Objective: A3 adenosine receptor (A3AR) is overexpressed in the skin and peripheral blood mononuclear cells of psoriasis patients. We investigated the efficacy/safety of piclidenoson (CF101), an orally bioavailable A3AR agonist that inhibits IL-17 and IL-23 production in keratinocytes, in moderate-to-severe plaque psoriasis. Methods: The randomized, placebo- and active-controlled, double-blind phase 3 COMFORT-1 trial randomized patients (3:3:3:2) to piclidenoson 2 mg BID, piclidenoson 3 mg BID, apremilast 30 mg BID or placebo. At Week 16, patients in the placebo arm were re-randomized (1:1:1) to piclidenoson 2 mg BID, piclidenoson 3 mg BID or apremilast 30 mg BID. The primary end point was the proportion of patients achieving >= 75% improvement in Psoriasis Area and Severity Index (PASI) from baseline (PASI-75) at Week 16 versus placebo. Results: A total of 529 patients were randomized and received >= 1 dose of study medication (safety population). The efficacy analysis population for the primary end point included 426 patients (piclidenoson 2 mg BID, 127; piclidenoson 3 mg BID, 103; apremilast, 118; placebo, 78). Piclidenoson at 2 and 3 mg BID exhibited similar efficacy. The primary end point was met with the 3 mg BID dose: PASI 75 rate of 9.7% versus 2.6% for piclidenoson versus placebo, p = 0.037. The PASI responses with piclidenoson continued to increase throughout the study period in a linear manner. At week 32, analysis in the per-protocol population showed that a greater proportion of patients in the piclidenoson 3 mg BID arm (51/88, 58.0%) achieved improvement from baseline in Psoriasis Disability Index (PDI) compared to apremilast (59/108, 55.1%), and the test for noninferiority trended towards significance (p = 0.072). The safety/tolerability profile of piclidenoson was excellent and superior to apremilast. Conclusions: Piclidenoson demonstrated efficacy responses that increased over time alongside a favourable safety profile. These findings support its continued clinical development as a psoriasis treatment ( identifier: NCT03168256).

Background The Gi protein associated A3 adenosine receptor (A3AR), is over- expressed in inflammatory cells and this high expression is also reflected in the peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory diseases. CF101, a selective agonist with high affinity to the A3AR, is known to induce robust anti-inflammatory effect in experimental animal models of adjuvant, collagen and tropomyosin induced arthritis. The effect is mediated via de-regulation of the NF-kB and the Wnt signal transduction pathways resulting in apoptosis of inflammatory cells. Objectives To evaluate A3AR as a therapeutic target and biological predictive marker in rheumatoid arthritis patients' response to CF101. Methods CF101 administered twice daily to patients with active RA for 12 weeks. A3AR expression levels were measured at baseline. Results CF101 was found to be safe and well tolerated in all preclinical, Phase I and Phase II human clinical studies. CF101 showed significant anti-rheumatic effect in 2 phase II studies as a standalone drug and a direct significant correlation was found between receptor expression at baseline and patients' response to the drug. In a phase II study, patients were included to the trial based on the expression levels of the A3AR mRNA in the PBMCs (A3AR ≥1.5). CF101 results in ACR20 was 48.6%, statistically significantly higher than that of the placebo group (25.0%) at week 12 (P=0.0352) and also showed superiority in ACR50 and ACR70 values vs. placebo Conclusions The A3AR is a promising therapeutic target in rheumatoid arthritis and can be used also as a biological marker to predict patients' response to CF101. This is a unique type of a personalized medicine approach which may pave the way for a safe and efficacious treatment for this patient population. References Fishman P, Bar-Yehuda S, Madi L, Rath-Wolfson L, Ochaion A, et al. (2006) The PI3K-NF-kB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant induced arthritis. Arthritis Research & Therapy, 8:R33. Madi L, Cohn S, Ochaion A, Bar-Yehuda S, Barer F, et al. (2007) Over-expression of A3 Adenosine Receptor in PBMNC of Rheumatoid Arthritis Patients: Involvement of NF-kB in mediating Receptor Level. J. Rheumatology. 34:20-26. van Troostenburg AR, Clark EV, Carey WDH, Warrington SJ, Kerns WD, Cohn I, Silverman MH, Bar-Yehuda S, Fong KLL, Fishman P. (2004) Tolerability, pharmacokinetics, and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men. Int J Clin Pharmacol Ther. 42: 534-542. Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Bar Yehuda S, Fishman P. (2008) Clinical Evidence for Utilization of the A3 Adenosine Receptor as a Target to Treat Rheumatoid Arthritis: Data from a Phase II Clinical Trial. J. Rheumatology. 35:1-7. Ochaion A, Bar-Yehuda S, Cohen S, Barer F, Patoka R, et al. (2009) Fishman. The anti-inflammatory target A3 adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn's disease. Cellular Immunology 258:115–122 Disclosure of Interest S. Cohen Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, Z. Harpaz Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, M. Farbstein Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, S. Fishman Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, F. Barer Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, P. Fishman Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd

