West Nile Virus infection triggering autoimmune encephalitis: Pathophysiological and therapeutic implications.

BACKGROUND: A contributing factor in triggering autoimmune phenomena is pathogen infections. Here we describe a case that expands the spectrum of infection-associated autoimmune encephalitis and discuss plausible pathogenetic mechanisms. DESIGN: Case report and in silico analysis. RESULTS: A patient with West Nile Virus infection developed autoimmune encephalitis with positive anti-glycine receptor antibodies. Combination therapy with corticosteroids and intravenous immunoglobulin resulted in the resolution of encephalitis signs and symptoms. An in silico analysis unveiled certain sequence similarities between viral antigens and receptor sequence fragments suggesting a molecular mimicry autoimmunization process. CONCLUSIONS: Our case indicates that West Nile Virus infections can trigger autoimmune encephalitis. Our finding expands the spectrum of autoimmune conditions that can develop following an infection. Whether the autoimmunization process is due to molecular mimicry or due to the expansion of natural autoantibody clones merits further investigation.

A case of Alemtuzumab-induced neutropenia in multiple sclerosis in association with the expansion of large granular lymphocytes.

BACKGROUND: Alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in Multiple Sclerosis (MS) patients compared to ß-interferon. It acts against CD52, leading primarily to lymphopenia. Recent data have shown that mild neutropenia is observed in 16% of treated MS-patients whereas severe neutropenia occurred in 0.6%. CASE PRESENTATION: Herein, we present the case of a 34-year-old woman with relapsing-remitting MS, with a history of treatment with glatiramer acetate and natalizumab, who subsequently received Alemtuzumab (12 mg / 24 h × 5 days). 70-days after the last Alemtuzumab administration, the patient displayed neutropenia (500 neutrophils/µL) with virtual absence of B-cells (0.6% of total lymphocytes), low values of CD4-T-cells (6.6%) and predominance of CD8-T-cells (48%) and NK-cells (47%); while large granular lymphocytes (LGL) predominated in the blood-smear examination. Due to prolonged neutropenia (5-days) the patient was placed on low-dose corticosteroids leading to sustained remission. CONCLUSION: This is the first case of a patient with relapsing-remitting MS with neutropenia two months post-Alemtuzumab, with simultaneous presence of LGL cells in the blood and a robust therapeutic response to prednisolone. We recommend testing with a complete blood count every 15 days in the first 3 months after the 1st Alemtuzumab administration and searching for large granular lymphocytes cell expansion on microscopic examination of the peripheral blood if neutropenia develops.

Interleukin-17 and interleukin-23 are elevated in serum and cerebrospinal fluid of patients with ALS: a reflection of Th17 cells activation?

BACKGROUND: There is evidence that immunological factors may involved in pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Th17 cells are characterized by predominant production of IL-17 and are suggested to be crucial in destructive autoimmunity. Interleukin-23 (IL-23) appears to play a supporting role in the continued stimulation and survival of Th17. PATIENTS AND METHODS: We measured by enzyme-like immunosorbent assay (ELISA) serum and cerebrospinal fluid (CSF) levels of IL-17 and IL-23 in 22 patients with ALS and 19 patients with other non-inflammatory neurological disorders (NIND) studied as a control group. IL-17 and IL-23 serum and CSF levels were also correlated with duration of the disease, the disability level and the clinical subtype of the disease onset in patients with ALS. RESULTS: IL-17 and IL-23 serum levels were higher in patients with ALS as compared with patients with NIND (P = 0.015 and P = 0.002 respectively). IL-17 and IL-23 CSF levels were also increased in patients with ALS (P = 0.0006 and P = 0.000001 respectively). IL-17 and IL-23 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients. CONCLUSIONS: Our findings suggest that these molecules may be involved in the pathogenetic mechanisms acting as potential markers of Th17 cells activation in ALS.

Serum uric acid and multiple sclerosis.

