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Introduction. The aim of this study is to compare outcomes in three groups of STS patients treated in our specialist centre: patients referred immediately after an inadequate initial treatment, patients referred after a local recurrence, and patients referred directly, prior to any treatment.Patients and methods. We reviewed all our nonmetastatic extremity-STS patients with a minimum follow-up of 2 years. We compared three patient groups: those referred directly to our centre (group A), those referred after an inadequate initial excision (group B), and patients with local recurrence (group C).Results. The study included 174 patients. Disease-free survival was 73%, 76%, and 28% in groups A, B, and C, respectively (P<.001). Depth, size, and histologic grade influenced the outcome in groups A and B, but not in C.Conclusion. Initial wide surgical treatment is the main factor that determines local control, being even more important than the known intrinsic prognostic factors of tumour size, depth, and histologic grade. The influence on outcome of initial wide local excision (WLE), which is made possible by referral to a specialist centre, is paramount.

Paraneoplastic neurological syndromes (PNS) are rare manifestations of malignant disease. It is currently believed that most, if not all, PNS are autoimmune in nature. Proteins expressed on the surface of tumor cells trigger an immune response that cross-reacts with similar proteins in the nervous system, resulting in damage. Moreover, recent studies propose that the appearance of autoimmune phenomena in patients with malignant melanoma implies a strong antitumoral activity and constitutes a marker of improvement in overall survival. We describe a most unusual case of chronic inflammatory demyelinating polyneuropathy (CIDP) occurring in a patient with metastatic malignant melanoma of unknown primary origin who received treatment with interferon alpha-2b. We also review the relevant literature about this infrequent association, discuss on its pathogenesis and underline its importance as surrogate marker, useful to verify the antineoplastic treatment efficacy.

Background. 5-HT3-receptor antagonists are one of the mainstays of antiemetic treatment, and they are administered either i.v. or orally. Nevertheless, sometimes neither administration route is feasible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to evaluate the bioavailability of s.c. granisetron. Patients and Methods. Patients receiving platinum-based chemotherapy were randomized to receive 3 mg of granisetron either s.c. or i.v. in a crossover manner during two cycles. Blood and urine samples were collected after each cycle. Pharmacokinetic parameters observed with each administration route were compared by analysis of variance. Results. From May to November 2005, 31 patients were included and 25 were evaluable. Subcutaneous granisetron resulted in a 27% higher area under the concentration–time curve for 0–12 hours (AUC0–12h) and higher levels at 12 hours, with similar values for AUC0–24h. The maximum concentration was lower with the s.c. than with the i.v. route and was observed 30 minutes following s.c. administration. Conclusion. Granisetron administered s.c. achieves complete bioavailability. This is the first study that shows that s.c. granisetron might be a valid alternative to i.v. delivery. Further trials to confirm clinical equivalence are warranted. This new route of administration might be especially relevant for outpatient management of emesis in cancer patients.

To evaluate the pharmacodynamics effects and antitumor activities of immunostimulatory mAb, we have developed a “humanized” murine model in which the receptors targeted by such mAbs become expressed. Human lymphocytes transferred into immunodeficient mice undergo activation and redistribute to organs with surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations result in lethal xenograft-versus-host disease, which is aggravated when mice are given clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab) mAbs. In mice engrafted with either a human colorectal carcinoma cell line (HT-29) and allogeneic human PBMCs or a primary gastric carcinoma and PBMCs from the patient, urelumab and nivolumab significantly slowed tumor growth (p Citation Format: Miguel F. Sanmamed, Inmaculada Rodriguez, Carmen Oñate, Arantza Azpilikueta, Maria E. Rodriguez-Ruiz, Aizea Morales-Kastresana, Sara Labiano, Jose L. Perez-Gracia, Salvador Martín-Algarra, Carlos Alfaro, Kurt A. Schalper, Guillermo Mazzolini, Francesca Sarno, Manuel Hidalgo, Alan J. Korman, Maria Jure-Kunkel, Ignacio Melero. Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 261. doi:10.1158/1538-7445.AM2015-261

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Nivolumab, a fully human anti-programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has shown encouraging clinical activity in melanoma. We evaluated the pharmacodynamic effects of nivolumab on immune endpoints in patients (pts) with advanced melanoma in an exploratory phase 1 study ([NCT01621490][1]). Methods: 85 pts (41 and 44 anti-CTLA-4 therapy-naive and refractory, respectively) received nivolumab 3 mg/kg IV Q2W in 56-day cycles. Tumor biopsies were obtained at baseline (B/L) and on treatment during Cycle 1, Week 4 (C1Wk4). Response was assessed during the last week of each cycle. The primary objective was to evaluate the pharmacodynamic activity of nivolumab on immune biomarkers, including circulating T-cell subsets (by multiparametric flow cytometry), serum interferon (IFN) and IFN-induced factors (by multiplex immunoassay), and T-cell infiltration in the tumor microenvironment (by immunohistochemistry for CD3, CD4, CD8, PD-1 and FOXP3). Secondary objectives included safety, efficacy, and the association between tumor PD ligand-1 (PD-L1) expression and clinical responses. Results: Across all 85 pts, the objective response rate was 25%, with 2 pts having a confirmed complete response. The safety profile was consistent with prior nivolumab monotherapy trials. Of 85 pts, 34 had evaluable biopsies at B/L and C1Wk4. Increases in tumor infiltrating lymphocytes (TILs) at C1Wk4 relative to B/L were seen in most pts; 65% of pts had an increase in CD3+ T cells. Expression of other TIL markers CD4, CD8, FOXP3 and PD-1, correlated well with one another and CD3 after treatment (C1Wk4; r = 0.69-0.93, P

