Hyperhomocysteinaemia and immune activation in patients with cancer.

BACKGROUND: Recently, homocysteine production was observed in tumour cell lines and homocysteine was proposed as a tumour marker. Furthermore, homocysteine production by activated immunocompetent cells was demonstrated. METHODS: In this study, homocysteine metabolism and immune activation status were investigated in 128 patients suffering from various types of cancer (haematological disorders, lung cancer, gastrointestinal tumours, gynaecological cancer and tumours of other localisation) and healthy age-matched controls. RESULTS: A high percentage of patients (39.1%) showed moderate hyperhomocysteinaemia, while cysteine, folate and vitamin B(12) concentrations were within reference ranges. Most patients were found to have elevated concentrations of the immune activation and inflammation markers neopterin and C-reactive protein (CRP), as well as a higher erythrocyte sedimentation rate (ESR). Patients of different cancer groups differed significantly regarding vitamin B(12) and neopterin concentrations; higher B(12) levels were also associated with tumour progression. Univariate regression analysis showed that CRP, ESR and neopterin were suited best to predict death. In multivariate analysis, neopterin was best suited to predicting death, while homocysteine and B vitamins were not associated with patient outcome. Homocysteine concentrations were correlated with folate and cysteine levels. Higher neopterin concentrations coincided with lower folate concentrations, but higher vitamin B(12) concentrations. CONCLUSIONS: Associations between neopterin and folate concentrations may indicate that cellular immune activation might partly contribute to the development of folate deficiency in cancer patients, thus possibly also impairing homocysteine remethylation.     

Determination of neopterin in serum and urine

Concentrations of neopterin, a product of activated macrophages, in serum from 662 apparently healthy individuals (ages 1 to 97 years, median 22 years) were measured by radioimmunoassay and the results statistically analyzed. Consistent with prior investigations on the urinary excretion of neopterin, we found no significant sex dependence, but values for subjects younger than 18 or older than 75 years were significantly higher. Renal clearance of neopterin in nine healthy individuals was 218 (SD 44) mL/min, which suggests that the kidneys have an active role in neopterin excretion. Results for neopterin concentrations measured in serum by RIA and "high-performance" liquid chromatography (HPLC) are consistent, but for urinary neopterin the concordance between methods was weak. Therefore, the RIA should be used only for measuring neopterin in serum. In comparison of the clinical utility of serum neopterin and urinary neopterin/creatinine concentrations, in patients with gynecological tumors, the latter values (measured by HPLC) discriminated slightly better between patients with favorable and unfavorable prognoses.     

Prognostic significance of urinary neopterin levels in patients with hepatocellular carcinoma

Urinary neopterin levels were measured by high-performance liquid chromatography in 15 patients with liver cirrhosis, 18 patients with hepatocellular carcinoma and 20 normal subjects. The mean levels of urinary neopterin in patients with hepatocellular carcinoma were significantly elevated (p less than 0.01) compared to those in cirrhotics and normal subjects, but did not significantly differ between cirrhotics and normal subjects. Urinary neopterin levels correlated significantly with tumor size in patients with hepatocellular carcinoma but not with serum alpha-fetoprotein. Hepatocellular carcinoma patients with high urinary neopterin levels appeared to have more serious hepatic dysfunction than those with normal urinary neopterin levels, and moreover, there was a significant difference (p less than 0.05) in survival between the two groups. These findings suggest that urinary neopterin excretion may be a good biochemical marker to assess the progression of tumor and a useful prognostic indicator in patients with hepatocellular carcinoma.     

