Daily Bolus Research Articles

A phase I study of the CDK4/6 inhibitor, palbociclib plus 5-fluorouracil (5FU) in patients with advanced solid tumor malignancies (NCT01522989).

2589Background: We demonstrated in mouse xenografts that CDK4/6 inhibition with palbociclib (P) is synergistic with 5FU in suppressing tumor growth. Based on these preclinical data, we initiated a Phase I trial to evaluate the safety and activity of P plus 5FU. Methods: Eligible patients (pts) had advanced, retinoblastoma (Rb)-positive (as demonstrated by IHC) solid tumors with an adequate performance status and intact organ function. The first stage of the study was a dose escalation to identify the recommended phase II dose (RP2D) of P in this combination (n = 21). The second stage is an ongoing schedule optimization, in which the timing of the P and 5FU are varied to identify the most effective sequence, as demonstrated by Ki67 suppression (n = 8 to date). All pts underwent tumor biopsies prior to treatment (tx), after 7 days of P, and again after the 5FU infusion. Results: Six pts were enrolled at a P dose of 50mg orally daily, Days 1-7, and IV 5FU as a 400mg/m2 bolus Day 8, and 2400mg/m2 continuous i...

(647) - Prolonged Administration of Twice Daily Bolus Intravenous Tacrolimus Early after Lung Transplantation

(647) - Prolonged Administration of Twice Daily Bolus Intravenous Tacrolimus Early after Lung Transplantation

OPTIMAL REGIMENS OF THE BASAL-BOLUS INSULIN THERAPY IN ADOLESCENTS WITH TYPE 1 DIABETES MELLITUS

This study was aimed to determine peculiarities in regimens of the pump insulin therapy and to reveal the optimal basal-to-bolus insulin ratio that are necessary for achieving optimal glycemic control in adoles-cents with type 1 diabetes mellitus (T1DM). 82 adolescents at the age of 14–18 with T1DM, using continuous subcutaneous insulin infusion (CSII) from 5 months to 7.5 years were monitored with continuous glucose monitoring (CGM) system «Guar-dian Real Time» or CGM system, built in MiniMed Paradigm Revel System 722 (Medtronic Minimed, USA). Assessing the quality of glycaemic control was based on the level of glycated haemoglobin (HbA1c). The results of CGM were reviewed and average for 3 days performances: total daily dose of insulin, dose of basal and bolus insulin, basal-to-bolus insulin ratio, carbohydrate content of the meal, expressed in BE, carbohydrate ratio, insulin sensitivity factor were determined. The patients were subdivided into 2 groups: group 1 – adolescents with the optimal/suboptimal glycemic control ( n = 55), 2 – adolescents with long-standing poorly controlled T1DM ( n = 27). Average total daily dose of basal insulin (U in a day, U per kg in a day) in adolescents group 1 was significantly higher, com-pared with patients in group 2 ( р = 0.043; р = 0.038 respectively). Patients in group 2 received more car-bohydrates with a meal intake and had higher doses of average total daily bolus insulin. The average ba-sal-to-bolus ratio from group 1 patients was 51/49%, compared with group 2 patients – 45/55% ( р = 0.026). An important condition for achieving optimal glycemic control is a high level of compliance and skills of adolescents. Optimal well-balanced basal-to-bolus insulin ratio in adolescents with T1DM on CSII, which can provide improvements in blood glucose management and reducing the risk of complications of the disease, is 51/49%.

Effect of a stable Angiotensin-(1-7) analogue on progenitor cell recruitment and cardiovascular function post myocardial infarction.