Gefitinib is the first inhibitor of the epidermal growth factor receptor that has shown activity in non–small-cell lung cancer (NSCLC), but its potential value in the treatment of central nervous system (CNS) metastases has been rarely assessed. We report 2 cases of patients with CNS metastases responding to gefitinib and a review of all the cases previously published in the literature. Computerized and manual searches were performed to identify reports of patients with NSCLC with CNS metastases treated with gefitinib. Ten reports including 16 cases were identified. Of 18 patients, which included our 2 cases, 14 (78%) were female and 4 (22%) were male. Histologic type was reported in 15 cases, and 12 of them (80%) were adenocarcinomas. Five patients exhibited a complete response (28%) and the rest were partial responses. In addition, we identified 5 series of NSCLC patients with CNS metastases treated with gefitinib, and response rates ranged from 0 to 33%. In conclusion, gefitinib can induce long-lasting responses in NSCLC patients with CNS metastases. Responses have been most frequently observed in female patients with adenocarcinoma. Gefitinib may be an effective and well-tolerated option for selected NSCLC patients with CNS metastases.

In this case report we present the clinical signs and symptoms of cardiac tamponade of tumor origin. We explain the clinical investigations for its diagnosis as well as its specific differential diagnosis in cancer patients. The different therapeutic options are also presented together with a brief summary of the thymic carcinoma.

Purpose This study was undertaken to determine the feasibility of perioperative high-dose-rate brachytherapy (PHDRB) as an alternative to standard low-dose-rate brachytherapy in adult patients with soft tissue sarcomas. Methods and materials Twenty-five adult patients with soft tissue sarcomas of the extremities or the superficial trunk were treated with surgical resection and PHDRB (16, 24, or 32 Gy) for negative, close/microscopically positive, or grossly involved surgical resection margins, respectively. External beam radiation therapy (45 Gy) was added postoperatively. Adjuvant chemotherapy with ifosfamide and doxorubicin was given to patients with high-grade tumors. Results Resection margins were negative in 6 patients (24.0%), close/microscopically positive in 18 (72.0%), and grossly involved in 1 (4.0%). One patient (4.0%) with wound dehiscence needed reoperation. Three patients failed in the anatomical region treated, but relapse sites were not adjacent to the area treated with PHDRB. After a median followup of 23.2 months (range 2.8–48.0), the 4-year local and regional control rates were 100% and 80.5%, respectively. Four-year overall survival was 78.2%. Conclusions Locoregional control and survival results are encouraging for this high-risk patient population. PHDRB results seem to be similar to those obtained with low-dose-rate brachytherapy.

The requirement for a second assessment to confirm initial tumour response is required by all response guidelines. Its rationale, however, is not clear. We have conducted this study to compare validity of response rate assessment determined with and without secondary confirmation. Using specified criteria, nine trials of one single cytotoxic drug including 416 patients were selected from a pharmaceutical database. Objective response rates were determined by a single determination and by two separate determinations. 81 responses (19.5%, [15.8-23.6%]) were scored by the confirmation method and 97 responses (23.3% [19.3-27.7%]) by the no-confirmation method. The Kappa (kappa) coefficient of 0.89 indicates good agreement between both methods. This is the first study that systematically compares response rates calculated with and without performing response confirmation. Results show good agreement between both methods. We suggest that assessing response without confirmation may be the preferred method. These results should be confirmed by additional studies in a variety of cancer settings.

Among B-cell malignancies, follicular lymphomas (FL) more frequently show acquired, potential N-glycosylation sites (AGS) within tumor-specific immunoglobulin. The aim of this study was to extend this observation and to evaluate the pattern of presentation of AGS within five different forms of B-cell lymphoma.We sequenced the tumor-specific immunoglobulin heavy chain variable region fragment, including complementarity-determining regions 2 and 3, of forty-seven consecutive patients with a B-cell malignancy enrolled in idiotype vaccine clinical trials. This sequencing approach is known to allow the identification of most AGS. We then statistically analyzed differences in presentation pattern, in terms of tumor histology, immunoglobulin isotype, AGS location and amino acid composition.All twenty-four FL cases presented with at least one AGS, whereas the vast majority of four B-cell lymphoma types other than FL did not. The non- FL group of tumors included four cases of Burkitt's lymphoma, six of diffuse large cell lymphoma, seven mantle cell lymphomas and six small lymphocytic lymphomas. Most IgM-bearing follicular lymphoma cases featured their AGS within complementarity-determining region 2, as opposed to those bearing an IgG, which mostly displayed the AGS within complementarity-determining region 3. The vast majority of AGS located within either complementarity-determining region ended with a serine residue, whereas those located within framework regions mostly featured threonine as the last amino acid residue.In our series, all cases of FL had AGS within their tumor-specific immunoglobulin heavy chain variable regions. In contrast, most B-cell malignancies other than FL did not. Further studies are warranted in order to establish the possible meaning of these findings in terms of disease pathogenesis, their diagnostic value in doubtful cases and their potential implications for immunotherapy.

