Biochemical relapse of prostate cancer. Evidence after radical surgery.

BACKGROUND: The aim of this study was to investigate, whether ultrasensitive PSA assays can help to find a lower cut-off value for biochemical recurrence of prostate cancer after resection. MATERIALS AND METHODS: This was a retrospective analysis of the patient files of 113 men with prostate cancer who underwent surgery. The mean follow-up time was 26 months. PSA measurements were performed with the ultra sensitive Immulite assay (DPC, USA), with an analytical sensitivity of 0.001 ng PSA/ml. Patients with baseline PSA levels > 0.1 ng/ml after surgery were excluded. Different cut-off levels for PSA were applied on the values and PSA doubling-times calculated. RESULTS: Maximum PSA 0.01 ng/ml, 0.05 ng/ml, 0.1 ng/ml, 0.2 ng/ml and > 0.4 ng/ml were reached by 87%, 61%, 50%, 42% and 20% of patients, respectively. From a cut-off point of 0.1 ng/ml the chance of further progression to PSA levels of 0.2 ng/ml and 0.4 ng/ml was 75% and 40%, respectively. The PSA doubling time was 2.1 months in patients with PSA values > 0.4, 15 months for patients below 0.4 ng/ml and 22.4 months for patients whose PSA never exceeded 0.1 ng/ml. CONCLUSION: PSA cut-off values below 0.4 ng/ml lack sufficient clinical significance. However, patients with PSA values > 0.1 ng/ml should be monitored thoroughly and at shorter intervals, as further increase, i.e. tumour progression, is very likely to occur.

Nondetected tumor (pT0) after prolonged, neoadjuvant treatment of localized prostatic carcinoma.

OBJECTIVES: 135 patients with stage T1-3N0M0 prostatic carcinoma were submitted to prolonged PSA-monitored neoadjuvant endocrine treatment (PPNET). The rate of pT0 reports was three times higher (15%) than after the standard 3-month therapy (5%). The present work was done to elucidate the initial characteristics of these tumors, to see if additional workup of these prostatectomy specimens is able to detect tumor vestiges and, if so, to describe their morphology. METHODS: The original clinical and histopathological data of 20 pT0 cases were reviewed and an additional histopathological workup of the prostatectomy specimens was done. RESULTS: The majority of patients had initially small (9 patients cT1, 8 patients cT2, 3 patients cT3) and well-differentiated tumors (18 patients Gleason score <7). Microscopic assessment of 4,503 slides revealed very small tumor remnants (mean volume 0.2 ml) in 13 of the 20 prostatectomy specimens. Severe tumor regression was seen in 3 cases, slight to moderate regression in 10 cases. CONCLUSIONS: A pT0 report following detailed routine histopathological workup has to be regarded as a maximal therapeutic effect, but not as tumor elimination. PPNET clearly increases the rate of pT0 reports, implicating that the conventional 3 months of pretreatment does not exploit the possibilities of neoadjuvant therapy.

Estimation of total PSA with a supersensitive PSA-assay during neo-adjuvant-chemotherapy of prostate cancer before radical resection of prostate.

43 patients with untreated and clinically localised prostate carcinoma (cT1-3NoM0) were submitted to neo-adjuvant complete androgen deprivation treatment and radical prostatectomy. Hormonal treatment was given until PSA (supersensitive Immulite 3rd generation assay) reached a value of < 0.1 ng/ml or the nadir value. The resultant mean duration of treatment was 6 months (3-22 months). 93% of our patients reached a PSA value of 0.1 ng/ml or below. The nadir of 6 patients was between 0.1-0.3 ng/ml. In one case it remained above 0.3 ng/ml. 82% had a measurable hypoechoic lesion on initial transrectal ultrasound. 84% of these became smaller, 7.5% remained unchanged and 8.5% increased. Of the patients with cT1-2 tumours 2% had a positive margin and in 28% of the specimens no tumour tissue could be detected at the time of prostatectomy. Of the initial patients with epithelial cells in bone marrow only 14% remained positive after controlled induction and all of them had fewer cells than before. Five patients relapsed showing raising PSA values > 0.1 ng/ml in the follow-up. In this group the mean PSA and the time of nadir was significantly higher (0.15 ng/ml) than the mean PSA at the time of nadir of the rest of the group (0.06 ng/ml). Supersensitive PSA assays like Immulite 3rd generation offer a valuable tool to collect data for clinical evaluation to optimise therapy of prostate carcinomas.

