Aims To evaluate the diagnostic performance of contrast-enhanced EUS(CH-EUS) and elastography(EUS-E) combination in the differential diagnosis(DD) between benign and malignant lymph nodes(LN).

Background: Gastric cancer is still a very poor prognosis disease. Surgery is the only potentially curative approach but the relapse risk remains very high and peri-operative chemotherapy has been widely adopted in order to improve outcome. Our study is a prospective analysis aimed at evaluating efficacy and feasibility of peri-operative chemotherapy in a real unselected population. Material and methods: From April 2013 to May 2016 we collected data about all consecutive patients affected by histologically confirmed resectable carcinoma of the stomach or gastro-esophageal junction that have referred to our Institution. Initial and pre-surgical staging included endoscopic ultrasound and contrast enhanced CT scan of the thorax and abdomen.According to our policy treatment plan consisted of 3 cycles of preoperative chemotherapy with epirubicin-oxaliplatin-capecitabine or 5-fluorouracil ic (EOX/EOF), restaging, surgery and other 3 cycle of postoperative chemotherapy with the same schedule; than started follow-up. Results: We observed 24 patients fulfilling these criteria, 19 (79%) male and 5 (21%) female. The median age was 72 years, ranged between 47 and 81 years.In 5 patients the treatment is ongoing. Among 19 patients in follow-up, 3 (15%) patient discontinued preoperative treatment because of hematological and gastrointestinal toxicity and underwent surgery, 1 (5%) patients doesn't receive postoperative chemotherapy because of poor performance status. Among 15 pt have terminated peri-operative CT, 9 (60%) patients achieved partial response, 6 (40%) obtained a stable disease. 7 (47%) underwent partial gastrectomy and 8 (53%) total gastrectomy; D2 lymphadenectomy was always performed. 2 (13%) patients that have terminated peri-operative chemotherapy was relapsed:1 relapsed on abdominal lymphnode (time to progression – TTP- of 21 months) and 1 relapsed on peritoneal cavity (TTP of 10 months).Median Progression Free Survival (PFS) was 9,63 months, and median Overall Survival (OS) was 14,26 months. These are only preliminary data because the follow-up period is very short. Conclusions: In our experience peri-operative chemotherapy represents an interesting and feasible option to reduce relapse risk in gastric cancer cancer. The toxicity was moderate and 15 patients (79%) have completed treatment plan, emphasizing one of the most important advantages of preoperative therapy that is its superior tolerability prior to a potentially debilitating surgery.

2058 Background: Following the EORTC/NCIC trial investigating temozolomide concurrent and adjuvant to radiotherapy, this regimen is considered standard treatment for newly diagnosed glioblastoma (GBM). However, although some studies report a marked difference between the incidence of grade 3/4 neutropenia in males and females, the role of gender as a prognostic factor has not yet been evaluated. Methods: We analyzed the charts of all patients with newly diagnosed GBM treated in our department with the EORTC 22981/26981-NCIC trial in order to assess whether there is a correlation between gender and outcome. Results: In the 105 GBM patients (median age: 54 [range 18-70] years; male/female: 63 42) evaluated, resection was total in 49 and subtotal in 56; MGMT promoter was methylated in 45 (43%) and unmethylated in 60 (57%). Median time to disease progression was 11.5 (95%CI: 9.4–13.6) months, and median survival (mOS), 18.7 (95%CI: 16.8–20.7) months; MGMT methylation status (p=0.04), gender (p=0.03) and age (p=0.02) significantly influenced survival. The interaction found between gender and MGMT methylation was significant, females harbouring MGMT methylation surviving longer than other patients (MGMT methylated/unmethylated males and unmethylated females): mOS, 28.6 months (95%CI: 24.7–32.5) and 18.2 months (95%CI: 16.0–20.4), respectively (Table). Findings at multivariate analysis confirmed that age (p=0.004) and interaction between gender and MGMT status (p=0.008) significantly correlate with OS. Conclusions: Since no biological or clinical explanations are available to explain the above findings, we advocate the inclusion of gender as a potential prognostic factor in future trials. mOS (months) 95% CI (months) Overall 18.7 16.8 – 20.7 Male / MGMT methylated 17.7 14.2 – 21.3 Female / MGMT methylated 28.6 24.7 – 32.5 Male / MGMT unmethylated 18.2 14.1 – 22.4 Female / MGMT unmethylated 18.7 13.4 – 23.9

