bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linac-stereotactic radiosurgery (LSRS) in the management of trigeminal neuralgia
Authors: Gurley S. , Mark R. , Anderson P. J. , Neumann T. , Nair M. 
Published: April 2020

18603 Background: Stereotactic Radiosurgery (SRS) with the Gamma Knife (GK) has been used successfully in the treatment of Trigeminal Neuralgia (TN). Results have been comparable to open surgery. There have been few reports with the use of LSRS in the management of TN. We report our updated results with LSRS in the treatment of TN. Methods: Between 2000 and 2006, 37 patients with medically refractory TN were treated with LSRS. Prior neurosurgical intervention had been performed in 28 patients. Ten patients had one procedure, 10 patients two, and 3 patients three interventions. All patients had typical TN. LSRS was given to the cranial nerve V entry root zone into the brainstem. Targeting was defined by CT and MRI Scans, and CT Cisternogram, utilizing axial, coronal, and sagittal images. Treatment planning was accomplished thru the Radionics Treatment Planning System. The dose was 87 Gy to Dm, in one fraction using the 5 mm collimator and 6 arcs with the 20% Isodose line just touching the brainstem. This dosimetry is similar to Gamma Knife. The dose rate was 400 MU/min. Average Arc length was 130 degrees. Response to treatment was defined as excellent (no pain, off analgesics), good (no pain, with analgesics), and poor (continued pain despite analgesics). Results: With a median follow-up of 40 months (range 6–72 months), 73% (27/37) of patients have reported an excellent or good result after LSRS. One patient has sustained permanent ipsilateral facial numbness. Conclusions: LSRS offers comparable results to Gamma Knife SRS, with respect to both pain relief and complications, in the management of TN. No significant financial relationships to disclose.
Effect of melanoma on immune function in regional lymph nodes (LN)
Authors: Negin B. P. , Panka D. , Wang W. , Tawa N. , Mullen J. , Tahan S. , Mandato L. , Polivy A. , Mier J. , Atkins M. 
Published: April 2020

8000 Background: Metastatic melanoma is associated with various measures of systemic and local immune suppression. We hypothesized that immune suppression in the regional LN basin exists and may facilitate melanoma progression. Methods: We collected portions of regional LNs from tumor uninvolved sentinel LNs (USLN) (remote from primary melanoma removal) and from macroscopically involved nodes (TILN) from therapeutic node dissections in successive melanoma patients. Lymphocytes were extracted, stained using surface and internal antibodies to T cell receptor zeta chain (TCRζ), T regulatory cells (CD4+CD25+ Fox 3p+) (Tregs) and tumor associated myeloid cells (CD11b+ CD14- CD15+) (TAMC), and analyzed via flow cytometer. Results from USLN specimens were compared with TILN. Results: 30 LNs (14 USLN/16 TILN) from 30 patients were evaluated. Median age of patients was 48 years (range 30–83); 20 were male. USLN patients were stage IB (12) or IIA (2); TILN patients were stage IIIB (5), IIIC (5), and IV (6). 7 patients with TILN and none with USLN have progressed. TILN had significantly less TCRζ chain expression than SLN (62% vs. 85%; p = 0.0001). This amounts to a localized decrease of 23% of TCRζ expression (95% CI 13%; 34%). No significant relationship between lymph node involvement and Treg or TAMC was documented. Conclusion: Regional LN involvement with melanoma is associated with a significant reduction in lymphocyte TCRζ expression indicating immune suppression. The mechanism for this is uncertain, but does not appear to be related to changes in Tregs or TAMC (arginase producing cells). We plan to further investigate TCRζ expression in microscopically involved SLNs and SLNs removed at time of primary excision to see if immune changes precede macroscopic tumor involvement. Supported by Harvard Skin SPORE Project 5 and Immune Monitoring Core P50CA93683–01 No significant financial relationships to disclose.
