Use of urinary hydroxyproline excretion as a tumor marker in diagnosis and follow-up of prostatic carcinoma

Urinary hydroxyproline/creatinine ratio was measured in 49 patients of prostatic carcinoma and 13 patients with benign prostatic hypertrophy, the latter group serving as controls. The results show that it is a very sensitive indicator of osseous metastases in prostatic carcinoma. The ratio was also measured in 18 patients of prostatic carcinoma with bony metastases before commencement of treatment and during treatment. The results show that the elevated pretreatment values were significantly reduced in those who responded to therapy whereas in nonresponders, the values remained high. Changes in urinary hydroxyproline appeared to reflect the nature of response to treatment better than other parameters.     

Serial spot hydroxyproline/creatinine ratios in metastatic prostatic cancer

Analysis of urinary hydroxyproline levels offers a marker to monitor osseous involvement in patients with metastatic malignancies. Such a marker is needed in patients with prostatic cancer when bone metastases predominate. Thirty-two men with stage D2 prostatic cancer were monitored by bone scan, acid and alkaline phosphatase values, and urinary hydroxyproline, beginning from 4 to 36 months after initiation of hormonal manipulation and/or systemic chemotherapy. In patients with disease progression determined by bone scan serial urinary hydroxyproline values progressively increased and were significantly elevated compared to urinary values obtained from patients with a stable or improving scan (p less than 0.001). Simultaneous alkaline phosphatase determinations showed less significant differences between patient groups. Acid phosphatase did not reliably indicate osseous response to therapy. These data suggest that urinary hydroxyproline values are predictive as an early objective sign of osseous response in patients receiving therapy for stage D2 prostatic cancer.     

Urinary hydroxyproline levels in patients with prostatic carcinoma

In this study daily urinary hydroxyproline (HOP) levels were evaluated in 26 patients with advanced prostatic cancer and 15 patients with BPH. In patients with prostatic cancer — the ones with bone metastases proved by bone scanning — urinary HOP levels were found to be 69.58 mg/l/day and in those without metastases the levels amounted to 22.55 mg/l/day. In patients with BPH, serving as controls, urinary HOP was 12.80 mg/l/day. Urinary HOP levels in cancer patients were statistically higher than in the control group. This difference was even more significant in patients with bone metastases. The method detects small metastatic foci of low activity, therefore it may be used also in smaller centres and for effective monitoring of therapy.     

Bone-Turnover Metabolites as Clinical Markers of Bone Metastasis in Patients with Prostatic Carcinoma

Background : Candidate markers of prostatic metastases to bone, urinary deoxypyridinoline, serum carboxy-terminal propeptide of type 1 procollagen (P1CP), and pyridinoline cross-linked carboxy-terminal telopeptide of type 1 collagen (1CTP), were measured to evaluate their prognostic efficacy.
Methods : Urinary levels (mean ± SD) of deoxypyridinoline were measured by a competitive immunoassay, and serum levels of P1CP and 1CTP were measured by radioimmunoassay in 30 patients with benign prostatic hyperplasia, 18 patients with prostatic carcinoma without bone metastases, and 27 patients with prostatic carcinoma and bone metastases.
Results : Urinary concentrations of deoxypyridinoline (pmol/μmol creatinine) in patients with prostatic carcinoma and bone metastases (10.4 ± 7.7) were significantly higher than those in similar patients without bone metastases (4.3 ± 1.3) and those in patients with benign prostatic hyperplasia (3.8 ± 1.2). Serum levels of P1CP and 1CTP (ng/mL) in patients with prostatic carcinoma and bone metastases (262.6 ± 188.7 and 10.3 ± 9.5, respectively) were significantly higher than those in similar patients without bone metastases (118.1 ± 30.2 and 4.3 ± 1.4, respectively) and those in patients with benign prostatic hyperplasia (93.9 + 25.1 and 3.3 ± 1.1, respectively). Serial measurements of urinary deoxypyridinoline and serum P1CP and 1CTP were correlated with a positive response to treatment (reduced measurements) and with the clinical progression of disease (increased measurements) before detection of new bone lesions by bone scintigram.
Conclusion :Urinary deoxypyridinoline, serum P1CP, and serum 1CTP should be useful markers in confirming and monitoring prostatic carcinoma metastases to bone.     

Urinary Pyridinoline and Deoxypyridinoline as Potential Markers of Bone Metastasis in Patients with Prostate Cancer

Purpose

The levels of probable markers of bony metastatic disease were measured to evaluate their efficacy as predictors of disease and therapeutic outcome.

