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Biomedical subjects

A Hobisch

Publications and source records attributed to A Hobisch.

At least 19 recordsLinked to original sources
PubMed2001

Interleukin-6 and prostate cancer progression.

Prostate cancer, while initially dependent on androgens for proliferation, progresses to an androgen-independent state. Evidence has been accumulating that interleukin-6 (IL-6) may contribute to prostate cancer progression. Serum levels of IL-6 correlate with prostate tumor burden and patient morbidity. The prostate tissue itself appears to be a source of IL-6 and its receptor. Furthermore, experimental data suggest that IL-6 is an autocrine and paracrine growth factor for androgen-independent prostate cancer cell lines. For example, inhibition of IL-6, with anti-IL-6 antibody, sensitizes androgen-independent prostate cancer cells to chemotherapeutic agents in vitro. Finally, IL-6 activates a variety of signal transduction cascades, some which stimulate androgen receptor activity, in prostate cancer cells. These data suggest that targeting IL-6 may have multiple benefits in prostate cancer patients.

Animals↗
PubMed2001

Laparoscopic retroperitoneal lymph node dissection.

PURPOSE: Retroperitoneal lymph node dissection is the most sensitive and specific diagnostic modality for detecting occult lymph node metastases in clinical stage I testicular tumor. In stage II disease, residual tumors after chemotherapy have to be removed surgically. To reduce the morbidity of these procedures we have replaced open surgery by laparoscopy. PATIENTS AND METHODS: Between August 1992 and December 1999 125 patients underwent laparoscopic RPLND (stage I: 76 pts., stage II: 49 pts.) RESULTS: Laparoscopic RPLND could be completed as planned in all but two patients in whom bleeding required conversion to open surgery. Once the learning curve had been overcome, mean operative time decreased significantly from 476 to 219 min for stage I and averaged 226 min in stage IIB disease. Only minor postoperative complications occurred such as asymptomatic lymphoceles (7 pts.) and chylous ascites (6 pts.). Mean post-op hospital stay was 3.3 and 3.5 days, respectively (stages I and II). Mean followup is currently 46 months for stage I and 35 months for stage II tumors. Over this period a single retroperitoneal recurrence was observed (stage I), which, however, was not due to surgical failure, but to false negative histologic findings. All other patients have remained free of relapse. CONCLUSIONS: Laparoscopic RPLND is a demanding procedure with a long and steep learning curve. It has proved feasible also after chemotherapy. The diagnostic accuracy of laparoscopic RPLND was as good as that of the open procedure, while the morbidity is significantly lower. Tumor control was not compromised by the laparoscopic approach.

Adolescent↗
PubMed2001

Photodynamic diagnosis with 5-aminolevulinic acid in the treatment of secondary urethral tumors: first in vitro and in vivo results.

OBJECTIVES: Photodynamic diagnosis (PDD) is able to detect dysplasia and transitional cell cancer of the bladder. We report our first experiences using PDD in the urethra. MATERIALS AND METHODS: Three patients with secondary transitional cell cancer of the urethra were treated by using PDD. 5-Aminolevulinic acid (ALA) was applied in a mixture with lubricant to achieve long enough contact with the urothelium. Negative effects were tested in vitro on three bladder cell lines. RESULTS: In vitro assays showed no enhanced negative effects on the viability of bladder cells using the combination of ALA/lubricant and medium in comparison to lubricant/medium alone. All patients showed markedly fluorescent areas, which were resected. The treatment was well tolerated without side effects attributable to the photosensitizer containing lubricant. CONCLUSION: Lubricant with ALA forms a viscous solution, which can successfully be used for PDD in the urethra. Thus marking tumors by fluorescence may improve transurethral resection and thus preserve the urethra.

Adult↗
PubMed2001

Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion.

