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The primary tumor side is emerging as a prognostic factor for patients with liver metastatic colorectal cancer (mCRC). In a combined analysis of data from 2 randomized studies, the addition of selective internal radiation therapy to first-line chemotherapy in patients with mCRC was associated with statistically and clinically significant overall survival gains for patients with a right-sided primary tumor. Background: The primary tumor side is emerging as a major prognostic factor for patients with metastatic colorectal cancer (mCRC). We examined the survival data from 2 randomized studies to determine whether the outcomes differ between patients with mCRC with right-sided primary (RSP) tumors and those with left-sided primary (LSP) tumors after selective internal radiation therapy (SIRT) plus mFOLFOX6 (folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) chemotherapy, versus chemotherapy alone. Patients and Methods: Separate and combined analyses were performed on the data from the SIRFLOX and FOXFIRE global trials, which compared chemotherapy plus SIRT with chemotherapy alone for patients with mCRC liver metastases. The primary tumor side data were prospectively collected. The principal outcome measure was overall survival (OS) stratified by treatment and primary tumor side. Results: In the combined analysis of all 739 patients enrolled, SIRT had no effect on OS (median OS, 24.3 vs. 24.6 months; hazard ratio [HR], 1.021; P = .810). For the 179 patients (24.2%) with a RSP tumor, OS was improved with the addition of SIRT (median, 22.0 vs. 17.1 months HR, 0.641; P = .008). The addition of SIRT was not associated with a significant difference in OS among the 540 patients with a LSP tumor (median, 24.6 vs. 26.6 months; HR, 1.120; P = .264). A test of treatment interaction by primary tumor side was statistically significant for RSP and SIRT (P = .002). Conclusion: The addition of SIRT for patients with RSP tumors, but not for those with LSP tumors, was associated with a statistically and clinically significant OS gain. (C) 2018 Elsevier Inc. All rights reserved.

BACKGROUND Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting. METHODS We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines. RESULTS Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P

This observational study was conducted to document the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical conditions.ML20431 was a prospective, multicenter, non-interventional, observational study. It was designed to answer five research questions relating to safety, dosage and administration, and discontinuation from capecitabine-based adjuvant therapy. Patients were required to have R0 resected stage III colon cancer and have started treatment with capecitabine-based adjuvant therapy based on a decision by the investigator. Patients were followed over an observation period of ≤6 months after initiation of therapy. Investigators were required to complete the study case report form at study entry, each treatment cycle, and at the final examination.A total of 1485 patients were included in the study, and 1481 patients were treated with capecitabine and formed the analysis population. Most patients had colon cancer (78.3%), followed by rectal cancer (16.4%). Most patients had stage III disease (69.3%); the remaining patients had stage II disease (30.7%). The most common all-grade adverse reactions were hand-foot syndrome (46.9%), diarrhea (34.4%), and hemoglobin decreases (31.5%). Grade 3/4 adverse reactions were infrequent (4%). Serious adverse events were reported in 96 patients (6.5%). Six or more cycles of treatment were completed by 77.9% of patients. Approximately two-thirds of patients (67.3%) received capecitabine monotherapy and the remainder (32.7%) received capecitabine in combination with ≥1 drugs, most commonly oxaliplatin (460 cases). Discontinuation of capecitabine was documented in 344 patients (23.2%).no efficacy data were collected; the questionnaires for patients' expectations and satisfaction were not formally validated; and a few patients (1.5%) had some retrospective data.The safety profile of capecitabine-based adjuvant therapy in a broad patient population with colon cancer is similar to that previously documented in phase III clinical trials.

Dipeptidyl peptidase IV (DP IV, CD26), known as an activation marker of T lymphocytes, is a proline-specific protease thought to be involved in the regulation of the immune response. The physiological role of dipeptidyl peptidase IV in the immune system and the molecular events of lymphocyte activation mediated by this enzyme are only partly established. Former results suggested the occurrence of different molecular forms of DP IV in distinct human sources. As yet it has been unknown whether DP IV from human hematopoetic cells also appears in different forms and whether similar structural modifications are involved in functional processes of the regulation of the immune response. Here we describe that lymphocytic DP IV/CD26 occurs in various molecular forms and that some of them are associated with the activation process. In cell lysates of mitogen-activated lymphocytes at least 5 enzymatically active DP IV forms and up to 11 immunoreactive molecular forms of this enzyme with isoelectric points between pH 3.5 and 5.9 were discernible. Corresponding analyses of soluble and membrane cell fractions of human lymphocytes showed significant differences in the staining pattern of molecular DP IV structures. After mitogenic stimulation a special molecular form of DP IV arises in the membrane, which was originated either from the soluble part of the cell (translocation) or represents a new synthesized form. Particularly, changes of molecular DP IV forms after mitogenic stimulation strongly suggest that special forms/epitopes of this enzyme are directly involved in the process of lymphocyte activation and growth. Importantly, different monoclonal DP IV antibodies partly define different molecular forms of DP IV. Moreover, the pattern of immunostaining and enzymatic staining (Gly-Pro-β-methoxynaphtylamide) also reveals drastic differences. These data strongly suggest a direct relationship between the expression/recognition of special DP IV epitopes and the contradictory functional effects of monoclonal DP IV antibodies found by us and other groups.

The Protein disulphide-isomerase (PDI, EC 5.3.4.1, Thiol-proteindisulphide oxidoreductase, EC 1.8.4.2) is thought to regulate the sulfhydryl status of cells and to catalyze thiol/disulphide exchange reactions involved in the post-translational processing of disulphide containing secretory proteins. The aim of the present investigations was to study the possible function of this enzyme in differentiation of B lymphocytes and immunoglobulin synthesis. Non-adherent human mononuclear cells or purified T cells were cultured in presence and absence of Pokeweed mitogen over 3, 5 and 7 days. Monoclonal antibodies and a rabbit polyclonal antiserum specific for human liver PDI were produced to determine the concentration of PDI by an ELISA technique and cytoplasmic immunofluorescence. After PWM stimulation, both, the cellular content of PDI as well as that of immunoglobulin, particularly IgM, have been found to be induced in a time dependent manner with a 2-3 fold increase in comparison to unstimulated cells. The specific induction of PDI in human B lymphocytes was also confirmed in Western blotting. Our findings suggest that PDI plays a critical role in the final stages of B cell differentiation and immunoglobulin synthesis by activated B cells and plasma cells, respectively.

Purpose To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin. Patients and Methods This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor–expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m2 day 1 followed by 250 mg/m2 weekly) plus irinotecan (350 mg/m2 every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL). Results Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P ≤ .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms. Conclusion Cetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.

3509 Background Treatment with capecitabine (XELODA), a tumor-activated oral fluoropyrimidine, led to significantly superior response rates and improved safety over bolus 5-FU/LV in 1st-line metast...