Search

Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p AR normal vs patients with AR gain (not reached vs 8.17 months, p AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

Noise complaints in restaurants have been accelerating and unpleasant sounds erode customer satisfaction. Restaurant ambient noise, such as background and physical sounds influence customer satisfaction and effectively controlling the sound environment in restaurants is challenging, particularly situational sounds generated by customers. Situational sounds address how customers are influenced by other customers dining in the same restaurant and highlight a type of sound that cannot be easily managed by employees. Situational sounds can be loud conversation among fellow customers or misbehaving children. Concerns with situational sounds are less about how they impact customer satisfaction, and more about the way in which managers handle them. Thus, managers find a proactive service approach to be most effective when handling situational sounds in a restaurant. For example, strategically placing a large noisy group in a separate room or further away from other customers in the restaurant can mitigate the negative impact to other diners. The results of this study confirmed that background sounds, physical sounds, and managers’ proactive customer service regarding situational sounds impact customer satisfaction. However, the interactive effects of background sounds, physical sounds, and managers’ proactive customer service regarding situational sounds do not influence customer satisfaction. Based on the results, recommendations for restaurant managers are provided to decrease controllable unpleasant noises caused by background and physical sounds as well as strategies for effectively executing proactive customer service to handle situational sounds.

Corporate social responsibility (CSR) has become a popular, and even expected, strategy for promoting an organization’s public persona. CSR is particularly important in the casino industry since many customers associate the casino industry with negative images such as crime and drugs; therefore, casinos try to enhance their social image through CSR activities. This study investigated how casinos’ CSR activities (economic, legal, ethical, and philanthropic) influenced customer loyalty (CL). Partial Least Squares (PLS)-structural equation modeling analysis was used to examine the hypotheses on a sample of 251 casino’s customer in the United States. Results of this study showed that the dimensions of philanthropic and legal responsibilities had varying effects on CL. In contrast, economic and ethical responsibilities didn’t significantly affect CL.

Background High-dose interleukin-2 (HDIL-2) represents a curative treatment option in metastatic melanoma (MM) and renal cell carcinoma (RCC) patients, although still in need of improving its therapeutic efficacy. Radiotherapy (XRT) strongly synergizes with immunotherapy and may boost the effects of HDIL-2 allowing for less toxic schedules. Methods In this proof-of-principle phase II study, biological markers of immunological response were considered as primary endpoints in previously treated MM and RCC patients. The treatment consisted of 3 daily doses of XRT (6-12 Gy) delivered to one lesion before the first and third IL-2 infusion (18 MIU/m2/day by IV infusion for 72 h), repeated every 3 weeks for a maximum of 6 cycles. In a first stage, 4 out of 7 enrolled patients showed an immunological response allowing the recruitment of a further 12 patients according to the minimax two-stage Simon design. The immunological efficacy of the combined XRT/HDIL-2 treatment was assessed measuring the proportion of circulating immune effectors specific for tumor antigens known to be expressed in MM and in RCC (i.e. Tyrosinase, gp100, Mart-1, 5T4, CAIX/G250, EGFR, survivin, MAGEA3 and NYESO1) by means of INF-γ Elispot assay. Moreover, the predictive value of pre-treatment serum biomarkers was also assessed. Results Since September 2012 a total of 19 patients have been enrolled (9 RCC and 10 MM patients of which 6 uveal, 2 mucosal and 2 cutaneous) with a median age of 55 years. Assessed clinical responses were 4 PR (3 RCC and 1 MM), 6 SD (2 RCC and 4 MM) and 9 PD. Median PFS was 3.2 and 2.9 months and median OS was 8.7 and 6.7 months, for RCC and MM respectively. According to CTCAE 4.0, the majority of toxicities was grade 1-2. IL-2 dose was never reduced, nor was the infusion interrupted. Interestingly, we found an enhancement greater than 10% of antigen-specific spot-forming cells (SFCs) for at least one tumor antigen after treatment in 16 out of 19 patients. Moreover, we detected much lower serum basal levels of IL-8 and IL-1b in responders (CR/PR/SD=10) compared to non responders (PD = 9). Conclusion HDIL2/XRT combined treatment is well tolerated and fairly active in the MM and RCC settings. Clinical trial identification EudraCT: 2012-001786-32. Legal entity responsible for the study The authors. Funding Italian Ministry of Health as part of the “Ricerca Finalizzata 2009 - Direzione Generale della Ricerca Scientifica e Tecnologica” Call for Project Proposals. Disclosure All authors have declared no conflicts of interest.