BackgroundAngiotensin‐(1–7) improves cardiac function and remodeling after myocardial infarction (MI). This may involve recruitment of hematopoietic progenitor cells that support angiogenesis. However, angiotensin‐(1–7) is rapidly metabolized in plasma and tissue. The authors investigated in mice the effect of a metabolically stable angiotensin‐(1–7) analogue, cyclic angiotensin‐(1–7), on progenitor cell recruitment and on the heart post MI, when given in the angiogenesis phase of remodeling.Methods and ResultsAngiogenic progenitor cell recruitment was measured by using flow cytometry 24 and 72 hours after a daily bolus injection of cyclic angiotensin‐(1–7) in healthy C57BL/6 mice. Further, mice underwent MI or sham surgery and subsequently received saline or 2 different doses of cyclic angiotensin‐(1–7) for 3 or 9 weeks. Cyclic angiotensin‐(1–7) increased circulating hematopoietic progenitor cells at 24 hours but not 72 hours. Post MI, cyclic angiotensin‐(1–7) diminished cardiomyocyte hypertrophy and reduced myogenic tone, without altering cardiovascular function or cardiac histology at 9 weeks. Importantly, cyclic angiotensin‐(1–7)–treated mice had reduced cardiac capillary density at 3 weeks after MI but not after 9 weeks. Finally, cyclic angiotensin‐(1–7) decreased tube formation by cultured human umbilical vein endothelial cells.ConclusionsOur results suggest that cyclic angiotensin‐(1–7), when given early after MI, recruits progenitor cells but does not lead to improved angiogenesis, most likely because it simultaneously exerts antiangiogenic effect in adult endothelial cells. Apparently, optimal treatment with cyclic angiotensin‐(1–7) depends on the time point of onset of application after MI.

Comparison of efficacy and tolerance of first-line palliative chemotherapy EOX and mDCF regimens in patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors.

135 Background: The aim of the study was to compare efficacy and tolerance of first-line palliative chemotherapy EOX (epirubicin/oxaliplatin/capecitabine) and mDCF (docetaxel/cisplatin/5FU/leucovorin) regimens in patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors. Methods: Each chemotherapy regimen was assigned with 21 patients. Planned treatment consisted of 12 every-two-weeks mDCF cycles (docetaxel 40 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 bolus day 1, 5FU 1000 mg/m2/d days 1 and 2, cisplatin 40 mg/m2 day 3) or 8 every-three-weeks EOX cycles (epirubicin 50mg/m2 day 1, oxaliplatin 130mg/m2 day 1, capecitabine 1250mg/m2/d days 1 to 21). The primary endpoint was overall survival in all patients who commenced at least one chemotherapy cycle. Results: Median progression-free survival was 5.8 months in EOX group and 7.5 months in mDCF group (p=0.11), and median overall survival was 8.5 months and 12.0 months respectively (p=0.219). Due to toxicity, patients in the EOX arm had more frequent reductions of cytostatics doses (42.9% vs 5.0%; p=0.009) as well as delays in the administration of subsequent chemotherapy cycles (81.0% vs 65.0%; p=0.424). Rates of all grade 3 or 4 adverse events were comparable between both arms (76.19% in the EOX vs 70.0% in the mDCF; p=1.000). Toxicities that occurred more frequently in the EOX group compared to mDCF group were: nausea (28.6% vs 5.0%; p=0.093), thromboembolic events (19.0% vs 10%; p=0.663) and grade 3 or 4 neutropenia (71.4% vs 55.0%; p=0.443). Conclusions: In this patients population with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors treatment with mDCF regimen was associated with a statistically non-significant 3.5 month longer median overall survival without increase in toxicity. Updated data will be presented.

Insulin Pump Termination in Adult Patients

Introduction: Insulin pump therapy presents an increasingly used method. Its usage has been steadily increasing within last 40 years and number of studies concerning the insulin pump therapy commencement and various aspects arising in course of the treatment, was presented. But only few studies dealing with the patients after insulin pump treatment termination exist. Furthermore, the majority of these studies are focused on pediatric population. Objectives: to determine, whether the glycemic control changes after insulin pump termination regardless of the type of diabetes or method of treatment withdrawn (pump withdrawn by a physician vs. patient’s wish). To evaluate whether the glycemic control after insulin pump termination differs in type 1 and type 2 diabetic patients and if there are any changes after insulin pump termination due to the method of treatment withdrawn (pump withdrawn by a physician vs. patient’s wish). Methods: The CSII treatment was terminated to a total of 228 patients in 2001 - 2012. 74 patients had sufficient data to analyze four variables: HbA1c, weight, total daily bolus insulin dose, and total daily basal insulin dose. The initial values was derived from data 3-6 months before the treatment withdrawal, other data were collected at time of withdrawal, and at 3, 6, 12 and 24 months following the CSII treatment termination. Total length of follow-up was 2.5 years. Results: There was no significant change in HbA1c: it was 78.5 mmol/mol (interquartil range 69; 95) at time of insulin pump treatment (specifically in the last half year prior to treatment withdrawal) and 81 mmol/mol (68; 93) at time of treatment termination (p=0,365). The median of weight was 81 kg (interquartil range 67; 95) 3-6 months prior to treatment termination and 80 kg (interquartil range 66,8; 97) at time of withdrawal. These changes are also nonsignificant (p=0,963). The only significant change observed was the increase in the total daily bolus insulin dose after the treatment termination - median at time of termination 20 IU/day and after withdrawal 30 IU/day (p=0,001). The dose of basal insulin was not significant (p=0,619). The evaluation of subgroups (type 1 diabetes versus type 2 diabetes and pump withdrawn by a physician versus patient’s wish group) was the same results - e.g. the only significant change was in the dose of bolus insulin. Conclusions: In our study, we were not able to demonstrate any impact of insulin pump treatment termination on the further development of glycemic control of the patients.

