Microalbuminuria in Hodgkin's disease.

In some malignant disorders, it was reported that urinary albumin excretion (UAE) was correlated with the prognosis and the extent of the disease. In this study, 24-h UAE was determined in 34 Hodgkin's disease patients without prior treatment and 19 healthy controls. Microalbuminuria (MAU) was defined as UAE > or = 20 microg/min. In patients with MAU, UAE was determined again after the treatment. Mean UAE was 31.2 microg/min in the patient group and 5.6 microg/min in the controls (p = 0.005). Whereas MAU frequency was 47% in the patients, there was no MAU in the controls. Mean UAE tended to be higher in advanced stage patients compared to early stage patients (p = 0.051). Also, MAU frequency tended to be higher in the advanced stage group compared to the early stage group (p = 0.196). In four patients in whom remission could not have been achieved, although UAE was reduced, MAU did not disappear. In conclusion, UAE was increased in Hodgkin's disease. However, there is no significant correlation between UAE and the disease extent.

Increased urinary coproporphyrin excretion observed in patients with differently staged Hodgkin's disease treated with chemotherapy.

It has been reported that patients with Hodgkin's disease (HD) show altered porphyrin metabolism, and suggested that the cause is the neoplastic process itself. If this is true, disease progression should be associated with higher levels of porphyrin excretion. The aim of this study was to evaluate urinary coproporphyrin levels in patients with Hodgkin's disease at different stages. As many of the patients received chemotherapy, another aim was to verify experimentally whether chemotherapeutic agents might increase porphyrin levels in rabbits. All of the patients had above-normal urinary coproporphyrin levels. On the other hand, rabbits receiving the porphyrin precursor 5-aminolevulinic acid (5-ALA), and also treated with doxorubicin, showed very high plasma porphyrin levels. The increased levels of urinary coproporphyrins seem to be due to the disease itself, since the patients in stages III and IV had higher excretion values, presumably due to biochemical heme synthesis lesions that lead to the availability of the porphyrin precursor, as well as coproporphyrin accumulation and excretion. The altered porphyrin synthesis may be attributable to the cytotoxic oxygen species generated in the presence of NADH and iron. As the patients also received extensive chemotherapy regimes, the altered porphyrin metabolism may be affected by antineoplastic treatment generating oxygen reactive radicals. The alterations in porphyrin metabolism induced by chemotherapeutic agents appear to be demonstrated in rabbits in which doxorubicin increases porphyrin synthesis after porphyrin precursor treatment.

Prognostic markers of disease activity in Hodgkin's disease.

The erythrocyte sedimentation rate (ESR), liver alkaline phosphatase (ALP), serum copper (Cu) and urinary nucleoside excretion (UNs) have been proposed as independent prognostic markers in Hodgkin's Disease (HD). However, their prognostic value has not satisfactorily been directly compared to recognised clinical prognostic factors. One hundred and sixty-eight patients with HD had the above markers performed prior to initial treatment. At a median follow-up of 10.9 yrs, the predicted 10 year relapse free survival (RFS) and overall survival (OS) for the entire cohort is 64% and 66%, respectively. In general, patients with elevated markers were significantly less likely to achieve CR, remain in CR and survive. However, multivariate analysis revealed this was due to the association of elevated markers with stage and constitutional symptoms. Following therapy, elevated markers were also correlated with evidence of clinically detectable disease. We conclude that although UNs, Cu, ALP and ESR reflect disease activity, they do not provide independent information beyond that of clinical assessment.

Serum and urinary monoclonal immunoglobulins in Hodgkin's disease. Report of two cases.

Two patients with histologically unequivocal Hodgkin's disease (HD) (lymphocyte-depleted type, stage IIIA, and mixed cellularity variety, stage IVA) were found to have, respectively, a serum IgGk M-component and pure Bence Jones proteinuria of the lambda type. Unlike most of the previously reported patients with HD-associated monoclonal gammopathy (MG), they had simultaneous occurrence of HD and M-components, and no evidence of concurrent multiple myeloma or any other related B-lymphoproliferative disorder was found either at presentation or at postmortem examination. Both M-components were demonstrated before starting any cytotoxic treatment, and their appearance was unrelated to other disorders which may be associated with persistent antigenic overstimulation. In both patients the size of the M-components was reduced significantly by treatment for HD. Such findings make these patients of interest for exploring the significance of the coexistence of HD with MG.

Soluble interleukin-2 receptor and urinary neopterin concentrations in malignant lymphoma.