Methods: The objectives of this trial are to evaluate the safety and pharmacokinetic (PK) behavior of CF102 in HCC patients. Utilizing a “3+3” design, successive cohorts of patients with advanced HCC were enrolled at CF 102 doses of 1, 5, or 25 mg twice daily, given orally in continuous cycles of 28 days each. Progression to a higher-dose cohort was based on first cycle toxicity. Standard safety and PK assessments were performed; αfetoprotein (AFP) levels were obtained each cycle, and tumor imaging was obtained every other cycle.

Aims CF101 demonstrated a marked anti-inflammatory effect in Phase 2 studies conducted in patients with rheumatoid arthritis and dry eye syndrome. The aim of this study was to evaluate the safety and efficacy of CF101 for the treatment of patients with moderate to severe plaque-type psoriasis.Materials and methods This was a phase 2, multicentre, randomized, double-blind, dose-ranging, placebo-controlled study. Seventy five patients with moderate to severe plaque-type psoriasis were enrolled, randomized and treated with CF101 (1, 2, or 4 mg) or placebo administered orally twice daily for 12 weeks. Safety and change from base line of Psoriasis Area and Severity Index (PASI) score and physician's global assessment (PGA) score over 12 weeks.Results In the 2 mg CF101-treated group, a progressive improvement in the mean change from baseline in the PASI score vs. placebo throughout the study period was observed, with a statistically significant difference on weeks 8 and 12 (P = 0.047; P = 0.031, respectively). In this group, 35.3% of the patients achieved PASI >= 50 response, and 23.5% of the patients achieved a PGA score of 0 or 1. CF101 was safe and well tolerated.Conclusions CF101 was well tolerated and demonstrated clear evidence of efficacy in patients with moderate to severe plaque psoriasis. Received: 21 November 2010; Accepted: 24 March 2011

13082 Background: The A3 adenosine Gi protein-coupled receptor is highly expressed in malignant compared to normal cells. Activating the A3 adenosine receptor (A3AR) with the highly selective non-cytotoxic agonist, CF101 (IB-MECA), inhibit of colon, prostate, melanoma, pancreatic and hepatocellular cancer growth in experimental animal models, via down-regulation of the Wnt and NF-κB signal transduction pathways. Oral CF101 has been shown to inhibit colon, prostate, melanoma, pancreatic and hepatocellular cancer growth in experimental animal models. Methods: A phase II dose-finding, randomized, blinded study of oral CF101 (0.1, 1& 4 mg PO BID), was conducted to define activity and safety in heavily pre-treated metastatic colorectal cancer pts. From 6/1/2003–7/4/2004, 70 pts, median age 62 with measurable colorectal cancer, PS ≤2 were enrolled, 21 pts progressed after irinotecan and 49 pts after both irinotecan and oxaliplatin-based regimens. Results: The median time on treatment was 10.3 weeks. No objective response was observed; however, SD for 8 wks duration was achieved in 24 pts (34%), for 16 weeks in 8 pts (11%) and 2 pts were treated for more than 24 weeks. The median time to treatment progression was 72 days and for overall survival was 254 days without any significant difference among the 3 trial doses [8 survivors till today]. There were no obvious treatment related serious adverse events. Conclusions: The final results of the study show that CF101 is well tolerated and may stabilize disease for at least 2 months in 35% of the pts. The median survival time (8 months) compared with other targeted therapy investigated lately is encouraging. Combining CF101 with chemotherapy may be beneficial in the treatment of metastatic colorectal cancer. No significant financial relationships to disclose.

