Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group

PURPOSE: To investigate if double modulation of fluorouracil (5-FU) with leucovorin (folinic acid [FA]) and interferon alfa-2b (IFN 2b) improves responses and survival in comparison to single modulation of 5-FU with FA. PATIENTS AND METHODS: One hundred six patients with histologically confirmed advanced colorectal cancer, measurable disease, and without previous chemotherapy were prospectively randomized into two groups. Patients in group A received 5-FU 450 mg/m2 as an intravenous bolus in the midinfusion of FA weekly. FA was given at a dose of 200 mg/m2 in 500 mL 0.9% normal saline solution in 2-hour infusion. Patients in group B received exactly the same regimen plus IFN 2b 5 million units subcutaneously three times weekly. RESULTS: All patients were well balanced in both groups regarding age, sex, performance status, number, and site of metastasis. One hundred two patients were assessable. All patients have died. There was no difference in response between the two groups (7.8% v 9.8%). Median survival was 10.1 months in group A, and 7.2 months in group B (P = .00189). Median time to progression was 8.4 and 5.2 months, respectively (P = .00196). Overall, better performance status and older age had a positive impact on survival. Toxicity was the most important and catastrophic aspect of this study. Patients who received IFN 2b had significantly worse anemia, neutropenia, diarrhea, anorexia, weight loss, flu-like syndrome, and psychological reactions. CONCLUSION: Based on this final analysis, the addition of IFN 2b to the combination of 5-FU and FA enhances toxicity and contributes to decreased survival.     

Insulin-like growth factor-I and binding protein-3 in relation to childhood leukaemia

The aetiology of most cases of childhood leukaemia remains unknown, but several studies have indicated that increased birthweight and height are risk factors for the disease. Since insulin-like growth factor-I (IGF-I) mediates the effect of growth hormone and has been positively associated with prostate cancer, we have evaluated the role of this hormone and its principal binding protein, IGFBP-3, in the aetiology of childhood leukaemia. Incident cases of childhood leukaemia from those recorded by a national network of childhood oncologists were enrolled in our study. Controls were children hospitalised for acute conditions of no more than moderate severity with matching for gender, age and maternal place of residence. Blood measurements of IGF-I and IGFBP-3 were undertaken using commercially available radioimmunoassays. Serum IGF-I values decreased by about 1.7% per month, and the rate of decline was higher, though not significantly so, among cases (2.1% per month) than among controls (1.4%). There was no significant association between IGF-I and the likelihood of childhood leukaemia, but an increment of 1 microg/ml of IGFBP-3 was associated with a substantial and statistically significant reduction of childhood leukaemia by 28% (95% confidence interval 7% to 45%). Because IGFBP-3 is essentially a binding protein, we interpret our findings as indicating that bioavailable IGF-I may play an important role in the aetiology of childhood leukaemia. The much smaller quantities and the inherent instability of IGF-I in the blood in comparison to those of IGFBP-3 are likely to hinder documentation of an underlying positive association of IGF-I with the disease.     

Long-term survival data and prognostic factors of a complete response to chemotherapy in patients with head and neck cancer treated with platinum-based induction chemotherapy: a Hellenic Co-operative oncology Group study

Sudden infant death syndrome (SIDS) is the most common cause of postneonatal infant death in developed countries. The causes of SIDS remain unknown. The principal hypothesis appears abnormality of cardiorespiratory control, sleep-wake regulation. Also in our personal date the autopsy have not been of sufficient specificity and sensitivity to explain the disease.     

Radiation and concurrent carboplatin administration in locally advanced head and neck cancer. A Hellenic Cooperative Oncology Group Study

We report our first experience with a laparoscopic treatment of congenital choledochal cysts involving the total cyst resection and the reconstruction of the biliary and gastrointestinal tracts through a transmesocolic hepatic-jejunal Roux-en-Y loop anastomosis. The procedure was carried out in a 14-kg 6-year-old girl with a congenital choledochal cyst of the first type, according to the Alonso-Lej classification. The cyst was divided using a Multifire EndoGIA 30 stapler. Hepatic-jejunal and jejunojejunal anastomoses were made with 4.0 chrome catgut interrupted sutures. Intestinal recanalization occurred on the 2nd postoperative day and the postoperative course was uneventful. The laparoscopic approach affords several advantages: excellent intraoperative visualization of tiny structures and, therefore, great surgical accuracy; early resumption of peristalsis; no postoperative pain; no laparocele; prevention of adhesions; excellent esthetics; and quicker resumption of school and sports activities.     

