High sFas Research Articles

Abstract PO3-15-11: Soluble sFas, sFasL, sPD1, and sPD-L1 analyses in the blood peripheral of locally advanced breast cancer women before and after neoadjuvant chemotherapy

Abstract Assess soluble sFAS, sFASL, sPD1, and sPD-L1 levels in patients with HER2 or triple-negative (TN) breast cancer submitted to neoadjuvant chemotherapy. A prospective cohort study was performed with TN and HER2+ breast cancer patients between 2015 and 2018. Soluble levels of sFasL, sFas, sPD-L1, and sPD1 were collected before and after neoadjuvant chemotherapy (NAC). NAC regimens included a dense dose of Adriablastin and cyclophosphamide during four cycles, followed by Paclitaxel for 12 weeks. No clinical evidence of tumor in the breast and axillary lymph nodes was defined as a pathological complete response (pCR). Twenty-one women with TN (56,7%) and 16 (43,3%) HER2+ breast cancer were included. Twenty-one women (56.7%) presented complete pathological response (pCR) after neoadjuvant chemotherapy (NAC), defined as the absence of invasive disease in the breast and lymph nodes. High sPD1 and sFas levels in the TN and HER2+ patients compared to the control group (P< 0.05). In paired analysis, statistical differences of sFas and sFasL levels in TN and HER2+ patients before and after NAC (P< 0.05). Low levels of sPDL1 in HER2+ patients with pCR compared to non-pCR (P< 0.05). High sFasL levels in TN patients with pCR compared to the non-pCR group (P< 0.05). Conclusion: soluble sFas, sFas-L, sPD1, and sPD-L1 levels were apoptosis-related markers with potential predictive value of neoadjuvant chemotherapy response in TN and HER2+ breast cancer. Keywords: breast cancer; FAS receptor; Programmed death 1, HER2+, Triple negative Citation Format: Carolina Vasconcelos, Marcelo Salgado, Carlos Eduardo Anunciação, Denise Viana, Leuridan Torres, Nathália Valois Montarroyos de Moraes. Soluble sFas, sFasL, sPD1, and sPD-L1 analyses in the blood peripheral of locally advanced breast cancer women before and after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-11.

Serum Soluble Fas Levels and Incidence of Liver Cancer in Nested Case-Control Study.

Soluble Fas (sFas) plays various roles in carcinogenesis and tumor dissemination by preventing apoptosis via binding to Fas ligand. We analyzed associations of serum sFas levels with the incidence of liver cancer in a prospective case-control study nested in the Japan Collaborative Cohort Study. A baseline survey was conducted from 1988, with blood samples obtained from 39,242 subjects. Patients diagnosed with liver cancer were regarded as cases. Two or three controls were selected and matched for sex, age, and geographic area. Conditional logistic regression was used to estimate ORs for cancer incidence associated with sFas. This study contained 86 cases and 249 controls. After controlling for alcohol intake, body mass index, smoking, and hepatitis viral infection, participants with high sFas showed elevated risk of cancer (Ptrend = 0.003) and the third tertile of sFas showed a higher risk compared with the first tertile [OR, 3.53; 95% confidence interval (CI), 1.28-9.69]. In hepatocellular carcinoma, high sFas was associated with elevated risk (Ptrend < 0.001). In men and the elderly, subjects in the highest tertiles showed higher cancer risk. Limiting subjects to those followed for 3 years, high sFas was related to liver cancer risk (Ptrend = 0.033) and the third tertile showed a higher risk compared with the first (OR, 2.94; 95% CI, 0.94-9.14). High serum sFas may be related to future risk of liver cancer. Our findings highlight this biomarker for further analysis in pooled investigations with different/larger prospective cohorts.