A phase III randomized trial of adjuvant biochemotherapy (BC) versus interferon-α-2b (IFN) in patients (pts) with high risk for melanoma recurrence
Authors: Kim K. B. , Legha S. S. , Gonzalez R. , Anderson C. , Papadopoulos N. E. , Eton O. , Plager C. , Roe A. , Liu P. , Bedikian A. Y. 
Published: April 2020

8003 Background: High-dose IFN (HDI) is associated with significant toxicity, and its clinical benefit as an adjuvant therapy for melanoma has been often debated. BC is associated with higher response rates than other regimens, but it has never been tested in an adjuvant setting. Methods: We conducted a prospective randomized phase III study comparing the clinical benefit of IFN and BC in pts who had undergone lymphadenectomy within 56 days for melanoma metastatic to regional lymph nodes. Pts were randomized to receive BC (Cisplatin 20 mg/m2 IV [d1–4]; Vinblastine 1.5 mg/m2 IV [d1–4]; DTIC 800 mg/m2 IV [d1]; IFN 5 MU/m2 SQ [d1–5]; IL-2 9 MU/m2 continuous IV infusion [d1–4] every 3 wks for 4 courses) or IFN, and those who were randomized to IFN were further randomized to either HDI (20 MU/m2 IV for 5 d/week for 4 wks and 10 MU/m2 SQ 3 times a wk for 48 wks) or intermediate-dose IFN (IDI) (10 MU/m2 SQ 3 times a wk for 1 year). The primary end points were overall survival (OS) and relapse-free survival (RFS). Using 80% power and 5% significance level, 200 pts would be required to detect the difference in median RFS of 18 vs. 36 months and in OS of 40 vs. 80 months between IFN and BC groups. Results: An interim analysis was performed because of slow accrual. 138 pts were enrolled between 1995 and 2003, with 71, 33 and 33 in the BC, HDI and IDI group, respectively. There were no significant differences in both RFS and OS between HDI and IDI groups. With median follow up of 49.3 months, neither the BC or IFN had reached the median RFS and OS. Log-rank test was used to compare RFS (p=0.96) and OS (p=0.52) between 2 groups. RFS and OS data are presented below. Pts in the BC arm had more grade 3–4 fatigue, nausea, anorexia, capillary leak syndrome, diarrhea and myelosuppression. Conclusions: There were no significant differences in both OS and RFS between the BC and IFN groups. This interim analysis supports terminating this trial before achieving the specified target for patient accrual. Supported in part by Schering-Plough. [Table: see text] [Table: see text]
XIAP is highly expressed in melanoma and is associated with chemotherapy resistance
Authors: Kluger H. M. , McCarthy M. , Alvero A. , Divito K. , Camp R. , Rimm D. , Mor G. 
Published: April 2020

8008 Background: Chemoresistance is a major problem in treating melanoma. The X-linked inhibitor of apoptosis (XIAP) is associated with chemoresistance in other cancers. Here we characterize XIAP expression in primary and metastatic melanomas and determine whether XIAP plays a role in chemoresistance. We report differential expression of XIAP between primary and metastatic melanomas and benign nevi. We demonstrate that inhibition of XIAP expression by Phenoxodiol can reverse chemoresistance. Methods: We employed tissue microarrays containing specimens from 548 melanoma patients and 540 benign nevi. XIAP expression was evaluated by an automated method for in situ quantitative analysis of protein levels (AQUA). We use S100 to define pixels as melanoma (tumor mask) within the array spot, and measure intensity of XIAP expression using Cy5 conjugated antibodies within the mask. AQUA scores were correlated with clinical and pathological variables. Cell viability after exposure to Carboplatin and Phenoxodiol was determined in 3 melanoma cell strains using the CellTiter 96 Assay. Apoptosis was measured using the Caspase-3/7 GloTM Assay, and levels of XIAP and Caspase 2 were assessed by Western blots. Results: XIAP expression was significantly higher in melanomas than in nevi (P<0.0001), and higher in metastatic than in primary specimens (P<0.0001). All three melanoma cell strains examined were highly resistant to Carboplatin, and moderately resistant to Phenoxodiol. Pre-treatment with Phenoxodiol prior to Carboplatin induced a significant decrease in XIAP expression, which correlated with remarkable sensitization to Carboplatin. Conclusions: XIAP expression is higher in malignant melanocytes than in their benign counterparts. Expression is higher in early stage disease specimens than in metastatic specimens, suggesting an association with disease aggression. Phenoxodiol is a well tolerated drug, and has been shown to inhibit XIAP expression in ovarian cancer. Here we demonstrate that melanoma is resistant to Carboplatin, possibly due to XIAP expression. In vitro inhibition of XIAP by Phenoxodiol sensitizes melanoma cells to Carboplatin. This drug combination warrants further investigation as a therapeutic approach for metastatic melanoma. [Table: see text]
A phase II pilot trial of low dose, continuous infusion, or “metronomic”, paclitaxel and oral celecoxib in patients with metastatic melanoma
Authors: McDermott D. F. , Cho D. C. , Merchan J. R. , Bhatt R. S. , Seery V. , Mosher J. L. , Farquhar M. B. , Mier J. W. , Atkins M. B. , Sukhatme V. P. 