The serum concentrations of soluble interleukin-2 receptors and urine neopterin were studied in 82 patients with malignant lymphomas (25 patients with Hodgkin's disease and 57 patients with non-Hodgkin's lymphoma. Increases in soluble interleukin-2 receptors and in urinary neopterin were significantly correlated with the clinical phase of the disease. The average values in both Hodgkin's disease and non-Hodgkin's lymphoma patients suffering from the disease in its active phase were significantly higher than those of patients in complete remission. Neopterin concentrations (but not soluble interleukin-2 receptor concentrations) were also elevated in clinical stages III-IV of each disease. Urinary neopterin correlated directly and significantly with the erythrocyte sedimentation rate and inversely with haemoglobin. Finally, a longitudinal analysis showed a general tendency for the markers to return to normal values, in accordance with the favourable outcome of therapy; this was more evident for urinary neopterin than for soluble interleukin-2 receptors. These findings seem to confirm that soluble interleukin-2 receptors and especially urinary neopterin can be useful markers for monitoring and prognosis of malignant lymphomas.

High molecular weight transforming growth factor beta is excreted in the urine in active nodular sclerosing Hodgkin's disease.

To measure the in vivo secretion of high molecular weight (HMW) transforming growth factor (TGF)beta by Reed-Sternberg cells from patients with nodular sclerosing Hodgkin's disease, we studied the urine samples from untreated patients. The urinary proteins did not promote the proliferation of NIH-3T3 cells in monolayer culture and contained similar amounts of total TGF activity when compared with normal controls. Urinary proteins from 24 different control and test urines were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Either of two primary antibodies were used for immunoblot detection: (a) affinity column purified polyclonal anti-TGF beta 1 prepared against platelet TGF beta 1 or (b) monoclonal anti-HMW-TGF beta prepared against HMW-TGF beta secreted by cloned L-428 Reed-Sternberg cells. All patients with active nodular sclerosing Hodgkin's disease had a detectable HMW-TGF beta (approximately 300,000) which cross-reacted with both anti-TGF beta 1 and anti-HMW-TGF beta. Purification demonstrated HMW-TGF beta which was active at physiological pH. Twelve control urine samples from healthy adults and 5 follow-up samples from the Hodgkin's patients after successful treatment contained no detectable urinary HMW-TGF beta. The in vivo production of HMW-TGF beta in untreated nodular sclerosing Hodgkin's disease supports the conclusion that this growth factor is secreted in large amounts by Reed-Sternberg cells or cells stimulated by Reed-Sternberg cells.

Urinary gonadotropin fragment measurements in patients with lung and esophageal disease.

Urinary gonadotropin fragment (UGF), a small glycoprotein and an intracellular processing product of human chorionic gonadotropin, has been demonstrated in trophoblast tissue and in nontrophoblastic cancers. Levels of UGF were assayed in 107 patients with malignant and benign pulmonary and esophageal lesions to determine if elevated levels were associated with the presence or progression of malignancy. There were 64 patients with primary bronchogenic carcinoma, 9 with metastatic pulmonary malignancies, 7 with lymphoma, 2 with mesothelioma, 9 with esophageal carcinoma, 1 patient each with metastatic cancer to chest wall and carcinoid, and 14 patients with benign pulmonary and esophageal lesions. Sensitivity was only 24% for urine samples from patients with demonstrable cancer. False-positive rates were 6% and 12% for urine samples from patients with benign lesions and those without evidence of residual cancer following treatment, respectively. Although elevated levels of UGF are present in some patients with pulmonary and esophageal cancer it is neither sensitive nor specific enough for use as a tumor marker.

Urinary neopterin in malignant lymphoma.

Urinary neopterin levels were studied in 96 patients with malignant lymphomas. Twenty-eight had Hodgkin's disease and 68 non-Hodgkin's lymphoma. Neopterin excretion was significantly related to the clinical stage of the disease. Mean neopterin excretion in patients with active disease (634 +/- 527 mumol neopterin/mol creatinine) was significantly higher (p = 0.000) than in patients in complete remission (198 +/- 105 mumol neopterin/mol creatinine). Mean neopterin levels of patients in stage III-IV were higher than for patients in stage I-II. These findings were the same in patients with Hodgkin's disease and those with non-Hodgkin's lymphoma (659 +/- 593-425 +/- 316 mumol neopterin/mol creatinine), regardless of the histological subtype. A significant correlation was found between neopterin excretion, ESR (r = 0.31; p = 0.003) and hemoglobin (r = -0.40; p = 0.000). Longitudinal analysis showed a trend towards a correlation between response to therapy and neopterin excretion. These findings suggest that neopterin may be a useful prognostic marker in non-Hodgkin's lymphoma.

