bluuebunny/crossref_metadata_2025 huggingface dataset:
The changing face of cancer in the elderly—Only a demographic change?
Authors: Rottenberg Y. , Peretz T.
Published: April 2020

18597

Background: In industrial countries, the cancer burden of the elderly is high and is increased. One reason is longer life expectancy. Increasing age standardized rates of cancer in this age group compared to younger groups may also explain this phenomenon. Methods: Two age groups were examined, above and below 65 years. Each age group was further divided into men and women. The age standardized rates for all cancers combined among the Jewish population in Israel were identified through the Israel Cancer Registry during the years 1973–2002. In addition, lung and colorectal cancers according to sexes, prostate cancer in men and breast cancer in women were examined. Results: Between the first 5 years of the study (1973–1977) and the last 5 years (1998–2002) the age standardized rates for all cancers combined were raised by about one third in the two age groups. In males, the overall change was higher in the older group (42% in men aged 65 years and older compared to 31% in men younger than 65). However, the rise in the younger group was more prominent in females (42% in women younger than 65 years compared to 33 % in women aged 65 and older). The most outstanding increase was in prostate cancer in men, but mainly in the younger group (176% in the older group and 368% in the younger group) followed by breast cancer in women, more prominent in the older group (64% in the older group and 50% in the younger group). In both sexes, more noticeable increases were noted in the older groups in colorectal cancer and in lung cancer. Between the years 1993–1997 and 1998–2002 shifts towards stabilization and even a decrease was noted in some of the cancers that were examined. In men aged 65 years and older rates for all cancers combined were decreased by 2.5%, among the specific tumors and a decrease was noted in lung cancer (6.7%) and prostate cancer (5.8%). The rates for all cancers combined among the older women were slightly decreasing (2.0%). No decrease was noted in the specific tumors in this group. Among the younger groups in both sexes, no decrease (defined >0.5%) was noted. Conclusions: These data argue against the hypothesis that the overall change in the cancer burden in the aged could be also explained by differences changes in the risk of developing cancer between these two age groups.

No significant financial relationships to disclose.
Evaluation for cardiac toxicity with MRI in young adult survivors of acute lymphoblastic leukemia (ALL)
Authors: Wright J. A. , Reimold S. C. , Winick N. J. , Turoff A. , Brooks S. , Eshelman D. , Oeffinger K. C.
Published: April 2020

18604

Background: Long-term survivors of childhood cancer treated with a moderate to high cumulative dose (≥300mg/m2) an anthracycline are known to be at risk for cardiac toxicity. It remains unclear what cardiac risk exists for survivors who received a low cumulative dose (<300mg/m2) of an anthracycline. Methods: We are conducting an NIH sponsored trial in 120 young adult survivors of ALL to determine the prevalence of cardiovascular risk factors and to determine the effectiveness of an exercise intervention. As part of their cardiovascular risk assessment, participants undergo cardiac MRI, a tool with excellent reproducibility in assessing left ventricular (LV) size and function. The aim of this component of the study is to determine the prevalence of cardiac toxicity in survivors treated with low dose anthracycline in comparison to those who did not receive any anthracycline. Descriptive statistics, chi-square analysis, and spearman correlation coefficients were used to examine the relationship between anthracycline dose and measures of cardiac function. Results: This study represents a work in progress. Preliminary results from the first 22 participants who have had a cardiac MRI do not show a significant difference in ejection fraction, LV mass, cardiac output, or mass to volume ratio between those treated with low cumulative dose anthracycline versus no anthracycline. Available cardiac MRI data for all participants will be presented at the meeting. Conclusions: With the continued use of an anthracycline at cumulative low doses, particularly in upcoming ALL standard risk trials, it is particularly important to determine if there is a risk of cardiac toxicity after low doses with aging.

No significant financial relationships to disclose.
Impact of a functional polymorphism in the IL12B promoter region on survival in patients with malignant melanoma
Authors: Schadendorf D. , Ugurel S. , Paschen A. , Kern K. , Hill B. , Morahan G. , Müller-Berghaus J.
Published: April 2020

8001

Background: Interleukin-12 (IL-12), a heterodimeric cytokine, is important in the generation of a Th1-biased immune response. Several polymorphisms have been described in IL12B, the gene encoding the p40 subunit of IL-12. A bi-allelic polymorphism within the IL12B promoter region has been reported to show association with diseases as diverse as severe childhood asthma and fatal cerebral malaria. Methods: In order to define the molecular basis for these disease associations we investigated the secretion of IL-12 by human monocyte-derived dendritic cells. The amount of IL-12p40 and p70 produced by DCs from normal blood donors was determined following CD40L activation. Subsequently, we therefore sought to investigate the frequency of IL12B genotypes and their impact on the outcome of patients with malignant melanoma. Genomic DNA was isolated from 75 normal blood donors and 80 melanoma cell lines and used for genotyping the IL12B polymorphism. Corresponding clinical data were retrieved from the in-house melanoma database. Results: Allele frequency for IL12Bpro-1 is 0.45 and for IL12Bpro-2 0.55. Homozygotes for the IL12B promoter polymorphism showed a 10-fold difference in median p70 secretion in response to CD40 ligation. Remarkably, this difference resulted from the inability of most allele 1 homozygotes to secrete heterodimeric IL-12. In contrast, most of the donors homozygous for allele 2 had detectable secretion. Distribution of genotypes in melanoma patients was not significantly different from normal blood donors. Kaplan-Meier survival analysis showed significantly decreased survival of patients homozygous for the longer allele, previously defined as being associated with decreased IL-12 secretion (log-rank p=0.015). Subgroup analysis indicated that this survival advantage was seen exclusively in female patients. Conclusions: The recently described IL12B promoter polymorphism is highly correlated with secretion of bioactive IL-12 and has a significant impact on the clinical course of disease in patients with melanoma and may therefore be useful for prognostic stratification.