Blood soluble Fas concentrations and ischemic stroke patient mortality

ABSTRACT Background Fas is a major receptor for cell death by apoptosis. Higher blood concentrations of soluble Fas (sFas) have been reported in patients with ischemic stroke compared to control subjects. The aim of this study was to explore the existence or not of an association between blood sFas concentrations and mortality in patients with ischemic stroke. Methods This study included patients admitted to Intensive Care Units with severe and malignant middle cerebral artery infarction (MCAI), defined as acute infarction, in more than 50% of this territory on computed tomography and less than 9 points on the Glasgow Coma Scale (GCS). Serum sFas levels were determined at the time of diagnosis of MMCAI. Results Non-surviving severe MMCAI patients (n = 27) showed lower platelet count (p = 0.004), higher serum sFas (p < 0.001), and lower GCS (p = 0.001) compared to surviving patients (n = 27). Multiple logistic regression found an association of serum sFas levels and mortality at 30 days (OR = 1.015; 95% CI = 1.002–1.027; p = 0.02) after control for CGS and platelet count. Conclusions The main novelty of our study was the existence of an association between high blood sFas concentrations and mortality in patients with ischemic stroke.

Blood concentrations of proapoptotic sFas and antiapoptotic Bcl2 and COVID-19 patient mortality

ABSTRACT Background: There are no data on circulating concentrations of sFas (proapoptotic protein of extrinsic pathway) and Bcl2 (antiapoptotic protein of intrinsic pathway) in COVID-19 patients. Thus, our objective study was to determine whether an association exists between serum concentrations of sFas and Bcl2 and COVID-19 patient mortality. Methods: This observational and prospective study of COVID-19 patients was performed in eight Intensive Care Units (ICU) from Canary Islands (Spain). Serum levels of sFas and Bcl2 at ICU admission were determined. Mortality at 30 days was the end-point study. Results: Surviving patients (n = 42) compared to non-surviving (n = 11) had lower APACHE-II (p < 0.001), lower SOFA (p = 0.004), lower serum sFas levels (p = 0.001) and higher serum Bcl2 levels (p < 0.001). Logistic regression showed an association between high serum sFas levels and mortality after controlling for APACHE-II (OR = 1.004; 95% CI = 1.101–1.007; p = 0.01) or SOFA (OR = 1.003; 95% CI = 1.101–1.106; p = 0.004), and between low serum Bcl2 levels and mortality after controlling for APACHE-II (OR = 0.927; 95% CI = 0.873–0.984; p = 0.01) or SOFA (OR = 0.949; 95% CI = 0.913–0.987; p = 0.01). Conclusions: Thus, to the best of our knowledge, this is the first study reporting blood levels of sFas and Bcl2 in COVID-19 patients and its association with mortality.

Associations of serum soluble Fas and Fas ligand (FasL) with outcomes in systemic lupus erythematosus

ObjectiveFas/Fas ligand (FasL) and B cell-activating factor (BAFF) signalling have pivotal roles in SLE pathogenesis. We investigated the clinical associations of serum concentrations of soluble Fas (sFas) and soluble FasL...

Microencapsulation of healthier oils: an efficient strategy to improve the lipid profile of meat products

Meat products have high SFAs levels and a high n-6/n-3 ratio, with negative effects on human health. The replacement of animal fat by oils rich in n-3 PUFAs is an efficient strategy to improve the lipid profile of meat products. However, the technological properties, oxidative stability, and sensory quality of meat products can be impaired by this lipid reformulation. Recently, microencapsulation has stood out as a promising tool to improve the oxidative stability of oils, allowing their application in meat products. Considering the growing interest in this topic among the population, this short-review aims to highlight the recent studies on the microencapsulation of healthier oils as a strategy to improve the lipid profile of meat products.

FAS promoter polymorphisms and serum sFas level are associated with increased risk of nerve damage in Bangladeshi patients with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system triggered by molecular mimicry between pathogen lipopolysaccharides and host nerve gangliosides. Polymorphisms in the Fas receptor (FAS) and Fas ligand (FASL) genes may potentially alter the elimination of autoreactive immune cells and affect disease susceptibility or disease severity in GBS. We detected single nucleotide polymorphisms (SNPs) in FAS (-1377G/A and -670A/G) and FASL (-843C/T) in a prospective cohort of 300 patients with GBS and 300 healthy controls from the Bangladeshi population. Genotype distributions were not significantly different between patients with GBS and healthy controls. The FAS -670 AG heterozygous (P = 0.0005, OR = 2.5, 95% CI = 1.5–4.2) and GG homozygous (P = 0.0048, OR = 2.6, 95% CI = 1.3–5.0) genotypes were more common in patients with anti-GM1 antibodies than patients without anti-GM1 antibodies. The FAS -670 G allele was more prevalent in anti-GM1 antibody-positive than -negative patients (P = 0.0002, OR = 1.9, 95% CI = 1.4–2.7) and also in patients with the axonal subtype than demyelinating subtype (P < 0.0001, OR = 4.8, 95% CI = 2.3–10.1). The 1377G/-670G GG haplotype was significantly associated with the axonal subtype (P < 0.0001) and anti-ganglioside antibody-positivity (P = 0.0008) in GBS. Serum sFas (237.5 pg/mL vs. 159.5 pg/mL; P < 0.0001) and sFasL (225.1 pg/mL vs. 183.4 pg/mL; P = 0.0069) were elevated in patients with GBS compared to healthy controls, and among patients with high serum sFas was associated with severe GBS (P = 0.0406). In conclusion, this study indicates FAS-FASL promoter SNPs may promote the production of cross-reactive anti-ganglioside antibodies in GBS.