Abstract 15120: Nanoparticle-Mediated Delivery of Pitavastatin into Small Pulmonary Arteies by Intravenous Administration Attenuated the Progression of Already Established Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Background: Pulmonary arterial hypertension (PAH) is an intractable disease of small pulmonary artery in which multiple pathogenetic factors are involved. We have previously reported that poly(lactic acid/glycolic acid) (PLGA) nanoparticle (NP)-mediated targeting of pitavastatin into lungs by intratracheal instillation attenuated the development of PAH. In the present study we examined the effects of intravenous treatment with pitavastatin-NPs on the progression of already established PAH induced by monocrotaline (MCT). Methods and Results: Male Sprague-Dawley rats (200 to 230 g) were injected subcutaneously with 60 mg/kg MCT to induce PAH. At day 17 after MCT injection when PAH had been already established, animals were randomly divided into 4 groups, which treated with intravenous daily bolus administration of the following drugs for consecutive 4 days from 17 to 20 days after MCT injection; 1) vehicle, 2) FITC-NPs, 3) pitavastatin alone (1, 3, 10 or 30 mg/kg), or 4) pitavastatin-NPs (containing 1 or 3 mg/kg pitavastatin). Treatment with pitavastatin-NPs, but not with pitavastatin alone attenuated the progression of established PAH (Fig. A) associated with the reduction of inflammation and small pulmonary artery remodeling (stenosis and obstruction of pulmonary arterial branches) (Fig. B). In trace experiments, intravenous administration of FITC-NPs revealed the targeting of FITC-NPs into small pulmonary artery in rats with MCT-induced PAH, but not in normal animals. Importantly, in a separate protocol, treatment with pitavastatin-NPs improved the survival rate at day 35 (30% in pitavastatin-NP group vs. 61% in FITC-NP group, P<0.05 by Kaplan-Meier). Conclusion: A novel NP-mediated targeting of pitavastatin into small pulmonary arteries by intravenous administration attenuated the progression of established PAH and improved survival associated with anti-inflammatory and anti-remodeling effects in a rat model of MCT-induced PAH.

Does Internal Mammary Node Irradiation Have Survival Benefit for Clinical Stage II-III Breast Cancer Patients After Neoadjuvant Chemotherapy?

and each assessment consisted of graduation of RDT severity, and documentation of any treatment interruptions and expenditures related to local care of RDT. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE v4.0). Results: The incidence of grade 3 RDT in groups A, B, C, and D were 0%, 0%, 13%, and 88%, respectively. For HR group, there was a significant difference between the arms C and D (pZ 0.007), regarding grade 3 RDT. For SR group, there was no difference between the arms A and B (p Z 0.69), regarding grade 2 and lower toxicity. The only factors associated with the development of grade 3 RDT were daily use of bolus (p Z 0.0007) and supraclavicular fossa irradiation (p Z 0.016). Mean expenditures with local care in groups A, B + C, and D were $68, $70, and $258, respectively (p < 0.001). For the whole group, three treatment interruptions occurred, all in the HR arms, with no difference regarding the pattern of bolus use (p Z 0.93), A relation between the severity of the RDT after the second week of treatment and the appearance of grade 3 RDT was observed, with daily use of bolus. Conclusions: The use of daily 5 mm bolus is associated to higher incidence of grade 3 RDT. Daily bolus was also associated to higher expenditures with local care related to RDT. Further studies are necessary to evaluate the oncological benefit and cost-effectiveness of tissue-equivalent bolus in PMRT. Author Disclosure: L. Sapienza: None. M.J. Chen: None. K.C. Trigo: None. M.L. Silva: None. D.G. Castro: None. R.C. Fogaroli: None. A.C. Pellizzon: None. M.C. Maia: None.

