Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child–Pugh B; CPB) in a phase I/II clinical study. This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to twice a day (BID) namodenoson (25 mg; n = 50) or placebo (n = 28). The primary endpoint (overall survival [OS]) was not met. Median OS was 4.1/4.3 months for namodenoson/placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI] 0.49–1.38; p = 0.46). Pre-planned subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed a nonsignificant improvement in OS/progression-free survival (PFS). OS: 6.9 versus 4.3 months; HR, 0.81; 95% CI: 0.45–1.43, p = 0.46. PFS: 3.5 versus 1.9 months; HR, 0.89; 95% CI: 0.51–1.55, p = 0.67 (log-rank test). The difference in 12-month OS was significant (44% versus 18%, p = 0.028). Response rates were determined in patients for whom ≥ 1 assessment post-baseline was available (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3/34 (8.8%) and 0/21 (0%) patients, respectively. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported; no patients withdrew due to toxicity. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in HCC CPB.

Pancreatic ductal adenocarcinoma (PDAC), which is notorious for its aggressiveness and poor prognosis, remains an area of great unmet medical need, with a 5-year survival rate of 10% - the lowest of all solid tumours. At diagnosis, only 20% of patients have resectable pancreatic cancer (RPC) or borderline RPC (BRPC) disease, while 80% of patients have unresectable tumours that are locally advanced pancreatic cancer (LAPC) or have distant metastases. Nearly 60% of patients who undergo upfront surgery for RPC are unable to receive adequate adjuvant chemotherapy (CHT) because of postoperative complications and early cancer recurrence. An important paradigm shift to achieve better outcomes has been the sequence of therapy, with neoadjuvant CHT preceding surgery. Three surgical stages have emerged for the preoperative assessment of nonmetastatic pancreatic cancers: RPC, BRPC, and LAPC. The main goal of neoadjuvant treatment (NAT) is to improve postoperative outcomes through enhanced selection of candidates for curative-intent surgery by identifying patients with aggressive or metastatic disease during initial CHT, reducing tumour volume before surgery to improve the rate of margin-negative resection (R0 resection, a microscopic margin-negative resection), reducing the rate of positive lymph node occurrence at surgery, providing early treatment of occult micrometastatic disease, and assessing tumour chemosensitivity and tolerance to treatment as potential surgical criteria. In this editorial, we summarize evidence concerning NAT of PDAC, providing insights into future practice and study design. Future research is needed to establish predictive biomarkers, measures of therapeutic response, and multidisciplinary strategies to improve patient-centered outcomes.

The roles of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9) in monitoring the patient response to chemotherapy for metastatic colorectal cancer (mCRC) are not clearly defined, and inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII), have been sparsely investigated for this purpose. To aim of this study was to evaluate the relationship between the kinetics of CEA, CA19-9, NLR, LMR, PLR and SII in serum and patient response to chemotherapy estimated by computed tomography (CT) in patients with unresectable mCRC. Patients with mCRC treated with a 1^st-line and 2^nd-line chemotherapy underwent at least 3 whole-body spiral CT scans during response monitoring according to the Response Evaluation Criteria in Solid Tumour 1.1 (RECIST 1.1), and simultaneous determination of CEA, CA19-9, neutrophil, lymphocyte, platelet and monocyte levels was performed. The kinetics of changes in the tumour markers and inflammatory indices were calculated as the percentage change from baseline or nadir, while receiver operating characteristic curves were drawn to select the thresholds to define patients with progressive or responsive disease with the highest sensitivity (Se) and specificity (Sp). The correlation of tumour marker kinetics with inflammatory index changes and RECIST response was determined by univariate and multivariate logistic regression analysis and the clinical utility index (CUI). A total of 102 patients with mCRC treated with chemotherapy were included. Progressive disease (PD), defined as a CEA increase of 25.52%, resulted in an Se of 80.3%, an Sp of 84%, a good CUI negative [CUI (Ve-)] value of 0.75 and a good fraction correct (FC) value of 81.2; at a CEA cut-off of -60.85% with an Se of 100% and an Sp of 35.7% for PD, CT could be avoided in 25.49% of patients. The 21.49% CA19-9 cut-off for PD had an Se of 66.5%, an Sp of 87.4%, an acceptable CUI (Ve-) value of 0.65 and an acceptable FC value of 75. An NLR increase of 11.5% for PD had an Se of 67% and an Sp of 66%; a PLR increase of 5.9% had an Se of 53% and an Sp of 69%; an SII increase above -6.04% had an Se of 72% and an Sp of 63%; and all had acceptable CUI (Ve-) values at 0.55. In the univariate logistic regression analysis, CEA (P < 0.001), CA19-9 (P < 0.05), NLR (P < 0.05), PLR (P < 0.05) and SII (P < 0.05) were important predictors of tumour progression, but in the multivariate logistic regression analysis, CEA was the only independent predictor of PD (P < 0.05). CEA is a useful marker for monitoring the chemotherapy response of patients with unresectable mCRC and could replace a quarter of CT examinations. CA19-9 has poorer diagnostic characteristics than CEA but could be useful in some clinical circumstances, particularly when CEA is not increased. Dynamic changes in the inflammatory indices NLR, PLR and SII could be promising for further investigation as markers of the chemotherapy response.