UNLABELLED: Peroxynitrite (PN) has been implicated in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis. Uric acid (UA) serum levels of MS patients, a natural scavenger of PN, were found lowered in some recent studies. OBJECTIVE/PURPOSE: The objective of our study was to correlate UA serum levels and several clinical parameters of MS. We also tried to investigate serum UA changes during treatment with immunomodulating or immunosuppressing drugs in the last 6 months. PATIENTS AND METHODS: We measured UA serum levels in 190 patients with MS and 58 age and gender matched patients with inflammatory (IND) and non-inflammatory diseases (NIND) studied as control groups. UA levels were correlated with clinical parameters as type of the disease, duration, disability, magnetic resonance imaging (MRI) activity and female gender. RESULTS: In the overall MS group, patients were found to have significantly lower mean serum uric acid levels compared with the IND (p = 0.0029) and the NIND group (p < 0.0001). UA serum concentrations were not inversely correlated with duration of the disease (p = 0.87), with disability as assessed by Expanded Disability Status Scale (EDSS) score (p = 0.67) and MRI activity (p = 0.36). Treatment with immunomodulating or immunosuppressing drugs had no influence in UA levels (p = 0.85). Patients with Clinically Isolated Syndromes (CIS) were found to have significantly lower UA concentrations compared with IND and NIND patients (p = 0.009 and <0.001, respectively). CONCLUSIONS: Our findings suggest that lower serum UA levels in MS patients may represent a primary, constitutive loss of protection against nitric oxide and the development of CNS inflammation and tissue damage may not have a direct effect to UA serum levels. They also provide support that the earlier increase of UA serum levels might be beneficial in the future treatment of MS.

IL-15 is elevated in serum and cerebrospinal fluid of patients with multiple sclerosis.

UNLABELLED: Interleukin-15 (IL-15) is a novel proinflammatory cytokine having similar biological activities to IL-2 which is implicated in the pathogenesis of multiple sclerosis. It is produced by activated blood monocytes, macrophages and glial cells. There is little information about the involvement of IL-15 in the development of multiple sclerosis (MS). The objective of our study was to measure IL-15 serum and cerebrospinal fluid (CSF) levels in MS patients and to correlate serum and CSF IL-15 concentrations with clinical parameters of the disease. CSF IL-15/Serum IL-15 ratio (c/s IL-15 ratio) was introduced to assess the origin of elevated IL-15 levels. MATERIALS AND METHODS: We measured serum and CSF IL-15 levels in 52 patients with MS and 36 age and gender matched patients with inflammatory (IND) and non-inflammatory neurological diseases (NIND) studied as control groups. IL-15 levels were correlated with clinical parameters as duration, disability, MRI activity and clinical subtypes of the disease. RESULTS: MS patients were found to have significantly higher serum IL-15 levels compared with IND (p=0.00016) and NIND patients (p=0.00045). Elevated levels of IL-15 were also found in CSF samples from MS patients compared with patients with IND (p=0.00034) and NIND (p=0.0003). Among MS subgroups there were no statistically different IL-15 serum and CSF concentrations. No significant correlation of serum and CSF IL-15 concentrations with MRI activity, disability assessed by EDSS score and duration of the disease were also found. C/S IL-15 ratio was found lower in MS patients compared with IND (p=0.01) and not significantly different compared with NIND patients (p=0.14) suggesting that systemic activation might be the source of high CSF IL-15 levels in MS patients. CONCLUSIONS: Our findings suggest a possible role of IL-15 in the immunopathogenetic mechanisms of MS.

Methotrexate-paclitaxel-epirubicin-carboplatin (M-TEC) combination chemotherapy in patients with advanced bladder cancer: an open label phase II study.