Published: April 2020

8010 Background: In patients (pts) with metastatic melanoma (MM), tumor angiogenesis has been associated with tumor progression and survival (Ugurel et al, JCO 19:577). Microtubule and cyclooxygenase (COX)-2 inhibitors, both alone and in combination, have been shown to have inhibitory effects on endothelial cells and tumor angiogenesis both in vitro and in vivo (Merchan et al, Int J Ca 113:490. Jones et al, Nat Med 5:1418). We tested the safety and efficacy of a regimen involving low dose, continuous infusion (CIV) paclitaxel and oral celecoxib in pts with MM. Methods: Pts received paclitaxel 10mg/m2 for 96 hours weekly by CIV and Celecoxib 400 mg po/bid. Systemic tumor response was assessed at 6 wk intervals (1 cycle (C)). Pts without unacceptable toxicity or clinically significant disease progression (PD) received additional cycles. Pts exhibiting PD after C 2 relative to end of C 1 were removed from study. Pts on anticoagulants, with recent MI or untreated brain metastases were ineligible. Results: 20 pts (12 M/ 8 F), median age 55 (range 44–65), ECOG PS 0/1/2 (5/13/2), M1a/M1b/M1c: 1/1/18 (90%), and prior systemic therapy regimens 0/1/2/3+: 1/7/5/7 were enrolled in the protocol. Sites of systemic disease included: lung (13 pts), LN (14), soft tissue (13), liver (9), bone (4), brain (6), other (11). 3 pts came of study prior to treatment with rapid disease progression. Treatment related grade 3–4 toxicities included line related (LR) bacteremia (3 pts), LR DVT (3 pts), LR PE (3). There were no grade 3–4 toxicities attributed to paclitaxel or celecoxib. No pt exhibited a major tumor response; 6/20 (30%) pts had stable disease for 17, 18, 18, 18+, 30+, 60 wks. Median TTP was 6 wks (range 3- 60); median overall survival was 6 months (range 1–29). Conclusions: Low-dose, CIV paclitaxel and oral celecoxib leads to disease stabilization in a significant portion of previously treated pts with MM. This suggests a role for combination anti-angiogenic therapy in MM. The incidence of LR toxicities indicates that alternative microtubule inhibitors, such as oral taxanes, should be considered in combination with COX-2 inhibitors for future studies. Results of biomarker studies will be presented at the meeting. Supported by Pfizer Inc. and NIH R21 CA097730. [Table: see text]
Temozolomide (TMZ) in combination with pegylated interferon alfa-2b for stage IV metastatic melanoma: A multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG)
Authors: Spieth K. , Dummer R. , Leiter U. , Garbe C. , Gille J. , Becker J. C. , Hauschild A. , Tilgen W. , Kaufmann R. , Schadendorf D. 