Neopterin and beta 2-microglobulin and the assessment of intra-blood-brain-barrier synthesis of HIV-specific and total IgG

In HIV-seropositive patients, we evaluated the clinical utility of measuring combinations of serum and CSF levels of neopterin and beta 2-microglobulin (beta 2-M) (by RIA), as well as the intra-blood-brain-barrier (IBBB) IgG synthesis rate, IgG index, and HIV antibody index (by rate nephelometry, EIA, and formulae) for the assessment of HIV infection of the CNS. We studied paired sera and CSF from 31 HIV-seropositive patients: asymptomatic (16), ARC (12), and AIDS (3). A normal serum neopterin level predicts normal levels of serum beta 2-M, CSF neopterin, or CSF beta 2-M in 90%, 100%, and 100%, respectively, of our patients. An elevated serum neopterin level predicts an elevated level of serum beta 2-M or CSF neopterin in 81% and 62%, respectively, of cases. The HIV antibody index and IBBB IgG synthesis rate or IgG index must be determined separately because they do not predict each other and are not predicted by levels of neopterin or beta 2-M.     

The clinical importance of the dynamic determination of the serum neopterin level in patients with dilated cardiomyopathy]

Serum neopterin was measured over time (from 3 to 24 months) by RIA in 15 patients with dilated cardiomyopathy. Comparison with the clinical data revealed that the initially normal concentration of neopterin (less than 9 nM/l) was associated with a stable disease course on a long-term observation (group I). The second group with an initially high neopterin concentration showed an objective improvement of the health status together with normalization of the neopterin level. The third group of patients were characterized by an increase of the neopterin level measured over time, coupled with a disease progress. It should be noted that 5 out of 8 patients died. In addition to neopterin measurements, the patients with dilated cardiomyopathy were examined for serum beta-2-microglobulin (beta-2M). Analysis of the data obtained has demonstrated a similar relationship between the level of neopterin and beta-2M and the clinical course of dilated cardiomyopathy. Still, neopterin is a more sensitive marker. Therefore, the data obtained attest to a possibility of the use of serum neopterin as a prognostic marker in patients suffering from dilated cardiomyopathy.     

非霍奇金淋巴瘤患者血清和尿新喋呤的表达研究

为了研究血清和尿液中新喋呤、血清LDH和β2微球蛋白的表达水平与非霍奇金淋巴瘤疗效的相关性,采用酶联免疫吸附试验(ELISA法)检测27例非霍奇金淋巴瘤患者治疗前后血清和尿液中的新喋呤含量,同时检测血清LDH水平和血清β2微球蛋白含量,分析比较治疗前血清和尿液中的新喋呤水平、血清LDH、β2微球蛋白与患者疗效的关系。研究结果显示:完全缓解和部分缓解的患者治疗前后的血清和尿液中新喋呤水平、血清LDH、β2微球蛋白值均明显低于稳定和进展组患者(P<0.05)。结论:治疗前血清和尿液中新喋呤值、血清LDH、β2微球蛋白值均可作为预测非霍奇金淋巴瘤疗效的重要指标,其中检测尿液中新喋呤值更为稳定和方便。     

Endocrine interrelationships in patients with malignant testicular tumours (author's transl)

Testicular function was investigated in 40 patients with malignant testicular tumours of different histology and tumour stage, by spermatological and endocrinological analyses. In patients without ectopic production of beta-HCG in the tumour tissue a hypergonadotropic tubular disfunction of the testis was present, resulting in elevated plasma FSH concentrations and moderate to severe oligozoospermia. Ectopic production of beta-HCG in the tumour stimulates the secretion of 17 beta-oestradiol, particularly in the Leydig cells, which suppresses pituitary gonadotropin secretion via negative testicular pituitary feedback. Spermatological analyses showed severe spermatogenetic disorders. Prolactin levels, however, were not altered in patients with testicular cancer.     

Neopterin is an independent prognostic variable in females with breast cancer.