Monoclonal free light chains in urine and their significance in clinical diagnostics: are they really tumor markers?

Bence Jones proteins (monoclonal free light chains of immunoglobulins) are the earliest known biological markers of malignant cell dyscrasia; Bence Jones proteinuria is also present in many types of B cell-related neoplasms. Sometimes, it may also occur in Hodgkin's disease. In some cases, benign monoclonal gammapathy was found to be associated nontumorous diseases as well. The type of monoclonal light chain, the degree of polymerization, and the isoelectric point of the molecule may affect the course of the disease. Urine samples from 637 patients with true or suspected lymphoproliferative diseases were investigated over a 2-yr period by different immunochemical methods. Bence Jones proteinuria was identified in 71 cases by isoelectric focusing combined with immunofixation, while the pathological protein was detected only in 63 cases by conventional methods. Bence Jones proteins can be detected by this new method at a level below the sensitivity of conventional procedures. Bence Jones proteins in the urine may signal a malignant tumor or malignant transformation of an earlier disease. The early detection of monoclonal immunoglobulin light chains in the urine may be important in clinical diagnosis, therapy, and follow-up.

[The significance of analysis and detection of Bence Jones protein in the urine in clinical laboratory diagnosis]. / A vizelet Bence Jones fehérje kimutatásának és vizsgálatának jelentösége a klinikai laboratóriumi diagnosztikában.

Bence Jones proteins (monoclonal free light-chains of immunoglobulins) are the earliest known biologic markers of malignant plasma cell dyscrasia, but Bence Jones proteinuria is also found in many types of B-cell related neoplasms. In some cases it may occur in Hodgkin disease. In some cases benign monoclonal gammopathy related to non-tumor conditions was found. The type of the monoclonal light-chain, the polymerisation and the isoelectric point of the molecules are considerable factors in the development of the disease. Urine specimens from 637 patients with (or suspected) lymphoproliferative diseases were investigated in a two year period using different immunochemical methods. Bence Jones proteinuria was found in 71 cases with the new method (isoelectric focusing combined with immunofixation) and 63 cases by the conventional ones. Bence Jones proteins can be detected by this new method at level below the sensitivity of conventional procedures. Bence Jones proteins in the urine may call the attention to the malignant tumor or the malignant transformation of the disease. The early detection of the monoclonal light-chain excretion may be important in the respect of clinical diagnosis, therapy and the follow-up the clinical status of the patient.

Urinary 6-keto-PGF1 alpha level in patients with childhood leukemia/lymphoma; a possible indicator of vascular damage.

To determine the effect of anti-neoplastic chemotherapy on the vascular system(s) of children with leukemia/lymphoma, urinary excretion of 6-keto-PGF1 alpha was measured by radioimmunoassay (RIA). In 4 patients receiving therapy, 6-keto-PGF1 alpha increased to a mean of 148 (range; 126-170)% during therapy, then returned to pre-treatment level 3-5 days later. In 18 long-term survivors who had completed therapy, 6-keto-PGF1 alpha was determined to be a mean of 275 (range; 52-905) ng/g creatinine, and in the healthy control children the mean was 146 (range; 71-348) ng/g creatinine. These results were contrary to our hypothesis that chemotherapy might cause a decreased synthesis of PGI2, a precursor of 6-keto-PGF1 alpha, and suggest that increased urinary 6-keto-PGF1 alpha reflects a vascular response to acute exposure to chemotherapeutic drugs and possible vascular damage due to long-term intensive chemotherapy in pediatric patients with leukemia/lymphoma.

Urinary neopterin levels in hematologic malignancies.

We studied urinary excretion levels of neopterin in 30 cancer patients affected by non-Hodgkin's lymphomas, Hodgkin's disease and multiple myeloma compared to 30 healthy subjects. Mean value of neopterin excretion in cancer patients (576.01 +/- 620.37) appeared significantly increased (p less than 0.001) compared to normal controls (134.40 +/- 41.65). A neopterin excretion above the upper normal limit was observed in 23/28 (82%) patients with active disease. A trend to an increased urinary level of neopterin with more advanced stage was observed, namely in patients with bone marrow involvement and constitutional symptoms. We suggest that the evaluation of urinary neopterin levels may be of value in the diagnosis and follow-up of hematologic malignancies.

Modified nucleosides in body fluids of tumor-bearing patients.