The present phase II study aimed to define the application of a novel regimen incorporating methotrexate, paclitaxel, epirubicin, and carboplatin (M-TEC) in advanced bladder cancer, essentially as an M-VAC-like regimen, by substitution of cisplatin by carboplatin, doxorubicin by epirubicin and vinblastine by paclitaxel. Forty patients with advanced bladder cancer entered the study; 34 males/6 females, median age: 68 (range, 59-76), median PS (Karnovsky): 80, without receiving prior chemotherapy. Disease extention was as follows; 11/40 had local recurrence, 6/40 liver metastases, 14/40 lung metastases, bone and lymph node 8/40, bones-lymph node-lung metastases 4, lymph node and liver 4/40, lymph node-liver and lung metastases 2/40. Drug schedule and doses were as follows: paclitaxel 180 mg/m2, carboplatin AUC = 5 (according to creatinine clearance, based on Calvert's formula), and epirubicin 40 mg/m2 were administered during day 1, whereas methotrexate 30 mg/m2 and epirubicin 40 mg/m2 were administered on day 14. All patients were evaluable for response with 24/40 responding [response rate (RR) 60%]; 10/40 (25%) CR, 14/40 (35%) PR, 9/40 (22.5%) SD, and 7/40 (17.5%) PD. Symptomatic improvement was observed in 50% of patients. The median duration of response was 22 (14-32) weeks, median time-to-progression (TTP) 33 (12-44) weeks, and median survival was 56 (20-84) weeks. Toxicity was well accepted and was mainly neutropenia > grade 3: 17%, anemia >grade 3: 16%, thrombocytopenia > grade 2: 6%, nausea & vomiting mainly > grade 2: 31%, according to the administered chemotherapy cycles, whereas fatigue grade 2-3: 19%, neurotoxicity grade 1-2 13% of patients, and alopecia grade 2 was observed in all patients. The present pilot study indicates the feasibility of the M-TEC combination for bladder cancer with acceptable toxicity.

Serum levels of soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble endothelial leukocyte adhesion molecule-1(s-ELAM-1) in amyotrophic lateral sclerosis.

Immunological disturbances have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Adhesion molecules are markers of activated endothelial cells up-regulated by action of cytokines. To investigate the activation or inactivation of the vascular cells in ALS, serum soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble E-selectin (s-ELAM-1) were evaluated (ELISA) in 16 patients with ALS, 30 patients with non-inflammatory neurological diseases (NINDS) and 15 healthy control subjects. Patients with ALS had no higher s-ICAM-1 levels compared with the NINDS patients and the control subjects (p<0.31 and p<0.21, respectively). s-ELAM levels were not statistically significant compared with the NINDS patients and healthy subjects (p<0.21 and p<0.24, respectively). We conclude that the low values of s-ICAM-1 and s-ELAM-1 in the serum of ALS patients do not exclude the presence of immunological abnormality in this disorder. Soluble E-selectin is a glycoprotein which is considered an exclusive marker of endothelial activation. Its low level in our study may suggest a neural rather than an endothelial s-ICAM origin in patients with ALS.

The role of soluble intercellular adhesion molecules in neurodegenerative disorders.

UNLABELLED: Immunological disturbances have been implicated in the pathogenesis of some neurodegenerative disorders like Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Adhesion molecules are markers of activated endothelial cells upregulated by action of cytokines. MATERIALS AND METHODS: To investigate the activation or not of the vascular cells in AD and ALS, serum soluble intercellular adhesion molecule-1 (ICAM-1) and soluble E-selectin were evaluated (enzyme-like immunosorbent assay, ELISA) in 22 patients with Alzheimer's disease (AD), 20 patients with amyotrophic lateral sclerosis (ALS), 34 patients with non-inflammatory neurological diseases (NIND) and 15 control subjects. RESULTS: Patients with AD had higher s-ICAM-1 levels compared to NIND patients and control subjects (p<0.0027 and p<0.04, respectively). Patients with ALS had not higher s-ICAM-1 levels compared to NIND patients and control subjects (p<0.21 and p<0.31, respectively). Soluble-E-selectin levels in AD and ALS patients were not statistically different compared to NIND patients and controls (p<0.4, p<0.9 and p<0.3, p<0.19, respectively). CONCLUSIONS: The presence of high s-ICAM values may be related to immunological processes involved in pathogenetic mechanisms of AD. The not statistically significant values of s-E selectin, a glycoprotein considered an exclusive marker of endothelial activation, seem to suggest the neural rather than the endothelial s-ICAM origin in patients with AD. The low values of s-ICAM-1 and sE-selectin in the serum of ALS patients do not exclude the presence of an unconventional immunological abnormality in this disorder.

Leucovorin and 5-fluorouracil versus levamisole and 5-fluorouracil as adjuvant chemotherapy in rectal cancer.