BACKGROUND: Neopterin, produced by human monocytes/macrophages upon stimulation by interferon-gamma, is a sensitive marker for monitoring Th1-cell immune response in humans. In malignant diseases, the frequency of increases in neopterin in the serum and urine of patients depends on tumor stage and type. METHODS: In a retrospective study comprising 129 females with breast cancer, urinary neopterin/creatinine ratios were measured at the time of diagnosis. Tumor characteristics were determined concomitantly. RESULTS: Urinary neopterin was increased in 18% of the patients. It did not correlate with tumor size or lymph node status, but it was influenced by the presence of distant metastases (P <0.05) and by tumor differentiation (P = 0.01). When product-limit estimates were calculated after follow-up for up to 13 years (median follow-up, 56 months), the presence of distant metastases (P <0.001), neopterin (P <0.001), tumor size (P = 0.001), and lymph node status (P <0.01) were significant predictors of survival. By multivariate analysis, a combination of the variables presence of distant metastases (P <0. 001), neopterin (P <0.01), and lymph node status (P <0.05) was found to jointly predict survival. In lymph node-negative patients without distant metastases, the relative risk of death associated with increased neopterin concentrations was 2.5 compared with patients with neopterin concentrations within the reference interval. CONCLUSION: Urinary neopterin provides additional prognostic information in patients with breast cancer.     

Serum neopterin, tumor necrosis factor-alpha and soluble tumor necrosis factor receptor II (p75) levels and disease activity in Egyptian female patients with systemic lupus erythematosus

OBJECTIVE: To determine the clinical value of assaying serum levels of neopterin, tumor necrosis factor-alpha (TNF-alpha) and soluble tumor necrosis factor receptor II (p75) (sTNFRII) in patients with systemic lupus erythematosus (SLE), manifested clinically with lupus nephritis (LN), neuropsychiatric lupus erythematosus (NPLE), and/or vasculitis compared with established parameters (complements C3 and C4). PATIENTS AND METHODS: Serum concentrations of neopterin, TNF-alpha and sTNFRII were studied in 40 female patients with SLE at various degrees of disease activity and in 10 healthy controls, matched for age and sex, using an ELISA kit. Disease activity was assessed by the SLE disease activity index (SLEDAI) score. Thirty-five, 30 and 28 of our patients presented with LN, NPLE and/or vasculitis, respectively, as the main clinical manifestation. RESULTS: Serum levels of neopterin, TNF-alpha and sTNFRII were significantly increased, while the TNF-alpha/sTNFRII ratio, C3 and C4 levels of SLE patients were significantly lower than those of healthy controls. Neopterin and sTNFRII were the only parameters that showed significantly higher levels in SLE patients with mild activity compared to normal subjects and were the only parameters that showed a significant elevation in membranous nephritis and in mild NPLE compared to patients without nephritis and NPLE. Patients with vasculitis had significant elevation of serum neopterin, TNF-alpha and sTNFRII levels compared to patients without vasculitis. We found significant correlations between all measured variables and the SLEDAI score. Also, serum neopterin levels showed significant positive correlation with serum TNF-alpha, sTNFRII and TNF-alpha/sTNFRII levels. Serum neopterin and sTNFRII could be used to identify SLE patients from normals with a sensitivity and specificity of 100%. Multivariate linear regression analysis showed that serum sTNFRII was the only significant independent variable among parameters for prediction of SLE disease activity. CONCLUSION: We suggest that serum sTNFRII and neopterin are more sensitive markers of disease activity than TNF-alpha, C3 or C4. However, sTNFRII may be a clinically useful independent marker for prediction of SLE disease activity and to differentiate normal subjects from those having mild SLE.     

