Background: Nausea and vomiting (N/V) are relatively common toxic effects related to administration of temozolomide. Due to its oral route of administration, N/V could represent a relevant issue for patient adherence to treatment and absorption of TMZ.We evaluated efficacy of granisetron transdermal delivery system (GTDS) in preventing CINV in pts with GBM treated with single-agent temozolomide after completion of oncomitant radiochemotherapy (CRC). Patients and methods: From September 2014 to January 2016 we consecutively recruited 16 pts with GBM treated with CRC. Mean characteristics of pts were as follows: median age 56 yrs (range: 41-69 yrs), M:F = 11:5, median ECOG PS 1 (range: 0-2). All enrolled pts had responding or stable disease after CRC.After completion of CRC, in case of responding or stable disease, patients were treated with single-agent temozolomide 150-200 mg/mq/die dd.1-5 q28d up to 12 cycles.For each patient, 24 hours before chemotherapy initiation (day 1), was applied a patch of GTDS (one patch, 7 days, 3,1 mg/24h). All pts were receiving steady doses of dexamethasone (4-12 mg/die) as supportive care. The primary end point was the Complete Response (CR) defined as no vomiting and no rescue therapy during overall phase (0-168 hours). Secondary endpoints included CR during the 0-120 h and 121-168 h phases and complete control (CC: CR and no more than mild nausea) during the 0-120 h, 120-168h and 0-168h phases. Results: All enrolled patients were evaluated for efficacy and safety after the first cycle of adjuvant temozolomide. CR in the 0-168h phase was 87% (14/16 pts). CR in 0-120h phase and 121-168 phase were 87% (14/16 pts) and 100%(16/16 pts), respectively. CC during 0-120h phase, 120-168h phase and 0-168h phase were reported in 87%,100% and 94% of pts, respectively. GTDS was well tolerated: 3 pts (19%) experienced G1-2 constipation easily managed by the administration of common laxatives; in 2 pts (12%) was reported G1 headache.No cases of nausea >G2 were reported. Vomiting and/or nausea never altered the administration of TMZ. Conclusions: Despite the small number of pts involved in this experience, GTDS applied 24 hours before chemotherapy initiation seems to be really effective in preventing N/V in patients with GBM treated with adjuvant single-agent temozolomide and could represent an interesting antiemetic option in this setting.

declined to relatively lower level of QOL and then steadily back to moderate QOL".The third type of QOL covered 39.6% of patients and represented "steadily moderate level of QOL".The factors significantly related to the first type of QOL trajectory were physical function, pain, poor appetite, uncertainty, and self efficacy; pain, uncertainty and self-efficacy were related to the second type of QOL trajectory; and depression and uncertainty were related to the third type of QOL trajectory.Conclusion: Based on the QOL trajectories and identified factors, the timely and tailoring interventions should be developed, applied to and tested for their clinical effectiveness in enhancing advanced lung cancer patients' QOL during the most distressful first 6 months of having lung cancer.

ABSTRACT Introduction Itching is a common dermatologic side effect of anti-epidermal growth factor receptor antibodies and tyrosine kinase inhibitors and may have a dramatic impact on patients' quality of life. Aprepitant, a neurokinin receptor inhibitor, showed efficacy in treating refractory pruritus. We designed a pilot single-center phase-II study evaluating the effects of aprepitant in managing biological therapy-induced pruritus. Methods Forty-five cancer patients treated with biological therapies were enrolled and divided in: 1) patients affected by itch refractory to standard treatment (“refractory-group”) and 2) patients who did not receive any treatment for pruritus (“naive-group”). The intensity of itch was evaluated with Visual Analogue Scale (VAS)-score. All included patients had severe pruritus (VAS-score ≥ 7). In the refractory group aprepitant (125 mg on day 1; 80 mg on day 3 and on day 5) was administered after at least 1-week of standard systemic treatment (steroid and/or antihistaminics). In the naive-group aprepitant was administered, with the same schedule, after first severe pruritus onset. Results Forty-five (25 males and 20 females) patients were enrolled, 24 in the refractory group and 21 in the naive-group. The median age was 64 years. Among the enrolled patients, 38% (n = 17) were affected by lung cancer, 44% (n = 20) by colorectal cancer, and 18% (n = 8) by other tumors. Severe itching occurred in 16 patients treated with erlotinib, 23 with cetuximab, 1 with lapatinib, 3 with sunitinib, 1 with imatinib and 1 with gefitinib. The median decrease in pruritus intensity at 1-week after aprepitant introduction was 93% (p Conclusions This single-center phase-II study showed a new therapeutic activity of aprepitant in treating biological therapy-induced pruritus, both after standard antipruritic-medication failure and as a first-line therapy. Disclosure All authors have declared no conflicts of interest.