[Results]: KIT expression was detected in 4 of 4 Ewing Purpose and Experimental Design]: The stem cell factor/KIT receptor loop may represent a novel target for molecular-based therapies of Ewing tumor. We analyzed the in vitro impact of KIT blockade by imatinib in Ewing tumor cell lines. tumor cell lines and in 49 of 110 patient samples (44.5%) by immunohistochemistry and/or Western blot analysis. KIT expression was stronger in Ewing tumors showing EWS-FLI1 nontype 1 fusions. Despite absence of c-kit mutations, constitutive and ligand-inducible phosphorylation of KIT was found in all tumor cell lines, indicating an active receptor. Treatment with KIT tyrosine kinase inhibitor imatinib (0.5–20 μM) induced down-regulation of KIT phosphorylation and dose response inhibition of cell proliferation (IC50, 12–15 μM). However, imatinib administered alone at doses close to IC50 for growth inhibition (10 μM) did not induce a significant increase in apoptosis. We then analyzed if blockade of KIT loop through imatinib (10 μM) was able to increase the antitumor in vitro effect of doxorubicin (DXR) and vincristine (VCR), drugs usually used in Ewing tumor treatment. Addition of imatinib decreased in 15–20 and 15–36% of the proliferative rate of Ewing tumor cells exposed to DXR and VCR, respectively, and increased in 15 and 30% of the apoptotic rate of Ewing tumor cells exposed to the same drugs. [Conclusions]: Inhibition of Ewing tumor cell proliferation by imatinib is mediated through blockade of KIT receptor signaling. Inhibition of KIT increases sensitivity of these cells to DXR and VCR. This study supports a potential role for imatinib in the treatment of Ewing tumor., Grants FIS 02/0828 (to E. d. A.) and FIS 01/0013-01 (to F. P.) from the Ministry of Health of Spain, (Madrid, Spain).

Background and Objectives. Among B-cell malignancies, follicular lymphomas (FL) more frequently show acquired, potential N-glycosylation sites (AGS) within tumor-specific immunoglobulin. The aim of this study was to extend this observation and to evaluate the pattern of presentation of AGS within five different forms of B-cell lymphoma. Design and Methods. We sequenced the tumor-specific immunoglobulin heavy chain variable region fragment, including complementarity-determining regions 2 and 3, of forty-seven consecutive patients with a B-cell malignancy enrolled in idiotype vaccine clinical trials. This sequencing approach is known to allow the identification of most AGS. We then statistically analyzed differences in presentation pattern, in terms of tumor histology, immunoglobulin isotype, AGS location and amino acid composition. Results. All twenty-four FL cases presented with at least one AGS, whereas the vast majority of four B-cell lymphoma types other than FL did not. The non- FL group of tumors included four cases of Burkitt’s lymphoma, six of diffuse large cell lymphoma, seven mantle cell lymphomas and six small lymphocytic lymphomas. Most IgM-bearing follicular lymphoma cases featured their AGS within complementarity-determining region 2, as opposed to those bearing an IgG, which mostly displayed the AGS within complementarity- determining region 3. The vast majority of AGS located within either complementarity- determining region ended with a serine residue, whereas those located within framework regions mostly featured threonine as the last amino acid residue. Interpretation and Conclusions. In our series, all cases of FL had AGS within their tumor-specific immunoglobulin heavy chain variable regions. In contrast, most B-cell malignancies other than FL did not. Further studies are warranted in order to establish the possible meaning of these findings in terms of disease pathogenesis, their diagnostic value in doubtful cases and their potential implications for immunotherapy.

Extensive prior treatment with cytotoxic agents is associated with impaired mobilization of hematopoietic cells. To assess the effect of a single course of standarddose chemotherapy (CT), we compared the results of filgrastim-induced mobilization among two sequential groups of grade III–IV malignant glioma patients included in a hematopoietic transplantation program. The first group (21 patients) had never been treated with CT until 2 days after surgery, when they received a course of 100 mg/m2 BCNU (IV) and 100 mg intracarotid cisplatin for cytoreduction (not for mobilization). At 1 month after this CT, they were mobilized with 12 lg/kg filgrastim. The second group (22 patients) was mobilized with the same dose of filgrastim directly after the surgery, without having ever received any prior CT. The blood level of CD34þ cells was significantly lower in the CT-treated patients, both on the fourth day of filgrastim (15 vs 36 cells 106/l; P¼0.01) and on the fifth (25 vs 58 cells 106/l; P¼0.003), as it was the number of CD34þ cells collected per apheresis (1.3 vs 3.5 106/l; Po0.0005). The toxic effect of a single course of BCNUcisplatin CT led to significant impairment of the filgrastim-induced mobilization response. Bone Marrow Transplantation advance online

Objective: Paclitaxel-cisplatin is considered to be a standard therapy for metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the activity and toxicity of this combination with vinorelbine or gemcitabine as front-line therapy in brain metastases from NSCLC. Methods: Twenty-six chemotherapy-naive patients with an ECOG performance status of 0–2 were treated with paclitaxel (135 mg/m2) on day 1, cisplatin (120 mg/m2) on day 1, and either vinorelbine (30 mg/m2) on days 1 and 15 or gemcitabine (800 mg/m2) on days 1 and 8. Whole-brain irradiation was offered early in case of progression and later as consolidation treatment. Results: All patients were evaluated for toxicity and 25 for response. An intracranial response rate was observed in 38% of the patients (95% CI: 22–59%). WHO grade 3–4 neutropenia and thrombocytopenia occurred in 31 and 4% of the patients, respectively. There was one treatment-related death. Non-hematological toxicities were mild. After a median follow-up of 46 months, the median overall survival for all patients was 21.4 weeks and the median time to progression was 12.8 weeks. Conclusions: Paclitaxel and cisplatin combined with vinorelbine or gemcitabine as front-line therapy in brain metastases seem to achieve responses similar to those for extracranial disease, suggesting a meaningful role in this setting.