Published: April 2020

8017 Background: Modifying the pharmacokinetic profile of IFN alfa-2b (PegIFN) may improve its activity and tolerability. Specifically, the conjugation of recombinant IFN alfa-2b with a 12 kDa polyethylene glycol (Peg) chain results in a prolonged half-life and has been previously demonstrated to increase efficacy in hepatitis C patients compared to nonpegylated IFNs. We therefore evaluated the combination of TMZ with PegIFN in stage IV metastatic melanoma. Methods: This open-label, phase II study was conducted by the DeCOG at 10 study sites. Eligible pts were between 18 and 75 yrs, had a histologically confirmed diagnosis of metastatic melanoma (stage IV AJCC), no brain metastases and no prior chemotherapy. Pts were required to have a Karnofsky score of > 60% as well as adequate renal, liver and bone marrow function. Informed consent from all participants and approval from the corresponding ethic committees was provided. The regimen (28 d cycles) consisted of TMZ (200 mg/m2 d 1–5) in combination with PegIFN (100 μg sc d 1, 8, 15 and 21). Patients received 2 cycles before reevaluation (WHO response criteria). OR and OS were primary and TTP and toxicity were secondary endpoints of the trial. Results: 124 pts were accrued between 10/02 and 7/04, 8 pts were ineligible or withdrew consent, and thus 116 pts were treated per protocol. At the time of data analysis, 81.0% of pts had died from melanoma and median follow up time was 9.4 months. OR was 18.1% (2 CR, 1.7%; 16 PR; 16.4%); 25.0% of pts presented with SD and 54.3 % progressed (2.6% not evaluable). Median TTP was 2.8 months, median OS 9.0 months (95% CI 7,4;10,6). Grade (gr) 3/4 leucopenia occurred in 22.8% and gr 3/4 thrombocytopenia in 20.3%. Gr 1/2 nausea and emesis experienced 37.5% of the pts; severe nausea (gr 3/4) was rare (1.7%). Liver enzyme elevation occurred in 30.5 % (26.3% gr 1/2; 4.2% gr 3). Conclusions: Combination therapy with TMZ and pegylated interferon alfa-2b constitutes a manageable treatment option in the outpatient setting for advanced metastatic melanoma. Its primary advantage is an increased patient convenience as a result of oral intake of TMZ and once weekly application of PegIFN. [Table: see text]
Phase II trial of sequential temozolomide (TMZ) and high-dose bolus (HDB) IL-2 in patients with metastatic melanoma
Authors: Agarwala S. S. , Tarhini A. A. , Kirkwood J. M. , Cai C. , Stover L. , Moschos S. , Gooding W. 
Published: April 2020

8037 Background: Previous biochemotherapy (BCT) regimens for metastatic melanoma have utilized lower doses of IL-2 and multiple chemotherapeutic agents, adding to toxicity, but not to efficacy. Methods: We designed a 2-stage Simon phase II study testing a unique BCT approach of single agent chemotherapy with TMZ given in an extended schedule (75 mg/m² per day for 3 weeks PO) followed by HDB IL-2 (600,000 U/Kg/dose, maximum 14 doses administered over 5 days). Cycles were repeated every 28 days with a two-week interval between alternate cycles. The first stage accrued 20 patients with promising activity and safety permitting enrollment of additional patients. Results: Thirty-one patients (20 male, 11 female), age 27–74 (median 47) have been enrolled to date. All had AJCC stage IV melanoma (7 M1a, 5 M1b, 19 M1c) and had not previously received therapy for metastatic disease. Twelve had received prior adjuvant interferon. A total of 88 cycles of therapy have been administered (median of 2 cycles per patient; 5 patients continue on therapy). The median number of doses was 9 (range 7–12) during cycle 1, and 6 (range 4–11) during cycle 2. Three patients did not receive any IL-2 due to disease progression, and 6 patients received only one cycle of IL-2. Twenty two patients who received at least 2 cycles are evaluable for response. All 31 patients are evaluable for toxicity. Grade 3 toxicities included hepatic (8), hematologic (4 leukopenia, 2 thrombocytopenia), diarrhea (1). No grade 3–4 cardiovascular or renal toxicities were noted. Overall response rate is 22.7% (2 complete lasting 10.8 and 17+ months, 3 partial lasting 3.7 and 16+ months, 1+ month). Responses were seen in both M1a and M1c disease. Fourteen patients had stable disease after 2 cycles and 10 of these have progressed. As of 12/31/2005, the 4 month PFS rate is 74% [40%, 88%], median TTP is 24 weeks [11, 32] and median OS is 71 weeks (31.4, inf). Conclusions: HDB IL-2 can be safely administered in combination with single agent temozolomide in an extended schedule and appears to have promising efficacy and lower toxicity than previously used BCT regimens. Further follow-up will determine if durability of response exceeds that of single agent HDB IL-2. [Table: see text]
A phase II study of ABT-510 for the treatment of metastatic melanoma
Authors: Markovic S. , Suman V. , Rao R. , Creagan E. , Maples W. , Kaur J. , McWilliams R. , Allred J. , Pitot H. , Croghan G. , Humerickhouse R. 