No significant financial relationships to disclose.
Phase II study of volociximab (M200), an α5β1 anti-integrin antibody in metastatic melanoma
Authors: Cranmer L. D. , Bedikian A. Y. , Ribas A. , O’Day S. , Forero-Torres A. , Yazji S. , Kirkwood J. M.
Published: April 2020

8011

Background: Integrin α5β1 has been reported to be unregulated in metastatic melanoma and in tumor angiogenesis. A critical survival step in angiogenesis is the ligation of fibronectin in the extracellular matrix to α5β1 on endothelial cells. M200 is an IgG4 chimeric monoclonal antibody targeting α5β1, inducing apoptosis of proliferating endothelial cells. M200 activity is independent of growth factor stimulus, suggesting that binding of fibronectin to α5β1 occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, single cohort, pilot phase II study of 40 patients (pts) in metastatic melanoma. Pts received M200 10 mg/kg IV every 2 weeks with DTIC 1g/m2 monthly until disease progression. Pts were evaluated for efficacy every 8 weeks by objective response using RECIST criteria. Additional evaluations included pharmacokinetics and immunogenicity profile. An independent data safety monitoring board was utilized to review safety data. Results: A total of 40 pts have been enrolled to date. All pts were evaluable for safety and 30 pts for objective response using ITT population. Median age was 58.8 years, with 26 (65%) male. ECOG score was 0–1 in 37 (92%) pts. Up to 14 doses of M200 (median 4 doses) and 7 doses of DTIC (median 2) have currently been administered, with dosing continuing. Thirty-one (77.5%) pts have had at least 1 AE with 8 (20%) pts at least 1 SAE. The most frequent adverse events for M200 were nausea 17.5%, constipation 10% and vomiting 10% and for DTIC were nausea 35%, vomiting 20% and pyrexia 15%. Fifteen SAE’s with 2 possibly related to M200 including hypertension and deep vein thrombosis. Four pts died in the study, all with progressive disease (PD). Best overall response at 8 weeks was stable disease (SD) in 16/30 pts and PD in 14/30 pts. Median time to progression was 72 days. Conclusions: M200 appears to be well tolerated at 10 mg/kg Q2W in combination with DTIC.

[Table: see text]
Phase I trial of lomeguatrib (PN) combined with dacarbazine (DTIC) for treatment of patients with melanoma and other solid tumors: Initial results
Authors: Tawbi H. , Tarhini A. , Moschos S. , Sulecki M. , Viverette F. , Radkowski R. , Shipe-Spotloe J. , Kunkel C. , Rae M. , Kirkwood J.
Published: April 2020

8016

Background: TheDNA repair enzyme O6-Alkylguanine Alkyltransferase (AGT) directly reverses the O6-methylguanine (O6-MeG) base lesion induced by treatment with DTIC. Depletion of AGT using O6-MeG analogs enhances the cytotoxicity of DTIC in preclinical models and in early phase trials of O6-Benzylguanine. Lomeguatrib (Patrin, PN) is an orally bioavailable highly potent O6-MeG analog that is well tolerated as a single agent. We report the first phase I experience of PN combined with DTIC in patients who have failed prior systemic therapy. Methods: This open-label phase I study was performed to determine the toxicity profile and maximum tolerated dose (MTD) of PN given orally for 5 or 10 days (d) combined with a single dose of DTIC administered IV on d 2, repeated on a 21 d schedule. Of 30 pts enrolled 25 (83%) had metastatic melanoma, and all had ECOG PS ≤2. Dose escalation started at 40 mg of PN once daily for 5 d and 500 mg/m2 of DTIC. 6 pts failed prior chemotherapy, 16 failed prior immunotherapy, and 3 failed both. 5 pts had no prior systemic therapy. Results: Adverse events observed in more than 50% of pts included gr 1–2 nausea and vomiting and gr 1–2 fatigue. Hematologic toxicity was prominent with gr 3–4 neutropenia (13/30, 43%) and gr 3–4 thrombocytopenia (4/30, 13%) even at doses of DTIC 50% of usual clinical doses. Prolonged neutropenia accounted for all dose-limiting toxicities (DLT) observed so far. The MTD has not been reached, however hematologic toxicities requiring dose modifications of DTIC have been frequent (42% of all cycles administered). 16 pts (53%) had stable disease as their best response with a median time to progression of 53 days (95% C.I. 40–86 days). Conclusions: Oral administration of PN substantially alters the toxicity and tolerance of DTIC inducing prolonged hematologic toxicity at doses <50% of doses in routine usage. The study is ongoing to determine the MTD of PN combined with DTIC after which a phase II trial will be completed in pts who have not had prior chemotherapy. Pending completion of accrual (total of 40 pts by May 2006) the recommended phase II dosage appears to be PN 40 mg orally BID for 10 days combined with 400 mg/m2 of DTIC.

[Table: see text]
Prognostic significance of children with cutaneous melanoma: Implications for treatment
Authors: Kavanagh M. A. , Essner R. , Chen S. L. , Wanek L. A. , Scheri R. P. , Morton D. L.
Published: April 2020