The association between choline uptake and androgen receptor (AR) expression is suggested by the upregulation of choline kinase-alpha in prostate cancer. Recently, detection of AR aberration in cell-free DNA as well as early 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) were associated with outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone and enzalutamide. We aimed to make a direct comparison between circulating AR copy number (CN) and choline uptake at FCH-PET/CT. We analysed 80 mCRPC patients progressing after docetaxel treated with abiraterone (n = 47) or enzalutamide (n = 33). We analysed AR CN from plasma samples using digital PCR and Taqman CN assays and total lesion activity (TLA) and metabolic tumor volume (MTV) on FCH-PET/CT at baseline. A meaningful correlation was showed among AR gain and TLA/MTV compared to AR non-gained cases (P = 0.001 and P = 0.004, respectively), independently from type of treatment. Multivariate analysis revealed that AR CN and only TLA were associated with both shorter PFS (P AR and FCH-PET/CT in mCRPC patients.

Background Abiraterone and enzalutamide represent the standard treatment in castration resistance prostate cancer (CRPC) patients, however, some patient displays primary resistance, and several studies investigated the role of the androgen receptor (AR) as a predictive biomarker of response to treatment (Conteduca, et al. Ann Oncol. 2017;28(7):1508-1516; Del Re, et al. BJU Int. 2019 doi: 10.1111/bju.14792). The present study is aimed at evaluating the role the AR in liquid biopsy to predict response to hormone treatment in CRPC patients. Methods Six ml of plasma samples were collected from patients affected by castration-resistant prostate cancer before the beginning of first-line hormonal treatment. Circulating free DNA and exosome-RNA were isolated for analysis of AR-gain and AR-V7 by digital droplet PCR. Results Eighty-four CRPC were prospectively enrolled in this study. 40 patients received abiraterone and 44 patients received enzalutamide as first-line hormonal therapy. AR-gain was detected in 12 patients (14.3%) and 36% were AR-V7+ at baseline. Median PFS and OS were significantly longer in AR-V7- vs AR-V7+ patients (24.3 vs 5.4 months, p Conclusions The present study demonstrates that cfDNA and exosomal RNA are a reliable source of AR-variants and their detection predicts resistance to anti-hormonal therapy. The method is sensitive, fast and represents a convenient alternative to other potentially more expensive and less sensitive approaches. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure V. Conteduca: Travel/Accommodation/Expenses: Janssen; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Bayer. U.F.F. De Giorgi: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Astellas; Advisory/Consultancy: Byer; Advisory/Consultancy: BMS; Honoraria (self): Ipsen; Advisory/Consultancy: Janssen; Advisory/Consultancy: Merk; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: Janssen; Travel/Accommodation/Expenses: Pfizer. All other authors have declared no conflicts of interest.