Materials and Methods

Urinary pyridinoline, urinary deoxypyridinoline, serum alkaline phosphatase and serum osteocalcin were measured in patients with benign prostatic hyperplasia, clinically localized prostate cancer and prostate cancer with bone metastases. Also, urinary pyridinoline and deoxypyridinoline were compared in 2 groups of patients with metastatic prostate cancer of the bone who demonstrated progression or positive response to treatment. Urinary pyridinoline and deoxypyridinoline were determined by high performance liquid chromatography and were normalized to urinary creatinine.

Results

Levels of pyridinoline and deoxypyridinoline in urine, and the level of alkaline phosphatase in serum from patients with bone metastatic prostate cancer were significantly greater than levels in patients with benign prostatic hyperplasia or localized prostate cancer. Serum osteocalcin levels failed to separate the 3 groups. Serial measurement of urinary pyridinoline and deoxypyridinoline was correlated with a positive response to treatment (decreased) and with clinical progression of disease (increased) before detection of new bone lesions by bone scintigraphy.

Conclusions

Measurement of urinary pyridinoline and deoxypyridinoline may provide a useful marker of prostate cancer metastatic to bone and may be useful in monitoring the response to treatment.     

Biochemical markers and skeletal metabolism in carcinoma of the prostate. Use of decision matrix theory and ROC analysis

The discriminative ability of several skeletal and tumour markers was assessed in 102 patients with prostatic disease. These comprised serum acid and alkaline phosphatase, serum albumin and osteocalcin, urinary excretion of calcium, hydroxyproline and 6-oxo prostaglandin F1 alpha. None of the tests was of value in distinguishing patients with benign prostatic disease from those with tumour not involving the skeleton. Values of serum osteocalcin, urinary excretion of calcium and urinary 6-oxo prostaglandin F1 alpha failed to discriminate significantly between patients with or without metastases. The remaining four markers were compared by decision matrix analysis and receiver operating characteristic (ROC) curves. Serum alkaline phosphatase provided the most sensitive marker of skeletal metastases (80.5%), followed by serum acid phosphatase (80%), hydroxyproline (68%) and albumin (30%). ROC analysis suggested that alkaline phosphatase conformed most closely to the "ideal marker" with highest specificity and sensitivity.     

Radioimmunoassayable prostate-specific acid phosphatase in peripheral and bone marrow sera compared in diagnosis of prostatic cancer patients

Measurements of human prostate-specific acid phosphatase by radioimmunoassay in peripheral and bone marrow sera were compared. We studied 20 patients with benign prostatic hyperplasia, 27 with untreated prostatic cancer without bone metastases and 11 with metastases, in addition to 7 with cancer treated by hormonal therapy. The prostate-specific acid phosphatase concentrations in peripheral and bone marrow serum samples were equal and did not exceed the upper limit of our health-associated reference interval, 2.8 microgram. per 1. (mean plus 2 standard deviations) in patients with prostatic hyperplasia. Of 27 prostatic cancer patients without bone metastases the concentration of prostate-specific acid phosphatase was elevated in the peripheral sera of 20 and in the bone marrow sera of 21, and 21 had an extracapsular tumor (stage T3 to T4). Prostate-specific acid phosphatase concentrations were elevated in peripheral and bone marrow serum specimens of all 11 patients with metastases and bone marrow cytology studies were positive in 2. There was no difference in prostate-specific acid phosphatase concentrations in peripheral and bone marrow serum specimens from prostatic cancer patients undergoing hormonal treatment. We conclude that the use of bone marrow serum for the measurement of radioimmunoassayable prostate-specific acid phosphatase in prostatic cancer patients does not provide any further information in regard to the detection of prostatic cancer compared to the use of peripheral serum specimens. Falsely positive findings in bone marrow specimens were not observed with the method used.     

Urinary hydroxyproline excretion in carcinoma of the prostate. A comparison of 4 different modes of assessment and its role as a marker

Urinary hydroxyproline (HP) excretion has been estimated without prior dietary restriction in 33 patients with carcinoma of the prostate and expressed as either 24-h HP output or as the hydroxyproline/creatinine (HP/Cr) ratio in 24-h urine sample, an early morning urine sample or a spot urine sample. The early morning urine hydroxyproline/creatinine ratio (EMU HP/Cr) appears to be the most accurate and avoids the disadvantages of formal dietary restriction and prolonged urine collection. The rest is useful in monitoring the responses to treatment of a patient with bony metastatic disease and relapse of a patient when his tumour ceases to be hormone sensitive. Furthermore, changes in EMU HP/Cr occur earlier than changes in other clinical or investigative variables, giving the test predictive value.     