Comparative immunocytochemical assessment of isolated carcinoma cells in lymph nodes and bone marrow of patients with clinically localized prostate cancer.

After radical prostatectomy for clinically localized prostate cancer, biochemical progression is seen in up to 40% of the patients due to persistent local and/or systemic remnants. Isolated disseminated carcinoma cells, undetectable by current staging methods, are of special interest as potential precursors of subsequent overt metastases. In the present study, immunohistochemistry (IHC) was performed to evaluate simultaneously the frequency of occult carcinoma cells in both lymph nodes (LNs) and bone marrow (BM) obtained from the iliac crests of 45 prostate cancer patients with untreated stage T(1-3) pN0 M0 prostatic carcinoma. IHC using monoclonal antibodies (MAbs) against epithelial cytokeratins was performed on 521 paraffin-embedded LNs histopathologically classified as tumorfree (pN0), as well as on BM cytospin preparations. To confirm the prostatic origin of positive cells in LNs, additional IHCs for prostate-specific antigen (PSA) and epithelial glycoproteins were performed. In total, isolated tumor cells in LNs and/or BM were detected in 17 of the 45 patients. Parameters such as tumor stage, grade and volume of the primary tumor as well as blood serum PSA levels could not detect patients harboring disseminated single tumor cells in LNs or BM. Following a median observation time of 24.9 months, no significant correlation between IHC positivity and PSA progression as a measure of early relapse was observed. Although the overall incidence of occult tumor cell spread corresponds to similar incidence of relapses after radical prostatectomy as reported by others, the fate of these cells needs to be evaluated in longer follow-up studies.

Supersensitive PSA-monitored neoadjuvant hormone treatment of clinically localized prostate cancer: effects on positive margins, tumor detection and epithelial cells in bone marrow.

OBJECTIVE: The present study was done to investigate the effects of supersensitive PSA-controlled inductive treatment on positive margins, detection of tumor and epithelial cells in bone marrow of 101 patients with untreated and clinically localized prostatic carcinoma (cT1-3N0M0). METHODS: Hormonal treatment was given until PSA (DPD Immulite(R) third-generation assay) reached <0.1 ng/ml or the nadir value, as shown by two consecutive measurements at monthly intervals. RESULTS: The resultant median duration of treatment was 6 months (range 3-22). Ninety-three (93%) of our patients reached a PSA value <0.1 ng/ml. The nadir of 6 patients (6%) was between 0.1 and 0.3 ng/ml, and it remained >0.3 ng/ml in only 1 case. Of the 101 patients, 82 had a measurable hypoic lesion on initial transrectal ultrasound. 84% of these became smaller, 7.5% remained unchanged and 8.5% increased. Of the 101 prostatectomy specimens, 20 (20%) were margin-positive. The incidence of affected margins was relatively high (35% from 55 patients) with cT3 tumors, but almost negligible (2% from 46 patients) in cT1-2 tumor. Our pathologists, despite their great experience in evaluating hormonally treated prostates (>500 cases) and using immunohistochemical staining, were unable to detect carcinoma in 15 (15%) specimens. Whereas only 2 (4%) of the 55 cT3 specimens were without detectable tumor, this incidence rised to 28% (13 of 46 prostates) in patients with cT1-2 tumors. Of the initial 29 patients with epithelial cells in bone marrow, only 4 (14%) remained positive after controlled induction and all of them had fewer cells than before. CONCLUSION: Endocrine induction controlled by a supersensitive PSA assay and continued until reaching PSA nadir is highly effective in clearing surgical margins and eliminating tumor cells from bone marrow. It seems to be clearly superior to the conventional 3 months of pretreatment at least in cT1-2 tumors in respect to surgical margins and detectability of tumor in the resected prostate. A definitive statement about the value of endocrine induction can only be given by prospective randomized studies, with optimal drugs, doses and treatment time. But the conventional 3 months of pretreatment are far from exploiting the possibilities of this therapeutic option.