Sex differences in seasonal variations in P300

Previous reports of seasonal variations in P300 were based on cross-sectional observations of subjects tested at different times of the year. In this study, we tested three groups of subjects in each of two seasons: winter and spring, spring and summer, and summer and winter. We found winter or spring maxima in auditory and visual P300 and visual slow wave. This pattern of results, with the amplitude of P300 being inversely related to the amount of sunlight in a season, supports the hypothesis that the allocation of processing resources varies across the seasons. Our results also suggest a trend for an increased sensitivity of women, as compared with men, to seasonal influences on P300. Although our findings do not provide strong evidence that P300 varies systematically as a function of season, seasonal factors appear to affect cognitive processing (as indexed by P300) differentially in men and women.     

Performance evaluation of PCA-based spike sorting algorithms

Deciphering the electrical activity of individual neurons from multi-unit noisy recordings is critical for understanding complex neural systems. A widely used spike sorting algorithm is being evaluated for single-electrode nerve trunk recordings. The algorithm is based on principal component analysis (PCA) for spike feature extraction. In the neuroscience literature it is generally assumed that the use of the first two or most commonly three principal components is sufficient. We estimate the optimum PCA-based feature space by evaluating the algorithm's performance on simulated series of action potentials. A number of modifications are made to the open source nev2lkit software to enable systematic investigation of the parameter space. We introduce a new metric to define clustering error considering over-clustering more favorable than under-clustering as proposed by experimentalists for our data. Both the program patch and the metric are available online. Correlated and white Gaussian noise processes are superimposed to account for biological and artificial jitter in the recordings. We report that the employment of more than three principal components is in general beneficial for all noise cases considered. Finally, we apply our results to experimental data and verify that the sorting process with four principal components is in agreement with a panel of electrophysiology experts.     

In quest of the missing neuron: spike sorting based on dominant-sets clustering

Spike sorting algorithms aim at decomposing complex extracellular signals to independent events from single neurons in the electrode's vicinity. The decision about the actual number of active neurons is still an open issue, with sparsely firing neurons and background activity the most influencing factors. We introduce a graph-theoretical algorithmic procedure that successfully resolves this issue. Dimensionality reduction coupled with a modern, efficient and progressively executable clustering routine proved to achieve higher performance standards than popular spike sorting methods. Our method is validated extensively using simulated data for different levels of SNR.     

Treatment of renal cell carcinoma with escalating doses of alpha-interferon

Forty-one patients with advanced renal cell cancer started treatment with recombinant alpha-interferon intramuscularly, beginning at a dose of 5 x 10(6) U x 3/week, progressively increasing doses every week, from 5 x 10(6) U x 3/week to 10 x 10(6) U x 3/week, to the highest dose of 15 x 10(6) U x 3/week. No complete response was achieved, partial response was achieved in 6 (13%) patients with a median duration of 45.2 (13-134) weeks. The majority of side effects from interferon treatment evaluated according to WHO classification were seen during the first 2 months and they were fever (after interferon administration) in 95% patients, chills (51%), flu like syndrome (65%), fatigue (87%), anorexia (80%), worsening in performance status (56%), nausea and vomiting (19%), weight loss (> 10% during therapy) (26%), leukopenia (14%), anemia (75%), neurological symptoms (43%), psychological symptoms (19%) and dyspnea (9%). The results are similar to other studies and toxicity was only moderate.     