Serum prostatic acid phosphatase determination in prostatic diseases: a critical comparison of an enzymatic and a radioimmunologic assay

A prospective study comparing a new radioimmunologic and a classical enzymatic assay for prostatic acid phosphatase was done to evaluate their respective roles in patients with prostatic diseases. We studied 50 patients with cancer of the prostate, 101 with benign prostatic hypertrophy and 17 with prostatitis as well as patients with nonprostatic malignancy, and various hematological and bone diseases. The results showed a low incidence of elevated values in patients with early cancer of the prostate and a high incidence of false positive values with the radioimmunoassay in patients with benign prostatic diseases, especially prostatitis. These data suggest that tests for serum prostatic acid phosphatase levels remain disappointing in the assessment of prostatic disease regardless of the technique used.     

Comparative performance of three radioimmunoassays for prostatic acid phosphatase

Three commercial radioimmunoassays and one enzymatic assay for prostatic acid phosphatase (PAP) have been tested on 122 patients to determine their relative specificity, sensitivity, and diagnostic value. Each of the three radioimmunoassays was found to have special merits. For distinguishing Stage IV prostatic cancer from normal patients without prostatic disease, the Smith Kline (SKF) and New England Nuclear (NEN) assays provide more significant differences. The SKF test also best distinguishes all stages of prostatic cancer from benign prostatic hyperplasia (BPH), but is inferior to the Malinckrodt (MAL) assay for contrasting Stage IV prostatic cancer from BPH. Values obtained with the NEN assay best distinguish the stages of prostatic cancer. Only with the MAL assay are significantly higher PAP values obtained in patients with metastases to bone than those without positive bone scans. Viewed from the point of sensitivity, the SKF assay proves best at all levels of specificity examined in detecting all stages (I-IV), and Stage IV prostatic cancer. By none of the assays can estrogenized Stage III and IV cancer patients be distinguished from those not on estrogen.     

Kinetics of99mTechnetium-Tin-methylene-diphosphonate in normal subjects and pathological conditions: A simple index of bone metabolism

Summary The blood clearance and the urinary excretion of the bone scanning complex technetium-tin-methylene-diphosphonate (^99mTc-Sn-MDP) administered intravenously have been measured in 27 normal subjects and 104 patients with post-menopausal osteoporosis, osteomalacia, primary hyperparathyroidism, Paget's disease, pagetoid metastases of prostatic cancer, osteolyses, chronic renal failure, and liver cirrhosis to quantitate the skeletal uptake of the radiopharmaceutical. Kinetic analysis of the data was performed in terms of a four-compartment model; correspondent rate constants and fitted values were estimated. In normal subjects the whole-body retention (WBR) up to 24 h was 33.3%±7.4 SD, whereas significantly more elevated values were observed in several pathological conditions, the highest values being ascertained in patients with pagetoid metastases, primary hyperparathyroidism, and chronic renal failure and whenever large osteoid seams were present. Differences were found between osteoporosis and osteomalacia, monostotic and polyostotic Paget's, pagetoid and osteolytic metastases of bone. In Paget's disease significant correlations have been observed between WBR and the exchangeable calcium pool, WBR and the serum alkaline phosphatase, and WBR and the urinary excretion of hydroxyproline. Kinetic analysis demonstrated that WBR provided overestimate of the skeletal retention by an average of 16%, the retention in the “extravascular space” being greater in patients with chronic renal failure. This simple method shows significant promise for a quantitative approach to the skeletal turnover in metabolic bone disease.     

Bone marrow calcium in cancer of prostate and bladder

A comparative evaluation of bone marrow and serum calcium levels and their relation to the bone marrow and serum acid phosphatases were studied in 10 patients with benign prostatic hypertrophy and 23 patients with inoperable prostate cancer. None of the 33 patients had hypercalcemia at the time of the study. Calcium metabolism at the metastatic foci was discussed, and the marrow/serum calcium ratio is suggested as helpful in the staging of prostate and bladder cancer as an additional parameter.     

Patterns of urinary flow in benign prostatic hypertrophy.