8021

Background: The incidence of melanoma in pediatric patients, particularly teenagers, is increasing. Treatment strategies employed for adult patients with melanoma have been applied to pediatric populations with minimal data to support similar efficacy. We performed a matched-paired analysis to compare the prognosis of pediatric (≤19 yrs old) and adult melanoma patients. Methods: Single institution, prospectively obtained melanoma database containing >14,000 records was queried for children ages 1–19 years treated for cutaneous melanoma. We identified 197 pediatric patients seen at our institute over the last 35 years. After excluding patients not seen within 4 months of initial diagnosis, 115 pediatric patients were matched to adults (age 20–70 years) chosen from the database by gender, stage, primary site and tumor characteristics (Clark level, Breslow thickness, and ulceration). Overall survival was compared between cohorts by the Kaplan-Meier method. Results: For the pediatric patients, median age at diagnosis was 17.7 years (range 7–19 years). Patients were almost equally distributed between girls (47%) and boys. AJCC stage I and II disease at presentation was most common (73%), with stage III and IV occurring much less frequently (25% and 2%). Most pediatric patients had Clark level IV (37%) lesions; Clark level II (25%), III (25%), V (4%), and I (2%) lesions were less common. Breslow thickness ranged between <1.0mm (38%), 1.1–2.0mm (20%), 2.1–4.0mm (17%), and >4.1mm (12%). The two predominant histologic types were superficial spreading (52%) and nodular (22%) melanoma. 14% of the primary lesions were ulcerated. Rates of disease-free and overall survival were 75%± 4% and 84%± 4% at 5 years and 74%± 4% and 77%± 5% at 10 years, respectively, with a median follow up of 5.1 years (range 1–30 years). Matched pediatric and adult patients showed no difference in survival from time of initial diagnosis and stage of presentation (log rank p=0.24). Conclusions: Stage-specific survival in pediatric and adult melanoma patients is similar. In the absence of specific pediatric trials, standard treatment for children with melanoma should be consistent with that for adults.

No significant financial relationships to disclose.
Lymphodepletion with high-dose interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF) in metastatic melanoma patients: An interim analysis
Authors: Ketchum S. L. , Cole B. , Margolin K. , McDermott D. , Crocenzi T. , Roberts J. , Crosby N. , Meehan K. , Fisher J. , Ernstoff M. S.
Published: April 2020

8034

Background: Lymphocyte depletion followed by homeostatic recovery has been shown to break tumor-specific tolerance. We have initiated a clinical trial of chemotherapy-induced lymphodepletion followed by high-dose (HD) IL-2 + GM-CSF in metastatic melanoma (MM) patients (pts). Methods: Pts with PS 0–1, normal organ function and with measurable MM were treated with intravenous cyclophosphamide 60 mg/kg (day 1–2), fludarabine 25 mg/m2 (day 3–7) followed by two 5-day (d) courses of intravenous HD bolus IL-2 600,000 IU/kg (d 8–12 and 21–25) and daily subcutaneous administration of GM-CSF 250 mcg/m2 (d 8 until granulocyte recovery). Results: 8 pts are presently evaluable in this first stage of accrual to confirm safety and immunomodulation. A mean of 25/28 IL-2 doses were delivered. All pts experienced transient myelosuppression with ANC < 500 cells/mm3 for a median of 7d (range 5–11d) and platelets <50,000/mm3 for a median of 5.5 days (range 0–7d). Pts exhibited reversible capillary leak associated with high-dose IL-2. With the exception of myelosuppression, no grade 4 toxicities occurred. All pts experienced neutropenic fever and 2 developed line infections. CD4+/CD25high/CD62L+ T cells rebounded by d 14, peaked around d 28 and returned to baseline by d 85. CD8+/CD28- T cells recovered to levels lower than baseline for the first 28d but then showed persistent elevation through d 113. Skewing of T-cell populations based on TCR Î² chain expression was observed. One pt achieved complete response, 2 achieved partial responses, and 5 progressed. Conclusions: Lymphodepletion followed by high-dose IL-2 can be safely administered, affects immune reconstitution, and has activity in MM that may be useful as a platform for enhancing immunotherapeutic strategies. The trial continues to accrue in order to better estimate antitumor activity and immunomodulation.

No significant financial relationships to disclose.
Phase I clinical trials of ticilimumab: Tumor responses are sufficient but not necessary for prolonged survival
Authors: Bulanhagui C. A. , Ribas A. , Pavlov D. , Bozon V. , Sharma A. , Gomez-Navarro J. , Camacho L.
Published: April 2020

8036

Background: Clinical studies examining anti-CTLA4 monoclonal antibodies (mAb) provide evidence of the biologic and clinical activity of this class of agents. Two Phase 1 studies with ticilimumab, a fully human anti-CTLA4 mAb, have been reported previously. In both studies, objective responses (OR) were seen in some patients (pts) with melanoma. In addition, we observed highly favorable outcomes among several pts who did not experience objective responses. This may indicate a positive impact of ticilimumab on melanoma in these pts, not well reflected by traditional response criteria. Long-term follow-up data on survival for pts enrolled in these Phase 1 studies is now reported. Methods: We studied the safety, pharmacokinetics, immunostimulatory activity, and clinical activity of ticilimumab in 53 pts with solid malignancies. Ticilimumab was administered, as a single agent, at single dose levels ranging from 0.01 to 15 mg/kg and at multiple dose levels ranging from 3 to 15 mg/kg. The dosing regimens included either a single dose, multiple doses given q3 months, or multiple doses given q1 month. Results: The two studies included 43 pts with measurable melanoma. Ticilimumab proved safe and overall was well tolerated (Ribas et al. ProcASCO 2005, and JCO Dec2005). Of the 43 pts with measurable melanoma, 18 were alive at >12 months (range: 13 - 42+) after initial treatment with ticilimumab. This includes 5 pts with an OR who continue on ticilimumab, either on-study or as part of a single IND, and 13 pts without an objective response. Among the pts who did not experience an OR, 5 had surgical resection of metastatic lesions and remain relapse free, and 8 are alive with disease. Conclusions: In pts with melanoma treated with ticilimumab, long-term survival has been achieved by all 5 pts who experienced an OR and in 13 pts who did not experience an OR. These findings suggest that lack of objective response is a poor predictor of long-term survival following ticilimumab therapy.