Neopterin as a predictive marker for disease progression in human immunodeficiency virus type 1 infection

We assessed the value of urinary neopterin concentrations for prognosis of disease progression in HIV-1-infected patients. Sixty-eight anti-HIV-1 seropositive homosexuals with lymphadenopathy syndrome were tested for urinary neopterin and T-cell subset counts in 1982-83, and the incidence rate at which they developed acquired immunodeficiency syndrome (AIDS) between then and May 1988 was evaluated. Overall, 21 of 68 (30.9%) cases progressed to AIDS, with a yearly progression rate of 4-9%. The predictive value of urinary neopterin concentrations was higher (P = 0.0042) than that of CD4+ T-cell counts (P = 0.015) or the CD4+/CD8+ T-cell ratio (P = 0.022). Counts of CD8+ T-cells failed to show predictive significance (P = 0.29). Similarly, multivariate-regression analysis indicated that neopterin concentrations and CD4+ T-cell numbers were significant copredictors. Produced by human macrophages activated by interferon gamma, neopterin is thus a marker of macrophage activation via T cells. We conclude that these data demonstrate a correlation between the amount of T-cell-macrophage activation, as measured by urinary neopterin concentrations, and the progression of the disease.     

Plasma spermidine concentrations in patients with tumours of the breast or prostate or testis

Plasma spermidine concentrations were measured by radioimmunoassay in normal subjects and in patients with various tumours of the breast, prostate or the testis. The sensitivity of the method was 0.45 pmol spermidine/20 microliter plasma and the cross reactivity was 13% with putrescine and 2% with spermine. Plasma spermidine concentrations were raised in 25% of the patients with prostatic cancer (mean concentration 316.7 +/- 240.69 nmol/l) and in 8% of the patients with benign prostatic hyperplasia (mean concentration 198.9 +/- 169.92 nmol/l). No correlation was found between elevated plasma levels of spermidine in the prostatic cancer patients and tumour stage or metastatic status of the patients. No correlation of plama spermidine concentrations and age was found in 61 normal male subjects (mean concentration 200.3 +/- 137.71 nmol/l plasma). Only 29% of the patients with breast carcinoma had elevated levels of spermidine compared to normal female subjects. Plasma spermidine concentrations did not correlate with clinical stage or oestrogen receptor status in these patients. Patients with testicular tumours had elevated mean concentrations of plasma spermidine. One out of five patients with seminoma of the testis and six out of 16 patients with teratoma of the testis had significantly elevated concentrations.     

Experiences in the treatment of advanced nonseminomatous testicular tumor

48 patients with nonseminomatous testicular tumours were treated between 1980 and 1984. 19 patients had bulky stage II c or disseminated disease; according the Royal Marsden staging classification 5 patients had stage II c, 2 patients III and 12 patients stage IV. The pT stage of the primary tumour showed no correlation to low stage disease, but pT was only found in advanced disease. In disseminated disease histological examination revealed more cases of malignant teratoma undifferentiated (MTU) and malignant teratoma trophoblastic (MTT) than malignant teratoma intermediate (MTI). Before therapy 14 patients had elevated serum markers, whilst in 5 patients markers were negative. Combination chemotherapy with Vinblastin, Bleomycin and Cisplatin (Einhorn) was given and afterwards 13 patients had to undergo operation to remove a residual mass. Scarring was found in 4 patients (31%), teratoma in 6 (46%) and active tumour in 3 (23%). At a median survival time of 3 years 16 of 19 patients (84%) are alive. The two patients with elevated tumour markers before operation are also alive and disease-free. Altogether out of 48 patients with advanced nonseminomatous testicular tumours 94% of the patients are alive.     

Urinary neopterin in patients with systemic lupus erythematosus

Concentrations of neopterin were measured in urine specimens from 35 patients with active and eight with inactive systemic lupus erythematosus (SLE). Compared with those of apparently healthy controls, neopterin concentrations were higher in patients with active disease (P less than 0.001) and with inactive disease (P less than 0.01), those in patients with active disease being significantly higher than those in patients with inactive disease (P less than 0.001). The correlation between the neopterin concentration and evidence of disease activity was good. All of the patients with clinically active SLE had increased neopterin, but for only 37.5% (three of eight) did the neopterin concentration exceed the upper normal limit during clinical remission. The increase in neopterin concentration did not correlate with clinical courses or severity of renal function. Moreover, serial determinations of neopterin in active SLE patients showed a rapid decrease of initially high concentration, paralleling a decline of clinical activity after initiation of medical therapy. Thus, urinary neopterin may be a useful marker for monitoring disease activity in SLE patients.     