In metastatic colorectal cancer (mCRC) patients, the efficacy of anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, is limited to patients with KRAS wild-type tumours [1.Lièvre A. Bachet J.B. Boige V. et al.KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab.J Clin Oncol. 2008; 26: 374-379Crossref PubMed Scopus (1351) Google Scholar]. However, not all mCRC patients with KRAS wild-type tumours respond to this treatment. Therefore, there is a need for additional predictive markers. A mutation in B-type Raf kinase (BRAF), located downstream of KRAS, has been implicated in the response to anti-EGFR treatment [2.Di Nicolantonio F. Martini M. Molinari F. et al.Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.J Clin Oncol. 2008; 26: 5705-5712Crossref PubMed Scopus (1455) Google Scholar]. The V600E is the most common oncogenic mutation of BRAF in cancer and is mutated in ∼5%–10% of mCRC patients. Moreover, BRAF mutational status also appears to have prognostic value in patients with mCRC independently from anti-EGFR therapies [3.Tol J. Nagtegaal I.D. Punt C.J.A. BRAF mutation in metastatic colorectal cancer.N Engl J Med. 2009; 361: 98-99Crossref PubMed Scopus (3) Google Scholar]. Although different studies have demonstrated a high concordance rate between primary tumour and metastasis in the KRAS gene status, only limited data on BRAF status are available for this concordance. Italiano et al. [4.Italiano A. Hostein I. Soubeyran I. et al.KRAS and BRAF mutational status in primary colorectal tumors and related metastatic sites: biological and clinical implications.Ann Surg Oncol. 2010; 17: 1429-1434Crossref PubMed Scopus (101) Google Scholar] reviewed the literature and reported an identical mutational pattern of BRAF in primary tumours and matching metastases in all but 2 (3%) of 95 patients, mostly with synchronous metastases. The aim of our study was to investigate in a large series of KRAS wild-type tumours the grade of concordance in terms of BRAF status between primary tumours and related metastases and, in particular, to exclude the acquisition of a BRAF mutation during metastatic progression. The level of concordance of BRAF status between primaries and related metastatic samples was stated at a minimum desirable level of 90%, while it was not acceptable at a level <80%. Using the design proposed by A'Hern [5.A'Hern R.P. Sample size tables for exact single-stage phase II designs.Stat Med. 2001; 20: 859-866Crossref PubMed Scopus (303) Google Scholar] for the binomial distribution, it was necessary to carry out both evaluations in at least 167 patients. We retrospectively analysed BRAF V600E mutation in the primary tumours of 208 mCRC patients with KRAS wild-type tumours. DNA was extracted from paraffin-embedded tumour, and BRAF V600E mutation in exon 15 was investigated according to standard procedures. We detected 13 patients with a BRAF mutation in the primary tumour (6.25%). Then we investigated BRAF V600E mutational status at metastatic sites in the 195 patients with BRAF wild-type primary tumours. A total of five patients were excluded from this analysis for the absence of tumour tissue in the analysed metastatic sample. The majority of the 190 remaining patients had metachronous metastases (125 patients, 65.8%) with the liver as the predominant site and had a median age at diagnosis of 74 years (range 32–86 years). Only 1 of 190 patients (0.5%) showed a BRAF V600E mutation in the metastatic site (liver). On the other hand, in the 13 patients with a BRAF mutation in the primary tumour, we observed a BRAF wild type in the corresponding metastases in five patients (38.5% of concordance). Our results show a high concordance in BRAF wild-type status between primary and metastatic tumours, but the level of concordance is lower when the primary tumour harbours a BRAF mutation. For this latter finding, we have no explanation. We recommend that BRAF mutational status of metastases is not required when the primary tumour is BRAF wild type.

There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3′-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS / BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab–irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type ( P =0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS ( P =0.001) and PFS ( P =0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.

4527 Background: To assess the clinical significance of tumor-infiltrating FOXP3-positive Tregs in patients with R0, stage II-III, GC. Methods: From a single-institution database, tumors of 110 consecutive GC patients who underwent R0 resection for stage II- III disease were studied for FOXP3-positive Tregs by immunohistochemistry. A minimum 3-year follow-up time and the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria were used for planning the study. The recurrences of GC had to be confirmed by cytology biopsy or surgery. None of the patients received chemotherapy or radiation therapy before or after surgery as a part of an adjuvant program. The study was conducted in a blinded fashion so that patients’ outcomes were unknown to investigators performing immunohistochemistry. The observed median number of FOXP3-positive Tregs was used as cut-point in analyses (<6 vs. >6 count). To explore the association between overall survival (OS) and relapse-free survival (RFS) with FOXP3 count stratified log-rank tests were used. To further define these relationships, Cox proportional hazards models for multivariate analyses with Hazard Ratio (HR) and 95% confidence interval (95%CI) were employed. Results: Tregs numbers were significantly higher in GC than in normal tissue (p=0.0001) and Tregs count >6 was significantly associated with vascular/lymphatic/perineural invasion (VELIPI) in the tumor (p=.03). Forty-eight patients (44%) relapsed and died after receiving cisplatin/fluorouracil-based palliative chemotherapy. In multivariate analysis, adverse RFS was associated with grading 3 (HR=2.15; 95%CI 1.19–3.89, p=0.01), stage III (HR=2.34; 95%CI 1.20–4.57, p=0.01), VELIPI (HR=1.96; 95%CI 1.08–3.55, p=0.02) and Tregs count >6 (HR=2.00; 95%CI 1.10–3.65, p=0.02), while adverse OS was associated with grading 3 (HR=2.21; 95%CI 1.22–3.98, p=0.008), stage III (HR=2.40; 95%CI 1.23–4.67, p=0.01) and Tregs count >6 (HR=2.34; 95%CI 1.27–4.28, p=0.006). Conclusions: Quantification of FOXP3-positive Tregs may be a novel marker for identifying high-risk GC patients. Present findings deserve additional investigation as Tregs may also represent an innovative therapeutic target. No significant financial relationships to disclose.