[Table: see text]
Long-term clinical results of the combination of cisplatin (C), vinblastine (V), DTIC (D) and interferon-alfa (I) with or without tamoxifen (T) for metastatic melanoma
Authors: Sanguino A. M. , Bedikian A. Y. , Legha S. S. , Detry M. A. , Papadopoulos N. E. , Hwu P. , Hwu W. , Kim K. B.
Published: April 2020

8039

Background: According to 2001 AJCC data, 1-yr, 2-yr, 5-yr, and 10-yr survival of melanoma patients (pts) with stage M1c were 40.6%, 23.6%, 9.5% and 6.0%, respectively. Previously, we reported the interim results of a randomized phase II trial comparing the response rates (RR) of CVDI vs. CVDI +T. Here we report long-term survival results of these pts. Methods: Chemo-naïve pts between 16 and 75 yrs of age, with histologically documented diagnosis of advanced melanoma and without symptomatic brain metastasis, were randomized to receive either CVDI (group A) or CVDI+T (group B). The dose of each drug is as follows: C 15 mg/m2 IV (d 2–5), V 1.2 mg/m2 IV (d 1–5), D 600 mg/m2 IV (d 1), I 5 MU/m2 SQ 3 times a wk and T 20 mg twice a day. The treatment was administered every 3–4 wks. After the interim analysis, the arm with a higher RR was selected for an expansion cohort (group C). The primary endpoint was the RR of CVDI regimen with or without T. The secondary endpoint was overall survival (OS) evaluation. Results: A total of 104 pts were enrolled, among which 36 and 34 were randomized to group A and B, respectively. After interim analysis of 70 pts, the CVDI regimen was selected for group C. There were no significant differences in both RR (p= 0.126) and OS (p= 0.095) between group A and B. When all 104 pt data were combined, the overall response rate (ORR) was 37.5% with a complete response rate (CRR) of 8.7% and the median survival of 10.4 months. One-yr, 2-yr, 5-yr, and 10-yr OS were 43%, 20%, 7% and 4%, respectively. Conclusions: Although the combination of CVDI with or without T is an active regimen for treatment for metastatic melanoma, long-term survival of pts receiving this regimen is similar to historical controls.

[Table: see text]

No significant financial relationships to disclose.
Phase II trial of the mTOR inhibitor everolimus (RAD-001) in metastatic melanoma
Authors: Rao R. D. , Windschitl H. E. , Allred J. B. , Lowe V. J. , Maples W. J. , Gornet M. K. , Suman V. J. , Creagan E. T. , Pitot H. C. , Markovic S. N.
Published: April 2020

8043

Background: Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that regulates the production vascular endothelial growth factor (VEGF) and cell growth and proliferation. Inhibitors of mTOR have anti-mitotic and anti-angiogenic effects in various cancers (including melanoma). Everolimus (RAD-001), an orally administered inhibitor of mTOR, is well tolerated at a dose of 30 mg/week. We conducted a phase II study to evaluate the role of RAD-001 in treating patients with metastatic melanoma (MM). Methods: A 2 stage, phase II multi-institutional trial was conducted in patients with MM to assess progression free survival (PFS) rate at 16 weeks was at least 50% against the alternative it was at most 30%. Data about expected baseline PFS were derived from historical controls. Each cycle was 8 weeks in duration. Inclusion criteria: measurable disease, ECOG performance score (PS) of 0–2. Exclusion criteria: presence of intracranial metastases, concurrent use of inducers of cytochrome 3A4 and abnormal hepatic, renal or bone marrow function. Correlative studies included changes pharmacodynamic endpoints to evaluate effect of therapy on signaling pathways. Results: 24 patients with MM were enrolled. Median age was 56 years (33–79), 21 (88%) had at 2 or more sites of metastatic disease. Most (75%) had stage M1c, with 13% each having 1a and 1b disease. PS was 0, 1 and 2 in 58, 38% and 4%, resp. All but 9 had received previous therapy for MM. Planned interim analysis was done after 20 patients were enrolled. Of these, 7 (i.e., 35%) were PF at 16 weeks, which exceeded the decision rule for restarting accrual. No patient had an objective response; all 7 had stable disease. There were no grade 3 toxicities. Grade 2 toxic events (at least possibly related to therapy) were: fatigue (17%), diarrhea (8%) and anemia (8%). Patients had a clinically relevant benefit, with the median PFS for all 24 patients of 3 months. Median overall survival was not reached. Three patients continue on therapy. RAD-001 treatment resulted in changes in serum VEGF levels. Conclusion: Interim analysis after enrollment of 20 patients suggests that RAD-001 is well tolerated and has sufficient anti-tumor activity in MM to warrant the opening of enrollment to the second stage of this trial. Further accrual is planned.

No significant financial relationships to disclose.
A phase II multicenter study on the histone deacetylase (HDAC) inhibitor MS-275, comparing two dosage schedules in metastatic melanoma
Authors: Hauschild A. , Trefzer U. , Garbe C. , Kaehler K. , Ugurel S. , Kiecker F. , Eigentler T. , Krissel H. , Schadendorf D.
Published: April 2020