2027 Background: Temozolomide (TMZ), concomitant with and adjuvant to radiotherapy (RT), has become the standard treatment for newly diagnosed glioblastoma (GBM). The aim of the present analysis was to evaluate the recurrence pattern in GBM patients (pts) treated with this treatment and to assess its correlation with MGMT promoter methylation status. Methods: A review was made of brain MRI images available in 95 GBM pts enrolled from January 2005 to January 2007, all of whom had been prospectively treated with TMZ (75 mg/m2/day) concomitant with standard RT (60 Gy/30F), followed by adjuvant TMZ (150–200 mg/m2 days 1–5, q28, maximum 12 cycles if MRI findings were negative or until progression if MRI appeared positive. An analysis was made of the correlation between MGMT promoter methylation status (assessed with methylation specific PCR) and the recurrence pattern. Results: After a median follow-up of 18 months (range: 6.6 - 44.8), 79 pts (83%) presented GBM recurrence: 57 pts (72%) had recurrence within, ...

To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mg day(-1)) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1-36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2-104+) weeks and PFS-6 was 14.3% (95% CI 4.0-32.7%). The median overall survival was 24.6 weeks (range 4-104+). No grade 3-4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

Between November 2004 and August 2006 we treated 35 patients with concomitant temozolomide (TMZ) and radiotherapy. Twelve patients had very large or multicentric glioblastoma multiforme with a poor performance status and received TMZ plus radiation doses of 45–50.4 Gy. The median survival of these patients was only 3.8 months. Twenty-three patients would have been eligible for randomisation in the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC) trial comparing combined and adjuvant TMZ plus radiation against radiotherapy alone. This group of patients received 60 Gy in 30 fractions plus concomitant TMZ (75 mg/m2) but no adjuvant chemotherapy. At a median follow-up of 26 months, five of 23 patients are alive. The median survival time was 17 months (1.43 years; 95% confidence interval 0.96–1.55). Eighteen per cent were alive at 2 years. Toxicity from TMZ was infrequent. This series adds to indirect evidence that the concomitant rather than the adjuvant is the more efficacious part of the EORTC/NCIC schedule for this type of patient. Further trials should include a concomitant chemoradiotherapy regimen as well as concomitant plus adjuvant chemotherapy.

The authors investigated the safety of 75 mg/m2 temozolomide for 21 days every 28 days in glioma patients. This schedule could lead to DNA repair enzyme O6-alkylguanine-DNA alkyltransferase depletion, contributing to overcoming drug resistance. Although Phase III studies are forthcoming, no data are available on the long-term toxicity of temozolomide, which, in this series, incurred prolonged, cumulative lymphopenia, which leads to a high incidence of infections.