Published: April 2020

8041 Background: ABT-510 is a synthetic peptide analog of thrombospondin-1 demonstrating inhibition of VEGF/bFGF mediated human endothelial cell migration, proliferation, tube formation, cornea-neovascularization as well as inhibition of tumor growth in vivo (B16F10 melanoma). Having been found to be safe in phase I testing, ABT-510 has entered phase II trials. Presented are the results of a phase II study using ABT-510 for the treatment of stage IV melanoma. Methods: A two stage phase II clinical trial was conducted to assess the anti-tumor activity, safety profile and pharmacodynamics of ABT510 in patients with stage IV melanoma. Patients self-administered 100mg of ABT-510 subcutaneously twice/day. Therapy was continued in the absence of excessive toxicity or tumor progression. Primary endpoint was 18 week progression free survival rate. Enrolled were patients at least 18 years of age with measurable (RECIST) metastatic melanoma, ECOG performance status of 0–2 and normal pre-registration blood tests. Exclusion criteria included: cancer therapy less than 4 weeks prior to registration; failure to recover from prior therapy; brain metastases; significant recent bleeding; uncontrolled hypertension; and ongoing anti-coagulation. Pregnant or nursing women were not eligible. Results: Twenty-one patients (67% male) were enrolled with a median age of 55 years. Most patients had M1c disease (80%) and 62% had prior chemotherapy for stage IV melanoma. None of the patients were ineligible/canceled participation. After the first stage of the trial was complete, only 3 of the first 20 patients enrolled were progression-free at 18 weeks. Having not met the minimal clinical efficacy requirement (at least 7 of the first 20 patients progression-free at 18 weeks) the trial was closed to further accrual. Correlative laboratory studies suggested decreases in some of the measured parameters of angiogenesis (VEGFC, circulating endothelial cells) with no impact on immune homeostasis. Conclusions: Single agent ABT-510 therapy administered at 100mg twice/day to patients with previously treated metastatic melanoma did not demonstrate significant clinical efficacy. However, changes in measured parameters of angiogenesis suggest possible clinical efficacy with higher dosing or in combination with cytotoxic therapy. [Table: see text]
Phase II trial of extended-dosing temozolomide in patients with melanoma
Authors: Rietschel P. , Ejadi S. , Wolchok J. , Krown S. , Gerst S. , Jungbluth A. A. , Busam K. , Smith K. , Panageas K. , Chapman P. 