The risk profile of childhood leukaemia in Greece: a nationwide case-control study

The risk profile of childhood leukaemia in Greece was studied through a case-control investigation that included all 153 incident cases of the disease, ascertained throughout the country during 1993 and 1994, and two hospital controls for every case matched for gender, age and place of residence. The data were analysed using conditional logistic regression and the associations are expressed in terms of adjusted odds ratios (OR) and their 95% confidence intervals. Cases were born to mothers of a higher standard education, the OR for an increment of four schooling years being 1.48 (1.17-1.87) and had higher birth weight, the OR for an increment of 500g being 1.36 (1.04-1.77). Pet ownership and birth after a pregnancy with anaemia were associated with increased risk, the ORs being 2.18 (1.14-4.16) and 2.60 (1.39-4.86) respectively. From the frequency analyses, indicative inverse associations were found with birth order, household crowding and previous hospitalization with allergic diseases, whereas indicative positive associations were found with diabetes mellitus during pregnancy and with neonatal jaundice. Substantial or significant elevations were not found with respect to maternal smoking and coffee drinking during pregnancy, diagnostic radiography and ultrasonographic examinations or blood transfusions. A significant inverse association with maternal consumption of alcohol could be due to multiple comparisons, but a detrimental effect can probably be excluded. A non-significant positive association with total shots of viral vaccinations and a weak non-significant inverse association with breast feeding were also found. We interpret the findings of this study as being compatible with acute childhood leukaemia being linked with delayed development of herd immunity to fairly common infectious agents, in conjunction with accelerated perinatal and early post-natal growth.     

5-Fluorouracil, epirubicin, and mitomycin C versus 5-fluorouracil, epirubicin, mitomycin C, and leucovorin in advanced gastric carcinoma. A randomized trial

Leucovorin (LV) enhances the activity of 5-fluorouracil (5FU). Based on these data, we performed a randomized trial with 5FU, epirubicin (EPI), mitomycin C(MMC) with/ without LV in advanced gastric cancer (AGC). The purpose of our study was to investigate if the addition of LV improved the response rate of the combination 5FU EPI, MMC (FEM) over FEM. From January 1988 until April 1994, 88 patients with recurrent or metastatic AGC were randomly received 5FU, EPI, MMC with (group A) or without (group B) LV. Between the two arms of the study no difference was noticed in sex, performance status, primary site of tumor, and lymph node metastases. Therapy included group A (5FU 600 mg/m2/day, i.v. bolus, on days 1, 8, 29, 36, and EPI 45 mg/m2/day, i.v. bolus, on days 1 and 29, MMC 10 mg/m2/day, i.v. bolus, on day 1) and group B (the same as group A plus LV 200 mg/m2/day by 2 h intravenous infusion with 5FU intravenous push at midinfusion). No significant difference in response rate was noticed between the two treatment arms; there were two (5%) patients with complete response in group A, and five (12%) in A and 11 (26%) partial responders in group B (p < 0.1). A significantly higher number of patients achieving stable disease was observed in group B; 19 (44%) in comparison to group A 10 (24%) (p < 0.048). There were more patients with progressive disease in group A 25 (59%) than in group B 12 (28%) (p < 0.003) (Table 2). No difference was noted in mean duration of response: group A, 15.8 (6-31) weeks; and group B, 17.6 (6-28) weeks. The mean time to progression was for group A [11.4 (6-35) weeks] and for group B [17.6 (8-33) weeks]. Mean survival was for group A [27.4 (12-59) weeks] and for group B [30.6 (17-53) weeks], for 50% of patients. Causes of death were, for group A, 40 patients from disease progression and two sudden deaths; for group B, causes of death were for 41 patients disease progression and two sudden deaths. There were two patients in group A and one in group B that were not evaluable because they abandoned therapy after the first cycle. Toxicity was increased in group B; anemia, nausea and vomiting, and alopecia (p < 0.055) were more severe in group B, but not statistically different when compared to group A. Neutropenia, thrombocytopenia, mucositis, and fatigue of any grade were significantly more common and severe in group B. Significant dose reductions due to toxicity were required more commonly in group B. We conclude that the response rate was increased in the schedule with the addition of LV, at the cost of increased toxicity and with no difference in survival. A randomized trial comparing FEM-LV with new generation regimens would determine whether the addition of LV qualifies FAM equally active with these.