614TiP - Double-Blind, Placebo-Controlled, Multicenter, Randomized, Phase Ii Study of Nimotuzumab in Combination with Mitomycin, 5-Fluorouracil and Radiation in Immunocompetent Patients with Anal Carcinoma

ABSTRACT Background: Anal carcinoma is an uncommon malignancy associated principally with human papilloma virus. The epidermal growth factor receptor (EGFR) protein expression in this localization is frequent and a low rate of KRAS mutation has been described, as a result, the use of an EGFR inhibitor has been considered to be a promising avenue of investigation. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR with high affinity and specificity. It has shown antitumor activity similar to other anti-EGFR monoclonal antibodies with low rate of adverse events in different clinical settings. There is no clinical data regarding the impact of nimotuzumab in anal carcinoma. Trial design: Immunocompetent patients with histologically confirmed anal carcinoma (stage I-IIIB) received concurrent chemoradiotherapy with Mitomycin (10 mg/m2 IV bolus days 1 and 29) and continuous infusion of 5-FU (1000 mg/m2/d IV days 1-4 and 29-32) concurrently with RT (45-54 Gy) and combination with weekly Nimotuzumab (200 mg) for 12 doses. Treatment with nimotuzumab will be continue monthly up to one year treatment. The trial was designed to evaluate the safety and antitumor effect of nimotuzumab and chemoradiotherapy as primaries end points. Two years progression-free survival (PFS), overall survival (OS), colostomy rate, and over-expression of the EGFR and the correlation with the response rate and survival will be evaluated too. Disclosure: All authors have declared no conflicts of interest.

Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas

Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.

Long-term Follow-up and Pattern of Failure for T1-T2 Glottic Cancer After Definitive Radiation Therapy

To evaluate the impact of radiation therapy (RT) on the long-term outcomes and pattern of failure for T1-2 glottic cancer. This is a single-institution, retrospective study. From January (1997 to 2010), 253 patients with early glottic cancer underwent RT by 2-dimensional or 3-dimensional RT with Co or linear accelerator. Appropriate daily bolus was applied with linear accelerator-based RT to avoid under dosage of the anterior commissure. A total of 253 patients with T1-T2 glottic cancer were treated with definitive RT. The median age was 65 and males made up 87% of the population. T1 was 77% of the population. The median dose and fraction size were 63 and 2.25 Gy, respectively. After a median follow-up of 83 months, the locoregional control (LRC) for the whole cohort was 98%. Specifically, LRCs for T1 (195 patients) and T2 (58 patients) were 99.5% and 91%, respectively. Kaplan-Meier curve shows the 5-year cause-specific survival to be 100%. Single-modality RT provides an excellent and effective treatment for T1-T2 glottic cancer with remarkable functional preservation and 5-year LRC of 98% with negligible long-term toxicity.

Efficacy and tolerability of chemotherapy with modified dose-dense TCF regimen (TCF-dd) in locally advanced or metastatic gastric cancer: final results of a phase II trial

We previously studied a dose-dense TCF (TCF-dd) regimen demonstrating its feasibility and an activity comparable to epirubicin-based chemotherapy and TCF q3w in terms of overall survival and time to progression (TTP). We report here the final results of a phase II study of chemotherapy with a modified TCF-dd regimen in locally advanced or metastatic gastric cancer (MGC). Patients with histologically confirmed measurable MGC, not previously treated for advanced disease, received docetaxel 70mg/m(2) day 1, cisplatin 60mg/m(2) day 1, l-folinic acid 100mg/m(2) days 1 and 2, followed by 5-fluorouracil (5-FU) 400mg/m(2) bolus days 1 and 2, and then 600mg/m(2) as a 22-h continuous infusion days 1 and 2, every 14days, plus pegfilgrastim 6mg on day 3. Patients aged ≥65years received the same schedule with a dose reduction of 30%. Study duration: December 2007-November 2010. Forty-six consecutive patients were enrolled (78% male, 22% female; median age, 66 years, range, 38-76 years; ECOG PS: 0, 48%, 1, 46%). Primary endpoint was overall response rate (ORR). A median of four cycles (range, one to six) was administered. Forty-three patients were evaluated for response (93.5%) and all for toxicity: 3 complete response (CR), 25 partial response (PR), 10 stable disease (SD), and 5 progressive disease (PD) were observed, for an ORR by intention to treat (ITT) of 61% (95% CI 47-75). Median overall survival (OS) was 17.63months (95% CI, 13.67-20.67); median progression-free survival was 8.9months (95% CI, 6.5-13.4). Twenty-one patients (46.0%) were treated at full doses without any delay, thus respecting the dose-dense criterion. Most frequent grade 3-4 toxicities were neutropenia (20%), leukopenia (4%), thrombocytopenia (2%), anemia (2%), febrile neutropenia (6%), asthenia (22%), diarrhea (4%), nausea/vomiting (11%), and hypokalemia (6%). Overall, TCF-dd was shown to be safe. The TCF-dd regimen in locally advanced or MGC is confirmed to be feasible and very active and needs to be further tested in randomized studies.