PURPOSE: To evaluate the effectiveness of 6-month therapy with leucovorin (LV)+5-fluorouracil (5-FU) versus 12-month therapy with levamisole (LVS)+5-FU, as adjuvant chemotherapy in patients with completely resected Aster-Coller stage B(2) or C(1)/C(2) rectal cancer (RC). PATIENTS AND METHODS: One hundred and fifty patients with surgically resected RC were enrolled. Seventy patients with stage B(2) and 80 with stage C were randomly assigned to adjuvant chemotherapy with 5-FU+LXx6 months or 5-FU+LVSx12 months. Patient characteristics were equally balanced between the examined groups. Adjuvant chemotherapy consisted of LV 20 mg/m(2) intravenously (i.v.) plus 5-FU 450 mg/m(2) i.v. bolus every week plus LVS tablets 50 mg t.i.dx3 days every 2 weeks for 1 year. RESULTS: After a median follow up for survivors of 8.7 years (range 1.8-10.5), all of the patients were evaluable. There were no significant differences between the two treatment groups with respect to the recurrence rates (p=0.821). Moreover, there were no significant differences between the two tratment groups in disease-free survival (DFS) (p=0.84) [B(2)(p=0.805) and C (p=0.978)] and overall survival (OS) rates for patients of either stage B(2) or C (p=0.78). Toxicities were more frequent in the 5-FU+LVS versus 5-FU+LV group: myelosuppression (grade 3 leucopenia, 12 versus 4%, p<0.04), diarrhea (grade 0, 60 versus 76%, p<0.02), and liver toxicity (increase of transaminases >3-fold, 12 patients versus 2, p<0.03.). No patient stopped chemotherapy because of toxicity, and there were no treatment-related deaths. CONCLUSION: Adjuvant chemotherapy in RC with LV+5-FU for 6 months is equally effective and less toxic than LVS+5-FU for 12 months.

Breast cancer following curative chemotherapy for non-Hodgkin's lymphoma and the effect of drug resistance proteins to the final outcome. A retrospective study.

PURPOSE: To investigate the overall survival (OS) of patients developing breast cancer (BC) after curative chemotherapy for non-Hodgkin's lymphoma (NHL) and to evaluate the possible effect on the patients' outcome of the expression of drug resistance-related proteins (P-glycoprotein-Pgp, multidrug resistance-associated protein-MRP, and multidrug resistance-related vault lung resistance protein-LRP) in BC issue. STUDY GROUP: 25 female patients (median age 60 years, range 37-70) who developed BC after chemotherapy for high/intermediate grade B-cell NHL, treated with CHOP and achieving complete remission (CR). This group was further subdivided in subgroups A and B, according to the time interval between NHL and BC development ( 24 months, respectively). A matched-pair group of de novo BC patients formed the control group. BC tissue was immuno-histochemically stained for Pgp, MRP and LRP. RESULTS: The median interval between NHL diagnosis and BC development was 26 months (range 9-49). In both groups 14 patients had tumor grade II; 16 were negative for steroid receptors; 17 overexpressed c-erbB-2; 14 were stage IIIA/B, and 11 stage IV. CMF or CNF (mitoxantrone instead of doxorubicin) were given for BC. Early progression was noticed in all study group patients for which second-line chemotherapy was instituted. There was a better response for stage IV patients in the control versus the study group (p=0.07). More prolonged OS was demonstrate for patients with stage III in the control group (median 51 months) and in subgroup B (median 47 months) than in subgroup A (median 16 months; p=0.00012), as well as for patients with advanced disease (p=0.0045). Development of BC < 24 months after NHL resulted in reduced OS (p=0.017). No difference was noticed in the expression of drug resistance proteins between the study and control group or between subgroups A and B. CONCLUSION: BC developing shortly after a CR to NHL is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of Pgp, MRP and LRP failed to demonstrate significant difference between the study and control group, although indications exist that drug resistance mechanisms might be part of the aggressive disease phenotype, contributing to the poor outcome.

Serum levels of soluble intercellular adhesion molecule-1 and soluble endothelial leukocyte adhesion molecule-1 in Alzheimer's disease.

