Sensitivity of urinary mesothelin in patients with malignant mesothelioma.

INTRODUCTION: Malignant mesothelioma (MM) is an aggressive, uniformly fatal tumor usually caused by exposure to asbestos. Soluble mesothelin has been intensively investigated in the serum as a biomarker for this disease. As urine is less complex and less invasive to collect than serum and may be a more acceptable specimen for large-scale screening studies of asbestos-exposed individuals, we determined whether the sensitivity and specificity for MM could be improved by measuring soluble mesothelin in the urine. METHODS: Soluble mesothelin concentrations were determined using the MESOMARK assay in concurrent serum and urine samples from 70 patients with pleural MM, 111 patients with asbestos-related lung or pleural disease, and 45 patients with benign nonasbestos-related lung and pleural disease. Only patients with serum creatinine levels within the normal range were included in the study. Sensitivities were determined and receiver operator characteristic curves were generated to compare the diagnostic accuracy of mesothelin in the serum and urine. RESULTS: At a specificity of 95% relative to individuals with benign lung or pleural disease, serum mesothelin had a sensitivity of 66% and area under the curve of 0.882, whereas urinary mesothelin corrected for urine creatinine concentration had a sensitivity of 53% and area under the curve of 0.787. CONCLUSIONS: The sensitivity of urinary mesothelin does not warrant the use of urine as a biomarker specimen for MM diagnosis.

SV40, JC and BK expression in tissue, urine and blood samples from patients with malignant and nonmalignant pleural disease.

BACKGROUND: Polyomaviruses are expressed in both human tumors and immunodepressed patients. Malignant and nonmalignant pleural effusions create an environment that could favor the expression of opportunistic viral infections. We studied if SV40, JC, and BK viral DNA can be amplified from biopsies obtained from different pleural diseases. MATERIALS AND METHODS: DNA was extracted from mesotheliomas (MM), nonspecific inflammatory and tubercular pleural biopsies, blood and urinary sediments from patients with MM, and pleural effusion cytological specimens. SV40, JC and BK viral early regions were amplified by PCR and analyzed by Southern Blot hybridization with specific probes. RESULTS: SV40 was positive in 9/23 MM, 5/18 tubercular and 1/7 nonspecific inflammatory biopsies, and 5/12 pleural effusion cytological specimens. JC was positive in 2/23 MM and in 7/15 urinary sediments. All blood samples were negative and BK was also negative in all samples. CONCLUSIONS: Tissue specific factors, characteristic of MM and TB, may contribute to expression of SV40 in these diseases.

Angiostatin fragments in urine from patients with malignant disease.

Angiostatin, a family of fragments originating from the NH2-terminal portion of plasminogen, has been described as a potent inhibitor of angiogenesis. In order to examine to what extent angiostatin can be detected in cancer patients, urine was collected from 117 patients with different types of malignancies and subjected to Western blot analysis, utilizing antibodies raised against "kringles" 1-3 in plasminogen. A heterogeneous mixture of fragments was observed, with patterns that also varied between patients. Angiostatin fragments were quantified by densitometric scanning. The concentrations were 27 +/- 75 (SD) micrograms L-1 (range, 1-565 micrograms L-1) in urine from cancer patients, as compared to 3 +/- 2 (SD) micrograms L-1 (range, 1-10 micrograms L-1) in urine from healthy individuals. Thirty-three patients (28%) had elevated levels using a cut off level at 15 micrograms L-1 (clearly above the highest level obtained among control subjects). NH2-terminal amino acid sequence analysis of purified angiostatin fragments from one patient showed a heterogeneous pattern, but were consistent with the region between the preactivation peptide in plasminogen and "kringle" 1, as expected. Several of the patients with urinary angiostatin showed signs of poor kidney function. We conclude that angiostatin can be detected in urine from cancer patients, but at present, the clinical significance of this finding is unclear.

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 hypoxanthine and pseudouridine as indicators of tumor development in mesothelioma-transplanted nude mice.

A human mesothelioma was heterotransplanted to nude mice, and the urinary excretions of hypoxanthine, xanthine, pseudouridine, orotic acid, 7-methylguanine, and 1-methylhypoxanthine have been followed before and after the tumor transplantation. The compounds were measured by means of isotachophoresis, which has been found a rapid and precise method. The tumor reached maximum size within 30 days, and at this time a significantly increased excretion of pseudouridine and hypoxanthine was observed. Tumor growth was stopped by chemotherapy (vincristine, cyclophosphamide, prednisolone, and Adriamycin), and corresponding to this, a decrease occurred in both pseudouridine and hypoxanthine excretion to normal values.

Urinary excretion of modified nucleosides in patients with malignant mesothelioma.

Transfer RNA is the most complex biomacromolecule in both structure and function. The complexity of its structure is caused by a large variety of enzymes which add modifying groups to the four bases after the primary synthesis. The most abundant of these enzymes are the transfer RNA methylases, which add methyl groups at various positions in the macromolecule. These methylating enzymes were found to be, without exception, aberrantly hyperactive in every malignant tumor examined. In turn, every malignant tumor contains a few transfer RNAs that are different in structure from the transfer RNAs in the normal tissue. Again, there is no exception. These are the first qualitatively different biochemical components of every malignant cell, not more or less but different transfer RNAs. The late Alexander Gutman observed that cancer patients excrete in their urine elevated levels of certain methylated bases. From the structure of these bases and our knowledge of their method of synthesis, it became apparent that most of them come from the breakdown of transfer RNA. Their elevation in the urine stems from an extraordinarily high rate of turnover of transfer RNAs in tumor tissue. Highly sophisticated, sensitive methods of analysis were developed for the determination of the modified nucleosides in the urine of cancer patients. When related to the creatinine level of the urine, some of the modified nucleosides and products derived from them were elevated in a large variety of tumors. Perhaps more importantly, it was found that these elevated levels return to normal after effective chemotherapy. Thus, these markers may also be useful in monitoring the effectiveness of therapy. We report here initial studies on the detection of cancer in asbestos workers and possible premalignant conditions in workers with asbestosis.

Single-step high-performance liquid chromatographic method for the analysis of acetylated polyamines.

A high-performance liquid chromatography method for the determination of urinary acetyl derivatives of the polyamines putrescine, cadaverine and spermidine is described. This procedure utilizes an ion-exchange column for the separation of acetyl derivatives and the compounds are quantitated by fluorescence after reaction with o-phthalaldehyde. The steps necessary for sample preparation are minimized, and the assay is both sensitive and reproducible. This chromatographic procedure was used for the determination of the urinary acetylated polyamines of seven normal volunteers and three cancer patients.

Urinary gonadotropins in management and prognosis of testicular tumor.

Ninety-three cases of germinal testicular tumors with urinary gonadotropin (HCG) values, estimated by biologic or radioimmunoassay techniques, were reviewed. Preoperative values of HCG and subsequent postoperative values were related to response to treatment and prognosis. Twenty-five patients (26.9 per cent) comprised the seminoma group, and 68 patients (73.1 per cent) the nonseminomatous groups of germinal neoplasms. High HCG values were observed in the nonseminomatous group pre- and postoperatively by both assay procedures. Most significant was the high HCG values postoperatively (p smaller than 0.05, x2 equals 5.21 and p smaller than 0.05, x2 equals 5.23) for the biologic assay and radioimmunoassay, respectively, with high HCG values being associated with a poor cumulative 24 per cent two-year survival rate. Urinary HCG assay is of prognostic value in the ongoing management of testicular neoplasms. In the future, serum HCG assays may be of additional benefit.