To evaluate the feasibility and a possible activity range of combination irinotecan (CPT-11), oxaliplatin, and 5-FU in advanced colorectal cancer (ACC).A total of 53 patients (51% chemoresistant) were treated. Twenty-eight received monthly intravenous oxaliplatin (120 mg/m2) and CPT-11 (250 mg/m2) on day 1 and a course of 5-FU; these constituted the IRI250 group. Twenty-five received monthly intravenous oxaliplatin (120 mg/m2), CPT-11 (300 mg/m2) on day 1, and a course of 5-FU (IRI300 group). 5-FU administration was carried out as follows. Those with predominant hepatic disease (n = 32) received an intra-arterial infusion of 5-FU (2,500 mg/day on days 1-4); these were the IA-FU group. The remaining 21 patients received intravenous 5-FU (2,600 mg/m2 plus leucovorin 500 mg/m2 on days 1 and 15); these constituted the IV-FUFOL group.Intention-to-treat response rate was 54.7% (4 CR, 7.5%). Twelve patients (22.5%) had stable disease; only 4 (7.5%) progressed. Median progression-free and overall survivals were 10 and 18 months, respectively. One-year progression-free and overall survival rates were 44.3 and 67.4%, respectively. Grade 3-4 toxicities included diarrhea (45.3% of patients), neutropenia (52.8%), mucositis (13.2%), and emesis (11.3%). There were 3 treatment-related deaths (5.7%), all in the IA-FU/IRI300 subgroup. Severe adverse effects requiring chemotherapy dose adjustment were observed in 67.9% of the patients, with odds ratios 9.04-fold higher in the IA-FU/IRI300 group (95% CI: 1.07-76.20) and 0.23-fold lower in the IV-FUFOL/IRI250 group (95% CI: 0.05-0.97).This combination seems to have substantial activity in ACC. Overall toxicity was unacceptable in the IA-FU and IRI300 groups, with diarrhea and cytopenia constituting the dose-limiting side effects. Tolerance and efficacy profiles achieved with IV oxaliplatin (120 mg/m2 day 1), IV CPT-11 (250 mg/m2 day 1) and IV 5-FU 2.6 g/m2 with IV leucovorin (500 mg/m2 days 1 and 15) was favorable and deserves further investigation.

Aim: IL-8 is produced by multiple tumors and its functions include regulation of tumor angiogenesis and immune response. We evaluated the correlation of IL-8 with tumor burden and its potential role as a cancer biomarker by studying sequential levels of serum IL-8 in preclinical tumor models and in patients with multiple tumor types, at baseline and following anticancer treatment. Methods: IL-8 levels were monitored sequentially by sandwich ELISAs in three different models: a) cultured tumor cells supernatant; b) serum of tumor-xenografted mice and; c) serum and urine samples from 119 cancer patients, at baseline and following diverse anticancer treatments. We correlated IL-8 levels with tumor burden, treatment induced response and cancer prognosis. Results: IL-8 levels showed a strong correlation with tumor burden in all the models explored: a) in tumor cultures, IL-8 levels correlated accurately with the number of cancer cells; b) in tumor-xenografted mice, IL-8 serum levels correlated with tumor burden and rapidly dropped following surgical excision; and c) in patients with melanoma, renal-cell carcinoma, non-small cell lung cancer and hepatocellular carcinoma, serum IL-8 levels correlated with tumor burden and stage, survival and objective responses to therapy, including BRAF inhibitors and immunomodulatory monoclonal-antibodies. IL-8 concentrations in urine were mainly elevated in tumors with direct contact with the urinary tract. Conclusions: IL-8 levels correlate with tumor burden in preclinical models and in cancer patients and are a potentially useful biomarker to monitor response to cancer treatment. This might be particularly relevant to assess the therapeutic effects of drugs that may induce “pseudo-progressions”, such as immunomodulatory monoclonal antibodies. Disclosure: All authors have declared no conflicts of interest.

Aim: The primary analysis of BREAK-3 (NCT01227889) comparing progression-free survival in pts with BRAF V600E mutation-positive MM treated with D or DTIC was previously reported (Hauschild A, et al. Lancet 2012; 380:358–65). Median OS of D and DTIC last reported was 18.2 months (mo) (95% CI 16.6–NR) and 15.6 mo (95% CI 12.7–NR) at 14.4 mo median follow-up. Methods: From February to September 2011, 250 pts were enrolled at 93 centers globally. Pts were randomized to D and DTIC, 187 and 63 respectively; 37 (59%) of DTIC pts crossed over (xover) to D. After treatment discontinuation, pts were followed for OS and additional anticancer therapies. Pts could remain on D after disease progression (PD) at the investigator's discretion, with GSK approval. Results: OS hazard ratio (HR) was 0.77 (95% CI 0.52–1.13); median OS was 20.0 mo (95% CI 16.8–24.4) and 15.6 mo (95% CI 12.7–21.2) for D and DTIC, respectively, at 16.9 median mo follow-up. Estimated proportion alive was 45% vs. 32% at 2 years. Twenty-four (13%) of D pts and 3 (8%) of xover pts remained on D. No pts remained on DTIC. Out of these pts, 19/27 (70%) remained without PD on D. Median time on treatment for these 19 pts was 31.0 mo; (range 26.8–33.6 mo). Anticancer therapy after discontinuation of D was reported in 116 (62%) pts in D arm, including D (22%), ipilimumab (14%), DTIC (9%), vemurafenib (5%) and other therapies (12%). Anticancer therapy after discontinuation of DTIC was reported in 51 (81%) pts in DTIC arm, including D (60%), vemurafenib (10%), and ipilimumab (5%).The five most common adverse events (AEs) in D pts were hyperkeratosis (41%), arthralgia (37%), headache (36%), pyrexia (33%) and alopecia (29%). Serious AEs in ≥5% of D pts included cutaneous squamous-cell carcinoma/keratoacanthoma (10%) and pyrexia (5%). New non-cutaneous malignancies occurred in 4 (2%) pts taking D and 2 (5%) pts in xover pts vs. no events in the DTIC pts. Conclusions: Longer follow-up shows a stable HR for OS and safety profile. Median OS in the D arm was 20.0 mo vs. 15.6 mo in the DTIC arm. With approximately 60% of DTIC pts crossed over to D, it confounds effects of initial therapy on OS. Disclosure: A. Hauschild: Consult, Hon and Trial funding: Amgen,BMS,Celgene,Eisai,GSK,MelaSciences,Merck Serono,MSD/Merck,Novartis,Oncosec,Roche; J. Grobb: J-J. Grob has a compensated consultant or advisory relationship with GlaxoSmithKline, Roche, Bristol-Meyers Squibb, Merck and Celgene, and receives honoraria from GlaxoSmithKline and Roche; L. Demidov: L. Demidov is a consultant for GlaxoSmithKline, Merck and Roche, and receives support for clinical trials from Roche, Pfizer and Bristol Meyers-Squibb; T. Jouary: T. Jouary received personal fees and non-financial support from Roche, and provides expert testimony for GlaxoSmithKline IMS Health; R. Gutzmer: R. Gutzmer received support from GSK, honoraria from GSK, Roche, BSM, Novartis, MSD, Amgen, Almirall Hermal, LEO, Pfizer, Boehringer Ingelheim, Janssen, and participates in advisory boards for GSK, Roche, BMS, Novartis, MSD, Almirall Hermal and LEO; M. Millward: M. Millward receives clinical trial payments and participates in Advisory Boards for GlaxoSmithKline; P. Rutkowski: P. Rutkowski receives honoraria from GlaxoSmithKline, Roche and Bristol-Meyers Squibb, and participates in Advisory Boards for Roche, Bristol-Meyers Squibb and Novartis; C. Blank: C. Blank has an advisory role at GlaxoSmithKline, Roche, Bristol Meyers-Squibb, MSD and Novartia; W. Miller Jr.: W. Miller Jr received personal fees from Merck, Roche, Bristol-Meyers Squibb and Amgen; S. Martin-Algarra: Dr. Martin-Algarra reports personal fees for Advisory Boards and Lectures from GSK and fees fro Advisory Boards from Novartis, BMS and Roche; Chiarion Sileni: V. Chiarion Sileni receives compensation for advisory board participation from GlaxoSmithKline, Bristol-Meyers Squibb and Roche; G. Aktan: G. Aktan is an employee of GlaxoSmithKline and owns stock in the company; P. Haney: Pat Haney is an employee of GSK and has stock ownership and stock options; F. Jin: Fan Jin is an employee of GSK; J. Legos: Jeff Legos is a GSK employee and holds GSK shares; S. Swann: Suzanne Swann is a GSK employee and holds GSK stocks; P. Chapman: Glaxo Smith Kline: consulting fees, research support Genentech: consulting fees, research support. All other authors have declared no conflicts of interest.

