV) was given D1,4,8,11 q 3/52 until disease progression or toxicity. Where available, assessment of BRAF mutation (V600E) was performed on historical tissue. Results: 14 pts have been enrolled, 3 were non-evaluable. Data are available for the first 11 pts (9 evaluable) completing accrual to the 1st stage of the Simon design. Demographics: 8 M/6 F; median age 55 years (range 30, 83). A total of 30 treatment cycles were administered (n=11); with relative dose intensity of 89%; 1 pt required a dose reduction. Grade 1–2 toxicity included nausea, vomiting, diarrhoea, anorexia, fatigue, headache, raised alkaline phosphatase/ALT/AST, and back pain. Four pts (29%) experienced Grade 3–4 toxicities: 1) reversible metabolic acidosis with LFT and electrolyte abnormalities; 2) anorexia, dehydration and fatigue; 3) raised gamma-GT; 4) abdominal pain. Two pts withdrew due to toxicity. Of the 4 pts with available tissue: 2 had V600E BRAF positive mutations. One pt achieved a ≥ 24 week PFS, meeting the conditions for accrual of Stage 2. This pt (with V600E mutation) was assessed as having a best response of stable disease as per RECIST, in addition to reduction in size and number of extensive subcutaneous nodules. Conclusions: There is evidence of clinical activity of single-agent tanespimycin in metastatic melanoma. Further accrual with determination of BRAF status to a total of 30 pts will better define the activity of tanespimycin in this population. No significant financial relationships to disclose.
Aerosolized sargramostim for the treatment of metastatic melanoma to the lungs
Authors: Markovic S. N. , Suman V. J. , Schaefer P. , Morton R. , Rowland K. M. 
Published: March 2020

8565 Background: Previous studies using low-dose (250 ug/dose) aerosolized sargramostim (granulocyte macrophage colony stimulating factor: aero-GM-CSF) for the treatment of metastatic melanoma, revealed anecdotal clinical responses that appeared to correlate with an increase in the number of tumor specific cytotoxic T lymphocytes (CTL) in blood. Herein, we address whether or not further dose escalation of aero-GM-CSF is safe, results in greater increase of melanoma specific CTLs, and affects clinical outcomes. Methods: A 5+5 dose escalation clinical trial was conducted to determine the dose of aero-GM-CSF that would increase in the frequency of peripheral blood melanoma specific CTLs in HLA-A2+ patients with metastatic melanoma to the lungs. Aero-GM-CSF was administered twice daily on days 1–7 and 15–21 of a 28 day cycle at doses of: 500, 750, 1,000, 1,250, 1,500, 1,750, and 2,000 ug per cohort. If at most 2 of 5 patients at a dose level reported a 5-fold increase in CTLs, dose escalation occurred. If not, 5 additional patients were treated at that dose. Dose escalation continued until =2 of 5 patients at a dose level developed severe toxicity, at least 7 of the 10 patients at a dose level reported a 5-fold increase in CTLs, or all dose levels were exhausted. Results: The study accrued 40 patients from August 2002 to July 2006. Four patients cancelled participation prior to treatment. One patient was replaced (500 ug) as he died within 13 days of registration. Among the 35 remaining patients, median age was 58 (23–84), 72% were male, and 72% had a PS=0. Dose escalation was not terminated due to toxicity. Toxicities = grade 3 (at least probably treatment related) included: grade 3 fatigue (1) at 1,000 ug; and grade 3 cough (1), and grade 4 dyspnea (1) at 1,750 ug. At the 2,000 ug dose, most patients (4 of 5) exhibited a greater than 2-fold increase in melanoma specific CTLs. Two of these patients remain on treatment: one with partial response at 14.0 months and the other with stable disease at 6.5 months. A 5-fold increase in tumor specific CTLs was not achieved in any patient. Conclusions: Aero-GM-CSF therapy administered at up to 2,000 ug/dose appears safe and seems to correlate with increased frequencies of tumor specific CTLs in a dose-dependent fashion. Further dose escalation followed by clinical efficacy testing is warranted. No significant financial relationships to disclose.
The usefulness of positron emission tomography (PET) scanning to identify early recurrent melanoma in high risk resected stage III and IV patients: A retrospective review
Authors: Kottschade L. A. , Lowe V. , Markovic S. N. 
Published: March 2020

