Initial results of screening of nondiabetic organ donors for expression of islet autoantibodies.

CONTEXT: Type 1A diabetes is characterized by a long prodromal phase during which autoantibodies to islet antigens are present. Nevertheless, we lack data on the pancreatic pathology of subjects who are positive for islet autoantibodies (to islet autoantigens GAD65, insulin, and ICA512). OBJECTIVE: In this manuscript, we describe a novel strategy in obtaining pancreata and pancreatic lymph nodes from islet autoantibody-positive organ donors that involves careful coordination among the laboratory and the organ donor provider organization. DESIGN: We developed a rapid screening protocol for islet autoantibodies measurement of organ donors to allow identification of positive subjects before organ harvesting. In this way we were able to obtain pancreata and pancreatic lymph nodes from subjects with and without islet autoimmunity. SETTING: The organ donors used in this study were obtained from the general community. SUBJECTS: The population studied consisted of 112 organ donors (age range 1 month to 86 yr, mean age 39 yr). MAIN OUTCOME MEASURE: The main outcome measure of this study consisted of evaluating the pancreatic histology and identify T cells autoreactive for islet antigens in the pancreatic lymph nodes. RESULTS: To date we have identified three positive subjects and obtained the pancreas for histological evaluation from one of the autoantibody-positive donors who expressed ICA512 autoantibodies. Although this subject did not exhibit insulitis, lymphocytes derived from pancreatic lymph nodes reacted to the islet antigen phogrin. CONCLUSION: In summary, these results indicate that it is possible to screen organ donors in real time for antiislet antibodies, characterize pancreatic histology, and obtain viable T cells for immunological studies.

The combination of raltitrexed (Tomudex) and mitomycin-C in the treatment of advanced colorectal cancer--a phase II study.

AIMS: To investigate the combination of raltitrexed and mitomycin-C as first-line chemotherapy treatment in patients with advanced colorectal cancer. MATERIALS AND METHODS: A phase II study. RESULTS: In total, 22 patients were treated with a combination of raltitrexed 3 mg/m2 every 3 weeks and mitomycin-C 7 mg/m2 every 6 weeks for up to 24 weeks. The study was closed early for safety reasons as there were three unexpected treatment-related deaths. The overall response rate was 20%, and a further 40% achieved stable disease. The median time to progression was 3.9 months and the median overall survival time was 11.6 months. CONCLUSION: Owing to the potential for increased toxicity, the combination of raltitrexed and mitomycin-C cannot be recommended as first-line treatment in patients with advanced colorectal cancer.

Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer.

PURPOSE: Phase II studies have shown that the combination of interferon alfa-2b (IFN) and fluorouracil (5-FU) is active in patients with metastatic colon cancer. This study was designed to investigate whether treatment with the combination of IFN and 5-FU could improve the response rate, duration of response, or survival compared with treatment with 5-FU alone. PATIENTS AND METHODS: Patients with histologically confirmed advanced colorectal cancer were randomized to receive 5-FU 750 mg/m2/d by continuous infusion for 5 consecutive days followed by weekly bolus 5-FU 750 mg/m2 either with or without IFN 10 MU subcutaneously three times weekly. Treatment was continued until disease progression or unacceptable toxicity for up to 12 months. RESULTS: Radiologic response was observed in 26 of 106 assessable patients (25%): 10 of 52 (19%) in the group that received 5-FU plus IFN (all partial responses [PRs]) and 16 of 54 (30%) in the 5-FU-alone group (three complete responses [CRs] and 13 PRs) (P = .21). There was similarly no significant difference between the two groups in progression-free survival (median, 3 months), 1-year survival, or overall survival (median, 8 months). However, patients who received IFN did experience significantly more toxicity in the form of leukopenia (P = .013), lymphopenia (P = .01), depression (P = .014), and alopecia (P = .002), and were significantly more likely to be withdrawn due to adverse events (P = .003). There were four toxic deaths, all of which occurred in patients who had received IFN. CONCLUSION: At the doses and schedules used in this study, IFN affords no benefit to 5-FU in terms of response and survival and significantly increases toxicity for patients with advanced colorectal cancer.