A Phase 1 Study Of TH-302, An Investigational Hypoxia-Targeted Drug, In Patients With Advanced Leukemias

BackgroundTH-302 is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard designed to be selectively activated in hypoxic conditions. Preclinical data in mice with acute lymphoblastic leukemia (ALL) have demonstrated marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito et al., PLoS One 2011). TH-302 also exhibited specific hypoxia-dependent cytotoxicity when tested against primary ALL and acute myelogenous leukemia (AML) samples in vitro (Benito et al., ASH 2012). Based on these findings, a phase 1 study of TH-302 was designed for advanced leukemias. MethodsEligible patients had ECOG ≤ 3, relapsed/refractory leukemias for which no standard therapy options were available, and acceptable hepato-renal function. A standard 3+3 dose-escalation design was used with 40% dose increments. TH-302 was administered IV over 30-60 min daily, either by 30 min-bolus administration or as a continuous infusion on days 1-5 of a 21-day cycle. The objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of TH-302 with these schedules and to assess preliminary clinical activity of TH-302. ResultsA total of 49 patients with previously treated AML (n=39), ALL (n=9) or CML in blast phase (n=1) received TH-302 at bolus doses of 120 (n=4), 170 (n=4), 240 (n=3), 330 (n=3), 460 (n=20), 550 (n=4) mg/m2 or continuous doses of 330 (n=8) or 460 (n=3) mg/m2. Two of 3 evaluable patients treated with bolus TH-302 (550 mg/m2) experienced DLTs of grade 3 esophagitis; bolus administration MTD was established at 460 mg/m2. Two of 3 patients treated with continuous infusion of TH-302 (460 mg/m2) experienced DLTs of grade 3 mucositis or grade 3 hyperbilirubinemia; continuous administration MTD was established at 330 mg/m2. Thirteen patients received greater than 1 cycle. Generally, a significant rapid cytoreduction was evident early in the cycle, but was not maintained prior to initiation of the next cycle. Two AML patients who received 550 mg/m2 bolus TH-302 had complete resolution of leukemia cutis. One AML patient at 550 mg/m2 bolus TH-302 had a complete response with incomplete platelet recovery (CRp), and one AML patient at 440 mg/m2 bolus TH-302 had a CR. ConclusionsIn patients with advanced leukemias, MTDs were established for daily bolus infusion and 5-day continuous infusion of TH-302 at 460 mg/m2 and 330 mg/m2, respectively. Increased incidence of skin and mucosal toxicity were observed at higher dose levels with both administration schedules. Clinical activity of single-agent TH-302 has been noted with a few objective responses, but the majority of cytoreductions were transient. Disclosures:Konopleva:Threshold Pharmaceuticals: Research Funding. Handisides:Threshold Pharmaceuticals: Employment, Equity Ownership. Kroll:Threshold Pharmaceuticals: Employment, Equity Ownership. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Evaluation of PNC-27-mediated toxicity in an intraperitoneal mouse model of human ovarian cancer

Objectives: PNC-27 is a novel anti-cancer peptide explicitly cytotoxic against cancer cells via formation of trans-membrane pores while sparing normal cells. We sought to determine the effect of PNC-27 on the established ovarian cancer cell line SKOV3-luc-D3 in vitro. Then, utilizing murine nu/nu mouse models, we sought to determine the maximum tolerated dose (MTD) of daily bolus intraperitoneal (IP) injections in healthy mice and finally to determine the toxicity of PNC-27 around the determined MTD using SKOV3-luc-D3 cells in vivo.