8566 Background: The incidence of malignant melanoma has risen dramatically over the past decades. Prognosis for patients with metastatic melanoma is poor and treatment options are limited. Complete surgical resection is frequently front line therapy for patients with resectable metastases. However this is only an option if relapse is diagnosed early. PET imaging using 2-flourine-18, 2-fluro-2-deoxy-D-glucose (FDG) has been used successfully for staging of metastatic melanoma. However it's usefulness in surveillance for patients at high-risk of relapse (resected stage III and IV disease) has not been well studied. We conducted a retrospective review of our institutional experience using PET scanning as part of regular follow up in patients with resected stage III or IV melanoma for the purpose of detection of early recurrence. Methods: Retrospective review of the medical records of 667 consecutive patients seen at Mayo Clinic from 12/13/1999–1/1/2007, with the diagnosis of malignant melanoma for whom PET imaging was performed or reviewed at our institution. Eligibility criteria included: resected stage III or IV melanoma with at least 2 PET scans (<1 year apart) as part of regular clinical follow-up (surveillance). Frequency of PET scanning was variable and at physician discretion. Results: Of the 667 patients, 110 patients were deemed eligible for review. There were 98 recurrences among 65 patients. Of these 37 recurrences (38%) were found by PET scanning alone (asymptomatic); 61 recurrences (62%) were found by other methods (physical exam, CT, MRI, etc). Of the 37 recurrences found by routine PET scanning 17 (46%) were completely resected; of the other 61 recurrences found by other methods 33 (54%) were completely resected. Conclusions: PET scanning as regular surveillance for patients with high risk melanoma, may be a useful tool in early identification of asymptomatic melanoma relapse amenable to complete surgical resection (additional 1/3 of cases). Considering the potential clinical benefit of completely resected melanoma relapse, and the retrospective nature of this review, these data are hypothesis-generating and warrant further investigation. No significant financial relationships to disclose.
Preoperative lactate dehydrogenase (LDH) serum level has impact on survival of melanoma patients after therapeutic lymph node dissection (TLND) but not on patients after completion lymph node dissection (CLND)
Authors: Ruka W. , Nowecki Z. I. , Rutkowski P. , Dziewirski W. , Pienkowski A. , Salamacha M. , Zurawski Z. , Zdzienicki M. 
Published: March 2020

8568 Background: The aim of the study was to evaluate the additional prognostic value of preoperative LDH serum level on overall survival (OS) of AJCC stage III cutaneous melanoma patients. Methods: The preoperative LDH serum level was available in 402 consecutive melanoma patients, who underwent radical LND (196 CLND after positive sentinel node biopsy and 206 TLND for clinically/cytologically detected regional lymph node metastases) between 1994 and 2004. Median follow-up time was 36 months (range: 6–110 months). Results: LDH serum level was increased before LND in 92 patients (22.9%) in the entire group of stage III melanoma patients [56 patients (27%) in TLND group and in 36 patients (18.4%) in CLND group (p=0.03)]. There were significant differences for OS (calculated from the date of LND) between patients with normal and high preoperative LDH level in the entire group of patients: median OS time was 51.2 months (95% CI: 34.8–91.9) and 27.9 months (95% CI: 18.2-); 5-year OS rate was 45.2% and 37.5%, respectively (p=0.0079 in univariate analysis and p=0.02 in multivariate analysis). However, to these differences mainly contributed the patients from TLND group: for patients with normal and high preoperative LDH level median OS time was 36.6 months (95% CI: 24.9–57.6) and 15.1 months (95% CI: 12.4- 27.9); 5-year OS rate was 40.0% and 20.3%, respectively (p=0.0013 in univariate analysis and p=0.01 in multivariate analysis). We did not observe any differences between patients with normal and high preoperative LDH level in CLND group: median OS time was 60.0 months (95% CI: 39.8-) and 65 months (95% CI: 45.6-); 5-year OS rate was 51% and 58%, respectively (p=0.703 in univariate analysis). Conclusions: Pre-LND increased LDH serum level has additional negative impact on OS of melanoma patients with palpable nodal metastases after TLND. [Table: see text]
A phase II study of arsenic trioxide (ATO) in patients with metastatic melanoma
Authors: Tarhini A. A. , Kirkwood J. M. , Gooding W. E. , Stuckert J. J. , Agarwala S. S. 
Published: March 2020

8569 Background: Arsenic trioxide (ATO) is a promising new agent in the treatment of both solid and hematologic tumors. ATO cytotoxicity and apoptosis induction has been demonstrated in vitro with numerous human cancer cell lines including human melanoma. Methods: We conducted a safety and efficacy single arm study of ATO in patients (18 years or older) with inoperable AJCC stage IV melanoma. One cycle consisted of a loading dose of 0.32 mg/kg/day for 4 days in week 1, followed by 0.25 mg/kg/day twice per week for 6 weeks, followed by 1 week of rest for a total cycle length of 8 weeks when response assessment was performed. Results: A total of 21 patients (5 females and 16 males) were accrued with a median age of 63.8 years (range 32.9 - 81.6). All patients had metastatic melanoma including AJCC stage IV M1a (2), M1b (6) and M1c (13). ECOG performance included 0 (11) and 1 (10). One patient had metastatic choroidal melanoma and 20 had cutaneous melanoma. Twenty patients had received prior therapy including chemotherapy (17), immunotherapy (11) and radiation (3). Six patients completed 1 cycle, seven 2 cycles, one 3 cycles, one 4 cycles and two 5 cycles of ATO. Four patients did not complete the first cycle and are not evaluable for response. Possible treatment related Grade 3/4 toxicities included one case of idiopathic thrombocytopenic purpura and one case of elevated LDH. Among 17 evaluable patients, 1 (6%) had partial response lasting 7 months, 8 (47%) had disease stabilization after 1 cycle, but all eventually progressed. A total of 19 patients have died and 2 are alive at a median follow up of 17.5 weeks. Median time to progression is 14 weeks, 95% CI (9, 38) and median survival is 52.9 weeks, 95% CI (14.4, 66.1). Conclusions: ATO as a single agent is well tolerated with modest activity in metastatic melanoma that may be enhanced in combination with other agents that induce apoptosis. No significant financial relationships to disclose.
Phase II study of oxaliplatin, docetaxel, and sargramostim (GM-CSF) in patients with previously treated advanced melanoma
Authors: Locke F. L. , Clark J. I. , Gajewski T. F. 
Published: March 2020