Phase II study of continuous infusion fluorouracil and interferon alfa-2b in the palliation of malignant neuroendocrine tumors.

PURPOSE AND METHODS: Twenty-four patients with rapidly progressive neuroendocrine tumors were treated with a new regimen of continuous infusion fluorouracil for 20 weeks (200 mg/m2/d) together with interferon alfa-2b (5 MU three times per week). Maintenance interferon alfa at the same dose was continued after the initial 20-week period. RESULTS: Of 15 patients with carcinoid tumors, seven (47%) had an objective response, with a median duration of 20.5 months (range, 8.5 to 41), and five (33%) had stabilization of disease for between 3.5 and 42 months. Improvement in symptoms was reported by 10 patients (67%). Three early deaths occurred, all in patients with advanced disease. Of nine patients with neuroendocrine tumors other than carcinoid, three (33%) had an objective response that lasted 2.5 to 24.5 months, and five had disease stabilization for between 2.5 and 16 months. CONCLUSION: These data, particularly in respect to carcinoid tumors, are encouraging, especially since serious complications from treatment were limited. This regimen is not generally toxic, is well tolerated, and offers useful palliation and symptom control in patients with disease that does not respond to simple pharmacologic manipulations.

Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil.

PURPOSE: To investigate and measure the metabolism of colorectal cancer liver metastases using 18F-fluorodeoxyglucose positron emission tomography (FDG PET), before and during the first month of chemotherapy. The findings were compared with tumor outcome conventionally assessed using changes in tumor size. PATIENTS AND METHODS: Patients with colorectal cancer liver metastases were treated with fluorouracil (5FU) as a protracted venous infusion (300 mg/m2/d), with or without interferon-alpha 2b for two 10-week blocks separated by a 2-week break. Before and at 1 to 2 and 4 to 5 weeks on treatment, FDG PET scans were performed. Patients fasted, were injected intravenously with FDG (50 to 100 MBq), and scanned using a large-area positron camera; the image data was processed such that regions of interest could be identified. The results were expressed as a ratio of FDG uptake in the tumor and normal liver (T:L) or as a semiquantitative standardized uptake value (SUV). These measures were compared with the tumor dimensions measured on a computed tomographic (CT) scan performed at 12 weeks from commencement of chemotherapy. RESULTS: Twenty patients were studied; however, two did not have assessable liver metastases. Objective partial responses were observed in 11 of 18 patients. A total of 27 metastatic lesions were assessable. Pretreatment T:L ratios and SUVs did not correlate with tumor response, although response was associated with lower 1- to 2-week (1.84 v 2.17; t=2.667; P < .02) and 4- to 5-week (1.36 v 2.28; t=5.02; P < .001) T:L ratios, and 4- to 5-week (3.57 v 4.95; t=2.492; P < .05) SUVs. Expressed as a percent of the baseline values of the T:L ratio, responding lesions had a greater reduction in metabolism (67% v 99%; t=7.53; P < .001). The 4- to 5-week T:L ratio was able to discriminate response from nonresponse both in a lesion-by-lesion and overall patient response assessment (sensitivity 100%; specificity 90% and 75%, respectively). CONCLUSION: Positron emission tomography used to evaluate the uptake of FDG in tumors yields data that correlate with the antitumor effect of chemotherapy in patients with liver metastases from colorectal cancer.

ZD1694: A novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. Tomudex Colorectal Study Group.