Aim: To describe patterns of use of adjuvant Interferon alfa-2b (IFN-a2b): dose, schedule, duration, adherence to therapy as well as others factors, in an unselected cohort of patients with high-risk melanoma, treated in different hospitals of Spain between January 2000 and December 2009. Methods: A multi-institutional retrospective clinical trial, including a statistically predefined sample of 325 melanoma patients with stage IIB, IIC or III and treated with adjuvant IFN-a2b was considered feasible to fulfill the study objective. Eligibility criteria include: 1) Pathologically confirmed diagnosis of cutaneous melanoma in the established period; 2) Complete resection of disease; 3) Adjuvant therapy with at least one dose of IFN-a2b; 4) Complete treatment details and follow-up data available; 5) Written informed consent in all patients that were alive at the time of review. Results: From June 2013 to January 2014, a total of 347 patients were included. As of April 2014, data analysis has been performed for 126 patients. Preliminary results in this cohort are presented: Median age: 59 years, male/female: 58%/42%. Pathological stage (AJCC 2009): IIB 15%, IIC 7%, IIIA 30%, IIIB 33% and IIIC 15%. Breslow thickness: 4mm 39%. Ulceration: 51.4%. 90% of patients received high-dose IFN-a2b and 10% either low or intermediate doses. High-dose IFN-a2b induction phase was completed by 88% of patients, and 70% completed the maintenance phase, although dose delay and dose reduction due to toxicity were common in both periods. Sixty percent of patients have relapsed as per investigator's review. Final analysis including disease-free and overall survival will be completed in July 2014. Conclusions: Most patients included in this preliminary analysis receive both, high dose IFN-a2b induction and maintenance phases, although dose delay and dose reduction are common. The complete analysis of this study will provide relevant and detailed information about the feasibility of IFN-a2b adjuvant treatment programs used for high-risk melanoma in Spain. These results will be relevant for the design and interpretation of future trials of adjuvant therapy. Disclosure: S. Martin-Algarra: In the past 36 months I have participated in Advisory Boards of MSD, BMS, Roche, GSK and Novartis. In the past 36 months have given lectures in events organized/sponsorized by BMS, Roche and GSK; G. Nocea: Employee of Merck Sharp and Dohme Spain; K. Stevinson: Employee of Merck US; P. Del Barrio: Employee of Merck Sharp and Dohme Spain; M.V. Tornamira: Employee of Merck Sharp and Dohme Spain; E. Espinosa: I am participated in the Advisory Board of MSD (Merck Sharp and Dohme). All other authors have declared no conflicts of interest.

e22135 Background: IL-8 is a chemokine that is produced by malignant cells of multiple cancer types and that exerts various functions in shaping pro-tumoral vascularization and inflammation/immunit...

9033 Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall survival (OS) at 5 years is 62% due to high incidence of liver metastasis that are fatal wi...