Effects of 1α,25 Dihydroxyvitamin D3 on Pro-inflammatory Cytokines of Palmitic Acid Treated Thp-1 Cells.

The effect of vitamin D3 on chronic inflammation in obesity is uncertain. This study shows an in vitro possibility that vitamin D3 could exaggerate inflammation when combined with high SFAs. The idea of using vitamin D3 supplement to modulate inflammation in fat-related inflammation needs further refined experiments before its clinical application.

Value of detection of preoperative urinary soluble Fas expression in predicting the recurrence of non-muscle invasive bladder cancer

To investigate the clinical value of detection of preoperative urinary soluble Fas (sFas) expression in predicting the recurrence of non-muscle invasive bladder cancer (NMIBC). We performed a prospective research, which included 128 cases with NMIBC from January 2008 to April 2011. Expression levels of sFas in urine, which was saved at the first morning from preoperative NMIBC patients, were analyzed by ELISA. Clinical and pathological data, European Organization for Research and Treatment of Cancer (EORTC) risk group category, follow-up data and urinary sFas values were collected from each patient, and each prognostic outcome was evaluated by statistical analysis of non-parametric test. Urinary sFas values and recurrence-free probabilities were estimated by the Kaplan-Meier method and compared by the log rank test. Cox proportional hazards regression models were performed to determine the independent predictors of NMIBC recurrence. The prognosis index (PI) was established. The urinary sFas level was significantly elevated in the NMIBC cases with a higher stage or grade or high-risk EORTC group category than in those with a lower stage or grade or low-risk EORTC group category (each P<0.05), regardless of age or gender (P>0.05). Kaplan-Meier analysis revealed a significant increase in incidence of recurrence in the NMIBC patients with high sFas levels in the urine (P<0.001). According to Cox regression analysis, the urinary sFas level and EORTC risk group category (each P<0.05) were the independent predictors of NMIBC recurrence. Based on the outcome of Cox regression, the formula of PI=(0.004×sFas value+1.179×EORTC score) was established. Our study indicates that urinary sFas test may help to identify NMIBC patients at risk of tumor recurrence and it deserves further research.

APO-1/FAS Promoter (-670A/G) Polymorphisms and Risk of Lupus Nephritis in SLE Egyptian Female Patients

Background: Self-immunization in systemic lupus is driven by defective in apoptosis. Fas, is an apoptosis-promoting cell surface receptor. The present study evaluate the possible association between APO-1/FAS Promoter (-670A/G) Polymorphism and sFAS level with susceptibility to lupus nephritis in SLE patients. Design and Methods: This study was performed on 88 female patients with SLE (mean age, 39.82 ± 10.16 years). 82 patients with lupus nephritis (mean age, 42.50 ± 6.65 years). 150 age and sex-matched person served as controls. All participants were genotyped for the APO-1/FAS Promoter (-670A/G) Polymorphism, manifestations and serum sFAS were correlated with the genotypes. Results: Serum sFAS was significantly higher in patients with -670 AA genotype compared to others. (-670A/G) AA genotype frequencies were significantly higher in the lupus nephritis and SLE patients groups compared with the controls and were associated with increased risk for lupus nephritis and SLE development (odds ratio, 4.08 and 1.91 respectively). Conclusions: The APO-1/FAS Promoter (-670A/G) A allele can be used as a genetic marker for lupus nephritis susceptibility in SLE and was associated with high sFAS level.

