FDG PET for detection and therapy control of metastatic germ cell tumor.

UNLABELLED: We investigated the use of PET and 2[18F]fluoro-2-deoxy-D-glucose (FDG) for detection and therapy control of metastatic germ cell cancer in comparison to CT. METHODS: Fifty-four PET studies were performed in addition to CT in 33 patients with histopathologically proven germ cell tumors (14 seminomas, 18 nonseminomas, 1 not classified). The scans were done either after initial diagnosis (Group 1; n = 12), within 2 wk after completion of chemotherapy (Group 2; n = 13) or 14-375 days after chemotherapy (Group 3; n = 29). PET and CT were validated either by histology (n = 19) or clinical follow-up for 182-1704 days (n = 35). Focal pathological uptake with PET was quantified using standardized uptake values (SUVs). RESULTS: PET was significantly more accurate than CT (0.86 versus 0.59; p < 0.025) for detection of residual viable tumor in Group 3. While sensitivities of PET and CT did not differ markedly, PET was significantly more specific than CT. No significant differences between PET and CT were found in Groups 1 and 2. PET scans after therapy resulted in false-negative findings in five of nine cases of Group 2 but only in two of nine cases of Group 3. False-positive PET findings occurred in three inflammatory processes. SUV of seminomas was significantly higher than in nonseminomas (p < 0.01). CONCLUSION: PET using FDG is superior to CT for assessment of residual tumor after chemotherapy of germ cell cancer and may thus have an increased effect on patient management in the future. PET must be performed at least 2 wk after completion of therapy. Further data are necessary to determine the role of FDG PET for initial staging of germ cell cancer.

Increased discrimination between benign prostatic hyperplasia and prostate cancer through measurement of percentage free PSA.

OBJECTIVE: The value of Prostate-Specific Antigen (PSA) for the early detection of Prostate Cancer (CaP) is controversial due to an appreciable false positive rate causing unnecessary biopsies. As PSA exits in both free and bound forms the percentage of free PSA was found to be lower in CaP than in Benign Prostatic Hyperplasia (BPH). We investigated whether the percentage of free PSA offers better discrimination on the detection of CaP. MATERIAL AND METHODS: In a retrospective analysis the percentage of free PSA was determined in the sera of 50 consecutive patients with histologically proven BPH (n = 30) and clinically localised CaP without metastases (n = 20; pT1-3 No Mo). Serum levels of free PSA and total PSA were determined employing a chemiluminescent enzyme immunoassay. RESULTS: Patients with CaP demonstrated a lower percentage of free PSA (median: 8.5, range: 2.7-24.5) than patients with BPH (median: 22.35, range: 8.9-66.7). (p < 0.001). CONCLUSION: Determination of percentage of free PSA enhances the discrimination between BPH and CaP and may reduce the number of unnecessary biopsies in patients with elevated PSA.

Direct invasion of the renal vein by metastatic testicular cancer.

We report a case of metastatic seminoma with direct invasion of the left renal vein. A tumor thrombus was found in the renal vein while the vena cava thrombosis proved to be a noncancerous blood clot developing as an extension of the tumor thrombus. Primary chemotherapy could not be completed because of thrombotic growth requiring surgical intervention. Although surgical specimens were free of viable tumor and two cycles of adjuvant chemotherapy were applied, the tumor relapsed in the area of renal vein invasion.

Free-to-total prostate-specific antigen serum concentrations in patients with prostate cancer and benign prostatic hyperplasia.