Limitations of reverse-transcriptase polymerase chain reaction analyses for detection of micrometastatic epithelial cancer cells in bone marrow.

PURPOSE: This study was designed to evaluate the potential of reverse-transcriptase polymerase chain reaction (RT-PCR) analyses for the detection of micrometastatic carcinoma cells in bone marrow (BM). PATIENTS AND METHODS: The specificity of RT-PCR assays with primers specific for various tumor-associated and organ-specific mRNA species was examined by analysis of 53 BM aspirates from control patients with no epithelial malignancy. In addition, BM samples from 63 patients with prostate cancer (n = 53) or breast cancer (n = 10) were analyzed by RT-PCR with primers specific for prostate-specific antigen (PSA) mRNA. As a reference method, all samples were analyzed simultaneously by an established immunocytochemical assay, using monoclonal antibodies (mAbs) against cytokeratins (CK) for tumor-cell detection. RESULTS: Seven of eight marker species could be detected in a considerable number of BM samples from control patients: epithelial glycoprotein-40 (EGP-40; 53 of 53 samples), desmoplakin I (DPI I; five of five), carcinoembryonic antigen (CEA; five of 19), erb-B2 (five of seven), erb-B3 (six of seven), prostate-specific membrane antigen (PSM; four of nine), and CK18 (five of seven). Only PSA mRNA was not detected in any of the 53 control BM samples. In serial dilution experiments, the PSA RT-PCR assay was able to detect five LNCaP prostate carcinoma cells in 4 x 10(6) BM cells. CK-positive cells were found in 20 patients (37.7%) with prostate cancer, while PSA mRNA was found in only 15 (28.3%; P = .04). Moreover, despite the recent observation that PSA is also expressed in mammary carcinomas, none of the 10 CK-positive BM samples were PSA mRNA-positive. CONCLUSION: Limiting factors in the detection of micrometastatic tumor cells by RT-PCR are (1) the illegitimate transcription of tumor-associated or epithelial-specific genes in hematopoietic cells, and (2) the deficient expression of the marker gene in micrometastatic tumor cells.

Immunocytochemical monitoring of micrometastatic disease: reduction of prostate cancer cells in bone marrow by androgen deprivation.

Occult dissemination of tumor cells mainly determines the prognosis of patients with primary prostate cancer. The effect of androgen deprivation on micrometastatic tumor cells in these patients is currently unknown. We therefore used an immunocytochemical assay with monoclonal antibodies (MAbs) directed against epithelial cytoskeleton proteins (i.e., cytokeratins) to monitor the concentration of isolated tumor cells in the bone marrow of 36 prostate cancer patients (stage C), who underwent hormonal androgen deprivation with Flutamide and Leuprorelin acetate. Tumor cells in cytologic bone marrow preparations were detected using an assay that employed the MAb CK2 directed against cytokeratin (CK) 18 and the alkaline anti-alkaline phosphatase staining method. Prior to therapy, we detected between 1 and 38 CK-positive cells per sample of 2 x 10(6) nucleated cells in 21 patients, while the remaining 15 patients displayed tumor-free marrow samples. There was no significant correlation between the concentration of CK-positive cells and the volume of hypo-echogenic lesions as an indicator of the primary tumor volume or the serum level of prostate-specific antigen (PSA). After androgen deprivation, 20 of the 21 initially positive patients either became negative (n = 16) or showed at least a reduction in the concentration of CK-positive cells (n = 4). Moreover, only 2 of the 15 patients with negative pre-treatment findings became positive. All of the 7 patients with remaining tumor cells in the bone marrow after therapy showed no detectable amounts of PSA in their serum. Our findings suggest that serum PSA concentration is no indicator of micrometastatic disease in bone marrow. Neoadjuvant androgen deprivation appears to eliminate disseminated CK-positive tumor cells present in bone marrow, a preferred site of overt metastasis in prostate cancer patients.