BACKGROUND. Calcium supplements to the western-style diet may reduce the risk for colorectal neoplasia. Using rectal epithelial proliferation (REP) measurements as a biomarker of response to intervention, the authors evaluated the effects of 1-year calcium supplementation in adenoma patients and its possible interactions with the patients' dietary and lifestyle habits.METHODS. Consenting adenoma patients, without a family history of colorectal neoplasia, were randomly selected to receive 3.75 g calcium carbonate (1.5 g Ca(2+)) daily or to receive no treatment. All had their long-term dietary and lifestyle habits assessed and their REP labeling index (LI) evaluated before and at end of follow-up. The change in LI was compared between groups, and statistical associations were examined between mean nutrient consumption and treatment effect and between lifestyle and treatment effect.RESULTS. Fifty-two adenoma patients (33 treated and 19 untreated) completed intervention and follow-up. There were no significant differences between study groups in age, weight, cigarette smoking, or medication use. The LI decreased in 58% of calcium-intervened patients and in only 26% of nonintervened patients (P = 0.04); the mean LI x 100 (+/- standard deviation ) of the former fell from 5.04 +/- 1.93 to 4.54 +/- 1.58, and rose from 4.32 +/- 1.58 to 4.93 +/- 1.58 in the latter (P = 0.04). A lower fat, a higher carbohydrate, fiber, or fluid intake each interacted with the calcium supplementation to decrease the LI (P = 0.02, 0.001, 0.02, and 0.08, respectively).CONCLUSIONS. Long-term calcium supplements significantly suppressed REP in adenoma patients, and long-term dietary habits contributed to this effect. Patient diet should be assessed when researchers use REP as a biomarker in calcium chemoprevention studies. Study results indicated that relevant dietary counseling may be useful in addition to calcium supplements in persons at increased risk for colorectal neoplasia. (C) 2001 American Cancer Society.

Our aim was to evaluate the role of maternal nutritional habits during the period of gestation and of children subsequent diet in the etiology of pediatric brain tumors. All cases of incident nervous system tumors under age 18, diagnosed between 1984 and 1993 (n = 300) in Israel were identified. Two matched population controls per case were selected (n = 574). Personal interviews, using a semi-quantified three-step food frequency questionnaire, were performed. Univariate analysis showed that increased child consumption of vegetable fat [p trend 0.01; 95% confidence interval (CI) 1.1-3.2], carbohydrates (p trend 0.05; CI 1.0-5.9), and vitamin E (p trend 0.05; CI 1.0-3.3), were significantly associated with brain tumor risk. No associations were found with nitrate, nitrite or vitamin C. A significant positive association with potassium consumption (p trend 0.01; CI 1.1-3.7) was noted during gestation. Results of multivariate analysis showed that the only persisting associations were with vegetable fat (OR = 1.36; CI 1.06-1.73) in the child diet and potassium intake during gestation (OR = 1.44; CI 1.04-1.99). In conclusion, nutritional associations with pediatric brain tumor etiology, remain unsubstantiated.

BACKGROUND. Rectal epithelial proliferation (REP) measurements are used as a biomarker of risk for colorectal neoplasia and response to chemoprevention. The authors evaluated REP in screenees with and without a history of adenoma and its BACKGROUND. Rectal epithelial proliferation (REP) measurements are used as a association with demographic and adenoma characteristics, diet, and other lifestyle habits.METHODS. Long term lifestyle habits were evaluated and proliferation assessed by in vitro bromodeoxyuridine labeling of rectal biopsies in 223 screenees, 132 of whom had adenomas removed > 3 years previously. Analyses included the total population, screenees with a previous history of adenomas and adenoma free screenees separately, and a subgroup of 55 matched adenoma cases and controls.RESULTS. Crypt proliferation measurements were not elevated in screenees with a history of adenomas compared with adenoma free screenees (mean total labeling index [LI] of 4.8% and 4.9%, respectively). This was confirmed by the case-control analysis, in which the LI of the most superficial crypt compartment was lower in the adenoma cases (P = 0.05). Moreover, their total LI correlated negatively with the number of adenomas removed previously (P < 0.01). Proliferation was more frequent in the most superficial crypt compartments of female adenoma free screenees than in female screenees with a history of adenomas (P = 0.02), and in men age > 65 years compared with younger men (P = 0.06). In the total population, negative Spearman rank correlations were found between total LI and long term dietary intake of calcium (correlation coefficient [r] = -0.15; P = 0.02), LI of the two most superficial crypt compartments and intake of fiber (r = -0.18; P = 0.01), water (r = -0.12; P = 0.08), and carbohydrates (not significant). A positive correlation was found between LI of the most superficial crypt compartment and cigarette smoking (r = 0.4; P = 0.02).CONCLUSIONS. REP measurements did not discriminate between screenees with a history of adenomas and adenoma free screenees. Long-term lifestyle habits, gender, and age were associated with REP levels and need to be considered when evaluating human intervention studies. Cancer 1998;83:1319-27. (C) 1998 American Cancer Society.