OBJECTIVE: To determine whether the proportion of total serum prostate-specific antigen (tPSA) which is unbound or free (free PSA) offers a better discriminant for the detection of patients with prostate cancer (CaP) and those with benign prostatic hyperplasia (BPH) than does serum tPSA alone. PATIENTS AND METHODS: In a retrospective analysis, the proportion of free PSA was determined in the sera of 60 patients with histologically confirmed localized (n = 39; pT1-3NoMo) and metastatic (n = 21; T2-4NxM+) CaP and 45 patients with BPH. Forty patients with urolithiasis served as a control group. Serum levels of free and total PSA were determined using a chemiluminescent enzyme immunoassay. RESULTS: Patients with CaP had a lower percentage of free PSA (localized CaP median 8.8%; metastatic CaP median 7.1%) than patients with BPH (median 19.5%) and those with urolithiasis (median 18.8%: P < 0.001). The percentage of free PSA did not differ significantly between patients with clinically localized and metastatic disease. CONCLUSION: The determination of the proportion of free PSA enhanced the discrimination between BPH and CaP and may reduce the number of unnecessary biopsies in patients with an elevated PSA. The results warrant further investigations in a broader population to improve the clinical use of serum PSA as a tumour marker for discriminating patients with an early, potentially curable CaP from men with BPH.

Metabolic imaging of untreated prostate cancer by positron emission tomography with 18fluorine-labeled deoxyglucose.

PURPOSE: We evaluated positron emission tomograph (PET) with 18fluorine (18F)-labeled deoxyglucose for metabolic grading of untreated primary prostate cancer, and differentiation of benign and malignant prostatic disease. MATERIALS AND METHODS: A total of 48 patients with untreated prostate cancer of different stages and 16 with histologically confirmed benign prostatic hyperplasia (BPH) underwent static PET after intravenous injection of 150 to 300 MBq. 18F-deoxyglucose. 18F-deoxyglucose accumulation was quantitated by calculating differential uptake ratios and prostate-to-skeletal muscle ratios. RESULTS: Low 18F-deoxyglucose uptake was noted in the majority of primary tumors (81%). 18F-deoxyglucose accumulation did not correlate with increasing tumor grade or stage. There was a significant overlap in uptake values in BPH and malignant prostatic disease. A trend towards statistical significance was noted with lower prostate-to-skeletal muscle ratios in patients with BPH (p < 0.07). Increased 18F-deoxyglucose accumulation was detected in some patients with BPH and malignant prostatic disease, as well as in those with lymph node and bone metastases of prostate cancer. CONCLUSIONS: 18F-deoxyglucose PET does not allow for metabolic labeling in the majority of untreated primary prostate cancers. BPH and primary prostate cancer cannot be reliably differentiated on the basis of PET. Increased 18F-deoxyglucose accumulation occurs in some primary prostate tumors and in metastatic deposits of prostate cancer.

Current and future strategies to block tumor angiogenesis, invasion, and metastasis.

Progression of malignancy involves a series of sequential steps that ultimately lead to cancer-cell dissemination. In addition to the loss of growth control, an imbalanced regulation of motility and proteolysis is a prerequisite for invasion and metastasis. These factors are also necessary for angiogenesis-an integral process occurring at both the primary and the metastatic sites. Investigators have elucidated in detail many of the molecular mechanisms involved in the sequential steps of the metastatic cascade and have thereby provided new targets for therapeutic intervention. For each step, different model systems have been developed and various strategies for antimetastatic therapy have been tested in vitro as well as in murine systems. Difficulties in translating results obtained in preclinical models into the clinical setting have become apparent and have not been unexpected in light of the sometimes highly artificial interaction in the experimental setting. Nevertheless, continued development of model systems and further research into the genetic control of malignancy should lead to the identification of common signal-transduction pathways. Interference at such sites promises to be particularly effective in inhibiting proliferation and metastasis.

Clinical use of prostate-specific antigen and prostate-specific antigen density in the staging of patients with cancer of the prostate.