Clinical utility of urinary soluble Fas in screening for bladder cancer

Early diagnosis of carcinoma of urinary bladder remains a challenge. Urine cytology, as an adjunct to cystoscopy, is less sensitive for low-grade tumors. Soluble Fas (sFas), a cell-surface receptor and member of the tumor necrosis factor superfamily, is frequently expressed in urinary bladder carcinoma. The objective of this study was to investigate the urinary sFas for diagnosis of transitional cell carcinoma (TCC) of urinary bladder. We examined urinary sFas concentration in 74 controls and 117 cases of TCC, both primary and recurrent disease, by using enzyme-linked immunosorbent assay and compared it with urinary cytology. Urinary sFas concentration was found to be significantly higher in the patient as compared to control group (P < 0.05). An optimal cutoff value of 174.0 pg/mL was proposed. The urinary sFas level was found to have an approximate sensitivity and specificity of 88.03% and 89.19% (P < 0.001), whereas urine cytology had sensitivity of 66.67% and specificity of 95.95%. sFas had better sensitivity in higher grade and both primary and recurrent cases of urinary bladder cancer in comparison with cytology. Out of 15 node positive bladder cancer cases, 13 had high urinary sFas levels, whereas 12 were urinary cytology positive for malignancy. Urinary sFas can be used as a non-invasive diagnostic biomarker for TCC of urinary bladder, both for primary and recurrent disease.

FAS -670A>G promoter polymorphism is associated with soluble Fas levels in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Soluble Fas receptor (sFas) has been suggested as a Fas-mediated apoptosis blocker that could impair clonal deletion in infiltrated autoreactive cells. The FAS -670A>G promoter polymorphism has been studied in pSS. However, a relationship between FAS -670A>G promoter polymorphism and sFas levels in pSS had not been found. We examined this relationship in 77 Mexican pSS patients and 84 healthy subjects were included. Genotypes were identified by PCR-RFLP, and Fas soluble levels were quantified by ELISA. No significant differences between allele and genotype frequencies were found between these two groups. The sFas levels in the serum of pSS patients were significantly higher than in controls (9961 vs 8840 pg/mL, respectively). In addition, AA genotype carriers had significantly higher levels of sFas than GG carriers (pSS: 10,763 and 9422 pg/mL; controls: 9712 and 8305 pg/mL, respectively). An additive model analysis between genotypes (AG+GG vs AA) in both groups, demonstrated a significant association between carriers of the A allele and high sFas levels. In conclusion, carrying the double dose of A allele of FAS -670A>G polymorphism is associated with high levels of sFas in pSS, but it is not a susceptibility marker for pSS.

Altered serum content of brain-derived neurotrophic factor isoforms in multiple sclerosis

In multiple sclerosis (MS), brain-derived neurotrophic factor (BDNF) provides neuroprotection, but can also promote disease through the maintenance of autoreactive T cells. One aspect that has not been explored yet in MS is related to the opposite functions of BDNF protein isoforms consisting of the pro-BDNF precursor, which has pro-apoptotic effects, and two proteolytic isoforms, the mature BDNF with pro-survival effects and truncated BDNF, with unknown functions. Using ELISA and semi-quantitative Western-blot we determined the relative serum levels of BDNF isoforms in 20 relapsing–remitting MS patients without any disease modifying therapy and 20 age and gender-matched healthy controls and searched for clinical correlates. Total serum BDNF was lower in MS than in HC. We demonstrate that the capture and detection antibodies of the ELISA kit from Promega are able to recognize all three isoforms but with different efficiency. Using Western-blot analysis, we show that the percentage of serum mature BDNF and pro-BDNF with respect to total serum BDNF was significantly decreased, while truncated BDNF was increased. No correlation between BDNF isoform percentage and clinical or demographic features was found. Serum Fas (sFas) was increased. These results support and expand the current hypothesis on the role of BDNF in multiple sclerosis, in that low pro-BDNF and high sFas might result in a failure to limit autoreactive T cells by apoptotic deletion and decreased mature BDNF may not provide enough neuroprotection, while truncated BDNF percent increase could be a compensatory mechanism. Hence, future studies on MS should take into account BDNF proteolytic processing.