PURPOSE: Tomudex (ZD1694; Zeneca Ltd, Macclesfield, United Kingdom) appears to have a favorable toxicity profile (defined in phase I studies) and antitumor activity in a broad range of epithelial tumors. We report here the results of a large phase II study of Tomudex in advanced colorectal cancer (CRC). PATIENTS AND METHODS: One hundred seventy-seven patients were entered onto the study between October 1992 and September 1993. Patients were required to have advanced CRC without prior chemotherapy (adjuvant chemotherapy was permissible) and at least one measurable lesion. Tomudex (ZD1694) was administered at a dose of 3 mg/m2 intravenously once every 3 weeks in the absence of toxicity or disease progression. Patients were assessed for objective response, progression, and survival. RESULTS: Of 177 patients entered onto the study, 5% had received prior adjuvant chemotherapy and 83% had liver metastases. Objective responses were seen in 26% of patients (95% confidence interval, 19% to 33%; four complete responses [CRs] and 41 partial responses [PRs]) while median time to progression was 4.2 months and median survival 9.6 months. All sites were audited, and responses were reviewed by an independent panel. Common toxicities included mild reversible transaminitis, nausea and vomiting, and asthenia or flu-like symptoms, and World Health Organization (WHO) grade 3 and 4 leukopenia and diarrhea were seen in 6% and 9.8% of patients, respectively. Stomatitis and alopecia were common. CONCLUSION: In this large multicenter phase II study of patients with advanced CRC, interesting activity was seen (objective response rate, 26%). In addition, Tomudex has an acceptable toxicity profile and a convenient dosing schedule (single intravenous injection every 3 weeks) and thus appears to offer real potential as a novel agent for the treatment of patients with advanced CRC.

Measurement of plasma 5-fluorouracil by high-performance liquid chromatography with comparison of results to tissue drug levels observed using in vivo 19F magnetic resonance spectroscopy in patients on a protracted venous infusion with or without interferon-alpha.

PURPOSE: To measure plasma 5-fluorouracil (5-FU) levels using high-performance liquid chromatography (HPLC) and compare the findings to the tissue metabolism of 5-FU evaluated using 19F magnetic resonance spectroscopy (MRS), during a protracted venous infusion (PVI) with or without interferon-alpha. METHODS: Patients receiving PVI 5-FU (300 mg/m2/day) with or without interferon-alpha (5 x 10(6) units 3 times per week), had 2 weekly plasma 5-FU levels evaluated using reverse-phase ion-pairing HPLC. These samples were drawn just prior to the patient undergoing MRS using a 1.5T Siemens Magnetom whole body magnetic resonance system with a 16 cm surface coil placed over normal liver or metastatic tumour. Semi-quantitated MRS values were compared with the plasma 5-FU levels using linear regression analysis. Data were available from patients given interferon-alpha with PVI 5-FU from day 1 or at the point of 5-FU refractory disease. RESULTS: A total of 30 patients were studied. Plasma 5-FU concentrations while on a protracted venous infusion varied from <25 ng/ml (0.192 mu M) to 25,000 ng/ml (192 mu M). A high plasma 5-FU concentration was associated with an increase in patient toxicity. Patients given interferon-alpha with 5-FU had higher median plasma 5-FU levels higher than patients on 5-FU alone (6138 vs. 218 ng/ml; p = 0.03). There was no correlation between the plasma 5-FU concentration and tumour response. A comparison of the plasma 5-FU data to the MRS studies in normal liver revealed a positive correlation between plasma 5-FU and liver catabolite signal (r = 0.68; p = 0.016) but a negative correlation with the log plasma 5-FU concentration and 5-FU liver signal (r = -0.63; p = 0.022). The patients experiencing toxicity, in addition to having a higher plasma 5-FU concentration did not exhibit a liver 5-FU signal, while the reverse was true for those having no toxicity. CONCLUSIONS: Plasma 5-FU levels may show greater interpatient variation when given as a protracted venous infusion. Levels of 5-FU correlated with treatment toxicity but not with anti-tumour activity. The addition of interferon-alpha to 5-FU increases plasma 5-FU levels. MRS findings suggest patients with low plasma 5-FU levels have higher 5-FU levels in normal liver tissue than in those with higher plasma levels.