OBJECTIVE: To examine the efficacy of prostate-specific antigen (PSA) and prostate-specific antigen density (PSAD) in staging patients undergoing radical prostatectomy for clinically localized prostate cancer (CaP). PATIENTS AND METHODS: Prostate gland volumes were estimated in patients with clinically localized CaP (n = 119) performing transrectal ultrasound and employing the prolate ellipse formula. PSA was determined using an enzyme immunoassay. All patients underwent laparoscopic pelvic lymphadenectomy followed by radical perineal prostatectomy in No disease. The PSA density was calculated relating the Serum PSA to the sonographically estimated prostate volume. RESULTS: The pathological examination of the prostatectomy specimens revealed a pT2 tumor in 52 cases (43.7%) and a pT3 tumor in 41 cases (34.5%). In 26 patients (21.8%) the histological examination demonstrated metastases to the lymph nodes. Patients with a pT2No CaP demonstrated a median PSA level of 8.95 ng/ml and a median PSAD of 0.3, those with a pT3No CaP demonstrated a median PSA level of 12.3 ng/ml and a median PSAD of 0.38 and those with a T2-3pN + revealed a median PSA level of 22.9 ng/ml and a median PSAD of 0.7. CONCLUSIONS: Both marker, serum PSA as well as PSAD, did not sufficiently distinguish patients with organ-confined cancer from those with extracapsular tumor extension. In contrast, PSAD levels seem to provide useful additional information in the staging of patients with clinically localized CaP with regard to the lymph node status.

Evaluation of patients with diseases of the prostate using prostate-specific antigen density.

OBJECTIVE: To compare the efficacy of two tests, prostatic-specific antigen (PSA) and the PSA/prostate volume ratio (PSAD), as diagnostic and staging markers to discriminate patients with benign prostatic hyperplasia (BPH) from patients with cancer of the prostate (CaP). PATIENTS AND METHODS: Prostate gland volumes were estimated in 60 patients with BPH and 88 patients with clinically organ-confined CaP by performing transrectal ultrasonography (TRUS) and using the prolate ellipse formula. Serum PSA concentration was determined using an enzyme immunoassay. In patients with BPH, the prostates were removed either by transurethral resection or retropubic prostatectomy. Patients with CaP underwent laparoscopic pelvic lymphadenectomy followed by radical perineal prostatectomy. PSAD was calculated by relating the serum PSA level to the TRUS-estimated prostate volume. RESULTS: The median PSA level was 4.4 ng/mL in patients with BPH, 9.3 ng/mL in patients with CaP-NO disease and 24 ng/mL in those with CaP-N+ disease. However, imposing a PSA limit of 4 ng/mL for the diagnosis of CaP gave a positive predictive value of only 64.8%, whereas a limit of 10 ng/mL gave a positive predictive value of 71.4%. In contrast, the median PSAD was 0.086 ng/mL/cm3 in patients with BPH, but was 0.295 ng/mL/cm3 in patients with NO-disease and 0.775 ng/mL/cm3 in those with N(+)-disease. With a limit of 0.15 ng/mL/cm3 the positive predictive value of PSAD was 81%. Furthermore, a limit of 0.6 ng/mL/cm3 revealed a positive predictive value of 81% for the diagnosis of metastatic lymph node involvement. CONCLUSIONS: There was a considerable overlap of PSA concentrations in patients with BPH and CaP, and PSA was not sufficiently accurate to distinguish between them. In contrast, PSAD enhanced the discrimination between BPH and CaP and may provide additional information about the status of the lymph nodes in patients with CaP.

Theories on the metastatic process and possible therapeutic options.

A sequence of steps are prerequisite for cancer cells before metastases are established. Metastasis has been shown to be an inefficient process limited by both random and selective events. By differentiating invasion from metastasis, sequential steps in the metastatic cascade have been defined and studied separately. This approach has yielded a variety of new potential therapeutic strategies. However, increasing knowledge of the mechanisms relating to metastasis has also revealed the complexity of each step. In spite of difficulties in translating results obtained in preclinical models into the clinical setting, continued development of such model systems and further research into the genetic control of metastatic dissemination will lead to improved strategies for prevention of metastasis formation and for treatment of metastatic tumor cells.

Basic research in prostate cancer: molecular biology.