20064 Background: 1p and 19q deletions have been associated with a favorable response to chemotherapy and a good prognosis in patients (pts) with oligodendroglioma. MGMT promoter methylation has been associated with a longer survival in pts with glioblastoma who receive alkylating agents. As yet, there are no data on the expression of MGMT, and on the relationship between 1p/19q deletions and MGMT promoter methylation in low grade glioma (LGG). Methods: Pts that received a first line chemotherapy regimen with temozolomide for progressive LGG were enrolled in the study, designed to investigate the correlation between MGMT methylation status and 1p/19q deletions in this setting. 1p/19q deletions were analysed by FISH, and MGMT promoter methylation by methylation specific PCR (MSP). Results: Seventy-five pts (26 females, 49 males; median age 42 years: range 22–68 years) were accrued. Of these, 48 (64%) had oligodendrogliomas (O), 19 (25.3%) astrocytomas (A), and 8 (10.6%) oligoastrocytomas (OA); 44 (58.7%) had a history of epilepsy, 41 (54.7%) had a frontal tumor localization, 27 (36%) had MRI contrast enhancing lesions, and 35 (46.7%) had been pre-treated with radiotherapy. 1p/19q deletions, evaluable in 58 pts (77.3%), were both present in 36 pts (62%), (3 being A and 2 OA); 18 pts (31%) had no loss; 1 pt (1.7%) had 1p loss; 3 pts (5.2%) 19q loss. Combined 1p and 19q loss was not correlated with a frontal localization (p = 0.12), median age (0.47) and/or gender (0.62). MGMT promoter methylation, present in 17 (56.6%) of 30 assessable cases, was significantly associated with combined 1p/19q deletions (p = 0.03). MGMT promoter methylation was not significantly associated with age (p = 0.46), gender (p = 0.2), tumor localization (p = 0.12) and/or histology (0.37). Conclusions: 1p/19q deletions are strictly correlated to histology and to MGMT promoter methylation; further prospective trials are required to clarify the impact of these molecular signatures on clinical outcome. No significant financial relationships to disclose.

1514 Background: Encouraging results have been obtained inlow grade glioma (LGG) patients (pts) following TMZ therapy at the standard schedule of 200 mg/m 2 for five-days every 28 days. A continuous dose TMZ schedule leads to DNA repair enzyme AGAT level depletion in tumor cells. By removing TMZ-produced methyl adducts, AGAT contributes to the development of resistance to alkylating agents. Methods: Pts with a diagnosis of LGG received TMZ 75 mg/m 2 /d for 21 days every 28 days at clinical or radiological progression. MiniMax Simon’s design with P 0 =0.2, P 1 =0.4, α=0.1, β=0.1 was used and a sample size of 36 pts was planned. The primary end-point was to assess the response rate (RR=CR+PR), and the secondary end-point to investigate the correlations between 1p/19q deletions by FISH and MGMT promoter methylation by methylation specific PCR (MSP). Results: 22 oligodendroglioma (O), 4 oligoastrocytoma (OA) and 10 astrocytoma pts (A) were enrolled (median age of pts 47 years, range 24–69 years; median KPS 90, range 50–100). Eleven pts were pre-treated with radiotherapy; 5 (13.5%) had enhancing lesion at MRI scan. RR was 30.5% (11 PR), all RR being obtained in pts with non-enhancing lesions; 20 pts (55.5%) had disease stabilization; 8/11 responders were assessable for 1p/19 q deletions and, of these, 6 pts (75%) had combined 1p/19q deletion. Median PFS was 17.4 months (interquartile ranges, 9.3–25). PFS at 1 year was 73% (SE 8%). Preliminary data on molecular assessment are: 29 pts were assessable for 1p and 19q deletions, both being present in 19 pts (65.5%). 1p/19 q loss was significantly greater in pts with O/OA than A (p=0.01). Of 11 assessable pts, 7 (63.6%) presented MGMT promoter gene methylation and all 7 pts presented 1p and 19q deletions (p=0.03). Grade 3 lymphopenia was observed in 4 pts (11.1%) and 1 patient had G2 reversible renal toxicity. Conclusion: TMZ for 21 days every 28 is an active and well tolerated regimen in pts with LGG. The analysis to verify any correlation between molecular markers and clinical outcome is ongoing. [Table: see text]