Background Three recent RCT (Spartan, Prosper and Aramis) have demonstrated improved metastasis-free survival with new ARi Apalutamide (A), Enzalutamide (E) and Darolutamide (D), respectively, vs placebo (pl) in nmCRPC. We conducted a meta-analysis of RCT to evaluate the safety of ARi. Methods Random-effects meta-analysis was performed to describe pooled odds ratio (OR) vs pl and presence of heterogeneity in the effect among RCT. Network meta-analysis was performed to describe OR of indirect comparisons. Results 4104 patients were included in safety analysis. Many adverse events (AEs) (falls, fractures, fatigue, nausea, diarrhea, hypertension, rash) showed a significant difference in the incidence in patients receiving pl, mostly higher in the Spartan trial. The use of ARi was associated with an higher risk of developing selected AEs compared to pl: serious AEs (OR 1.28, 95%CI 1.10-1.50); falls (OR 1.81, 95%CI 1.40-2.34); fractures (OR 1.58, 95%CI 1.11-2.23); fatigue (all grades OR 2.00, 95%CI 1.68-2.39; severe OR 2.21, 95%CI 1.06-4.60); rash (OR 4.90, 95%CI 3.24-7.41); diarrhea (OR 1.24, 95%CI 1.00-1.54); hypertension (all grades OR 1.55, 95%CI 1.25-1.92; severe OR 1.44, 95%CI 1.08-1.92); dizziness (OR 1.67, 95%CI 1.26-2.21), mental impairment (OR 1.73, 95%CI 1.13-2.66). Significant heterogeneity in the effect among ARi was found for falls (D better than E: OR 0.29, 95%CI 0.14-0-60; D better than A: OR 0.48, 95%CI 0.25-0.91); fatigue all grades (D better than E: OR 0.59, 95%CI 0.39-0.88; A better than E: OR 0.61, 95%CI 0.44-0.84) and severe (D Better than E: OR 0.10, 95%CI 0.02-0.60); hypertension (D better than E: OR 0.51, 95%CI 0.27-0.98; A better than E: OR 0.53, 95%CI 0.31-0.92); mental impairment (D better than E: OR 0.15, 95%CI 0.04-0.58; D better than A: OR 0.24, 95%CI 0.06-0.90). No significant heterogeneity was found for other AEs. Conclusions With the limitations of the network meta-analysis, our findings suggest that the use of ARi in nmCRPC is associated with a statistically significant increased risk of developing selected AEs according to the type of agent used. Potential specific toxicities should be considered before starting ARi in nmCRPC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A. Altavilla: Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Janssen. M. Di Maio: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Janssen; Honoraria (self): Takeda; Research grant / Funding (institution): Tesaro. M. Tucci: Honoraria (self): Astellas; Honoraria (self): Janssen; Honoraria (self): Bayer; Honoraria (self): Sanofi. U. De Giorgi: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol Meyer Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest.

Interpersonal communication is a skill that is crucial to successful leaders (Brownell, 1992;Scudder & Guinan, 1989) however, English, Manton, and Walker (2007) found that most college graduates tend to be deficient in these skills when entering the business world. In the service industry, leaders interpersonally communicate with many constituents. The purpose of this study was to determine entry-level hospitality leaders’ perceptions of which interpersonal communication skills are important and whether their college curriculum prepared them to be competent interpersonal communicators. Participants rated the importance of all interpersonal communication skills evaluated as higher than their level of preparedness. The results will aid educators in better determining more selective criteria on which to design curricula and learning outcomes for interpersonal communication so that graduates will be more prepared when entering the hospitality industry as entry-level leaders.

Interpersonal communication is a skill that is crucial to successful leaders ( Brownell, 1992 , Scudder and Guinan, 1989 ); however, English et al. (2007) found that most college graduates tend to be deficient in these skills when entering the business world. In the service industry, a manager interpersonally communicates with guests, subordinates, peers, and superiors. In particular, a manager interpersonally communicates most often with their subordinates. The purpose of this study was to determine entry-level hospitality leaders’ perceptions of which interpersonal communication skills are important and whether their college curriculum prepared them to be competent interpersonal communicators when communicating with subordinates. The results indicated that participants believed that a lack of: (1) overall leadership experience, (2) exposure to dealing with a diverse audience, (3) giving feedback, and (4) dealing with confrontational situations contributed to why they rated the importance of all the interpersonal communication skills evaluated higher than their level of preparedness.