Immunocytochemical detection of isolated tumour cells in bone marrow of patients with untreated stage C prostatic cancer.

The micrometastatic spread of tumour cells is usually missed by conventional diagnostic techniques, although this spread largely determines the prognosis of patients with primary epithelial cancers. By use of the monoclonal antibody, CK2, to epithelial cytokeratin component number 18 (CK18), individual disseminated carcinoma cells present in bone marrow of cancer patients can now be identified. In the present study, this approach has been applied to patients with virginal stage C adenocarcinoma of the prostate. Double-sided aspirates of iliac bone marrow from 24 of 44 evaluable patients (54.4%) exhibited between one and 38 CK18-positive cells per sample of 2 x 10(6) mononuclear cells. In 13 of these 24 positive patients, CK-positive cells were only detected in one of the two aspirates analysed. There was no statistically significant correlation between this finding and established risk factors, such as the volume and histological grade of the primary tumour or the concentration of prostate specific antigen and prostatic acid phosphatase in serum. The follow-up time is too short to provide meaningful data on the prognostic significance of isolated CK18-positive cells in bone marrow, which, however, has been recently demonstrated in other types of primary epithelial cancers. In conclusion, the presence of prostatic tumour cells in bone marrow might be interpreted as an indicator of the metastatic capacity of an individual primary tumour. The immunocytochemical detection of these cells may, therefore, be useful for increasing the precision of current tumour staging, and to monitor minimal residual cancer in an individual patient.

[Demonstration of a fornix rupture in a newborn using 99mtc-mag3 kidney function scintigraphy]. / Nachweis einer Fornixruptur bei einem Neugeborenen mit Hilfe der 99mTc-MAG3-Nierenfunktionsszintigraphie.

In male newborns posterior urethral valves are the most frequent cause of subpelvine obstructions. A male newborn had to be delivered by caesarian section in the 36th week of pregnancy due to a progressive intrauterine hydronephrosis and excessive bladder filling. The condition could temporarily be normalized by catheterisation. However, following removal of the catheter on day 5 after birth an acute deterioration in the patient's general condition occurred due to an urine ascites. Scintigraphy using 99mTc-MAG3 led to the assumption that the cause was a fornix rupture in VURD syndrome (syndrome of posterior urethral Valve, Unilateral vesicorenal Reflux and renal Dysplasia), subsequently confirmed radiologically.

Downstaging of stage C prostatic carcinoma by inductive chemo-hormonal therapy?

One hundred and three patients with clinical stage C prostatic carcinoma (palpable extra-organ extension) underwent inductive chemo-hormonal treatment followed by radical retropubic prostatectomy with pelvic lymphadenectomy. First a careful noninvasive tumor staging was performed, which included a thorough digital rectal palpation, PSA, PAP, chest X-ray, bone scan, IVP, transabdominal and transrectal ultrasonography, CT and MRI. Then inductive chemo-hormonal therapy commenced. It consisted of total androgen deprivation plus the administration of cDDP or 5-FU + calcium folinate + mitomycin. After completion of chemotherapy (i.e. 4 months later), noninvasive staging was repeated. Then radical prostatectomy was carried out, followed by histologic work-up of the specimen. Postinductive, noninvasive examinations showed clinical downstaging in 49 of the original 103 patients (47.5%). Histopathology showed confinement of the tumor to the prostate in 40 specimens (38.8%). These results prove that chemo-hormonal induction is highly effective and suggest strongly but do not prove definitely histological downstaging in a significant percentage of the patients.

Lonidamine versus high-dose tamoxifen in progressive, advanced renal cell carcinoma: results of an ongoing randomized phase II study.