1564 Background: HGG comprehend a heterogeneous group of brain tumors with different histologies and prognosis. However, at second relapse, the response rate and PFS-6 are always discouraging for all subtypes. Methods: Adult pts with histologically confirmed HGG recurrent following first-line chemotherapy, were eligible. Pts were treated with Iressa 250 mg/day continuously until disease progression or unacceptable toxicity/pt refusal. Primary endpoint was disease-control rate (DCR=CR+PR+SD). Secondary endpoints were TTP, PFS-6, PFS-12, safety and OS. Results: Twenty-eight pts were enrolled and all were evaluable for activity and safety (median age: 55 years (range 29–70), male/female: 17/11, PS0/1/2: 3/21/4). Sixteen pts had GBM, 3 pts had anaplastic oligodendrogliomas and 9 pts had anaplastic astrocytoma. One pt had an unconfirmed PR (3.6%), 5 pts (17.9%) had confirmed SD, 3 pts (10.7%) had unconfirmed SD. The overall mTTP was 56 days (range 4–472) and PFS-6 and PFS-12 were 14.3% and 7.1%, respectively. In GBM pts subgroup the DCR was 12.5% (2/16), the mTTP was 60 days (range 28–472), PFS-6 and PFS-12 were both 12.5%. mOS was 172 days (range 28–607+), OS at 6 months was 50% and OS at 12 months was 14.3%. G3–4 toxicities consisted in: G3 diarrhoea in 1 pt, G3 neutropenia in 1 pt, G4 acute pulmonary oedhema in 1 pt, G4 pulmonary thromboembolism in 1 pt, G4 CNS hemorrage in 1 pt. G1–2 dermatological toxicity was common (32.1%). Conclusions: In our trial Iressa as second line treatment in HGG at the dose of 250 mg/day achieved interesting DCR and PFS-6. In the GBM subgroup, these data seem to confirm the results of the 500 mg/day previous study in terms of PFS-6. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough

Background: Protracted venous infusion of 5-FU increases response rates and reduces toxicity when compared to bolus administration: the mechanism of action of this drug appears to depend on the dose and on the schedule. In some trials 5FU was given as a rapid intravenous push: 30% incidence of severe mucositis or diarrhea was observed. These side effects decreased to less than 10% in trials in which 5 FU was infused over 30 min and much less toxicity was reported when the same dose of 5-FU was given over 1 hour or over 2 hours. The CMF i.v. schedule with bolus administration of all three drugs, in the adjuvant setting of breast cancer, has been shown to be associated with frequent toxicity. Protracted 5-FU infusion in the CMF schedule can reduce toxicity and improve the quality of life. Methods and Results: From July 2003 to December 2004, 42 patients with breast cancer, mean age 58 years (range 43–75) were treated with adjuvant CMF (1.8 every 28 days) with protracted 5-FU infusion (1 hour). Toxicity and compliance were compared to those of 40 patients previously treated in our institution with CMF bolus 5-FU (10 min). Six cycles were administered in all patients. Toxicity was coded by NCI – CTC. We observed that the patients treated with CMF protracted infusion 5-FU showed nausea G2/3: 28% vs 40%, emesis G2-3: 16% vs 27%, diarrhea G2: 0% vs 2%, asthenia: 14% vs 27%, neutropenia: G2: 21%, G3: 4%, G4: 4%, vs G2: 25%, G3: 7%, G4: 7%, mucositis G2-3: 10% vs 15%, and hand-foot syndrome: 2% vs 0%. Compliance in CMF protracted infusion 5-FU was: 6 cycles administered in 90 % vs 85%, day 8 omitted in 23 % vs 25%, dose reduction in 28% vs 30%. Conclusions: In our experience, protracted infusion 5-FU may reduce the gastrointestinal toxicity, particularly nausea compared to bolus infusion of the same drug. We suggest that less toxic treatment schedules are mandatory mainly in frail and/or elderly patients. These preliminary data need further investigations.