BACKGROUND: The effect of environmental factors has been demonstrated in the pathogenesis of inflammatory bowel disease (IBD). Nutrition may be one of them. AIM: To investigate the pre-illness diet in patients with recent IBD in comparison with matched population and clinic controls. METHODS: Quantified dietary histories were obtained from 87 patients with recent IBD (54 ulcerative colitis (UC) and 33 Crohn's disease (CD)) and 144 controls. Odds ratios (OR) for IBD were derived for intake levels of various foods. RESULTS: A high sucrose consumption was associated with an increased risk for IBD (OR 2.85 (p = 0.03) against population controls and 5.3 (p = 0.00) against clinic controls). Lactose consumption showed no effect while fructose intake was negatively associated with risk for IBD (NS). Similar trends were noted in UC and CD. A high fat intake was associated with an increased risk for UC; this was particularly marked for animal fat (OR 4.09, p = 0.02) and cholesterol (OR 4.57, p = 0.02). A high intake of fluids (p = 0.04), magnesium (p = 0.04), vitamin C, and fruits (NS) was negatively associated with the risk for IBD, while a positive association was found for retinol (p = 0.01). Most of the findings were similar in UC and CD except for potassium and vegetable consumption which showed a negative association only with risk for CD. CONCLUSIONS: An association was found between pre-illness diet and subsequent development of UC and CD. The effect of dietary components may be primary or modulatory.

Adenomatous polyps are neoplasms that may progress to colorectal cancer. The role of diet and other lifestyle habits in their etiology is now being elucidated. The aim of this study was to evaluate effects of nutritional habits, weight and weight gain, tobacco smoking, and physical activity in adenoma etiology. A quantified dietary history questionnaire was designed to evaluate long-term dietary habits in addition to more recent ones. The study population comprised 196 adenoma patients and matched asymptomatic, screened controls. Statistical analysis used multivariate conditional logistic models, adjusting for total energy intake and physical activity. Odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma associated with highest versus lowest tertiles of mean daily intake were as follows: for energy, OR 3.7 and CI 2.1-6.7; for animal fat, OR 2.4 and CI 1.2-4.7; for tobacco smoking, OR 3.1 and CI 1.1-2.8; and for weight gain, OR 2.2 and CI 1.2-4.1 (P for linear trend for all, < or = 0.01). Significant negative associations were found with intake of total carbohydrates (OR, 0.3; CI, 0.1-0.7) and fluids (OR, 0.4; CI, 0.2-0.8) (P for both < 0.01) as well as for physical activity (OR, 0.6; CI, 0.3-0.9; P = 0.03). Increased risk for adenoma was observed with decreased intake of carotene (OR, 0.6; CI, 0.3-1.0; P = 0.06), vitamin E (OR, 0.6; CI, 0.3-1.0; P = 0.07), and dietary fiber (OR, 0.6; CI, 0.3-1.3; not significant). The OR of interaction between water and dietary fiber was significant (OR, 0.7; CI, 0.6-0.9; P = 0.01), suggesting a synergistic protective effect. Specific dietary and lifestyle habits were identified as independent factors associated with colorectal adenomas; of special interest is the interaction between water and fiber intake. Avoiding these factors might delay or prevent neoplasia.

Background - TPA is marker of proliferation, in contrast to CA-15.3 and beta-2m which are markers of differentiation and tumor bulk. We have compared TPS to CA-15.3 in breast cancer patients.Methods - Serum levels of TPS, CA-15.3 and beta-2 microglobulin (beta-2m) were measured in 120 breast cancer patients and in 59 controls, using ELISA assays.Results - There was a significant difference between patients and controls with respect to the 3 markers. When new patients were compared with patients on long-term follow-up and patients with metastatic disease, a significantly higher TPS level was found in the last group than in new patients and in those on follow-up. Similar pattern was also observed for CA-15.3. For beta-2m the new patients had similar levels to the metastatic patients and both differed significantly from those on long-term follow-up. In metastatic patients TPS was elevated in 85% compared with 64% for CA-15.3, and 67% for beta-2m. Twenty patients from the new and follow-up groups developed metastasis. Although elevated levels of the markers were seen in some patients at diagnosis of the disease, these levels could not predict relapse.Conclusions - TPS measurement may be useful in monitoring the course of the disease and identifying patients who develop metastases in whom CA-15.3 is not elevated. This will enable the response to therapy to be followed.