Serum soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble E-selectin (s-ELAM-1) were evaluated in 25 patients with Alzheimer's disease (AD), 54 patients with noninflammatory neurological diseases (NIND), and 15 control subjects. Patients with AD had a higher s-ICAM-1 level compared with the NIND patients and the control subjects (P< .001 and P< .04, respectively). The presence of high s-ICAM-1 values may be related to immunological processes involved in pathogenetic mechanisms of AD. The not statistically significant values of (s-ELAM-1), a glycoprotein considered an exclusive marker of endothelial activation, compared with the NIND patients and healthy subjects (P< .47 and P< .17, respectively), seem to suggest the neural rather than the endothelial s-ICAM origin in patients with AD.

Leucovorin and fluorouracil vs levamisole and fluorouracil as adjuvant chemotherapy in rectal cancer.

The aim of this study was to evaluate the effectiveness of 6-month therapy with leucovorin (LV) + 5-fluorouracil (5-FU) vs 12 months of therapy with levamisole (LVZ) + 5-FU, as adjuvant chemotherapy in patients with completely resected Dukes' stage B2 or C rectal cancer. One hundred and fifty patients with surgically resected rectal carcinoma, were enrolled in the present study; Dukes' stage B2 (n=70) or C (n=80), were randomly assigned to chemotherapy with 5-FU + LV x 6 months or 5-FU + LVZ x 12 months. Patient characteristics were equally balanced between the examined groups. Adjuvant CT consisted of LV 20 mg/m(2) intravenously (i.v.) plus 5-FU 450 mg/m(2) i.v., on days 1-5 every 4 weeks for 6 cycles or 5-FU 450 mg/m(2) i.v. every week plus LVZ 50 mg t.i.d x 3 days for 1 year. All patients received radiotherapy with a three-field technique to a total dose of 45 Gy, over 5 weeks. After a median follow-up of 7.4 years there were no significant differences between the two treatment groups with respect to the recurrence rates (P=0.821). Moreover, there was no difference in disease-free survival for patients stage Dukes' B2 (log-rank p=0.73); median for LV group 90 (8-131) months, and for LVZ group 86.5 (3-129) months. No difference was noted in disease-free survival for patients stage Dukes' C (log-rank p=0.73); median for LV group 60 (17-128) months, and for LVZ group 64 (2-123) months. There was no difference in overall survival for patients stage Dukes' B2 (log-rank p=0.75); median for LV group 90 (22-131) months, and for LVZ group 86 (10-129) months. For stage Dukes' C (log-rank p=0.73); median for LV group 67 (17-128) months, and for LVZ group 64 (5-123) months. Toxicities were as follows in the 5-FU + LVZ vs 5-FU + LV group; myelosuppression (leucopenia grade 3, 12% vs 4%, p<0.04), diarrhea (grade 0, 60% vs 76%, p<0.02), and liver toxicity (increase of transaminases >3-fold, 12 patients vs 2, p<0.03), were more frequent in LVZ group. None of the patients stopped chemotherapy because of the toxicity, and there were no toxicity-related deaths. In conclusion, adjuvant chemotherapy in RC with LV + 5-FU for 6 months is equally effective and less toxic than LVZ + 5-FU for 12 months.

Breast cancer after curative chemotherapy in non-Hodgkin's lymphoma: examination of the role of drug resistance and retrospective comparison to the outcome of de novo breast cancer.

We examined the outcome of patients who developed breast cancer after curative chemotherapy (CHOP) for aggressive non-Hodgkin's lymphoma (NHL) in comparison to the outcome of a retrospectively selected matched-pair group of patients with de novo breast cancer, and evaluated the role of drug resistance-related protein (MDR, MRP, LRP) expression in breast cancer tissue. Twenty-two patients presented with breast cancer (BC) in complete remission after CHOP for NHL. The median age was 62 (49-70) years, each had high/intermediate grade B-cell NHL treated with 6 courses of CHOP, and were in complete remission. These patients were compared to a matched-pair group of de novo BC patients selected from our database over the same time period. Breast cancer tissue was stained by immunohistochemistry for drug resistance proteins LRP, MRP, and MDR. Breast cancer developed after a median of 26 (9-49) months of NHL diagnosis; breast tumor grades 1-2 were seen in 12, and grade 3 in 10 patients; 15 were negative and 7 weakly positive for estrogen and progesterone receptors. Twelve patients were stage IIIA/B, and 10 stage IV and were treated with conventional chemotherapy regimens. All progressed early in liver (n=13), brain (n=9), lung (n=6), bone (n=8), lymph nodes (n=7) and soft tissue (n=5), and received second-line chemotherapy with mitomycin-C + vinblastine or taxanes. The overall survival was 11.8 (6-26) months (p<0.01). Time from NHL to breast cancer development was 19 (14-27) months in patients with positive drug resistance proteins (group A), and 37 (26-56) months in patients with 1 or 2 positive resistance proteins (group B) (p<0.001). In patients with stage IIIA/B disease, there was no difference between the examined and control matched-pair group in median TTP, but there was in overall survival (OS) (23 vs 36 months, p=0.029). In advanced disease, there were more responders in the control vs the examined group (p=0.07). Patients in the control matched-pair group had more prolonged OS when compared to group A patients who developed BC in <24 months from NHL to BC (p=0.017). We conclude that breast cancer developing shortly after a complete response in NHL, is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of drug resistance mechanisms concerning MDR, MRP and LRP indicates that most of these patients have BC that overexpress these proteins leading to the suggestion that these mechanisms might be a part of the aggressive disease phenotype and partially explain the poor outcome.

Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination. A randomized study.

PURPOSE: To evaluate the efficacy and safety of irinotecan as second-line treatment in patients with advanced colorectal cancer (ACC) failing or relapsing after 5-fluorouracil (5-FU) plus leucovorin (LV) standard chemotherapy. PATIENTS AND METHODS: Irinotecan was randomly administered in two different schedules (once every 3 weeks, and every 10 days) in patients failing prior 5-FU plus LV. Patients were randomized to two treatment groups: group A received irinotecan 350 mg/m2 every 21 days and group B received irinotecan 175 mg/m2 days 1 and 10 every 21 days. RESULTS: Group A comprised 60 patients: 34 male/26 female, median age 64 years (range 48-70 years), and median Karnofsky performance status (PS) 90. Their metastatic sites included liver (n=47), lymph nodes (n=27), lung (n=14), abdomen (n=14), pelvis (n=8), "other" (n=2), and local recurrence (n=12). Group B comprised 60 patients: 36 male/24 female, median age 62 years (46-70 years), and median PS 90. Their metastatic sites included liver (n=49), lymph nodes (n=29), lung (n=17), abdomen (n=16), pelvis (n=11), "other" (n=2), and local recurrence (n=13). Group A showed the following responses: complete response (CR) 2, partial response (PR) 12, stable disease (SD) 21, progressive disease (PD) 26, overall response rate (ORR) 23%, tumor growth control 58%. Group B showed the following responses: CR 1, PR 14, SD 22, PD 23; ORR 25%; tumor growth control 62%. Toxicities included acute cholinergic syndrome (group A 53%, group B 19%; P<0.0001), late-onset diarrhea grade 1/2 (group A 21%, group B 46%) and grade 3/4 (group A 41%, group B 66%; P<0.0001), nausea and vomiting grade 1/2 (group A 34%, group B 59%) and grade 3/4 (group A 30%, group B 12%; P<0.0001), neutropenia grade 3/4 (group A 27%, group B 28%; P<0.03), with febrile neutropenia seen in only four patients in group A, anemia grade more than 2 (group A 28%, group B 12%; P<0.05), asthenia grade more than 3 (group A 24%, group B 18%; P<0.001), and alopecia grade more than 3 (group A 40%, group B 34%; P<0.2). CONCLUSIONS: . The present study indicates that, in patients with ACC who have relapsed after 5-FU plus LV, the administration of irinotecan fractionated into two doses every 21 days yields a similar efficacy to, but a much lower incidence of toxicity than, the same total dose of irinotecan administered once every 21 days.

Predicting live herbaceous moisture content from a seasonal drought index.