The purpose of this trial was to study feasibility and tolerance of a dose-intensive multicyclic alternating induction chemotherapy with repeated stem cell support in a series of 43 metastatic breast cancer patients. Anthracycline-naive patients (n = 21) received cyclophosphamide 2.5 g/m(2) plus doxorubicin 80 mg/m(2) alternating every 14 days with paclitaxel 200-350 mg/m(2) plus cisplatin 120 mg/m(2). Patients who had previously received anthracyclines (n = 22) received cisplatin 120 mg/m(2) plus etoposide 600 mg/m(2) alternating with paclitaxel 200-350 mg/m(2) plus ifosfamide 8 g/m(2). Peripheral blood stem cells were infused after every course except the first, with a median CD34(+) dose of 2.1 x 10(6)/kg per cycle. Positive selection of CD34(+) cells was performed in good mobilizers. The median number of cycles administered was six (4-8), and the time interval between them was 17 days. Median summation dose intensities (SDI) actually administered for the CA-TP and PE-TI protocol were 4.95 and 4.69, respectively (87% of scheduled SDI). There were 15 complete (35%) and 21 partial responses (49%), for an overall response rate of 84% (95% CI, 73%-95%). Infection or neutropenic fever occurred in 50% of the cycles. There was one treatment-related death. After a median follow-up of 26 months, the median event-free-survival was 12 months (95% CI: 10-14) and overall survival was 31 months. These high dose-intensity induction treatments seem to be feasible with sequential stem cell support.

e20015 Background: In addition to environmental factors and phenotype, melanoma risk is determined by familial background. It is estimated that 5-10% of melanoma cases occur in a familial setting. High susceptibility genes like CDKN2A and intermediate risk like M1CR are the most known, but explain less than 1/3 of the cases, most of them cases with 2 or more first degree relatives involved, the classical definition for familial melanoma (FM). In Spain there are several local studies about epidemiology and characteristics of FM, but there are no studies that cover all the territory. Methods: FAM-GEM-1 is a national, observational, 2 years-registry study (2011-2013), conducted by the Spanish Multidisciplinary Melanoma Group (GEM), whose principal objective is to assess the rate of melanoma patients with family history of melanoma in Spain. Secondary objectives are to analyze whether patients with family history are different from sporadic melanoma in terms of clinical, pathological and molecular features; and to constitute a registry of FM in order to deeper characterise these patients in further studies. We present the exploratory results of the first 219 patients registered Results: See Table. Conclusions: We have found that almost 9% of patients have family history of melanoma. Of them, almost 3/4 fulfils familial melanoma criteria. It seems that there are not relevant differences among sporadic and familial melanoma in our registry, except for sex, although the preliminary nature of the results makes necessary more patients in order to determine if there are clinical and/or pathological differences between both groups. [Table: see text]

TPS3114 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor expressed by T cells that negatively regulates T-cell activity and may promote tumor immune evasion by binding to its ligands (PD-L1/L2) on tumor cells and/or antigen-presenting cells. Nivolumab is a fully human IgG4 PD-1 receptor blocking monoclonal antibody that has shown antitumor activity in phase I trials in pts with solid tumors, including advanced MEL. Objective responses were observed in pts whose diseases were refractory to multiple prior therapies. We describe an ongoing exploratory, open-label, multicenter translational study designed to further investigate the immunoregulatory activity and mechanisms of action of nivolumab in advanced MEL, including ipilimumab (anti-CTLA-4) naïve and refractory pts. Methods: This study is enrolling advanced MEL pts who are either ipilimumab naive (n=40) or refractory (n=40). Eligible pts must not have received >3 prior therapies for metastatic disease and must consent to pre-and on-treatment biopsy (after 2 doses of nivolumab [Day 28]) of an accessible tumor. Nivolumab will be administered IV every 2 weeks (wks) at a dose of 3mg/kg and may continue for up to 13 cycles (104 wks) until clinically significant progression or treatment discontinuation criteria are met. Tumor responses will be assessed every 8 wks using RECIST 1.1 criteria. The primary objective is to investigate the pharmacodynamic (immunoregulatory) activity of nivolumab in the peripheral blood (PB), tumor, and tumor microenvironment. Secondary objectives include evaluation of safety and tolerability, preliminary antitumor activity, and immunogenicity of nivolumab, as well as the association between tumor PD-L1 expression and clinical efficacy. Exploratory objectives include characterization of pharmacokinetics (PK) and evaluation of the potential association between selected PB and/or tumor biomarkers and PK, clinical safety, and efficacy (eg, progression-free and overall survival). Clinical trial information: NCT01621490.

9074 Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p

e18008 Background: ALK gene rearrangements define a new molecular subtype of NSCLC with response to Crizotinib, a dual MET and ALK inhibitor. Analysis of ALK rearrangements has been performed in biopsies or surgical specimens. However, advanced NSCLC is often diagnosed by FNA cytology obtained through minimally invasive techniques, and frequently CS are the only tumour sample available. We assessed the feasibility of determining ALK rearrangements in CS. Methods: We studied prospectively ALK rearrangements in 53 CS from 53 NSCLC patients (30 M/23 F) by FISH (Vysis dual colour break apart probe). We considered positive for ALK rearrangement when > 15% of cells show splits signals. Tumor samples were obtained by bronchoscopy -FNA in 26 cases (49.1%), EBUS-FNA in 7 (13.2%), EUS-FNA in 3 cases (5.7%), CT-FNA in 3 (5.7%), and direct FNA in 6 cases (11.3%). Two cavity fluids (3.8%), 4 imprints (7.5%), and 2 cellblocks received for consultation (3.8%) were also studied. FISH was performed on non-stained ThinPrep in 28 cases (52.8%), Papanicolau stained smears in 15 cases (28.3%), cell block in 9 cases (17%), and 1 stained ThinPrep. All cases were tested for EGFR and KRAS mutations. Correlation cytological/paraffin embedded samples was performed in 4 paired cases. Results: Thirty-seven samples(69.8%) were adequate for FISH analysis. Three cases (8.1%) had ALK rearrangements: non-smoker women with adenocarcinoma, two of them with signet ring cells. One case had a concurrent EGFR mutation in exon 21. FISH study was unsuccessful in 16 cases (30.2%):10 Papanicolau stained smears (62.5%), 5 unstained ThinPrep (31.3%), and 1 cell block. Nineteen ThinPrep slides were adequate for FISH analysis (86.4%) as well as 8 out of 9 cell blocks. Concordance rate in paired cases were 100%. Conclusions: Determination of ALK gene rearrangements in CS is feasible. It is mandatory an exquisite management and care of the samples to preserve quality. ThinPrep and cell blocks are the most suitable samples for FISH analysis, while Papanicolau stained smears provide poor results. Coexistence of ALK gene rearrangements and EGFR mutations was observed in one case, indicating that such alterations are not necessarily mutually exclusive.

e21142 Background: Tumor histologic risk factors are inaccurate to predict risk of relapse in 25-30% of patients with clinical stage I germ cell tumors of the testis (CSIGCT), with important conseq...