Background/Aims: To evaluate the side effects of two antiplatelet agents - ticagrelor and eptifibatide - in mice with experimentally-induced inflammatory bowel disease. Methods and Material: This study was designed as a controlled, animal, drug safety investigation. C57Bl/6 mice were used to establish the ulcerative colitis model by exposure to dextran sulfate sodium (DSS), and divided into three experimental groups: eptifibatide-treated (150 µg/day intraperitoneally; n = 10), ticagrelol-treated (1 mg/day via gastric tube; n = 10), and DSS-control (plain drinking water; n = 10). An unmodeled non-DSS group served as the experimental control. Complete blood count was taken for all mice at baseline (day 0, treatment initiation) and after four days of treatment. On day 4, all animals were sacrificed for autopsy. The primary outcome measure was bleeding, and the secondary outcomes were change in platelet count, hemoglobin level, and hematocrit level. Results: Neither ticagrelor nor eptifibatide treatment produced a significant effect on DSS colitis mice for the safety parameters measured. Platelet count and hemoglobin and hematocrit levels were statistically similar between the three DSS groups and the non-DSS control group (P > 0.05). Autopsy found no evidence of recent bleeding in liver, spleen, central nervous system or serous cavities. Conclusion: The antiplatelet agents ticagrelor and eptifibatide were safe in DSS colitis mice, suggesting their potential in humans suffering from ulcerative colitis, and supporting future safety studies.

Background/Aim. We designed and conducted this study due to the fact that results of the previous studies about seroreactivity to low-molecular-weight Helicobacter pylori antigens, cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA) in patients with gastric cancer and peptic ulcer were conflicting. Methods. The Western blot test was performed in 123 patients, 31 with gastric cancer, 31 with duodenal ulcer, 31 with gastric ulcer, 30 with gastritis and functional dyspepsia in order to determine IgG antibodies to H. pylori antigens (CagA, VacA, Heat shock protein 60kDa, Urease B 66 kDa, Flagellin 55kDa, 50kDa, 30 kDa, Urease A 26 kDa, 24 kDa). In this study we analyzed: seroreactivity to H. pylori antigens between group with functional dyspepsia and others; between grades of different histopathological parameters of inflammation of antral and corporal mucosa and between antrum-predominant gastritis and corpus-predominant gastritis + pangastritis groups. Results. It was shown that seropositivity to 50 kDa antigen could be used as a biomarker for functional dyspepsia, seropositivity to 30 kDa antigen for antrum-predominant gastritis and H. pylori colonization in the antrum, to UreaseA26 kDa antigen for pangastritis and corpus-predominant gastritis and degree of inflammation in the corpus. Seropositivity to VacA was the biomarker for gastric cancer and peptic ulcer taken together and inflammation of antral mucosa. Seropositivity to CagA was associated with more intensive inflammation of antral and corporal mucosa, Urease B66 kDa with inflammation of corpus mucosa, but neither of them with specific outcome of H. pylori infection and topographic distribution of gastric inflammation. Conclusion. Serum IgG antibodies to H. pylori antigens 50kDa, and VacA may represent useful biomarkers for the specific outcome of H. pylori infection, while serum antibodies to 30 kDa and UreaseA26 kDa antigens might be used as specific biomarkers for different topographic distribution of inflammation in gastric mucosa.

10018 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major problem after oxaliplatin treatment. Calmangafodipir (CaM) has shown promising activities in model systems in preventing oxaliplatin-induced adverse effects. In a dose-escalating phase I study including 11 patients, doses up to 10 µmol/kg were well tolerated and had promising preventive effects on CIPN (Glimelius, MASCC 2015). A randomized placebo-controlled multicenter phase II study (NCT 01619423) assessed safety and efficacy of CaM in ameliorating CIPN. Methods: The PLIANT study included 173 mCRC patients treated with the FOLFOX-6 regimen (oxaliplatin 85 mg/m², calciumfolinate 200 mg/m², 5FU bolus 400 mg/m², 5FU infusion 2400 mg/m²) every fortnight either in first or second-line. Ten minutes prior to each chemotherapy cycle CaM 2 and 5 (initially 10) µmol/kg or placebo was given intravenously during 5 minutes. The primary endpoint was neurotoxicity according to the Oxaliplatin Sanofi Specific Scale (OSSS) each cycle up to cycle 8. Secondary endpoints included the patient reported outcomes Cold Allodynia Test (CAT) and the Leonard Scale (LS) at end-of-treatment (EOT) and during follow-up (FU) every 3 month (mo), tumor evaluations after 4 and 8 cycles and overall survival (OS). Results: CaM was well tolerated. CIPN according to OSSS was clearly less in patients treated with 5 µmol/kg after the 3^rd up to the 8^th cycle (OR (90%CI) 0.57(1.13), p=0.15). CaM had a dose-dependent and significant effect on persistent CIPN measured as mean sensory score on the LS at 3 and 6 mo FU. See table for further details († p<0.1, * p<0.05, **p=0.01 vs. placebo). Conclusions: The activity of the chemoprotector CaM is promising in preventing acute and persistent CIPN without any detectable negative influence on the antitumor activity of an oxaliplatin-5FU combination in patients with mCRC. A phase III trial using the 5 µmol/kg dose will be initiated. Clinical trial information: NCT 01619423.