新喋定、CA19-9和TPS在胰腺癌和慢性胰腺炎中的临床诊断价值

目的 研究新喋定、CA19-9和组织多肽特异性抗原（polypeptide-specific antigen,TPS）对胰腺癌和慢性胰腺炎的鉴别诊断价值.方法 选取2010-2012年75名胰腺癌患者和62例慢性胰腺炎患者,同时选择50例健康人作为对照,采集临床资料,检测血清CA19-9、新喋定和TPS,并进行统计学分析.结果 胰腺癌患者的新喋定（17.7 nmol/L）,CA19-9（102.2U/ml）和TPS（135.3 U/L）高于慢性胰腺炎患者（6.1 nmol/L,23.5 U/ml,61U/L）（p＜0.01）.慢性胰腺炎患者TPS和CA19-9高于正常对照组（40U/1,9.3 U/ml） （P＜0.01）,而新喋定差异无统计学意义（P＞0.05）.新喋定对胰腺癌的灵敏度和特异度（92.2％,87.3％）高于CA19-9（82.2％,75.3％）和TPS（72.2％,64.3％）.结论 新喋定对鉴别胰腺癌和慢性胰腺炎具有较好的诊断价值.     

Increased serum neopterin concentrations in patients with Alzheimer's disease.

We measured serum neopterin concentrations in 24 patients with Alzheimer's disease (8 males, 16 females; age: 73.1+/-6.2 years; free of any infectious process) and fourteen controls of similar age (4 males, 10 females; age: 69.7+/-8.8 years). Compared to controls, significantly higher concentrations of neopterin (p< 0.01) were found in patients with Alzheimer's disease. Among patients, concentrations of neopterin were higher in those with lower mini-mental-state (p < 0.05), and an inverse correlation existed between mini-mental-state and neopterin concentrations. No such association existed with the duration of the disease. There were also significant correlations between neopterin and serum concentrations of immune activation markers such as soluble tumor necrosis factor (TNF) receptor and soluble interleukin-2 receptor (all p<0.01). Thus, increased concentrations of neopterin in serum of patients with Alzheimer's disease correlate with the severity of dementia. The data imply a chronic state of peripheral immune activation in Alzheimer's disease.     

Neopterin as discriminating and prognostic parameter in healthy homosexuals, ARC and AIDS patients

Urinary neopterin, a sensitive marker for activation of cell mediated immunity, is compared to clinical and laboratory data in 5 patients with AIDS, in 15 patients with ARC and in 40 male subjects without AIDS-related clinical signs attending an AIDS outpatient clinic. The sensitivity of neopterin for AIDS-related diseases was higher than that of the CD4+/CD8+ subset ratio. The differences in neopterin levels between the controls, ARC and AIDS patients were found to be more significant than the T-cell subset data. The observation that the 3 AIDS patients with the highest neopterin levels have died whereas the two others with the lower levels are still alive also underlines the prognostic potential of urinary neopterin level determinations. Measurement of urinary neopterin is thus recommended as an additional criterion for monitoring ARC and AIDS patients.     

The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases.

The accumulated knowledge about the organization and function of the human immune system contributes to a better understanding of the pathogenesis of most diverse disorders and is opening new avenues for therapeutic regimens. To gain further insight into the complex interactions within the components of the immune system, it has become increasingly necessary to develop rapid and simple methods to monitor the status of the immune system in patients. The determination of neopterin concentrations in human body fluids allows to investigate sensitively the cell-mediated immune status to be investigated with considerable sensitivity. In recent years it was shown that production and release of neopterin is inducible in human monocytes/macrophages by interferon gamma. Increased neopterin levels indicate endogenous formation of gamma interferon, and monitoring of neopterin levels therefore permits the activation status of the cell-mediated immune system to be examined. Neopterin concentrations in serum and in urine increase in parallel to the clinical course of infections with viruses, intracellular bacteria, and parasites. In patients with human immunodeficiency virus infection neopterin concentration in serum and urine is a significant predictor of disease progression, the statistical power being similar to CD4+ T-cell numbers. In patients with autoimmune disorders, neopterin levels correlate with the extent and the activity of the disease. Neopterin concentrations are also sensitive indicators of immunological complications in allograft recipients. In certain malignant diseases neopterin concentrations correlate with the stage of the disease and bear prognostic information. Results of neopterin measurements agree with the important role that the cellular immune system plays in these disorders.     