While a general appreciation for the importance of chromosomes in the development of cancer has existed for decades, molecular genetic analyses have gained considerable attention in recent years through identification of proto-oncogenes and tumor suppressor genes. Several different chromosomal aberrations, alterations of proto-oncogenes and suppressor genes have been described in prostate cancer. Loss of genetic material has been found to occur most frequently on chromosomes 7, 8, 10 and 16. The existence of tumor suppressor genes relevant to prostate carcinogenesis is suspected in these chromosomal locations. Several investigators are currently trying to identify these genes. Altered expression of several different oncogenes has been reported in prostate cancer. Among these, the ras- and myc-families of oncogenes have been studied most intensively. Structural oncogene alterations have been detected infrequently, most of the changes appear to occur transcriptionally. Despite an abundance of clinical material, knowledge about genetic lesions in prostate cancer is still very limited and sometimes conflicting results have been reported. With recent methodologic improvements and a growing interest in correlating genetic alterations with clinical disease progression, definition of prostate carcinogenesis at the molecular level will advance rapidly in the near future.

p53 gene alterations in human prostate carcinoma.

Alterations of the p53 gene are among the most frequent genetic lesions in a variety of human malignancies. Their role in prostate cancer is, however, unclear. We have analyzed 10 primary and two metastatic human prostate carcinomas as well as 3 prostate cancer cell lines for mutations of the p53-gene. Using single strand conformational polymorphism analysis (SSCP) and direct sequencing of the polymerase chain reaction (PCR) products, p53 mutations were detected in 1 of 10 primary prostate cancers. By contrast, 1 of 2 metastatic tumors and all 3 prostate cancer cell lines (derived from metastases) were found to contain a mutant p53 gene. Thus, our data suggest that alterations of the p53 gene at the mutational "hot spots" appear to occur infrequently in primary human prostate cancer, but may emerge in later stages of tumor progression. Furthermore, we confirm that loss of heterozygosity at a locus telomeric to p53, but not including p53, is associated with metastatic progression in 1 case.

Expression of the matrix Gla protein in urogenital malignancies.

Matrix Gla protein (MGP), is a vitamin-K-dependent protein which is synthesized in a variety of tissues such as lung, heart, kidney, cartilage and bone. The function of MGP in these tissues is unclear. We have previously reported elevated MGP mRNA levels in a breast-cancer cell line, 600PEI, as compared to normal breast epithelium. Here we describe high MGP expression in primary renal-cell carcinomas, prostate carcinomas and testicular germ-cell tumors, as determined by Northern analysis. MGP was over-expressed in 21 out of 28 patients with renal-cell carcinoma, and in 16 out of 29 patients with testicular germ-cell tumors, as compared to matched normal tissues. For the renal-cell carcinomas, a statistically significant inverse correlation was observed between the level of MGP expression and tumor size, lymph-node metastasis and tumor grade. MGP was also highly expressed in 13 primary prostatic carcinomas as compared to prostate cell lines derived from metastatic tumors, and to lymph-node metastasis. Our findings indicate that the loss of MGP expression may be associated wih tumor progression and metastasis.

Prevalence of human papillomavirus types 16 and 18 in squamous-cell carcinoma of the penis: a retrospective analysis of primary and metastatic lesions by differential polymerase chain reaction.