In order to provide a relatively simple means of predicting live herbaceous plant moisture content from a readily available meteorological index with an accuracy adequate for fire hazard assessment, the moisture content fluctuations of certain species were correlated with the values of a seasonal drought index based on soil moisture deficiency. The simple linear regression models provided the best fit of the relationship between plant moisture content and the Keetch-Byram drought index (KBDI) values. KBDI predicted with accuracy, for two growing seasons, the moisture content of three annual herbaceous plants ( Piptatherum miliaceum, Parietaria diffusa, Avena sterillis) with shallow rooting systems, typical of the understory vegetation of Pinus brutia forests in the Mediterranean region of Crete, Greece. The greatest aberrations between measured and predicted values of plant moisture content were observed early (May) and late (September) in the growing season, when plant phenology (flushing and withering stages respectively) appears to become the dominant factor in determining plant moisture content regardless of the soil moisture conditions. The KBDI was poorly correlated with the live-needle moisture content of deeply rooted P. brutia trees and modestly with the soil water content of the upper layers. This indicates that the index adequately reflects the moisture condition of the surface soil layers but not the water content deeper in the soil.

Evaluation of the fire simulation processes of the National Fire Management System's Initial Attack Analysis processor.

The fire simulation processes of the National Fire Management System's (NFMAS) Initial Attack Analysis (IAA) processor were evaluated by conducting two types of sensitivity analysis: one based on a hypothetical set of data to assess IAA's outputs under a wide range of fire input values, and the other using an actual Stanislaus National Forest database to test IAA's validity with a real set of data. The results revealed that IAA's outputs (projected annual number of fires and area burned) were most sensitive, in descending order, to the input values of the fire spread rate, the productivity rates of the suppression forces, and the initial attack time, for all fuel models tested. In contrast, IAA's outputs were extremely insensitive to variations in the fire size at discovery. Changes are necessary in the ways IAA incorporates the fire size at discovery to facilitate the comparison among various fire detection options. The program's "escaped fire situation" analysis was found inadequate, because the projected annual frequencies and final sizes of the simulated escaped fire events produced unacceptable results with the Stanislaus National Forest database. Assigning final sizes to simulated escaped fires according to the fire intensity level in which they are historically expected to occur provides a consistent way of calculation of the projected annual area burned and the consequent cost plus net value change (C + NVC).

Irinotecan (CPT-11) in patients with advanced colon carcinoma relapsing after 5-fluorouracil-leucovorin combination.

The purpose of the present study was to investigate the association between performance status (PS) and mean dose of irinotecan (CPT-11) in patients with recurrent advanced colorectal cancer relapsing after 5-fluorouracil and leucovorin chemotherapy. Patients who had completed their last chemotherapy course with 5-fluorouracil and leucovorin for at least 6 weeks and progressed were included. Based on PS, we administered a starting dose of 250 mg/m(2) in patients with a PS 70-80 (group A), and 350 mg/m(2) for those with a PS > 80 (group B). Of a total of 90 treated patients, all were evaluable, 18 had a partial response (PR) (20%), 39 stable disease (43%), and 15 progressed (37%). No significant difference was noticed between patients with PS > or = 90 or < or = 80 (p = 0.925), or between those who received a mean dose of CPT-11 > or = 300 or < or = 300 (p = 0.602), for response, survival and time to progression. Toxicity was increased in group B as expected, with significant differences for acute cholinergic syndrome (p = 0.02), diarrhea after the first 24 h (p = 0.03) and severe diarrhea (p = 0.03). According to these results, we conclude that response to CPT-11 is independent of its dose, and that a dose of 250 mg/m(2) every 3 weeks might be a cost-effective and less toxic alternative in this setting. However, further adequately powered phase II or III randomized studies might be required in order to confirm this observation.

Efficacy of ondansentron treatment for acute emesis with different dosing schedules 8 vs 32 mg. A randomized study.

The aim of the present randomized study was to evaluate which dose of Ondansentron (OND)(32 versus 8 mg) is appropriate for the antiemetic treatment of a uniform group of patients (pts) with Non Small Cell Lung Cancer (NSCLC) who were treated with Cisplatin (CDDP) 100 mg/m2 in combination with other less emetogenic drugs. One hundred and ten patients, with histologically confirmed NSCLC entered this randomized study. They were between 50 - 70 years old, with no previous Chemotherapy, with a PS (Karnofsky) >60%. They were randomized into two groups; Group A: OND as a 32 mg dose the first 24 hours, followed by 8 mg every 8 hrs for the following four days, combined with dexamethasone, 8 mg i.v. the first day, and 8 mg p.o., in the morning, the following three days. Group B: OND as a 8 mg dose every day for 4 days, combined with dexamethasone 8 mg i.v. and 8 mg p.o. the following three days. In this randomized study, of the 110 patients who entered, 106 were evaluable. Clinical parameters were similar between the examined groups. A higher number of patients of Group A presented complete response (P 0.0001), compared to patients of Group B who failed (P 0.004), during the first 24 hours. In the 3 days that followed, a higher number of pts of Group A presented complete response to the antiemetic therapy (P 0.001, P 0.0001), while Group B failed (P 0.007, P 0.001, P 0.019), or presented minor response (P 0.0001, P 0.004). Patients who had no antiemetic response needed additional therapy and were excluded from the evaluatio (13 pts of Group B). Retches (P 0.0001, P 0.005), and nausea (P 0.0001, P were also frequent in Group B. We concluded that reduced OND doses (8 mg) are inadequate in the prevention of emesis after high dose CDDP (100 mg/m2) and should be avoided.