8044

Background: The acetylation of histones is a key component of gene regulation, which plays an important role in tumor initiation and progression. MS-275, an inhibitor of the benzamide series, is a synthetic orally available inhibitor of HDACs which showed anti-tumor activity in 3 phase 1 trials. Methods: A phase II, multicenter, randomized, parallel-group study of oral MS-275 evaluated the efficacy and toxicity in patients with non-resectable metastatic melanoma. Patients should have received at least one, but not more than two previous systemic therapies (chemo- and/or immunotherapy) for stage IV melanoma. Patients were stratified to receive either 3 mg MS-275 biweekly (days 1+15 of a 4-week cycle) or 7 mg MS-275 weekly (days 1+8+15 of a 4-week cycle) until disease progression or unacceptable toxicity. Study endpoints were the assessment of tumor response and toxicity. Results: A total of 28 patients have been randomized equally to the two dosing groups. Patients were classified as belonging to AJCC stage IVa (n=0), IVb (n=9; 32%), and IVc (n=19; 68%). In general, MS-275 was very well tolerated. No treatment-related SAEs have been observed. Most frequently reported side effects were nausea (CTC Grade 1+2, 32%) hypophosphatemia (CTC Grade 1–3, 29%), and diarrhea (CTC Grade 1+2, 18%). Stable diseases lasting from 8 wks to more than 48 wks have been observed in 4 pts (29%) in the 3 mg and 3 pts (21%) in the 7 mg dose group. Stabilizations occurred in these metastatic localizations: skin, peripheral and visceral lymph nodes, lung and bone, respectively. However, objective tumor responses were not observed. Conclusions: The results suggest that MS-275 is well tolerated and shows long-lasting tumor stabilizations in patients with pre-treated metastatic melanoma. The failure of objective tumor responses in the single-agent treatment with MS-275 warrants further evaluation also in combinational settings.

[Table: see text]
Results of the ESOPE (European Standard Operating Procedures on Electrochemotherapy) study: Efficient, highly tolerable and simple palliative treatment of cutaneous and subcutaneous metastases from cancers of any histology
Authors: Gehl J. , Sersa G. , Garbay J. , Soden D. , Rudolf Z. , Marty M. , O’Sullivan G. , Geertsen P. F. , Mir L. M.
Published: April 2020

8047

Background: By applying brief, electric pulses, cell membranes can be transiently permeabilised (electroporation). This can be applied focally to tumors, enhancing the uptake of certain chemotherapeutic agents dramatically (electrochemotherapy). Methods: From 2003 to 2005, patients with cancer of any histological diagnosis and symptomatic metastases to skin or subcutis were accrued in four cancer centers. Patients had been offered standard treatment options previously. Primary endpoint was response. One treatment was performed in either general anesthesia or local anesthesia, depending on anatomical site, size and number of tumors. The Cliniporator (IGEA, Italy) was used to deliver electric pulses, with 3 different electrode types: 1) Plate electrodes, 2) Linear array needle electrodes 3) Hexagonal needle electrodes. Eight pulses of 100 μs were applied using 1) 1300 V/cm, 2 and 3) 1000 V/cm. Either intravenous bleomycin 15000 IU/M-2, or intratumoral injections of either bleomycin or cisplatinum, were administered prior to application of electric pulses to the tumors. Responses were documented through direct tumor measurement and digital photography. Results: 41 patients, with altogether 171 cutaneous metastases of malignant melanoma (98 nodules, 57 %), carcinoma or sarcoma were treated. Overall, 145 (84.8%) of the treated nodules responded (CR or PR), with CR in 126 of the nodules (73.7%). Negative response was observed in very low percentage of the treated nodules being either NC (10.5%) or PD (4.7%). Treatment of melanoma and non-melanoma nodules was equally successful. Treatment time per session (one or more nodules) was median 25 min (range 6–60). Intravenous and intratumoral administration of bleomycin, or cisplatinum yielded similar results. No significant toxicity was found, and 96% of patients reported they would agree to another treatment if indicated. Conclusions: Electrochemotherapy is an efficient, safe and simple palliative treatment of cutaneous and subcutaneous metastases of cancers of various histologies. Patient acceptance of treatment was excellent and 73.7% of nodules were in CR after one single treatment.

No significant financial relationships to disclose.
Soluble VEGF-A and lymphangiogenesis in metastatic malignant melanoma patients
Authors: Soubrane C. , Mouawad R. , Sultan V. , Spano J. , Khayat D. , Rixe O.
Published: April 2020

8049

Background: Vascular endothelial growth factor (VEGF-A) and its circulating form (sVEGF-A) play a major role in tumor progression and angiogenesis. However, the clinical implications of circulating VEGF-A in metastatic malignant melanoma patients and its role in tumor-associated lymphangiogenesis and lymphatic metastasis remained unclear. Objectives: The aim of this study is to evaluate the potential role of circulating VEGF-A levels in lymphangiogenesis and its usefulness in metastatic malignant melanoma patients. Methods and Patients: using a sensitive enzyme-linked immunosorbent assays, VEGF-A level was measured in sera of 65 patients treated by biochemotherapy with a fully documented history of disease in comparison with 30 healthy controls. Results: A wide range (0- 566 pg/ml) of pretreatment sVEGF-A level was detected in the serum of MMM patients and the median level (40.5 pg/ml) was significantly higher (p=0.0007) than that of healthy donors (7.5 pg/ml). Age, gender and LDH were not associated with sVEGF-A levels. Regarding tumor burden, median pretreatment sVEGF-A level was higher in patients with high tumor burden (n= 40) as compared to patients with low tumor burden (n=25). Furthermore, the most surprising finding of our study was that patients with only lymph node metastasis (n=23) had a significantly (p= 0.021) higher median sVEGF-A levels (45.7 pg/ml) as compared to the 42 patients with different metastatic sites (16.6 pg/ml). Conclusion: these results suggest that sVEGF-A levels may predict lymph node metastasis in metastatic malignant melanoma patients. In addition, it may be promising targets for new therapeutic strategies in melanoma disease.