8570 Background: Although much focus has been placed on immunotherapy for melanoma, further development of chemotherapy approaches is needed. Melanoma is responsive to platinum compounds and taxanes, but there is limited experience with combinations of these agents. Oxaliplatin has been reported to have detectable activity in melanoma, and a phase I study has identified a tolerable dose and schedule of oxaliplatin in combination with docetaxel and hematopoietic growth factor support. GM-CSF has a theoretical advantage of immune potentiation. These considerations supported study of oxaliplatin, docetaxel, and GM-CSF in patients with advanced melanoma. Methods: Eligibility included intact organ function, PS=2, at most one prior chemotherapy and one prior immunotherapy, no prior treatment with oxaliplatin or taxanes, and no chremophor allergy. After premedication, docetaxel was administered day 1 at 85 mg/m2, then oxaliplatin on day 2 at 85 mg/m2. GM-CSF (5 μg/kg) was administered s.c. days 3–12. Cycles were 21 days in length, and disease reevaluation was performed every 2 cycles by RECIST criteria. Results: 20 patients were enrolled, 13 with 1 prior therapy, 5 with 2 prior therapies, and 2 previously untreated. Six patients did not complete 2 cycles and were not formally evaluable for response. One patient who failed 2 prior treatment regimens experienced a minor response and received 10 cycles of therapy, and 4 patients had stable disease. The rest showed PD after 2 cycles. Notable toxicities included 7 cases of grade III/IV neutropenia and 2 hypersensitivity reactions. Conclusions: This combination of oxaliplatin, docetaxel, and GM-CSF has limited clinical activity in previously treated patients with advanced melanoma. Exploration in treatment-naive patients may still be warranted. No significant financial relationships to disclose.
Clinical outcome of metastatic melanoma involving the CNS with or without (w/o) intracranial hemorrhage (IHC)
Authors: Cheng T. , Scott J. N. , Eigl B. , Corbett P. , McKinnon G. 
Published: March 2020

8577 Background: Melanoma has a high rate of ICH associated with CNS metastasis (mets). There is no data on the clinical outcome of these patients (pts) in the literature. Methods: A retrospective review of 52 pts with melanoma CNS mets diagnosed from 11/2001 to 09/2006 at our institution. Two pts were excluded due to a second malignancy. The clinical, radiological, and pathological characteristics of these pts were reviewed. Results: 39 pts were diagnosed after onset of neurological symptoms and 11 were diagnosed during staging. Of these, 14 (28%) were solitary, 23 (46%) were = 4, and 13 (26%) were multiple brain mets. Mean age at brain mets diagnosis was 55 years (range 24–88). Mean follow-up was 25 months (mos) (range 3–61) and 64% were male. ICH was found in 22 pts (44%) with 13 pts (26%) having frank hemorrhage on cranial CT and/or MRI scan. ICH was less common (9%) in pts with brain mets diagnosed on staging. 11 pts (8 with ICH, 3 w/o ICH) underwent CNS mets resection through craniotomy followed by whole brain radiation (WBRT) and/or stereotactic radiotherapy (STR). 7 pts received best supportive care. The remaining pts received WBRT and/or STR. The median survival (MS) for the entire group from CNS mets diagnosis was 7.6 mos. For pts with ICH, overall MS was 9.6 mos with MS of 21.2 mos for pts who underwent craniotomy vs 2.9 mos for pts w/o craniotomy. One pt refused therapy and later died from frank ICH. For pts w/o ICH, overall MS was 6.0 mos with MS of 21.3 mos for pts who underwent craniotomy vs 4.2 mos for pts w/o craniotomy. Pts who underwent craniotomy followed by WBRT and/or STR fared the best with MS of 21.2 mos. Of these, 2 pts with solitary brain mets (1 with ICH, 1 w/o ICH) were alive with no relapse at 58 and 53 mos respectively. The cause of death was disease progression in almost all pts and 85% of pts died from CNS disease progression. One pt died from post-operative complications of craniotomy. Conclusions: ICH by itself is not associated with a negative clinical outcome with appropriate clinical management. Aggressive surgical resection followed by radiotherapy in selected pts improves clinical outcome with prolonged survival possible in a minority of pts. No significant financial relationships to disclose.