Apoptosis markers soluble Fas (sFas), Fas Ligand (FasL) and sFas/FasL ratio in patients with bacteremia: A prospective cohort study

Recent studies have shown that immunoparalysis and lymphocyte apoptosis play a critical role in severe bacteremia. Monitoring apoptosis on a routine basis in septic patients has proved challenging. We here studied the prognostic value of apoptosis markers human soluble Fas (sFas), Fas ligand (FasL) and sFas/FasL ratio in patients with bacteremia. sFas (ng/ml) and FasL (ng/ml) concentrations in plasma were determined using commercial quantitative enzyme immunoassays (Quantikine®, R&D Systems Inc., Minneapolis, MN, USA) in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, β-hemolytic streptococcae or Escherichia coli. Maximum sFas, minimum FasL and high sFas/FasL ratio predicted high SOFA score in bacteremic patients (p<0.001, p=0.003 and p<0.001, respectively). AUC(ROC)'s in the prediction of high SOFA score for sFas, FasL and sFas/FasL ratio were 0.70 (CI 0.61-0.79), 0.65 (CI 0.56-0.75) and 0.72 (CI 0.63-0.80), respectively. High sFas concentrations and sFas/aFasL ratio, assessed using ROC curve as regards high SOFA (≥4) score, were associated with hypotension (p=0.001 and p=0.039, respectively). All of these markers predicted a high SOFA score independently in a logistic regression model. Maximum sFas, sFas/FasL ratio or minimum FasL during days 1-4 after blood culture were not associated with increased case fatality. Apoptosis markers sFas, FasL or sFas/FasL ratio are associated with high SOFA score in bacteremia.

The Prognostic Impact of Soluble Apoptosis-Stimulating Fragment on Mortality in Patients With Carotid Atherosclerosis

Markers of apoptosis are associated with cardiovascular disease. The soluble apoptosis-stimulating fragment (sFAS) was found to be a predictor for outcome in patients with heart failure, but its importance in patients with atherosclerotic disease has not been fully understood as yet. The aim of the present study was to investigate the impact of sFAS on all-cause and cardiovascular mortality in patients with atherosclerosis in the carotid arteries. We studied 981 of 1286 consecutive patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex Doppler sonography. Patients were prospectively followed for long-term all-cause and cardiovascular mortality. During a median follow-up of 6.2 years (interquartile range, 5.9 to 6.6 years), a total of 250 deaths (25.5%), including 165 (66%) cardiovascular deaths, were recorded. The risk for all-cause and for cardiovascular mortality, respectively, increased significantly with sFAS concentrations (P<0.001). The hazard ratio for all-cause death was elevated by 2.3-fold (P<0.001) and for cardiovascular death by 2.4-fold (P<0.001) in patients within the highest quintile of sFAS compared with patients within the lowest quintile, respectively. Results remained significant after adjustment for potential confounders and established cardiovascular risk factors, including high-sensitivity C-reactive protein. Patients with high sFAS but low high-sensitivity C-reactive protein had a comparable survival rate with those with elevated high-sensitivity C-reactive protein only (P=0.50). Markers of apoptosis, as measured by sFAS, were found to be independent risk predictors for death in patients with atherosclerotic disease in the carotid arteries.

Serum DNase I, soluble Fas/FasL levels and cell surface Fas expression in patients with SLE: a possible explanation for the lack of efficacy of hrDNase I treatment

The objectives of the study are to evaluate DNase I serum levels and their correlation with soluble Fas (sFas) and soluble Fas ligand (sFasL) and with cell surface Fas expression in patients with systemic lupus erythematosus (SLE), thus contributing to the dysregulated apoptosis typical of the disease. The methods include the following: Serum DNase I levels in patients and in controls were detected using the dot blot method and quantified by densitometry; sFas and sFasL were quantified using an ELISA system. Cell surface Fas expression was evaluated by FACS analysis. Apoptosis was studied by means of internucleosomal DNA degradation using a commercially available kit. The results are as follows: We found a significant difference in DNase I, sFas and sFasL serum levels between patients and controls. Levels of DNase I <7.79 ng ml(-1) are more represented in patients with SLE. Active SLE is strongly associated with high sFas levels and detectable sFasL. DNase I does not correlate with sFas or sFasL, whereas it correlates with T cell surface Fas expression that is higher in patients with active SLE than in healthy controls. Finally, administration of exogenous human recombinant DNase (hrDNase) I to freshly isolated T cells up-regulates cell surface Fas expression and induces increased susceptibility to Fas-mediated apoptosis. In conclusion, our findings confirm that DNase I is low in SLE and suggest that it may play a role in apoptosis in SLE by regulating the surface expression of the cell death molecule Fas. This role may contribute to explain the inefficacy of hrDNase I in SLE, a treatment proposed for the ability of DNase I to remove DNA from auto-antigenic nucleoprotein complexes.