Composite efficacy parameters and predictors of hypoglycaemia in basal‐plus insulin therapy—a combined analysis of 713 type 2 diabetic patients

We aimed to identify predictors of hypoglycaemia in patients with poorly controlled type 2 diabetes treated with a single daily bolus of insulin glulisine on top of insulin glargine and oral antidiabetic drugs (basal-plus regimen). We retrospectively analysed four large basal-plus trials including 713 patients (47% female) with type 2 diabetes, mean age of 59.9 ± 9.5 years and diabetes duration of 11 ± 7.0 years. Predictors for symptomatic, severe and nocturnal hypoglycaemia were identified by multivariate logistic regression analyses, calculation of odds ratios (ORs) and Wald 95% confidence intervals (CIs). Mean numbers of hypoglycaemic events per year were 4.64 ± 11.4 (symptomatic < 60 mg/dl), 0.59 ± 2.28 (nocturnal) and 0.03 ± 0.22 (severe). A total of 44.5% of patients reached the composite endpoint of glycated haemoglobin (HbA1c) <7.0% plus no severe hypoglycaemia, and 26.7% reached the composite of HbA1c <7.0% plus no symptomatic hypoglycaemia. Predictors of nocturnal and symptomatic hypoglycaemia were female gender (OR 1.82; 95% CI 1.07-3.11 and OR 1.89; 95% CI 1.31-2.78), diabetes duration >10 versus <5 years (OR 2.61; 95% CI 1.03-6.59 and OR 2.01; 95% CI 1.15-3.51) and higher basal insulin dose (per unit of increase) (OR 1.01; 95% CI 1.00-1.03 and OR 1.01; 95% CI 1.00-1.02). Conversely, a higher body mass index (BMI) (27-30 vs. <27 kg/m(2) and >30 vs. <27 kg/m(2) ) conferred a reduced risk of symptomatic hypoglycaemia with an OR of 0.53 (95% CI 0.31-0.90) and an OR of 0.61 (95% CI 0.39-0.97). Female gender, a long diabetes duration and higher basal insulin dose were predictors of hypoglycaemia, while protection was provided by BMI > 30. These results may help to successfully establish basal-plus insulin regimen in individual patients on their transition from basal-only to basal-bolus treatment.

Intermittent versus continuous central administration of clozapine in DBA/2 mice, improvement in sensory inhibition deficits

Deficient sensory inhibition, the failure to inhibit responses to repeated stimuli, is a hallmark of schizophrenia, and is thought to be related to difficulties with attention and working memory. Sensory inhibition is assessed by comparing the auditory-evoked EEG responses to 2 closely-spaced identical stimuli. Normal individuals show suppressed response to the second stimulus while schizophrenia patients have responses of similar magnitude to both stimuli. This deficit has been linked to polymorphisms in the promoter for the α7 nicotinic receptor gene, resulting in reduced numbers of receptors on hippocampal interneurons. This deficit is modeled in DBA/2 mice which also show a polymorphism in the promoter for the α7 nicotinic receptor gene and reduced numbers of hippocampal α7 receptors. Systemic administration of clozapine, the most efficacious antipsychotic medication, improves sensory inhibition deficits in both schizophrenia patients and DBA/2 mice. We have previously shown that acute intracerebroventricular (ICV) injections of clozapine induced similar improvement in sensory inhibition in DBA/2 mice. Here we demonstrate the efficacy of chronic ICV clozapine administration in improving sensory inhibition in DBA2 mice. Mice received ICV vehicle, 3, 7.5, 15 or 30μg of clozapine, either continuously or as a once-per-day injection. Mice were recorded on the 7th day of drug delivery. Both approaches produced improved sensory inhibition, but the daily bolus injection was effective at a lower dose (3μg/day) than the continuous delivery (15μg/day). The bolus injections also showed significant improvement up to 36h post injection thus suggesting that this approach may be more efficacious.