Published: April 2020

8042 Background: We previously reported a 30% response rate in metastatic melanoma (mel) patients (pts) treated with temozolomide (TMZ) using an extended dosing schedule of 6 weeks on/ 2 weeks off with either thalidomide or interferon. We hypothesized that these responses were largely due to TMZ alone and conducted a phase II trial using extended dosing TMZ alone. We also tested the hypothesis that a) mel expression of methylguanine methyltransferase (MGMT) would correlate with drug resistance, and b) TMZ would cause decreased CD4+ T cell function during the first cycle of therapy. Methods: A phase II trial stratified metastatic mel patients into two cohorts based on whether or not they had stage IV M1c. 25 patients/cohort are planned. No brain metastases or prior chemotherapy were allowed. Each cycle consisted of TMZ 75mg/m2/day for 6 weeks followed by 2 weeks with no treatment. Primary endpoint was the proportion of objective responses by RECIST criteria. The trial was powered to exclude the null hypothesis that the response rate in each cohort was ≤10%. MGMT promoter methylation status was assessed by methylation-specific PCR. MGMT tumor expression was measured by immunohistochemistry (IHC). CD4+ T cell function was assessed by measuring interferon-γ responses to CMV by intracellular cytokine FACS analysis (FastImmune, BD Biosciences) at pretreatment, week 4 and week 8 of cycle 1. Results: To date 19 evaluable pts, 8 in the M1c cohort, have progressed with no objective responses; 6 other patients are currently on study. 4/19 pts who have gone off study because of progression were stable for 6 months and received ≥3 cycles. To date, 14/15 tumors analyzed for MGMT promoter methylation were unmethylated (≤15%). Promoter methylation of 21% was seen in one tumor. Conclusions: The MGMT promoter of metastatic mel tumors are hypomethylated predicting expression of the enzyme. This is being assessed directly by IHC and will be correlated with promoter methylation and clinical response. The effect of TMZ on anti-CMV CD4+ T cell function is being assessed. Accrual is ongoing and will be completed in Spring 2006. The study was supported by Schering-Plough. No significant financial relationships to disclose.
Phase II study of pegylated arginine deiminase (ADI-PEG20), a novel targeted therapy for melanoma
Authors: Feun L. G. , Savaraj N. , Marini A. , Wu C. , Robles C. , Herrera C. , Spector S. , Luedemann K. , Moffat F. , Bomalaski J. 
Published: April 2020

8045 Background: Melanoma cells may be sensitive to arginine (Arg) deprivation due to lack of expression of argininosuccinate synthetase (ASS) which is needed to synthesize Arg, a nonessential amino acid in humans, from citrulline (Ctr). ADI-PEG20 lowers plasma Arg levels by catalyzing the conversion of Arg into Ctr. A phase I-II trial of ADI-PEG20 in metastatic melanoma (MM) showed intramuscular (i.m.) weekly doses of 160 IU/m² was well tolerated and resulted in responses in European patients (pts) (JCO 23:7660, 2005). Based on these encouraging results, we performed a phase 2 clinical and pharmacological study of ADI-PEG20 in USA pts with MM. Methods: Pts had weekly i.m. injection of ADI-PEG20 at a starting dose of 160 IU/m². Serum Arg levels were determined q 2 weeks. The dose of ADI-PEG20 was escalated up to 320 IU/m² weekly if Arg levels were still detectable. Tumor evaluation was done q 8 weeks. Tumor samples were assayed for ASS expression using immunohistochemical staining and/or PCR prior to start of therapy and at time of relapse. Results: 17 pts were treated and evaluable. Median age was 69 (range 29- 80). Median performance status was 90 (range 70- 100). Median number of metastatic sites was 2 (range 1- 8). 11 pts had stage M1c and 11 had prior chemotherapy and/or immunotherapy for advanced disease. Responses include partial response (PR) 4 pts (24 %), minor response 2(12 %), mixed response 2 (12%). Duration of PR from start of therapy was 4(+), 6(+), 12, and 16 months. Sites of response include soft tissue/nodal (3 pts) and lung (1 pt). Tumor tissue was available for ASS determination in 12 pts. ASS expression was associated with treatment failure and relapse. Conclusions: This work confirms that ADI-PEG20 appears to be active in MM. Side effects include minor discomfort at the injection site, slight fatigue, and mild elevation of serum uric acid consistent with tumor destruction. ASS expression may correlate with response. This study is continuing to accrue pts. ADI-PEG20 may be beneficial in MM. No significant financial relationships to disclose.