Background In clinical practice, discontinuation or dose reduction of everolimus may be induced not only by grade 3 or 4 toxicities but also by prolonged grade 2 toxicities, such as stomatitis and/or cutaneous toxicity, which share some pathogenetic mechanisms. We assessed the correlation between either everolimus discontinuation or dose reduction induced by stomatitis–cutaneous toxicity events (SCTE) and clinical outcome of patients with metastatic renal-cell cancer (mRCC). Patients and Methods We retrospectively reviewed the clinical data of patients with mRCC treated with everolimus in 2 Italian centers. Clinical evidence of SCTE was evaluated, and corresponding clinical data were reviewed for response and clinical outcome. Results Seventy-nine mRCC patients treated with everolimus (57 male, 22 female; median age 66 years; range, 44-88 years) were evaluated. SCTE were observed in 20 (25%) of 79 patients at a median of 30.5 days of everolimus treatment (range, 10-270 days). Partial response or stable disease was achieved in 15 (79%) of 19 evaluable patients with SCTE compared to 28 (48%) of 58 with no SCTE ( P = .03). At a median follow-up of 19 months, a significant difference was found in the median PFS equal to 7.8 months (95% confidence interval [CI], 2.8-24.4) in SCTE patients versus 4.3 months (95% CI, 2.7-7.5) in non-SCTE patients ( P = .029), and in the median OS equal to 30.6 months (95% CI, 19.6–not reached) in SCTE patients versus 13.5 months (95% CI, 9.9-17.7) in non-SCTE patients ( P = .0007). Conclusion These data suggest that SCTE may be a predictive marker of favorable outcome in mRCC patients treated with everolimus.

We conducted an echocardiographic study to determine the incidence and spectrum of morphologic and functional cardiac abnormalities in systemic lupus erythematosus (SLE) and to relate these findings to the disease activity and duration, and the presence of antiphospholipid (APL) antibodies. Thirty consecutive patients with LES (5 male and 25 female, mean age 37 +/- 11 years) were studied with a clinical cardiovascular examination and M-mode, 2-D Doppler echocardiogram. All patients fulfilled the American Rheumatism Association criteria for diagnosis of SLE. Disease activity was scored using the "Lupus Activity Criteria Count". The duration of the disease was less than 1 year in 5 patients (16.7%), between 1 and 5 years in 7 (23.3%), and superior to 5 years in 18 (60%). No patient had a history of rheumatic fever or infective endocarditis. All patients had received steroid therapy. In 26.7% of patients the disease was active, and in 33.3% APL antibodies were present. Patients were matched by number, age and sex with the control group. In 73.3% of the patients the echocardiogram resulted abnormal; valvular disease occurred in 30% and the echocardiographic features were of diffuse thickening, with 4 mitral and 2 aortic regurgitations. No valvular dysfunctions were significant, nor was Libman-Sacks endocarditis present. Pericardial disease, effusion or thickening was detected in 33.3% of the echocardiograms. Furthermore, there was one patient with left ventricular mild hypertrophy; 2 with a mild enlargement of the left ventricle with no segmental abnormalities of wall motion and no systolic disfunction; 8 patients (26.7%) were normal. Compared with the control group, patients with SLE had an increased prevalence of echocardiographic abnormalities, especially pericardial (p0.001) and valvular (p0.01). No association was found between activity, duration of the disease and prevalence of cardiac abnormalities. On the contrary, an association between the presence of APL antibodies and cardiac abnormalities at the echocardiographic examination was evident (p0.05).

The authors evaluated the efficacy of medium term prophylaxis of atrial fibrillation (AF) with propafenon (P) in 33 symptomatic patients. Consecutive patients were treated with P replacing previous therapy with amiodarone (A) withdrawn on account of adverse side effects occurring on average after 1.8 years' treatment. Quantification of AF episodes was based on symptoms reported by patients, ECG, and dynamic Holter-ECG performed every 3-6 months. During A treatment (average daily dosage 216 mg) 32% of patients had reported more than two episodes of AF, 52% one or two episodes, and 16 none during the last 6 months. During 6 months of P treatment (average daily dosage 586 mg) 28% had more than two episodes, 64% had one or two, and 8% had none. The difference of incidence of AF episodes between the two treatments was not statistically significant. Side effects requiring withdrawal of the drug were not observed with P. The results obtained confirm P as a valid therapeutic resource for treatment of recurrent paroxysmall AF. In addition, the drug was also well tolerated during medium term application.