Leucovorin + 5-fluorouracil plus dipyridamole in leucovorin + 5-fluorouracil-pretreated patients with advanced colorectal cancer: a pilot study of three different dipyridamole regimens.

Dipyridamole, an inhibitor of nucleoside transport, increases the activity of 5-fluorouracil in a dose-dependent manner. The purpose of the present study was to determine whether dipyridamole with 5-fluorouracil and leucovorin gave an improved therapeutic outcome. Sixty patients entered in the present pilot study had previously received 5-fluorouracil (450 mg/m2) and leucovorin (100 mg/m2), every week, and relapsed during this treatment, which ended at least 6 weeks prior to study entry. Dipyridamole was administered at three different dosing schedules (DS) and methods of administration in three groups of patients. DS I: dipyridamole, 30 mg/m2 in normal saline solution, in 90 min iv infusion, followed by leucovorin, 100 mg/m2 iv push, followed by 5-fluorouracil, 450 mg/m2 in normal saline solution, in 60 min iv infusion, dipyridamole tablets (75 mg) every 12 hrs, continuously during the time of chemotherapy. DS II: dipyridamole, 50 mg/m2 in normal saline solution, in 90 min iv infusion, and the rest was the same as DS I. DS III: without oral dipyridamole, patients received dipyridamole (50 mg/m2) iv in the same manner as in DS I and II. Treatment was continued until tumor progression or unacceptable toxicity. All patients (n = 60) entered in the present study were assessable for response and toxicity. No complete response was observed. No patient at DS I responded, whereas 2 patients at DS II and 3 at DS III had a partial response (P <0.1). Stable disease was found with DS I (n = 1), DS II (n = 8) and DS III (n = 9) (P <0.01). More patients progressed at DS I (n = 19) than at DS II (n = 10) and DS III (n = 8) (P <0.0007). The median duration of response was 11 weeks (range, 8-16). Time to progression was 17 weeks for DS I, 15 weeks (range, 10-19) for DS II, and 14 weeks (range, 11-21) for DS III (P = 0.43). Median survival did not differ significantly between DS I (29 weeks; range, 14-48), DS II(31.5 weeks; range, 17-63) and DS III (36 weeks; range, 16-58) (P = 0.2). Neutropenia was most severe with DS I (grade 2, P<0.01) and DS II (grade 1, P<0.05) and nausea/vomiting with DS I (grade 0, P < 0.0005, grade 1, P <0.0002, grade 2, P <0.02) and DS III (grade 3, P<0.0009). Diarrhea was most severe in DS II (grade 3, P <0.005). Mucositis was increased in DS II (grade 0, P <0.008), anorexia in DS II (grade 0, P <0.032) and fatigue in DS I (grade 0, P <0.003). More patients in DS I than with the other two DS experienced headache (P <0.044). According to the response achieved at DS III (15% partial response and 45% stable disease) and the toxicity which was well tolerated mainly in this DS (except for nausea and vomiting grade 3, P <0.009), it can be stated that DS III is the appropriate dose and the simplest schedule of administration (administration of dipyridamole during therapy only). In conclusion, it appears that dipyridamole might still have a role in enhancing the clinical activity of drugs involved in the inhibition of the thymidylate synthetase biochemical pathway and its activity in combination with these agents (5-fluorouracil + leucovorin) as frontline treatment should therefore be explored in future phase II studies.