Patients frequently complain about changes in their everyday life after radical cystectomy and urinary diversion. The aim of this study was to compare subjective morbidity of ileal neobladder to the urethra versus ileal conduit urinary diversion and to elucidate its influence on quality of life. A total of 102 patients who underwent radical cystectomy due to a bladder malignancy were included in the study: 69 patients (67.6%) with an orthotopic neobladder and 33 patients (32.4%) with an ileal conduit. The compliance was 99% and mean follow-up was 37 months. All patients completed two retrospective quality-of-life questionnaires, namely the QLQ-C30 and a questionnaire developed at our institution to elucidate specific items regarding urinary diversion. The questioning was performed by a nonurologist. The results obtained from the validated (QLQ-C30) and our self-designed questionnaire clearly demonstrate that patients with an orthotopic neobladder better adapt to the new situation than patients with an ileal conduit. In addition, neobladder to the urethra improves quality of life due to a better self-confidence, better rehabilitation as well as restoration of leisure, professional, traveling, and social activities, and reduced risk of inadvertent loss of urine. For example, 74.6% of neobladder patients felt absolutely safe with the urinary diversion in contrast to 33.3% in the ileal conduit group. Only 1.5% of neobladder patients had wet clothes caused by urine leakage during day versus 48.5% of ileal conduit patients; 92.8% of neobladder patients felt not handicapped at all; and 87% felt not sickly or ill in contrast to 51.5% and 66.7% of ileal conduit patients, respectively. Moreover, 97% of our neobladder patients would recommend the same urinary diversion to a friend suffering from the same disease in contrast to only 36% of ileal conduit patients. The results obtained by this study demonstrate that quality of life is preserved in a higher degree after orthotopic neobladder than after ileal conduit urinary diversion.

Cystectomy↗
PubMed2001

VI--choosing the right reconstruction for your female patients.

Like in male patients, selection of female patients for an orthotopic neobladder is important from an oncological and functional standpoint. The anatomy and the behavior of the isolated urethra in women had to be restudied because of the shorter urethra, the absence of the prostate, an undefined level of urethral dissection, and the different anatomy of the urethral sphincter-system. Retrospective long-term observations of female patients with primary bladder cancer revealed a 2% incidence of secondary urethral tumors in women. The only significant risk factor for urethral tumor involvement was primary bladder cancer at the bladder neck. Any type of gastrointestinal segment may be used for creating a pouch in women. As a result of an approximately 15% possibility of urinary retention or larger post-void residuals, the use of an efficient antireflux valve mechanism seems prudent. Clinical experience in an increasing number of women confirms the preliminary favorable results. Despite the selection criteria outlined in this article, most women can safely and rewardingly be offered an orthotopic neobladder.

Appendectomy↗
PubMed2001

Predictive value of total and percent free prostate specific antigen in high grade prostatic intraepithelial neoplasia lesions: results of the Tyrol Prostate Specific Antigen Screening Project.

PURPOSE: We evaluate the predictive values of total and percent free prostate specific antigen (PSA) in regard to high grade intraepithelial lesions in volunteers who participated in the Tyrol PSA Screening Project. MATERIALS AND METHODS: Between June 1995 and December 1998, 1,474 patients undergoing transrectal biopsy of the prostate were evaluated. The primary detection rates of prostate cancer and high grade intraepithelial lesions were evaluated. In addition, the rate of prostate cancer detected on biopsy in patients diagnosed with high grade prostatic intraepithelial neoplasia on the previous biopsy was assessed. Mean total PSA values and mean percent free PSA levels were determined for each study group and compared using the Mann-Whitney U test. RESULTS: A total of 1,077 (73.1%) volunteers had benign prostatic hyperplasia or prostatitis, and 327 (22.2%) had prostate cancer. The primary detection rate for high grade intraepithelial lesions was 4.7% (70 patients) and on repeat biopsy was 38.6% (27). Mean total PSA for the benign prostatic hyperplasia, prostate cancer, high grade and intraepithelial cancer groups were 6.0, 8.7, 5.9 and 5.2 ng./ml., respectively. Mean percent free PSA values for the various groups were 21.9, 12.1, 15.0 and 12.0, respectively. In regard to total PSA there was a statistically significant difference between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.016), as well as the prostate cancer and intraepithelial cancer groups (p = 0.028). However, the high grade and intraepithelial cancer groups did not differ significantly. In regard to percent free PSA there were statistically significant differences between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.0001), and the high grade and intraepithelial cancer groups (p = 0.013). CONCLUSIONS: In regard to percent free PSA our data indicate a significant difference between high grade intraepithelial lesion and intraepithelial cancer. Due to a substantial overlap in percent free prostate specific antigen between the 2 groups, a clinically useful cutoff point could not be established. Therefore, we recommend repeat biopsy in all patients with high grade intraepithelial lesions regardless of the percent free PSA.