Many side-effects of alpha interferon (alpha-I) therapy have occurred as a result of its widespread clinical applications. The hypothesis of alpha-I related cardiomyopathy is particularly interesting. Our study involved echocardiographic evaluation of left ventricular function and cardiovascular complications in 35 patients with chronic hepatitis treated with alpha-I at 20 MU/week for an average of 10.8 months. The results were compared with those of a control group. Of the values studied, only Max E V and the E/A ratio were statistically significant. No cardiovascular side-effects were found.

To ascertain whether the dawn phenomenon occurs in nondiabetic individuals and, if so, whether it is due to an increase in glucose production or a decrease in glucose utilization, we determined plasma concentrations of glucose, insulin, C-peptide, and counter regulatory hormones, as well as rates of glucose production, glucose utilization, and insulin secretion at one-halfhourly intervals between 1:00 and 9:00 a.m. in eight normal volunteers. After 5:30 a.m., plasma glucose, insulin, and C-peptide concentrations all increased significantly; rates of glucose production, glucose utilization, and insulin secretion also increased (all P < 0.05). Plasma cortisol, epinephrine, and norepinephrine increased significantly from nocturnal nadirs between 4:00 and 6:30 a.m. Plasma growth hormone, which had increased episodically between 1:00 and 4:30 a.m., decreased thereafter nearly 50% (P < 0.05). Plasma glucagon did not change significantly throughout the period of observation. These results indicate that a dawn-like phenomenon, initiated by an increase in glucose production, occurs in nondiabetic individuals. Thus, early morning increases in plasma glucose concentrations and insulin requirements observed in IDDM and NIDDM may be an exaggeration of a physiologic circadian variation in hepatic insulin sensitivity induced by antecedent changes in catecholamine and/or growth hormone secretion.

In order to assess whether the metabolic clearance of insulin changes overnight, 11 patients with Type 1 (insulin-dependent) diabetes and low insulin antibody titre, and 6 nondiabetic subjects were studied. In these studies insulin was always infused by a Harvard pump. Initially, the nocturnal insulin requirements were assessed in the diabetic patients by an overnight feedback insulin infusion to maintain euglycaemia. The insulin requirements decreased continuously after midnight to a nadir of 0.115 ± 0.014 mU · kg−1 · min−1 at 04.30 hours, but after 05.00 hours the insulin requirements increased nearly 40 percent to a maximum of 0.16 ±0.012 mU · kg−1 · min−1 at 07.00 hours. To assess whether plasma insulin clearance changes overnight, the diabetic patients were studied on two different occasions, from 22.00–02.30 hours and from 04.00–08.30 hours. During each of these two studies insulin was infused in sequential steps of 90 min each at the rate of 0.13, 0.40 and 0.20 mU · kg−1 · min−1. Despite changes in plasma free insulin concentration, the metabolic clearance of insulin in the interval 22.00–02.30 hours (12.6±0.17 ml · kg−1 · min−1) was no different from that of the interval 04.00–08.30 hours (12.5 ± 0.19 ml · kg−1 · min−1). The nondiabetic subjects were studied on two different occasions to assess whether the metabolic clearance of insulin changes overnight. Somatostatin (0.25 mg/h) and insulin (0.3 mU kg−1 · min−1) were infused from 22.00–02.30 hours on one occasion, and from 04.00–08.30 hours on the other. The metabolic clearance of plasma free insulin in the interval 22.00–02.30 hours was no different from that of the interval 04.00–08.30 hours (12.6 ± 0.20 vs 12.9 ± 0.25 ml · kg−1 · min−1 nor was it different from that of the diabetic patients. It is concluded that, first, the metabolic clearance rate of insulin does not change overnight either in diabetic or in nondiabetic subjects; second, that it is independent of plasma insulin concentration; and third, that its value is comparable in nondiabetic subjects and in diabetic patients with a low titre of insulin antibodies. Thus, changes in insulin sensitivity rather than changes in insulin clearance are implicated in the pathogenesis of the dawn phenomenon.