BACKGROUND. No data on the role of chemotherapy in recurrent ependymal tumors are available in adults. The aim of the current study was to investigate outcomes after salvage chemotherapy in this setting,METHODS. A retrospective review was made of the charts of 28 adults (>= 18 years) with progressive or recurrent ependymal tumors after surgery and radiotherapy, who received chemotherapy between 1993 and 2003 in 3 institutions of the Gruppo Italiano Cooperativo di Neuro-Oncologia network.RESULTS. Thirteen patients (46.3%) received cisplatin-based chemotherapy (Group A) and 15 (53.7%) received regimens without cisplatin (Group 13). Platinum-based chemotherapy yielded 2 complete responses (CR) (15.4%) and 2 (15.4%) partial responses (PR), whereas 7 patients (53.8%) remained stable (SD). After regimens without cisplatin, there were no CR, 2 PR (13.3%), and 11 SD (73.3%). The overall median time to progression was 9.9 months (95% confidence interval [95% CI], 7.5-21.7 months), 9.9 months (5.2-not reached) for Group A and 10.9 months (95% CI, 7.17-23.9 months) for Group B. The overall median survival (OS) was 40.7 months (95% Cl, 16-not reached), 31 months (21-not reached) for Group A and 40.7 months (13.4-not reached) for Group B.CONCLUSIONS. Cisplatin-based chemotherapy achieved a higher response rate, but did not prolong disease progression-free survival or OS. More active regimens for the salvage treatment of ependymal tumors have yet to be found. (c) 2005 American Cancer Society.

PURPOSE:Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O(6)-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival.PATIENTS AND METHODS:Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m(2) on day 1, TMZ 130 mg/m(2) bolus followed by nine doses of 70 mg/m(2) every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m(2) in 5 days.RESULTS:A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%).CONCLUSION:The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

1568 Background: Oligodendroglial tumors are chemosensitive diseases. The evaluation by fluorescence in situ hybridization has been used to assess 1p and 19q alterations that are considered the best chemosensitivity test in these tumors. Here we show another way to evaluate 1p and 19q chromosomal alterations by using microsatellite analysis that could be considered an useful tool in translational research for the accuracy of this method. Methods: Patients DNA was extracted from peripheral blood to define the wild type allelic condition, instead tumoral DNA was obtained from laser microdissected cells. We analized 4 microsatellites on Chr1p and 3 on Chr19q (chosen from sequences described by J.M. Nigro et al., Am J Path 2001); for each locus loss of heterozigosity (LOH), allelic imbalance or chromosomal instability were defined based on allelic peaks pattern. Chemotherapic regimens allowed were: PCV or Temozolomide or Carboplatin-Etoposide (CE). Results: At the time of abstract submission we evaluated 21 oligodendroglial tumor adult patients: 4 with oligodendroglioma, 12 with anaplastic oligodendroglioma and 5 with mixed oligoastrocytoma (2 G2 and 3 G3). In 10 patients both primary and recurrent disease samples were available. 16/21 patients were treated with chemotherapy. PCV combination was used as first line in 1 patient, Temozolomide was used as first line in 9 patients and CE combination was used as first line in 6 patients. Conclusions: The evaluation of 1p and 19q status by microsatellite analysis is feasible and provides useful informations about oligodendroglial tumors. Further results and correlations with response to radiotherapy and chemotherapy, and differences in 1p and 19q LOH pattern between primary and recurrence will be presented at the meeting. No significant financial relationships to disclose.

We present the results of a phase II trial of carboplatin and etoposide (CE) combination as first-line chemotherapy in patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) after surgery and radiotherapy. We assess the activity and the tolerability of this combination. 30 patients with GBM (25) and AA (5) were treated with VP-16 (etoposide) 120 mg m−2 and CBCDA (carboplatin) 100 mg m−2 for 3 days every 4 weeks. Moreover, we performed a retrospective analysis of topoisomerase IIα gene status using chromogenic in situ hybridisation. The median age was 54 years (21–73 years); Eastern Cooperative Oncology Group performance score was 0-1 in 25 patients and 2 in five patients. All patients had been previously treated with surgical resection (21 radical resections) followed by radiation therapy (40–60 Gy). We observed six (20%) complete responses, three (10%) partial responses and 12 (40%) stable diseases, with a response rate of 30%. The median time to progression was 4 months, while progression-free survival at 6 months was 33.3%. The median survival time was 10 months. Neutropenia occurred in 9 patients: four patients had grade 4, two patients grade 3 and three patients grade 2. In the conclusion of this clinical trial, the CE combination has shown activity in recurrent GBM and AA, with a good toxicity profile. Alterations in the copy number of topoisomerase IIα gene seem to be a rare event and in our series do not influence response to the CE combination.