The catabolism of nucleic acids, particularly tRNA, produces a variety of modified nucleosides which are not reutilized by mammalian cells. Investigation of these compounds in body fluids, mainly urine, has recently provided evidence of altered metabolic situations in tumor-bearing patients. The factors involved in the alterations of modified nucleosides formation are connected with altered tRNA-modifying enzymes and/or altered turnover of subpopulations of tRNA. A common pattern in tumor cells or tissues is the presence of isoaccepting tRNA species containing aberrant nucleoside modifications. Several modified nucleosides have been detected and quantitated by HPLC analysis of the urine of normal subjects and cancer patients. Results obtained, in the authors' laboratory, among others, indicate a possible correlation between urinary excretion of these compounds and the course of the disease, with implications for the follow-up of therapeutic treatment. Particular reference should be made to psi, which appears to be a suitable marker for monitoring these subjects. The data from the authors' laboratory also show that the analysis of modified nucleosides in blood may be considered a useful tool in the search for proper markers associated with the cancer status. In this respect psi is suggested as a biochemical indicator for cancer patients.

Polyamines as biological markers in malignant lymphomas.

The urinary polyamines putrescine (PU) and spermidine (SPD) were measured for 67 patients with lymphomas: 48 non-Hodgkin (NHL) and 18 Hodgkin's disease (HD). Monthly repeat measurements were obtained over an average follow-up period of 12.5 months. For NHL, a good association was observed between polyamine levels and the severity of the the stage; the distribution of values between nodular and diffuse forms was also significantly different. No such correlations were seen for HD. The evolution of PU values in time has been shown to reflect disease activity for NHL. Non-specific fluctuating Pu values were found in the case of HD. In the case of 20 patients with NHL undergoing chemotherapy, comparison of polyamine levels before and after chemotherapy allowed differentiation between the population of complete responders to treatment and those with only partial or no response.

[Paraneoplastic hypouricemia in Hodgkin's lymphoma secondary to a renal tubular reabsorption defect of uric acid (author's transl)]. / Hipouricemia paraneoplástica en el linfoma de Hodgkin por defecto en la reabsorción tubular postsecretora de ácido úrico.

A patient is reported with stage IV-B Hodgkin's lymphoma, lymphocyte depletion type, and associated hypouricemia (1,7 mg/dl). In the few cases described of this association hypouricemia was secondary to a high renal clearance of urate, but in no case was the involved tubular level precisely delimited. In the present case the pyrazinamide and the probenecid tests were performed, disclosing the existence of a possible defect in the postsecretory reabsorptive phase which was improved by therapy. The different pathogenetic mechanisms described to explain this transitory tubular defect are reviewed.

Increased urinary beta 2-microglobulin after cancer chemotherapy.

The serum and urinary concentrations of beta 2-microglobulin (beta 2-m) and creatinine and the urinary concentration of albumin and IgG were measured in 14 patients with hematologic malignancies before and during chemotherapy. There was a transient increase in urinary beta 2-m in nine of the 14 patients during chemotherapy. All of the nine patients but only one of the other five patients had had recent multiple chemotherapy. The urinary beta 2-m increased in 24 courses of chemotherapy given to these nine patients and was already abnormal before 13 of these courses. The increase in urinary beta 2-m was not associated with an increase in serum beta 2-m or a significant increase in urinary albumin or IgG excretion. These results suggest that chemotherapy causes a marked transient tubular proteinuria, particularly in patients who have had previous chemotherapy.

Individual changes of DNA catabolite excretion in the course of antitumor therapy of Hodgkin's disease.

In patients with morbus Hodgkin, treated primarily by the actino- and chemotherapy, the excretion was followed of DNA catabolites (deoxycytidine, deoxyuridine, thymidine and their sum) in the course of the therapy. The dynamics was studied of changes in the time interval of interest and attention was paid to its relation to the clinical and histological type of disease and to the successful character of the therapy defined by reaching a complete remission. The group of patients as a whole was characterized by an increased excretion of catabolites in the time interval of interest. No dependence was demonstrated between the catabolite excretion and extent of the disease similarly as between the excretion and successful character of the therapy. The dynamics of the changes in the time intervals of interest was neither remarkably nor continuously increased or decreased. The test of the excretion of pyrimidine deoxyribonucleosides possesses sufficient sensitivity for demonstrating laws in relation to the therapy during group evaluation. With respect to individual variability of values of particular patients and to the absence of the relations mentioned above the test is not suitable to indicate the individual response to the anticancer therapy.