Background Intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene have been recently described in gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS). We evaluated the copy numbers and gene expression levels of DMD in our series of GIST patients who were already studied with wide genome assays, to investigate more fully a correlation between dystrophin status and disease annotations. Findings Our study highlighted a recurrent intragenic deletion on chromosome X, involving the DMD gene that codes for human dystrophin in GIST patients. Of 29 KIT/PDGFRA mutant GIST samples, 9 (31%) showed deletions of the DMD gene, which were focal and intragenic in 8 cases, and involved loss of an entire chromosome in one case (GIST_188). DMD loss was seen in only 5 patients with metastasis, whereas 18 out of 20 patients with localized disease had wild-type DMD (P = 0.0004, Fisher exact test). None of the 6 KIT/PDGFRA WT GIST showed DMD alterations. Conclusions Our study confirms the presence of DMD deletions only in KIT/PDGFRA mutant GIST and this event is almost associated with metastatic disease. These findings are, of course, quite preliminary but support development of potential therapeutic strategies that target and restore DMD function in the treatment of metastatic GIST.

INTRODUCTIONThe peritoneum is one of the most common sites of distant gastrointestinal stromal tumor (GIST) metastases. In particular, GIST arising from the small intestine with resected minimal synchronous macroscopic peritoneal carcinomatosis or with primary tumor rupture has a higher risk of developing peritoneal recurrence. Current clinical practice does not envisage second-look surgery in GIST patients at high risk of developing peritoneal recurrence, and no literature data are available.PRESENTATION OF CASEWe describe a 45-year-old woman who underwent emergency surgical resection of jejunal GIST presenting with spontaneous tumor rupture, synchronous ovarian and minimal macroscopic peritoneal involvement, and subsequent second-look surgery after 13 months of imatinib treatment.DISCUSSIONSecond-look surgery confirmed a 2.6cm lesion close to the mesenteric border of the fourth jejunal loop, and 11 peritoneal lesions with a macroscopic necrotic aspect related to treatment response. After conversion to an open procedure, a segmental jejunal resection was performed with removal of all peritoneal lesions and macroscopic radical cytoreduction.CONCLUSIONSecond-look surgery in selected GIST patients may be performed after at least 12 months of medical treatment with tyrosine-kinase inhibitors to identify those patients with limited peritoneal disease not disclosed by instrumental imaging who could undergo radical cytoreduction of peritoneal lesions.

Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. Tumor resection is the treatment of choice for localized disease. Tyrosine kinase inhibitors (imatinib, sunitinib) are the standard therapy for metastatic or unresectable GISTs. GISTs usually metastasize to the liver and peritoneum. Bone metastases are uncommon. We describe three cases of bone metastases in patients with advanced GISTs: two women (82 and 54 years of age), and one man (62 years of age). Bones metastases involved the spine, pelvis and ribs in one patient, multiple vertebral bodies and pelvis in one, and the spine and iliac wings in the third case. The lesions presented a lytic pattern in all cases. Two patients presented with multiple bone metastases at the time of initial diagnosis and one patient after seven years during the follow-up period. This report describes the diagnosis and treatment of the lesions and may help clinicians to manage bones metastases in GIST patients.

10056 Background: Gastrointestinal stromal tumors (GISTs) are characterized by oncogenic mutations of KIT and PDGFRA receptors. However about 10%-15% of adult GISTs do not harbor any KIT or PDGFRA ...