8575 Background: Current advances in the understanding of melanoma biology and genetics gave a solid rationale to introduce different targeted therapies into clinical trials. In patients harbouring...

7560 Background: EGFR and K-ras mutations can help to guide treatment selection in NSCLC patients. Mutation status is routinely assessed in biopsy samples. Yet, lung cancer diagnosis relies to a large extent on cytological specimens which frequently are the only tumor samples available. We assessed EGFR and K-ras mutations in Papanicolau stained slides and cytological samples from NSCLC patients. Methods: DNA was extracted from cytological samples obtained by fine-needle aspiration (FNA) performed by bronchoscopy or ultrasound-guided endoscopy or from biological fluids. PCR and direct sequencing of exons 18-21 of EGFR gene and exon 2 of K-ras gene were performed using an ABI PRISM 310XL. Clinical activity of EGFR TKI was assessed and when biopsies were available, EGFR mutations were also determined in such samples. Results: From January 2007 to November 2009, 140 cytological samples were analyzed. DNA was extracted from: Papanicolau stained smears (111; 79%), cell block (9; 6%), fresh samples (9; 6%), Thi...

We report the results of intracarotid (IC) cisplatinum and intravenous carmustine (BCNU) in 26 patients with supratentorial malignant glioma and recurrent low grade glioma. A response rate of 53.84% (95% confidence interval 33.3%-73.4%) was found. The median survival for the whole group was 11 months (range 3-70), with 35% of patients surviving for 2 years. At the present time, 5 patients are still alive, with a median follow up of 68 months (range 56-70). Neurological toxicity has been low and transient, being attributable to the technical degree of care in catheter positioning, cisplatin dosage and the technique of drug administration into the carotid artery.

3758 Background: Preclinical data have shown a synergistic effect when MMC and CPT-11 are combined. In addition, this combination proved to be effective and well-tolerated in patients with fluoropyrimidine-resistant metastasic colorectal cancer Methods: To evaluate the safety and efficacy of MMC 5 mg/m2 day 1 plus CPT-11 200 mg/m2 on day 1, every three weeks, in a retrospective series of heavily pretreated metastasic CCR patients with good performance status (ECOG 1–2). Results: From September 2002 to October 2003, 20 pts (M/F: 13/7; ECOG 2: 50%; Median age: 55) were included. Sites of metastasic disease included peritoneal carcinomatosis (65%), lung (35%), liver (65%) and bone (15%). 12 pts (60 %) had received at least 3 lines of therapy. Prior chemotherapy included 5-fluorouracil (90%), oxaliplatin (100%) irinotecan (65%), capecitabine (85%) and raltitrexed (60%). Previous FOLFOX, FOLFIRI, FOLFOXIRI or XELOX had been administered in 50%, 15%, 25% and 35% of the patients, respectively. 4 pts (20%) achiev...

7535 Background: 18F-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET) has been reported to be a sensitive method for detecting mucocutaneous malignant melanoma (MM) metastases. The aim of this study is to analyse retrospectively the role of 18FDG-PET to stage, re-stage and follow-up of MM patients. Methods: Two hundred and ninety-six patients (135 men and 161 women) with MM were evaluated with 18FDG-PET from June 1996 to June 2002. Median age was 46 years (range:12–87). Location of primary MM was: extremities in 54%, trunk in 29%, head and neck in 11%, unknown origin in 4% and mucosas in 2% of the patients. Median Breslow thickness was 2 mm (range:0.2–20). According to the AJCC staging system, the distribution in stages I,II,III and IV at first diagnosis was 39%, 42%, 17% and 2% respectively. The role of PET was staging in 157 (53%) patients, re-staging in 54 (18%) patients and follow-up in 85 (29%) patients. Results: The sensitivity (S), specificity (E), accuracy (A), positive and negative pre...

8098 Background: Cancer patients are prone to develop renal complications due to their disease or to treatment. Some prognostic scores have shown to be useful to assess the risk of patients with Acute Renal Failure (ARF). However, none of them has been validated specifically in cancer patients. Therefore, we performed a prospective study to validate in cancer patients commonly used ARF prognostic scores. Methods: Cancer patients with ARF (>20% creatinine increase over baseline), were prospectively included. We collected clinical data (ARF etiology, Karnofsky performance status score -KPSS-, underlying disease and treatment), renal prognostic scores (Liano's Individual Severity Index -ISI- and Multiorgan Dysfunction Index -MFI-) and analytical parameters (serum creatinine and urine n-acetyl glucosaminidase -NAG-). Statistical analysis (chi-square, ANOVA, multiple regression analysis and logistic regression) was performed with SPSS 9.0. Results: From January 02 to April 03, 149 patients were assessed. Mean ...

4252 Background: To determine the activity and tolerance of gemcitabine, 5-fluorouracil, leucovorin and cisplatin in patients with metastatic pancreatic cancer. Methods: Thirty-two patients with co...