Prognostic value of baseline 18F-FDG-PET (PET) in anal cancer (AC) patients (pts): A Bologna Multidisciplinary Rectal Cancer Group analysis (BMRCG-AC01).

e15154 Background: The incidence of AC has increased. In locally advanced disease treatment is curative radio-chemotherapy (RCT) followed by brachytherapy boost (BRT) or external beam radiotherapy (EBR). The aim of this analysis is to evaluate prognostic factors in predicting disease recurrence. Methods: We retrospectively evaluated pts with diagnosis of T2-3-4, N-/+ AC. External RT was delivered up to a dose of 4,500 cGy in 25 fr and CT consisted in 5-fluorouracil CI day 1-4 and Mitomicin-C bolus day 1 in the first and fifth weeks of radiotherapy as per Nigroregimen. BRT or EBR were performed at the end of RCT. A PET scan was performed at diagnosis before starting treatment. The standard uptake value (SUV) was determined from the most active tumor site. Results: Between March 2006 and August 2012, 50 pts with AC accessed the BMRCG. In this analysis we considered 29 pts evaluated by PET. The pt characteristics were: 8(27.6%) men, 21(72.4%) women; median age 63 (42-89) years; 17(58.6%) squamous cell carcinoma (scc), 12(41.4%) basaloid carcinoma (bc); 6(20.7%) cT2N0, 5(17.2%) cT3N0, 7(24.1%) cT3N+, 2(6.9%) cT4N0, 9(31.1%) cT4N+. Twenty-six (90%) pts received full-dose standard protocol RCT and subsequent radiotherapy boost. After a median follow-up of 25 months we observed 4 (13.8%) recurrences: 3 local and 1 lung metastasis. No disease-related death occurred. Stage at diagnosis (T2-3N0 vs T3N+T4N+/-) and tumor histotype (scc vs bc) did not relate to DFS (p=0.67 and p=0.86 respectively). ROC analysis identified a SUV cut-off of 12.5 at the baseline PET related to recurrence. In 15(51.7%) pts the baseline SUV was ≤12.5 (low SUV) and in 14 (48.3%) it was &gt;12.5 (high SUV). Pts with high SUV had significantly worse DFS than those with low SUV (p=0.02). Multivariate Cox regression did not confirm any SUV prognostic value (p=0.95). Conclusions: These results suggest that high SUV could predict relapse in AC pts treated with curative RCT. The small number of pts rules out any definitive conclusion; a controlled trial should be conducted to explore the prognostic role of SUV to define good prognosis pts for “tailored” treatment and reduce therapy-related toxicities.

Phase II study of first-line combined chemotherapy bevacizumab with modified RPMI regimen for elderly or frail patients with unresectable or metastatic colorectal cancer (OGSG0802) update analysis.

e14601 Background: The first-line combined chemotherapy RPMI regimen with bevacizumab (Bmab) in AVF2192g tri al were active. According to the results of efficacy and safety, a fluoropyrimidine (FU) + Bmab regimen is regarded as one of treatment options for 1st-line chemotherapy in many guidelines. We planned a phase II study of modified RPMI regimen with Bmab especially for elderly or frail Pts. Methods: Pts with confirmed unresectable/metastatic colorectal cancer without previous chemotherapy, and not suitable for intensive chemotherapy were enrolled. Pts received modified RPMI regimen (5-FU 600 mg/m2 and l-leucovorin 200 mg/m2 bolus day 1, 8, 15) and Bmab 5 mg/kg day 1, 15, q4w) until disease progression or study withdrawal. The primary endpoint was overall response rate (ORR), and the secondary endpoints were PFS, OS and safety. Results: 41 Pts were enrolled from 13 institutions. Pts characteristics were as follows; median age 76 (range 56-90); male/female, 18/23; ECOG performance status 0/1/2, 21/19/1. The ORR, the rate of best response, the disease control rate (CR+PR+SD) were 36.6%, 56.1%, 85.4%, respectively. Median follow-up period was 14.4 months(Updated results will be presented). 28 Pts (68%) had objective progression and a patient (2.4%) died without progression. The median PFS and OS were 9.0 months (95%CI, 7.5–19.6) and 24.0 months (95%CI, 20.1–NR). The incidences of grade 3 or 4 adverse events were: leukopenia (7%), neutropenia (24%), thrombocytopenia (2%), diarrhea (5%), anorexia (10%), fatigue (5%), stomatitis (7%) and hypertension (5%). Grade 3 febrile neutropenia and grade 4 pulmonary embolism was observed in one pt. Five pts (12%) discontinued the treatment due to severe or uncontrollable adverse event. Conclusions: The modified RPMI regimen with Bmab showed promising activity, and was well tolerated for elderly or frail Pts. ORR and the median PFS of this regimen were similar to historical data with FU + Bmab. This regimen may be a good option for patients with poor PS or elderly with advantages of not requiring percutaneous port placement nor compliance or oral agents. Clinical trial information: UMIN000002182.