Sixty patients with metastatic renal cell carcinoma were entered into an ongoing randomized phase II study with lonidamine, 350 mg/m2 orally daily (arm A) and high dose tamoxifen, 150 mg/m2 orally daily for 6 months, afterwards 50 mg/m2 (arm B), until tumor progression. All patients had measurable disease and documented tumor progression prior to treatment. There were 1 complete and 1 partial remission among 19 evaluable patients in arm A (10.5%) and 2 complete and 1 partial remission among 25 evaluable patients (12%) in arm B. Objective responses were observed in pulmonary, nodal, and cutaneous metastases. In addition, in 63% and 64% tumor progression could be stopped in arm A and B, respectively. Median response duration was 100 days (range, 20-361) in arm A and 150 days (range, 28-355) in arm B. One year survival rate was 37.5% with lonidamine and 35% with tamoxifen. In arm A patients with tumor progression within 12 weeks after diagnosis of metastatic disease survived significantly shorter than patients with a longer interval (P less than 0.05). Nephrectomy or number and localization of metastatic sites failed to significantly influence probability of remission or survival. Toxicity was mostly mild to moderate. Four patients in the lonidamine arm had to discontinue treatment because of intolerable myalgias, which were immediately reversible. These data suggest that lonidamine and high-dose tamoxifen are moderately effective in widespread renal cell carcinoma where treatment intention is palliative.

[Cystic lymphangioma of the kidney. Clinical and morphologic findings]. / Zystisches Lymphangiom der Niere. Klinische und morphologische Befunde.

Lymphangiomas of the kidney are extremely rare hamartomatous benign tumors, previously never diagnosed preoperatively. By sonography and computer tomography the tumor is characterized by a polycyclic and polycystic well defined mass which also may involve the renal pelvis. Morphologically the tumor is a typical lymphangioma.

[Curative radiotherapy in stage C prostatic carcinoma. Experiences with radiotherapy-endocrine treatment]. / Kurative Radiotherapie beim Prostatakarzinom im Stadium C Erfahrungen mit einer radiotherapeutisch-endokrinen Behandlung.

In a prospective study 209 patients with prostatic cancer stage C who were seen between 1968-1974 received endocrine treatment and radiotherapy (6000 r) of the prostate without inclusion of regional lymph nodes. The patients were seen every 6 months up to 8 years. 247 transrectal biopsies and 7 transurethral resections of the prostate were performed. The analysis of the biopsies revealed that the combined endocrine and radiotherapy is followed by tumor neutralisation of about 70% in highly differentiated prostatic cancers and less effective in lower differentiated tumors. 80% of biopsies from tumors responding to therapy still show tumor cells. The 5-year-survival corresponded with tumor regression and tumor size. However a prognosis on the basis of these findings is not possible for the individual case.

[Sterile vesiko-ureteral reflux. Radiological kidney surface measurements as follow-up criteria]. / Steriler vesiko-ureteraler Reflux. Die Nierenflächenmessung als Parameter der Verlaufskontrolle.

33 patients with 46 sterile vesicoureteral refluxes were followed by repeated clinical-urological and radiological studies over a period from 1 to more than 6 years. The results of the evaluation, obtained by only looking at the urograms, were compared with the following measurements: the length of each kidney, the length ratio right to left, and the parenchymal area. At the end of the follow-up period, 2 out of 32 initially normal kidneys (about 6%) had pathologically low values, whereas 3 out of 14 already initially damaged kidneys (21,5%) showed a further decrease of these values. Preceding urinary tract infections with consecutive pyelonephritis, leading to a progressive shrinkage of the organ over many years, are thought and discussed to be more responsible for these results than the sterile reflux itself.

DNA content of human kidney carcinoma cells in relation to histological grading.

Ploidy and cell-cycle stage were determined by flow cytometry (FCM) in 46 human renal carcinomas. Cell populations with aneuploid DNA were detected in 46% of these. In the investigated samples, the fraction of cells with abnormal DNA content varied from 8 to 100%. The proliferative activity was generally low as indicated by the small fractions of cells in S and (G2 + M) phases. This was confirmed by the labelling indices on autoradiographic slides. The fraction of cells in phases S and (G2 + M) for tumours that were pre-irradiated with 15 or 25 Gy before nephrectomy was only slightly less than in unirradiated tumours. Comparison of the FCM ploidy with the results of histological grading showed that all cases classified as the most malignant grades IV or IIIB (according to the nuclear and to the combined grading system of Syrjänen and Hjelt (1978) were hyperdiploid. On the other hand, 45% of the hyperdiploid and 89% of the diploid tumours were of the low grades I and II. After a follow-up for 6 months to 2 years, 8/17 patients with hyperdiploid and only 1/14 patients with diploid tumours have died or relapsed with multiple metastases. The results indicate that the aneuploidy of tumours, measured by FCM, might provide useful additional information for prognosis.