Multiple urinary flow recordings were carried out on 51 men and without bladder outlet obstruction due to benign prostatic hypertrophy. All patients were over 50 years of age. Six urinary flow patterns (types 0-5) were defined. Types 0-3 were found in patients without obstruction, while all six patients were observed in those with clinical obstruction. Following prostatic surgery, only types 1, 2 and 3 were found. Only type 5 flow pattern can be determined by flow rate alone because it is by definition on the curve obtained when peak flow rate is below 4 ml per second. In this study, no type of flow pattern was characteristic of bladder outlet obstruction due to benign prostatic hypertrophy. The supposedly characteristic type of flow pattern in this clinical condition reported by earlier workers is mainly a result of a difference in the age distribution between their control and test groups.     

Biochemical effects of a single oral dose of calcium on bone metabolism in elderly Chinese women

Summary The biochemical effects of a single oral dose of 10 mmol of calcium on certain blood and urine variables were studied in 20 elderly postmenopausal subjects (mean age 72.3±6.2 years) with a very low dietary calcium intake (mean 7.2±3 mmol/day). Twelve hours after calcium administration, the plasma total calcium, phosphate and bicarbonate, and the urinary calcium/creatinine ratio rose, while the plasma parathyroid hormone and chloride, and urinary hydroxyproline/creatinine and phosphate/creatinine ratios fell. These results show that a single oral dose of calcium suppresses bone resorption in elderly women with low dietary calcium intake, and that long-term supplementation may be important in the prevention of osteoporosisrelated fractures.     

Clinical evaluation of bone turnover in patients with bone metastasis of various cancer of urogenital tract

To study the bone turnover in patients with bone metastasis from cancers of the kidney, bladder, prostate and other organs, Ca metabolism, vitamin D related hormones and various markers, such as bone glaprotein (BGP) and hydroxyproline, were investigated. In the group with osteolytic metastasis of non-prostatic cancer patients, BGP which is a measure of bone absorption was significantly increased and urinary excretion of hydroxyproline, Ca and P was elevated. Serum Ca was also higher and 1 alpha 25 (OH)2D and 250HD, measures of the metabolism of vitamin D, were lower. It was shown that bone absorption was promoted with the osteolytic findings by clinical X-ray examination, but osteoblastic changes which did not depend on osteoblast cells, seemed to exist in this group. On the contrary, in the group with osteoblastic metastasis from prostatic cancer, the level of BGP was not increased, but urinary hydroxyproline was moderately increased. Serum and urinary Ca and P levels were increased. In addition, 1 alpha 25 (OH)2D and 24 x 25 (OH)2D were lower than in the control group. These results indicate that urinary hydroxyproline is a useful marker for patients with bone metastasis, but BGP was correlative with neither the clinical findings of bone metastasis nor the bone turn over and metabolisms.     

Role in acute urinary retention

The relationship between prostatic infarction and acute urinary retention was studied. Serial sections of two groups of 100 prostates each were studied for evidence of infarction. One group consisted of patients with acute urinary retention while the other group consisted of patients with benign prostatic hypertrophy. Eighty-five per cent of the retention group had prostatic infarcts while only 3 per cent of the patients with benign prostatic hypertrophy had infarcts. Despite the close association of acute urinary retention with infarction of the prostate, the exact mechanism in the production of acute retention is as yet undetermined.     

Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer

Serum prostatic specific antigen and prostatic acid phosphatase levels were measured retrospectively and evaluated in 357 men with benign prostatic hypertrophy and in 209 men with various stages of prostatic carcinoma. Although prostatic specific antigen values were elevated in 21 per cent of the patients with benign prostatic hypertrophy, the elevations usually were low and did not interfere with clinical interpretation. Prostatic specific antigen was elevated in 98 per cent of 86 men with active stage D2 disease; in 22 per cent of the men prostatic specific antigen was the only elevated marker. In contrast, prostatic acid phosphatase was the only elevated marker in 1 per cent of the patients with stage D2 disease and neither marker was elevated in 2 per cent. Among 74 patients in whom prostatic specific antigen and prostatic acid phosphatase determinations were made before radical prostatectomy, prostatic specific antigen was elevated substantially (greater than 10 ng. per ml.) in 59 per cent (26 of 44) with extracapsular disease and in only 7 per cent (2 of 30) without extracapsular disease. More importantly, of those 28 patients with substantially elevated prostatic specific antigen levels 26 (93 per cent) had extracapsular disease. Serial serum measurements showed that prostatic specific antigen either reflected or predicted clinical status in more than 97 per cent of the patients. We conclude that prostatic specific antigen is an excellent serum tumor marker for monitoring patients with prostatic carcinoma and that it surpasses prostatic acid phosphatase in this regard. Prostatic specific antigen also may be useful in staging prostatic carcinoma and it may change our attitudes significantly about the therapeutic responses to this cancer.     