Neopterin--an early marker of surgical stress and hypoxic reperfusion damage during liver surgery.

Neopterin is elevated in infections, autoimmune diseases and post-transplant. Recently neopterin elevation was linked to stress response and malignancy. To determine early changes of serum neopterin caused by surgical stress and to investigate their association with other inflammatory markers and with malignancy, we measured neopterin, C-reactive protein (CRP) and procalcitonin (PCT) levels at four predefined time-points within 24 hours in 27 patients admitted for liver resection. Our results show that neopterin increased during operation and the increase was not related to preoperative neopterin levels. On the first day after surgery neopterin level was not significantly different from postoperative levels. In patients with malignant disease neopterin concentration before operation was higher than in patients with non-malignant disease, however, the increase in neopterin concentration during operation was not different between both patient groups. During surgery CRP and PCT did not increase significantly. On the first postoperative day CRP and PCT were elevated and their levels correlated with neopterin (Pearson's correlation coefficient r=0.51 and r=0.76, respectively). We conclude that neopterin elevation during liver resection contributes major part to the increased levels observed on the first postoperative day. Perioperative neopterin release can/may be related to stress response and hypoxia produced during operation. Using this marker, hypoxic reperfusion damage could be detected earlier and more accurately.     

血清免疫抑制酸性蛋白检测在妇科肿瘤中的应用价值

目的　评估血清免疫抑制酸性蛋白 (immunosuppressiveacidicprotein ,IAP)在妇科良、恶性肿瘤鉴别诊断及预后转归中的价值。方法　术后病理确诊的妇科疾病患者 15 0例 ,其中恶性 2 1例。术前全部检测血清IAP ,部分患者同时检测CA12 5。恶性患者化疗后及术后 2年随访IAP、CA12 5。结果　恶性肿瘤患者血清IAP高于良性疾病组 (P <0 .0 1) ;IAP阳性组中恶性肿瘤患者IAP值与良性疾病患者差异无显著性 (P >0 .0 5 ) ,但与除外炎症的良性疾病患者IAP值相比差异有显著性 (P <0 .0 1) ,随访化疗后及术后 2年恶性肿瘤患者IAP水平明显下降 (P <0 .0 1)。结论　IAP可作为妇科肿瘤鉴别诊断及预后随访的参考指标之一 ,IAP结合CA12 5检测有助于提高妇科恶性肿瘤的检出率     

Comparison of serum and urine neopterin concentrations in patients with HIV-1 infection

Urine and serum neopterin concentrations are now widely used to monitor patients with HIV-1 infection. However, there are no published studies comparing the levels in urine and serum, and relating both to the patients' immune status. Urine and serum neopterin concentrations correlated closely in our study population of 37 HIV-1 seropositive patients (34 homosexuals, 3 drug addicts) and 10 HIV-1 seronegative homosexuals. Our data further show that urine and serum neopterin concentrations correlate almost identically with the clinical and immunological presentation of HIV-1 infected individuals, as expressed by the Walter Reed Staging classification. In addition, there was no difference between the correlation of neopterin concentrations in either serum or urine with the Quetelet indices. It will depend on the clinical situation whether blood or urine sampling is preferred. Collection and handling of urine samples from HIV infected patients is less risky to health care personnel in HIV settings.