[Transplantation of human renal adenocarcinoma tissue on the nude mouse (author's transl)]. / Transplantation von menschlichem nierenadenokarzinomgewebe auf die nackte maus.

Tissues of human renal cell carcinoma and of its lymph-node metastases were transplanted between the 1st and the 4th passage on 80 nu/nu mice. Growth of tumor was observed in all cases. Chromosomal analyses proved the tumor origin of the transplants. The primary tumor showed two histological patterns: a granular solid cell carcinoma and sarcomatoid elements. The lymph nodes showed only sarcomatoid tissue of the primary tumor. Light-and electron-microscopic examinations showed that the transplanted tumor contained only the sarcomatoid tissue of the original tumor. The solid carcinomatous tissue was not found and, therefore, probably not transplanted. Flow cytometric investigations of the primary tumor revealed two cell populations with a DNA content of 6 and 10.8 pg. Both cell colonies were also discovered in the transplanted tumors as well. The transplants of the primary tumors grew significantly slower than those of the lymph-node metastases. After an initial inert phase, the transplanted tumors grew more rapidly in the male than in the female animals. Neither hematogenous nor lymphatic metastases were observed. After local excision, recurrent tumor development was found in 80% of the experimental animals.

[Possibilities of cytostatic therapy in adenocarcinoma of the kidney. I. Influence of vinblastine on the growth of transplanted tumors]. / Möglichkeiten der zytostatischen therapie beim adenokarzinom der niere. I. Einfluss von vinblastin auf das wachstum transplantierter tumoren.

The effect of vinblastine sulfate on the acceptance and growth of a very malignant, human adenocarcinoma of the kidney (RCCI) on nude mice was investigated. Without any treatment, this tumor has an acceptance rate of 100%. Subcutaneously transplanted pieces of tumor, measuring 3 X 3 X 1 mm, commence to grow rapidly 1 week after transplantation and reach a diameter of approximately 2 cm, 6 weeks thereafter. Tumors with a diameter of approximately 2 cm, treated during 6 weeks with vinblastine (0.6 mg/kg/week), continued to grow during treatment and thereafter. However, when these growing, pretreated tumors were transplanted on new experimental animals, they either were not accepted by them or grew very slowly. When animals with tumor transplants were treated for 6 weeks with vinblastine (same schedule as above), beginning on the 1st day after transplantation, tumor growth was markedly retarded in every case, but only very seldom the tumor was not accepted.

Flow cytometric and autoradiographic studies of human kidney carcinomas surgically removed after preirradiation.

In a randomized study of human renal adenocarcinomas the tumours were either preirradiated with 25 Gy of 42 MeV X-rays or removed without pretreatment. Nephrectomy was performed 3 1/2 weeks after the end of irradiation or in the untreated series immediately after diagnosis. The impairment of cell proliferation after irradiation was determined by flow cytometry (FCM) and 3H-autoradiography after in vitro incubation. From FCM DNA distributions the fractions of cells in the phases of cell cycle were computed. The results show good agreement between the S-phase fractions determined by FCM and autoradiography. Preliminary data from 14 patients, 5 preirradiated and 9 unirradiated show that the fraction of cells in S-phase was reduced from 0.06 +/- 0.03 in the unirradiated patients to 0.01 +/- 0.01 in the irradiated ones. 12 of the 14 adenocarcinomas had diploid DNA content (2C) and 2 were hyperdiploid. The results demonstrate that FCM can supplement the techniques available for the assessment of radiation response of human tumours.