Human papillomaviruses (HPV), particularly types 16 and 18, may be carcinogenic effectors in a variety of human lower-genital-tract malignancies. Using the highly sensitive technique of differential polymerase chain reaction (D-PCR) with amplimers from the E6 open reading frames of HPV types 16 and 18, a retrospective analysis of a 20-year institutional experience with squamous-cell carcinoma of the penis (SCCP) was performed to determine the prevalence of these HPV types in this malignancy. Paraffin-embedded surgical specimens of primary (N = 27), locally recurrent (N = 5), and metastatic deposits (N = 26) from 29 patients with invasive SCCP were analyzed, as well as primary (N = 3) and recurrent (N = 2) specimens from 2 patients with penile carcinoma in situ (CIS) (Bowen's disease). Nine of the 29 (31%) patients had invasive SCCP containing HPV 16 or 18 DNA, with HPV 16 found in 8 (28%) and HPV 18 in I (3%); no patient had both. In 7 patients in which only tissue from metastatic sites was available, 2 had HPV 16 detected in 2 separate metastatic sites each. Specimens from both primary and metastatic sites were available in an additional 6 patients, and HPV 16 was detected in specimens from 3 of these 6 patients. HPV was detected in comparable copy number at both sites in each patient, indicating that HPV DNA may be a stable component within cancer cells during disease progression. Of patients with CIS only, 1 of 2 was positive for HPV 16, and upon multifocal recurrence, showed persistence of the virus at 2 separate sites. Southern blotting was performed to confirm the presence of type-specific HPV DNA and showed complete concordance with D-PCR, but discordant hybridization intensities for HPV 18 were noted between the control and positive patient specimens; sequence analysis of the patient specimen revealed 4 point mutations in the HPV-18 target segment. Comparison of the HPV-positive (both HPV 16 and HPV 18) and HPV-negative groups revealed no statistical differences between groups in patients age or ethnic origin, tumor histologic grade, or incidence of nodal involvement. Kaplan-Meier analysis of both overall and cause-specific survival likewise was not different between groups. These data, particularly the presence of HPV in metastatic deposits, provide strong evidence for an etiologic role of HPV type 16 (and possibly 18) in a substantial sub-set of patients from the southeastern United States who developed SCCP.

Alterations of the P53 gene are associated with the progression of a human prostate carcinoma.

P53 is a tumor suppressor gene that has been implicated in the molecular genetics of many human malignancies. Nucleotide alterations, most commonly single point mutations, have been shown not only to abrogate the p53 suppressor function but also to contribute to the transformed phenotype. We report the detection of a p53 gene mutation in clinical specimens of a patient with relapsing prostate adenocarcinoma 14 years after definitive external beam radiation. The techniques of single strand conformation polymorphism analysis and direct sequencing of polymerase chain reaction generated products were used for this study. Analysis of tissue from different locations of the primary tumor revealed intratumoral molecular heterogeneity; the mutation was absent in 1 area but present in another. Tumor from a regional lymph node metastasis harbored the identical p53 mutation. Furthermore, an additional genetic alteration, an allelic loss on chromosome 17p but not including the p53 gene, was observed only in the metastatic tissue. These observations in clinical specimens of primary and metastatic sites provide evidence for the association of the p53 gene in the progression of human prostate carcinoma.

Human papillomavirus types 16 and 18 are not involved in human prostate carcinogenesis: analysis of archival human prostate cancer specimens by differential polymerase chain reaction.

Human papilloma viruses (HPV) have been implicated in the pathogenesis of a variety of malignancies, especially in carcinomas of the female genital tract. Recently, based on observations using the polymerase chain reaction amplification assay, HPV types 16 and 18 specific DNA sequences have been detected in prostate cancer specimens obtained by transurethral resection. Since HPV types 16 and 18 have been shown to possess oncogenic potential, an association between HPV infection and prostatic carcinoma has been suggested. In order to exclude potentially HPV-colonized urethral mucosa from analysis and restrict our study to predominantly malignant tissue, cancerous areas from a series of 30 paraffin-embedded prostate adenocarcinomas were microdissected and analyzed for the presence of HPV 16 or HPV 18 specific sequences by a modification of PCR (D-PCR) and Southern blot analysis. Despite the high sensitivity of our analytical technique, we found no evidence of HPV-DNA of either type in any of the 30 primary prostate cancers. In contrast, both HPV 16 (2/8 specimens) and HPV 18 (2/8 specimens) DNA was detected in randomly chosen cervical carcinomas using the D-PCR methodology. Our data would indicate that the oncogenic HPV-types 16 and 18 are unlikely effectors of prostate carcinogenesis.