Prognostic value of apoptosis markers in advanced heart failure patients

Apoptosis plays an important role in the progression of heart failure (HF). The purpose of this study was to assess whether the pro-apoptotic molecules apoptosis-stimulating fragment (FAS, CD95/APO-1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) predict event-free survival of HF patients. We assayed soluble (s)FAS and sTRAIL levels in 351 patients with advanced HF. During the median follow-up time of 16 months, 175 patients (50%) experienced the composite endpoints: rehospitalization and death. The hazard increased with sFAS concentrations, with a hazard ratio of 2.3 comparing fourth and first quartiles. This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model (P = 0.014). Patients with high sFAS but low BNP had a comparable event-free survival rate with those with elevated BNP only (P = 0.78). Conversely, high sTRAIL concentrations were related to a better prognosis. Particularly, the risk of mortality dropped by 70% in the fourth quartile of sTRAIL (P = 0.001, multivariable Cox regression model). sFAS is an independent risk predictor in advanced HF patients. It may be of particular value for the identification of high-risk patients in addition to BNP. Conversely, sTRAIL appears to be protective and could be an interesting therapeutic agent.

Second Report of Clinical Significance of sFas for DLBCL Treated with CHOP and New Analysis of sFas for DLBCL Treated with R-CHOP.

Introduction: We have previously reported serum concentration of sFas predict a clinical outcome of patients with DLBCL. Here, we added the number of patients and confirmed that a high serum sFas level was associated with unfavorable prognosis of patients with DLBCL.Patients and methods: We used a prospective, consecutive entry design, and the study protocol was approved by the Institution's Review Board. Between October 1995 and September 2002 previously untreated 132 patients with DLBCL (Group A: patients treated without rituximab) and between December 2002 and March 2007 previously untreated 75 patients with DLBCL (Group B: patients treated with rituximab) confirmed by biopsy participated in this study. We considered eligible for this study all patients with histologically confirmed diagnosis of DLBCL, according to the Working-Formulation and the WHO classification. Serum sFas was determined using ELISA. Patients were assigned to receive eight cycles of CHOP or THP (tetrahydropyranyl-adriamycin) -COP therapy before September 2002. The patients who had been registered after October, 2002 received the R-CHOP or R-THP-COP therapy. A serum sFas level of 3.0ng /ml was used as the cut-off value in this study. All follow-up data were updated on March 1, 2007.Results: In Group A: 132 patients were enrolled in this category (82 males, 50 females, age; 14 to 92 years, median; 66 years). IPI scoring was available in all patients; accordingly 18.2% patients were classified as low risk, 25.8% as low-intermediate; 32.6% as high-intermediate, and 23.5% as high risk. Overall, the CR rate was 73.5%; PRs were observed in 7.6% and failures in 18.9%. The CR rates for patients with an sFas level of 3.0ng /ml and over and less than 3.0ng /ml were 51.1% and 81.6%, respectively (P<0.0005). The 5-year OS rates for patients with an sFas level of 3.0ng /ml and over and less than 3.0ng /ml were 19.8% and 61.9%, respectively (P<0.0001). In Group B: 75 patients were enrolled in this category (42 males, 33 females, age; 24 to 88 years, median; 69 years). IPI scoring was as follows; 22.6% patients were classified as low risk, 26.6% as low-intermediate; 21.3% as high-intermediate, and 29.3% as high risk. Overall, the CR rate was 72.0%; PRs were observed in 22.7% and failures in 5.3%. The CR rates for patients with a sFas level of 3.0ng /ml and over and less than 3.0ng /ml were 65.6% and 76.7%, respectively (NS). The 2-year OS rates for patients with an sFas level of 3.0ng /ml and over and less than 3.0ng /ml were 54.7% and 92.2, respectively (P<0.01). Multivariate analysis using the proportional hazards model revealed that sFas concentration significantly correlated with overall survival in both group A and B (p<0.05).Discussion: The IPI is now considered as the most reliable index. After introduction of rituximab to treat for B cell lymphoma, the change of the prognostic factor is expected. In this examination, initially, we could confirm that sFas was an important prognostic factor for DLBCL in the patients who are treated with CHOP regimen as a result of extending the period of surveillance. In addition, we could show that sFas is a useful prognostic factor for DLBCL in the patients who are treated with R-CHOP regimen, too.Conclusion: Serum sFas is a significant prognostic factor for DLBCL and a useful tool for selecting the appropriate therapeutic strategy in patients with DLBCL.