No significant financial relationships to disclose.
Immunophenotype of regionally recurrent melanoma of the extremity in patients before isolated limb infusion (ILI)
Authors: Brady M. S. , Gnjatic S. , Ritter G. , Jungbluth A. A.
Published: April 2020

8052

Background: ILI is an effective, though palliative, treatment for patients with regionally recurrent melanoma of the extremity. Tumor-associated antigens such as the Cancer Testis (CT) antigens and melanocyte differentiation antigens (MDAs) have been used successfully as targets for vaccine-based immunotherapy trials in patients with recurrent melanoma. Little is known about expression of these antigens in patients with regional disease. Methods: Samples of regionally recurrent melanoma were obtained from patients prior to ILI as part of an ongoing clinical trial. 22 available samples were formalin-fixed, paraffin-embedded and analyzed by IHC for the following antigens (using the following monoclonal antibodies): CT antigens (MAGE-A1 [MA454], MAGE-A3 [M3H67], MAGE-A4 [57B], NY-ESO-1 [E978], CT7/MAGE-C1 [CT-33], GAGE) and MDAs (gp100 [HMB45], Melan-A/MART-1 [A103], tyrosinase [T311]). The presence of antibodies to CT antigens was analyzed by ELISA. Results: The antigen expression profile was as follows (positive/total): MAGE-A1 9/22 (41%); MAGE-A3 13/22 (59%), MAGE-A4 11/22 (50%), CT7 14/22 (64%), NY-ESO-1 8/22 (36%), GAGE 12/22 (55%), Melan-A 20/22 (91%), tyrosinase 20/22 (91%), gp100 19/22 (86%). The expression pattern was homogeneous for the vast majority of MDAs and for most CT antigens. No serologic response to any of the tested CT antigens was found in any of the patients. Conclusions: Regionally recurrent melanoma exhibits a homogeneous expression of melanocyte differentiation and CT antigens indicating expression similar to distant metastases. Despite the often prolonged course of patients with regionally recurrent disease, there is no evidence of an effective immune response to CT antigens.

No significant financial relationships to disclose.
The value of multi-marker reverse transcriptase-polymerase chain reaction (MM RT-PCR) assay in lymphatic drainage (LY) and peripheral blood (BL) for molecular staging of melanoma patients (pts) after lymph node dissection (LND)
Authors: Ruka W. , Nowecki Z. I. , Rutkowski P. , Kulik J. , Lorenc E. , Nasierowska-Guttmejer A. , Zurawski Z. , Zdzienicki M. , Siedlecki J. A.
Published: April 2020

8053

Background: We assessed the presence of melanoma cells in LY and BL in melanoma pts after LND with MM RT-PCR assay for the evaluation of disease outcomes. Methods: Between 05/2002 and 06/2005 we collected 24-hr LY in 207 stage III melanoma patients after radical LND (91 - completion LND after positive sentinel node biopsy - CLND and 116 - therapeutic LND for clinically/cytologically detected regional lymph node (LN) metastases - TLND). In 101 pts (since 02/2004) we have simultaneously collected a 5 ml sample of BL. In order to detect melanoma cells, RT-PCR assays with primers specific for tyrosinase, MART1 (MelanA) and uMAGE mRNA were applied. The drain fluid or BL sample was assumed to be positive if the presence of at least 1 marker was detected in the assay. Median follow-up time for survivors was 13 months (range: 4 - 39 months). Results: The LY MM RT-PCR assay results were positive in 57/207 pts (27.5%) - in 13 for tyrosinase only, in 17 for MART1 only, in 10 for uMAGE only, in 13 for a combination of the two markers and in 4 simultaneously for all three markers. We observed a significantly higher rate of recurrences in pts with positive LY MM RT-PCR results (44/57 cases; 77%) than in those with negative results (72/150 cases; 48%; p=0.0004). Positive results of the LY MM RT-PCR correlated with established predictive factors: the number of involved lymph nodes (p=0.03), extracapsular extension of LN metastases (p=0.004) and type of LND (CLND vs. TLND; p = 0.0004). We observed a significant relationship between positive LY MM RT-PCR results and shorter overall (OS) and disease free survival (DFS), both in univariate and multivariate analyses. In 107 pts, in whom the LY and BL MM RT-PCR assays were analyzed concurrently, we found positive results of the LY RT-PCR assay in 33 cases (32.7%) and the BL RT-PCR assay in 24 cases (23.7%) (17 of these positive results were detected in both tests), but longer follow-up time is necessary to perform a survival analysis in this group. Conclusions: We observed positive results of MM RT-PCR assay for melanoma cells in approximately 28% of LY after LND, which correlated significantly with early melanoma recurrences and shorter survival.

No significant financial relationships to disclose.
Impact of age and gender in patients with thin melanoma
Authors: Chang C. K. , Liu S. K. , Choi J. S. , Liu R. C. , Fuchshuber P. F.
Published: April 2020

8056

Background: The incidence of thin melanoma (≤ 1mm) continues to increase. The purpose of this study was to characterize the incidence and prognosis of thin melanoma among the various age groups. We analyzed the records of 15,267 patients diagnosed with melanoma of these we were able to identify 5573 patients with thin melanoma (≤ 1mm). Methods: A retrospective review was undertaken to identify patients with thin melanoma (<1mm) treated at all the Northern California Kaiser Permanente facilities. All patients received their treatment between January 1998 and December 2004. Univariate and multivariate analyses of predictive factors were evaluated with the log-rank test and Cox regression. In addition chi-square test of relevant clinicopathologic factors determined which factors were predictive of overall survival (OS). Results: Mean age was 55 years (range 8–101). Mean follow-up was 74 months (range 3–209) and 54% were male. Primaries were on the trunk (34%), lower extremities (19%), upper extremities (26%), or head/neck (20%). Mean thickness was 0.4 ± 0.25 mm. The most common histology was superficial spreading (88%). The overall 5 and 10 year survival were 89 and 79, respectively. By univariate analysis age, sex, location and histology were predictive of OS however by multivariate analysis only age and sex were predictive of OS. The female/male ratio was 2 in patients diagnosed before the 3rd decade, and this ratio approached 1 in the mid-5th decade. However, the female/male ratio was 0.5 among patients diagnosed with melanoma in their 8th decade. Conclusions: Females are more susceptible than men to the risk of melanoma at a younger age however this susceptibility changes with increasing age. Our results demonstrate that the incidence of melanoma may be influenced by age and gender.