5FU/LV with or without irinotecan in patients with resected stage II-III rectal cancer: Final analysis of R98 intergroup study.

3542 Background: The goal of the study was to test whether adding Irinotecan to a 5-FU/LV adjuvant regimen improves disease free survival (DFS) or overall survival (OS) in optimally resected stages II-III rectal cancers. Primary end-point was DFS. Methods: Six hundred patients were planned to be randomized between 5-FU/LV (control arm) or 5-FU/LV + irinotecan (experimental arm). As only 357 patients had been included from 03/1999 to 12/2005 (178 in control and 179 in experimental arm), the IDMC recommended to close accrual. The trial was stratified by control arm: Mayo-Clinic regimen (A: LV 20 mg/m², 5-FU 425 mg/m² bolus days (d) 1- 5 reapeted at d29,57,92,127 and 162) or LV5-FU2 regimen (A’: LV 200 mg/m², 5-FU 400 mg/m² bolus and 5-FU 600 mg/m² 22-hours infusion d1-2, q 2 w for 12 cycles). The experimental arm (B) was LV5-FU2 + irinotecan 180 mg/m² d1. Results: All 357 randomized patients were evaluable for efficacy. Patient characteristics were well balanced (median age 62 years, stage II 31 %, stage III 69 %, N0 31 %, 68 % received preoperative radiotherapy, and 80 % had sphincter conservation). With follow-up of 156 months, DFS and OS are not statistically increase (81vs 92 events for DFS in experimental and control arm, hazard ratio (HR)=0.805, p=0.154;63 vs 72 events for OS, HR=0.874, p=0.433). Patients allocated to the experimental arm had more grade 3-4 neutropenia when compared with the LV5FU2 control (33 % vs 16 %, p=0.03), but not when compared with the Mayo Clinic arm (32% vs 36%, p=0.84). Grade 3-4 diarrhea tend to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction p=0.44). Conclusions: In patients with resected stage II-III rectal cancer, adding irinotecan to 5FU/LV led to a non significant increase of DFS and OS. The analysis was planned to have a 60 % power to detect a significant difference with 220 events. With a long term follow up of 8 years only 173 events were observed in our trial. Lack of power and good patient prognosis (thirty one percent of node negative patients) may have impacted the results.

Long-Lasting Effect of Perinatal Exposure to L-tryptophan on Circadian Clock of Primary Cell Lines Established from Male Offspring Born from Mothers Fed on Dietary Protein Restriction

Background & AimsMaternal undernutrition programs metabolic adaptations which are ultimately detrimental to adult. L-tryptophan supplementation was given to manipulate the long-term sequelae of early-life programming by undernutrition and explore whether cultured cells retain circadian clock dysregulation.MethodsMale rat pups from mothers fed on low protein (8%, LP) or control (18%, CP) diet were given, one hour before light off, an oral bolus of L-tryptophan (125 mg/kg) between Day-12 and Day-21 of age. Body weight, food intake, blood glucose along with the capacity of colonization of primary cells from biopsies were measured during the young (45–55 days) and adult (110–130 days) phases. Circadian clock oscillations were re-induced by a serum shock over 30 hours on near-confluent cell monolayers to follow PERIOD1 and CLOCK proteins by Fluorescent Linked ImmunoSorbent Assay (FLISA) and period1 and bmal1 mRNA by RT-PCR. Cell survival in amino acid-free conditions were used to measure circadian expression of MAP-LC3B, MAP-LC3B-FP and Survivin.ResultsTryptophan supplementation did not alter body weight gain nor feeding pattern. By three-way ANOVA of blood glucose, sampling time was found significant during all phases. A significant interaction between daily bolus (Tryptophan, saline) and diets (LP, CP) were found during young (p = 0.0291) and adult (p = 0.0285) phases. In adult phase, the capacity of colonization at seeding of primary cells was twice lower for LP rats. By three-way ANOVA of PERIOD1 perinuclear/nuclear immunoreactivity during young phase, we found a significant effect of diets (p = 0.049), daily bolus (p<0.0001) and synchronizer hours (p = 0.0002). All factors were significantly interacting (p = 0.0148). MAP-LC3B, MAP-LC3B-FP and Survivin were altered according to diets in young phase.ConclusionsSequelae of early-life undernutrition and the effects of L-tryptophan supplementation can be monitored non-invasively by circadian sampling of blood D-glucose and on the expression of PERIOD1 protein in established primary cell lines.