The diagnostic value of intravenous pyelography in infravesical obstruction in males.

Intravenous pyelographies from 104 consecutive patients admitted for infravesical obstruction were studied with special reference to pathology of the upper urinary tract and the bladder, the size of the prostate and the bladder emptying. The incidental findings in the upper urinary tract did not influence the treatment of the infravesical obstruction. Furthermore the radiographic assessment of prostatic size, bladder trabeculation, bladder emptying, bladder stones and prostatic cancer was very uncertain. Thus intravenous pyelography in our opinion should not be performed as a routine procedure in patients with benign prostatic hypertrophy, but only on clinical suspicion of upper urinary tract pathology.     

Diagnostic accuracy of percent free prostate-specific antigen in prostatic pathology and its usefulness in monitoring prostatic cancer patients.

INTRODUCTION: The aim of our study was to evaluate the clinical usefulness of percent free prostate-specific antigen (PSA) [ratio of free PSA (fPSA) to total PSA (tPSA); f/tPSA] in prostatic pathology and its usefulness in monitoring prostatic cancer patients. PATIENTS AND METHODS: Our prospective study was carried out on 470 consecutive male patients referred to our outpatient urological clinic for observation. We looked for relationships between tPSA, fPSA and percent free PSA and the patient's age, prostatic volume and histologic diagnosis as assessed by prostatic biopsies or surgical specimens (benign prostatic hypertrophy, carcinoma, hypertrophy with inflammation). In all cases, we calculated the specificity, sensitivity and diagnostic accuracy of percent free PSA in the diagnosis of prostatic diseases, using cutoff values ranging from 14 to 20%. In prostatic cancer patients, we considered the relationships between the various PSA molecular forms and staging, grading and follow-up values. We also evaluated the effects of hormonosuppressive therapy on the serum markers and noted for which tPSA value percent free PSA possessed the greatest diagnostic accuracy. RESULTS: While tPSA and fPSA values appeared to be correlated with patient age and prostatic volume, percent free PSA did not show a relationship with these parameters. The specificity, sensitivity and overall diagnostic accuracy were better assuming a 16% cutoff value for percent free PSA than with other cutoff values. Prostatic inflammation associated with benign hypertrophy can cause false positives in both tPSA and f/tPSA measurements, since 60% of these patients have an f/tPSA ratio below 16%. In diagnosing carcinoma, the diagnostic accuracy of percent free PSA is 100% when tPSA is between 2.5 and 4.0 ng/ml. Percent free PSA is not linked with staging in prostatic cancer, but it does appear to be related to the Gleason score. In patients receiving hormonosuppressive treatment, f/tPSA decreased significantly, and more so in patients with a higher Gleason score. In patients with disease in rapid progression, percent free PSA was lower than in patients in a stable condition. CONCLUSIONS: Based on our experience, 16% as the f/tPSA cutoff value for discriminating between benign and malignant pathologies is the best possible choice, as it provides the highest overall values of sensitivity, specificity and diagnostic accuracy (80, 61.5 and 84.5%, respectively) in the diagnosis of prostatic cancer. We believe that f/tPSA is not a definitive test for diagnosing prostatic cancer. Our observations on the behavior of percent free PSA in relation to prostatic carcinoma grading and staging and in the follow-up of carcinoma patients are interesting; however, further studies are needed to define the appropriate role of f/tPSA in patients with an established diagnosis of prostatic carcinoma and in the follow-up of patients with prostatic cancer.     

Clinical and pathological study of tumor marker in benign prostatic hypertrophy and incidental prostatic cancer]

To determine the value of prostatic markers for prostate cancer, serum prostatic acid phosphatase (PAP), prostate specific antigen (PSA) and gamma-Seminoprotein (gamma-Sm) were measured in 81 patients with benign prostatic hypertrophy and in 12 patients with incidental prostatic cancer. gamma-Sm was the most sensitive but the least specific of the three markers. Large prostate glands, especially hyper-glandular type tended to be associated with high gamma-Sm levels in our study. Patients with acute urinary retention, acute prostatitis and necrosis also showed positive markers. Out of 12 patients with incidental cancer, 5 patients had more than 2 elevated markers. Four patients with poorly differentiated adenocarcinoma failed to show increased markers.