No significant financial relationships to disclose.
Sentinel lymph node biopsy (SLNB) in melanoma and a simple prognostic score in a prospective cohort with long term follow-up
Authors: Nasroulah F. , Gonzalez A. , Kaplan J. , Tajer C. , O'connor J. M. , Chacon M. R. , Costanzo M. V. , Sade J. P. , Varela M. M. , Chacon R. D.
Published: April 2020

8058

Background: Outcome of early stage melanoma is related to pathological and clinical findings like SLNB status, but a systematic approach to risk stratification is lacking. Objectives: To assess outcome, and clinico-pathological criteria associated to recurrence and death of patients (pts) who underwent SLNB Methods: From 11/1994 to 5/2005, 286 clinical stages I/II melanoma pts underwent SLNB in our Institution. Median follow up was 38 months. Prognostic factors were analysed with Logranktest and proportional hazard regression. Survival curves with Kaplan-Meier method. A score was derived from coefficients of multivariate analysis and evaluated with ROC curves on 259 pts with complete data. Results: Median age: 48yr; male sex: 54%; median Breslow (Br): 1.8mm. SLNB +: 46 pts (16.1%). Ulcerated: 31%. 5-yr overall survival was 56% in SLNB+ vs 84% in SLNB-, p=0.0002. Five-yr relapse free survival was 52% in SLNB+ vs 73% in SLNB-, p=0.0017. SLNB status, Br, Clark level, Age>50yr, male sex, and ulceration were related to death by univariate analysis, but in multivariate analysis, only SLNB status (HR 2.36), Br (HR 1.66 for each T level of TNM staging) and ulceration (HR 2.35) remained. The score derived from the model was: 5 points (p) for SLNB +; 4p for ulceration; and 0p for Br<1mm, 2p for Br 1–2mm, 4p for Br 2–4mm, and 6p for Br>4mm. Conclusions: SLNB status, Br, and ulceration were, in concordance with literature, statistically significant prognostic factors. This allowed us to build a simple score with good correlation with prognosis (c index: 0.79). This score could be a useful tool for clinical practice and for future clinical trials, but validation in different populations is required.

[Table: see text]

No significant financial relationships to disclose.
Results of FRESH START: A randomized controlled trial to improve diet and exercise behaviors in breast and prostate cancer survivors
Authors: Demark-Wahnefried W. , Clipp E. , Lipkus I. , Lobach D. , Peterson B. , Snyder D. , Sloane R. , Macri J. , McBride C. , Kraus W.
Published: April 2020

8503

Background: Cancer survivors are at increased risk for cardiovascular disease, diabetes, osteoporosis and other cancers. A healthy diet and regular exercise may improve the health and well-being of survivors and ultimately reduce health risks. Methods: 543 individuals within 9-mths of diagnosis with locoregional breast or prostate cancer were referred by 445 providers and recruited from 39 states and 2 provinces within North America. Subjects were randomized to an arm that received a 10-mth program of tailored mailed print materials to promote fruit and vegetable (F&V) consumption, reduce total/saturated fat intake and/or increase exercise or an arm that received a 10-mth program of non-tailored mailed materials on diet and exercise available in the public domain. Telephone surveys conducted at baseline and 1-yr follow-up assessed body mass index (BMI), and responses to the Diet History Questionnaire, the 7-Day Physical Activity Recall and psychosocial/behavioral indices. Anthropometric data were obtained on a 22% subsample to validate self-reports. Results: Complete baseline and follow-up data were obtained on 519 participants (4% attrition). Sample demographics were as follows: mean age = 57 (range: 22–85), 85% white, 56% female, and 64% overweight/obese (none were underweight). Uncontrolled analyses (t-tests) indicate that both arms significantly improved their diet and exercise behaviors (p’s <.05) over the 1-year study period; however significantly greater changes occurred in the experimental arm (see table). Conclusion: The FRESH START intervention was successful in changing the behaviors of individuals with newly diagnosed cancers. Serum assays and collection of 2-yr follow-up data (to determine the durability of longer term behavior change) are currently underway. Further study is needed to determine if the effects of this intervention generalize to other populations of cancer survivors (i.e., other cancers and individuals further-out from diagnosis).

[Table: see text]

No significant financial relationships to disclose.
Multicenter, randomized, double-blind, ondansetron (ond)-controlled, dose-ranging, parallel group trial of the neurokinin-1 receptor antagonist (NK-1 RA) casopitant mesylate for chemotherapy-induced nausea/vomiting (CINV) in patients (pts) receiving moderately emetogenic chemotherapy (MEC)
Authors: Arpornwirat W. , Albert I. , Hansen V. L. , Russo M. A. , Ross G. A. , Pence C. D. , Bandekar R. R. , Grunberg S. M.
Published: April 2020