Polymorphonuclear leukocyte (PMN) adherence to nylon was studied in the umbilical cord blood of 33 full-term, healthy newborns (NBs) during delivery. The results were compared to the adherence of PMN of peripheral blood in 50 healthy adult blood bank donors. PMN adherence in the NBs (56.64 +/- 3.24) was found to be significantly higher (p less than or equal to 0.01) than in the adults (47.03 +/- 2.01). PMN adherence, either in adults or NBs, is not related to leukocytes, platelets or hematocrit values. It was found to be related only to the percentage of total leukocyte adherence. Also using scanning electron microscopy (SEM), the ultrastructure of the adherence process was analyzed. In these studies we observed a higher tendency to adopt fusiform disposition in the PMN of the adult population. These results suggest that NB PMNs are hyperadherent and that they show a cellular rigidity and a resistance to deformation that could be responsible for the chemotactic alterations previously described in neonates.

The tumor registry (TR) of the Clinica Universitaria de Navarra is a hospital based registry which includes all patients with a diagnosis of neoplastic disease diagnosed and/or treated in the different departments of the hospital. The incidence of different tumors from January 1981 to December 1986, has been studied based on the following parameters: sex, age, diagnosis and tumor site. It is concluded that the results of 6 years indicate a specialised care in oncologic patients of different tumor sites, which represents an adequate volume of patients for a university oriented program of training and research, at the level of pregraduate and specialised postgrade cycles.

The usefulness of studying ABH isoantigens associated to bladder cancer cells with the specific red blood cells adherence assay, and immunohistochemistry methods in urinary bladder carcinoma biopsies, as well as its application as early predictors of tumor invasiveness and relapse, is reviewed.

Protein A defined as one of the components of the wall of Staphylococcus Aureus Cowans 1 has shown its effects as modifier of the immune response: it induce changes in cellular receptors, polyclonal activation of T and B lymphocytes, liberation of lymphokines, increase in the production of gamma-interferon (probably as the result of activation of NK cells). In the present work we have studied NK activity and its modifications by Protein A and gamma-interferon in blood of 50 patients with solid tumours. The method used was the Cr 51 liberation assay. The effectors cells were non-adherent lymphocytes treated with different doses and times of incubation of Protein A and gamma-interferon. As target cells we utilized the cellular line K-562 for NK activity and autologous tumoral cells isolated from surgical specimen for tumour-specific cytotoxicity. The results obtained allow us to state the following conclusions: 1. NK activity against K-562 cells is not always a specific parameter of such activity. 2. Tumour-specific cytotoxicity can vary according to the histological type of tumour. 3. Protein A is a potent inducer of tumour-specific cytotoxicity in a higher degree than gamma-interferon.

9039 Background: Melanoma risk is determined by environmental, phenotypical and familial background. Literature describes a 5-10% of melanoma cases in a familial setting. Familial melanoma (FM) is ...

5590 Background: Neoadjuvant chemotherapy and concurrent chemoradiotherapy induces high response rate, increase local control and probably reduces the risk of distant metastases in NPC patients (pt...

8150 Background: Acute Renal Failure (ARF) is a frequent cause of morbidity and mortality in cancer patients. The objective of this prospective study was to evaluate prognosis of ARF in these patie...

3754 Background: von Willebrand factor (vWf) is thought to mediate binding of tumor cells to platelets, favouring their spreading capacity. Platelets involved in tumor angiogenesis are capable of releasing vascular endothelial growth factor (VEGF). Levels of vWf and VEGF may correlate with cancer stage and predict clinical outcome. The aim of this study was to correlate vWf and VEGF levels in stage IV colorectal cancer (CRC) patients undergoing chemotherapy (CMT) with response to treatment and time to progression (TTP). Methods: 25 metastatic CRC patients attending the Department of Oncology of our institution were enrolled in the study. Blood samples were taken before and after fluoropirimidine-based CMT, and stored until further processing. vWf, VEGF, platelet count, carcinoembrionary antigen (CEA) and CA 19.9 were measured using standardised techniques. Tumor burden assessed by number of locations of disease was also considered. Patients received a median of 3 cycles of CMT (range: 2–10) between both b...

9013 Background: Dabrafenib is a selective BRAF inhibitor with demonstrated efficacy in BRAF V600E-positive mutation in MM. The primary analysis of BREAK-3 (NCT01227889) compared progression-free survival (PFS) in patients (pts) with BRAF V600E-positive mutation MM treated with dabrafenib or DTIC. Methods: Median PFS for dabrafenib of 5.1 months (mo) and study methods were previously described (Hauschild A, et al. Lancet. 2012,380:358–365). Independent review ended at the primary analysis. PFS was updated in Jun 2012 at median follow-up of 10.5 mo for dabrafenib (67% of PFS events), and 9.9 mo for DTIC. Median overall survival (OS) was not reached, so another analysis of OS and safety was performed with data as of Dec 2012, at which time the median follow-up was 15.2 (dabrafenib) and 12.7 (DTIC) mo. PFS of subjects who crossed over was also evaluated at that time. Results: PFS hazard ratio was 0.37 [95% CI; 0.23, 0.57]; median PFS was 6.9 mo dabrafenib and 2.7 mo DTIC. In Dec 2012, 36/63 DTIC pts crossed over; median PFS was 4.3 [95% CI; 4.1, 6.1] mos. OS is presented in the Table.The four most common adverse events (AE) on the dabrafenib arm were hyperkeratosis (39%), headache (35%), arthralgia (35%), and pyrexia (32%). Serious AEs ≥ 5% on the dabrafenib arm included cutaneous squamous cell carcinoma/keratoacanthoma (10%) and pyrexia (5%). Conclusions: Longer follow-up confirms the benefits of dabrafenib on PFS and response rate. Median OS in the dabrafenib arm was over 18 mo and over 15 mo in the DTIC arm. OS results are confounded by crossover of DTIC pts to dabrafenib and likely by subsequent therapy after progression. The effects of subsequent therapy results will be investigated. The safety profile had no significant changes. Clinical trial information: NCT01227889. [Table: see text]