10562 Background: The insulin-like growth factor 1 receptor (IGF1r) is a tyrosine kinase receptor that plays a key role in the growth of normal tissues. The aberration of IGF system has been found in many cancers. Some interesting results about IGF1r were published on GISTs. However, until now the real role on the pathogenesis of this disease and its clinical implications still needs to be defined. Methods: We studied IGF1r in 8 patients affected by gastric GIST. Seven patients underwent surgery at diagnosis, whereas one patient was operated after imatinib and sunitinib treatment. Two patients were young (< 30 years old), and other patients ranged between 54 and 85 years. IGF1r was studied as gene expression profiling performed with Affymetrix GeneChip HG-U133 Plus 2.0 arrays, as genomic copy number with SNP array analysis Affymetrix Genome Wide Human SNP 6.0 arrays, and with western blotting (WB) usinganti-IGF-IRβ (Santa Cruz Biotechnology). Results: The unsupervised analysis of gene expression profiling of our patients merged with a data set from a gastric GIST identified two groups with different regulation of IGF1r (FDR threshold to 0.2%). In particular, IGF1r was up-regulated in the two youngest patients (28 and 30 years-old). The SNPs array analysis gene copy number showed that none of the patients bore IGF1r amplification. The quantitative analysis of protein level by WB again showed that only the two youngest patients had an over-expression of IGF1r. In all the other patients the WB analysis was negative. Conclusions: These results suggest that IGF1r seems to be a novel signalling pathway other than KIT and PDGFRA in a subset of GISTs. The young adult patients had a strongly different molecular background in comparison to the other older ones. The correlation between IGF1r and mutational status of KIT and PDGFRA, clinical outcome, treatments responsiveness as well as its role as potential target deserves to be further investigated. No significant financial relationships to disclose.

10554 Background: The main treatment for localized GIST is complete surgical resection. The prognosis is strongly correlated with both tumor size and mitotic index. The aim of our study was to analyze retrospectively the outcome of patients affected by GIST related to microscopic margins of resection. Methods: The outcome of 122 patients surgically managed during the past 11 years, were evaluated. We analyzed the impact of R0 and R1 resection on DFS. Results: All patients but one, had a c-Kit positive GIST, 91% had primary disease without metastasis, 9% had metastasis. There were 46% high, 31% intermediate and 28% low risk GIST. The median age was 65 years (range 29–87). The most common sites of tumor origin were the stomach (54.9%) and the small bowel (36.9%). Sites of tumor metastasis were liver (18.2%), peritoneum (36.4%) or both (19.3%). R0 resection was achieved in 102 (83.6%) patients, while 16 pts (13.1%) had positive microscopic margins (R1). With a median follow up of 24 months (range 3–119), recurrence occurred in 34 (33.3%) R0 and in 9 (56.3%) R1 patients. The median DFS was 53.7 months and 35.6 months for the R0 and R1 group, respectively. The difference tested with univariate analysis using Long rank test, was not statistically significant (p= 0.228). Conclusions: In our series, the status of microscopic margins does not appear to be important for prediction of recurrence in patients affected by GIST. No significant financial relationships to disclose.

10559 Background: Besides mutually exclusive cKIT or PDGFRA mutations, sequential accumulation of other genetic events may be involved in GISTs development and progression, but very few data is still available. Methods: Fresh tissues specimens of GISTs from 10 patients (9 gastric and 1 intestinal) were collected and used for RNA and DNA extraction, labeled and hybridized to HG-U133Plus 2.0 and SNP array 6.0, respectively (Affymetrix). Six patients had exon 9 or exon 11 c-KIT mutation, two PDGFRA mutation, and other two wild-type disease. Gene expression data were quantified by the RMA algorithm, filtered and analysed with supervised techniques (SAM algorithm). Genomic copy number data were analysed with Partek Genomic Suite software against a reference set of 90 Ceu HapMap individuals using a segmentation algorithm with stringent p-value cutoff. Results: Almost all patients exhibited both macroscopic cytogenetic alterations and cryptic microdeletions or amplifications by SNP-array copy number data analysis. The most frequent chromosomal alterations were: 14q complete or partial deletion (7/10), chromosome 19 monosomy (3/10), 22q and 1p deletion (2/10), chromosome 5 trisomy (2/10). The minimal overlapping region ranged from 14q22.3 to 14q32.33, covering a region including 320 genes. The integration of copy number and gene expression data showed that at least 40% of the genes inside the 14q deleted region were significantly downregulated (FDR No significant financial relationships to disclose.