8512

Background: Casopitant mesylate is a potent, selective, oral NK-1 RA, which has shown activity in preventing CINV in preclinical studies. Based on phase I positron emission tomography (PET) studies, casopitant doses from 50–150 mg result in 70–95% saturation of NK-1 receptors. This phase II trial evaluated the addition of casopitant to standard prophylaxis (ond + dexamethasone [dex]) in pts receiving MEC. Methods: MEC regimens included ≥ 1 of the following (in mg/m2): cyclophosphamide (ctx) 500–1,500 with other MEC; ctx alone 750–1,500; oxaliplatin ≥ 85; doxorubicin ≥ 60; epirubicin ≥ 90; or carboplatin AUC ≥ 5. Pts were stratified by gender and taxane use. Pts in the first 5 arms received ond 8 mg BID days (D) 1–3 + dex 8 mg IV D1 with either placebo, casopitant 50 mg QD D1–3, casopitant 100 mg QD D1–3, casopitant 150 mg QD D1–3, or casopitant 150 mg D1. Arm 6 received a different ond regimen (16 mg QD D1–3) + dex 8 mg IV D1 + casopitant 150 mg QD D1–3. Primary endpoints were rates of complete response (CR [no vomiting, retching, rescue meds or premature withdrawal]) and no significant nausea (SN, assessed by visual analogue scale) during the first 120 h after initiation of MEC. Arms 5/6 were exploratory and not included in primary analysis. Planned enrollment was 118 pts/arm for intent-to-treat (ITT) analysis. Results: ITT group includes 719 pts (60% male, 40% female). CR rate (120h) was 70% with ond control; 81% for casopitant 50mg; 79% for 100mg; and 85% for 150mg (p=.012, Cochran-Armitage trend test). CR rates (24h) and no SN (120h) were similar among all groups. CR and no SN rates in the exploratory arms were 80% and 66%, respectively, in arm 5 and 84% and 70% in arm 6. Adverse events were similar across all arms, with nausea, fatigue, and neutropenia (≤ 24%) as most common. All casopitant doses were generally well tolerated. Conclusions: Casopitant demonstrated activity in control of CINV at all doses, with the 1-day dose of particular interest, when added to a standard ond + dex regimen in both male and female pts receiving a variety of MEC regimens.

[Table: see text]
Emotional responses of oncologists when disclosing prognostic information to patients with terminal disease: Results of qualitative data from a mailed survey to ASCO members
Authors: Wallace J. A. , Hlubocky F. J. , Daugherty C. K.
Published: April 2020

8520

Background: Prior studies describe physician reluctance to reveal prognostic information to advanced cancer patients (acp), but little data exists describing their actual disclosure practices. Methods: A mailed survey was conducted to assess medical oncologists’ (MOs) self-reported behaviors, beliefs, and attitudes regarding prognostic conversations with terminally ill acp. Following letter pre-notification, surveys were mailed to a systematic sample of 1,222 MOs with U.S. addresses listed in the 2004 ASCO Membership Directory. Surveys contained a $25 gift card. The survey included qualitative questions eliciting emotional responses when communicating prognostic information to acp. Results: 729 surveys were completed and returned (60% response rate) with 654 providing qualitative responses (90%). The median age was 51 (range, 34–80) with male predominance (80%). Practice representation was: 56% (private), 23% (academic-based) and 20% (other active practice). MOs most commonly (47%) expressed negative emotions including sadness, pain, depression, heartache, feelings of loss, guilt, anxiety, stress, and finally discomfort with how their patient might react. They reported these conversations as unhappy, unpleasant, frustrating, and bothersome. They also described them as difficult, hard, exhausting and/or draining. 31% of MOs reported empathy, sympathy, compassion, caring, supportiveness, comfort, or being calm during prognostic disclosure. 14% reported positive feelings including optimism, hope, helpfulness, gratification, reward, or relief. 11% related emotional objectivity, detachment, control, or neutrality. Finally, MOs responses listed younger acp age as being a determinant of negative emotions. Conclusions: Negative emotions are more commonly described by MOs when asked to discuss their feelings toward prognostic disclosure. A lesser proportion described objectivity or a lack of emotion. Some related positive emotions. This qualitative data provides a greater explanation for MOs reluctance to disclose prognostic information.

No significant financial relationships to disclose.
Assessment and quantification of taxane-induced neurotoxicity in a phase III randomized trial of breast cancer (AC followed by PAC/DOC vs. PAC/DOC alone): N-SAS BC 02
Authors: Shimozuma K. , Ohashi Y. , Takeuchi A. , Aranishi T. , Morita S. , Kuroi K. , Ohsumi S. , Makino H. , Watanabe T. , Hausheer F. H.
Published: April 2020

8523

Background: Chemotherapy-induced peripheral neuropathy (CIPN) commonly occurs during taxane chemotherapy (Tx). There is no standardized approach used in the assessment of CIPN. Physician-based instruments (e.g., NCI-CTC) are widely used for this purpose, but are associated with several important limitations. As current medical evidence suggests that physician-based assessments under-report the incidence and severity of subjective symptoms, they cannot reliably or accurately assess symptoms of CIPN. We prospectively assessed CIPN during Tx in a phase III randomized trial to evaluate the reliability and sensitivity of these different approaches. Methods: Three hundred breast cancer (BC) patients entered the National Surgical Adjuvant Study of Breast Cancer 02 (N-SAS BC 02), a phase III randomized trial comparing 4 cycles of AC followed by 4 cycles of Tx (paclitaxel [PAC] or docetaxel [DOC]) vs. 8 cycles of Tx alone in N+ BC patients after surgery. CIPN and QOL were secondary endpoints. Patient-based PNQ and FACT-Ntx were compared to the clinician-based NCI-CTC. Assessments were conducted at baseline, 3rd, 5th, 7th cycles, 8 months, and one year after starting adjuvant treatments. A linear mixed effect model was used to compare data in the two treatment groups across repeated cycles of treatment. Results: Average response rate of the instruments was > 90%. Sensory PNQ scores strongly correlated with sensory FACT-Ntx scores (r=0.70), while they weakly correlated (r=0.43) with NCI-CTC scores. NCI-CTC scores distributed between 0 and 2, while PNQ scores distributed between 0 and 4. Comparison of CIPN during the first 3 cycles showed that significantly higher overall incidence of sensory disturbance was observed in Tx compared with AC as assessed by both PNQ (PAC, P<0.0001; DOC, P=0.0007) and NCI-CTC (PAC, P<0.0001; DOC, P=0.0026). The PNQ appeared to detect more severe grades of sensory neuropathy compared to NCI-CTC. Conclusions: This study confirmed that physicians tended to underestimate CIPN, and patient-rated PNQ was a more reliable and valid instrument to assess CIPN. The development of new and reliable assessment methods would represent important medical advancements for cancer patients.

[Table: see text]