Discrepant expression of membrane and soluble isoforms of Fas (CD95/APO-1) in adult T-cell leukaemia: soluble Fas isoform is an independent risk factor for prognosis.

The Fas signalling system probably plays a critical role in the natural and chemotherapeutic cell death machinery, suggesting that aberrant Fas expression is involved in growth control of tumours. The membrane isoform (mFas) is a 45 kD cell surface protein containing a single transmembrane region, and induces apoptosis in normal or tumour cells, whereas the soluble isoform (sFas) lacks the transmembrane domain due to alternative splicing of the transcript and is thought to block Fas-mediated apoptosis. To clarify the clinical roles of expression of these two Fas isoforms in adult T-cell leukaemia (ATL), we investigated the levels of the Fas isoforms in 81 patients with ATL. The expression patterns of the Fas isoforms were heterogenous, and there was no significant correlation between mFas and sFas levels: 10/81 cases were negative for mFas and had high serum sFas levels, whereas the remaining 71 cases were positive for mFas and had various levels of expression of the two Fas isoforms. Irrespective of the status of mFas expression in leukaemic cells, the mRNAs encoding these isoforms were always detectable, indicating the potential for protein translation. Although mFas expressed on freshly isolated ATL cells could iduce apoptosis in vitro, positive versus negative mFas status was not associated with any clinical aspects of ATL, whereas the sFas level was strongly correlated with clinical parameters such as serum LDH activity, tumour burden, serum soluble IL-2R level, hypercalcaemia and prognosis. These results suggest that the ratio of Fas isoforms varies, and high expression of the sFas protein and message reflects the malignant behaviour of ATL and is an independent risk factor for the prognosis.

A high serum soluble Fas/APO-1 level is associated with a poor outcome of aggressive non-Hodgkin's lymphoma.

Soluble Fas (sFas) in the serum is believed to be able to inhibit apoptosis of lymphocytes. It has been reported that the serum sFas level is increased in various diseases, including malignant lymphoma and systemic lupus erythematosus. We studied the association between sFas and the prognosis of patients with aggressive non-Hodgkin's lymphoma (NHL). Compared with normal controls, the serum sFas level was increased significantly in patients with aggressive NHL and adult T cell leukemia/lymphoma. Among patients with aggressive NHL, the complete remission rate was significantly decreased in the subgroup having high serum sFas levels. Both the overall survival rate and the disease-free survival (DFS) rate were significantly lower for this subgroup than for patients with low serum sFas levels. The 5-year survival rates estimated by the Kaplan-Meier method for patients with high and low serum sFas levels were 27.6% and 68.3%, respectively (P = 0.0001). The 5-year DFS rates estimated for patients with high and low serum sFas levels were 44.7% and 71.9%, respectively (log-rank test: P = 0.0023, and generalized Wilcoxon test: P = 0.0014). Among patients with a low and low-intermediate risk group according to the International Prognostic Index (IPI), the 5-year survival rates for low and high serum sFas subgroups were 72.8% and 42.0%, respectively, showing a significant difference (Wilcoxon test: P = 0.0163, log-rank test: P = 0.0115). Among patients with a high-intermediate and high risk group, the 5-year survival rates for low and high serum sFas subgroups were 51.6% and 17.4%, respectively, again showing a significant difference (Wilcoxon test: P = 0.0001, log-rank test: P = 0.0002). Multivariate analysis of a series of prognostic factors, including the five used to calculate the IPI, showed that the serum sFas level was an independent prognostic factor for the overall survival. Based on these results, a serum sFas level of 10 ng/ml or more can be considered to indicate a poor prognosis in patients with advanced NHL, and this finding may be useful for developing strategies for further treatment.