Adult↗
PubMed2000

Expression and function of androgen receptor in carcinoma of the prostate.

This article reviews recent findings on androgen receptor expression, structure, and function in carcinoma of the prostate. In this decade, it became clear that androgen-resistant prostate cancers contain androgen receptors and, therefore, regulation of androgen receptor expression and function receives considerable attention. The article summarizes findings on regulation of androgen receptor expression by androgens, growth factors, and protein kinase A activators. In addition, modulation of function of the wild-type and mutant AR is discussed. Androgen receptor functional activity is up-regulated by androgens and nonsteroidal activators, which influence transcription of androgen receptor-regulated genes in a cell type-dependent manner. This study also contains a chapter on androgen receptor-associated proteins, coactivators, and coreppressors and their possible role in pathological situations.

Cell Differentiation↗
PubMed2000

Immunohistochemical localization of interleukin-6 and its receptor in benign, premalignant and malignant prostate tissue.

Interleukin-6 (IL-6) is a pleiotropic cytokine that interacts with its receptor in prostate cells, thus regulating proliferative response and differentiation. It also activates the human androgen receptor in prostate cancer cell lines. In order to assess the significance of these findings in vivo, the expression of key elements of the IL-6 signalling pathway, IL-6 and its receptor, was investigated in tissue samples obtained on radical prostatectomy from prostate cancer patients. IL-6 immunohistochemistry was performed on 17 frozen prostate cancer specimens. IL-6 receptor immunostaining was evaluated in 21 paraffin-embedded prostate tumour specimens. In both groups, adjacent areas of high-grade prostatic intraepithelial neoplasia and benign tissue were also investigated. In benign prostatic epithelium, IL-6 was localized predominantly in basal cells, whereas in prostate cancer tissues more IL-6-positive glandular cells were identified. No IL-6 expression was detected in stromal cells on immunohistochemistry, although IL-6 protein was measured in the supernatants obtained from cultured stromal cells by ELISA. IL-6 receptor was expressed in benign prostatic tissue in both epithelial and stromal cells. Furthermore, IL-6 receptor expression was observed in all tumour specimens investigated and the majority of Gleason patterns analysed had more than 50% of cells showing a positive reaction. IL-6 and IL-6 receptor expression patterns in high-grade prostatic intraepithelial neoplasia lesions were similar to those observed in tumour tissues. Taken together, the results of the present study imply that there are paracrine and autocrine IL-6 loops in benign and neoplastic prostate.

Adenocarcinoma↗
PubMed2000

Androgen receptor--an update of mechanisms of action in prostate cancer.

Androgen receptor (AR), a key nuclear transcription factor in the prostate gland, is expressed in all histological types and stages of prostate cancer. The AR regulates proliferation of prostate cancer cells by stimulation of cyclin-dependent kinases. However, in some prostate tumors AR stimulates expression of cell cycle inhibitors, thus leading to down-regulation of cellular proliferation. Androgens, by activation of the AR, control differentiation of prostate cells and synthesis of neutral lipids. There are several mechanisms by which prostate cancer cells adapt to an environment with low androgen supply during endocrine therapy. The AR expression and activity increase in several cell lines that are used as an in vitro model for monitoring changes during long-term androgen ablation. Mutant ARs are of importance for monitoring the natural course of the disease and for determining the response to anti-androgens in metastatic lesions from prostatic carcinoma. In addition, AR activity is up-regulated by various stimulators of intracellular protein kinases. Current research efforts are focused on elucidation of function of AR coregulatory proteins, coactivators and corepressors. Their inappropriate expression and/or function might critically influence cellular events in advanced carcinoma of the prostate. It is hoped that information on these coregulatory proteins will serve as a basis for a more efficient pharmacological inhibition of the AR in advanced carcinoma of the prostate.

Animals↗
PubMed2000

Quality of life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion.

The impact of bladder removal and urinary diversion for patients' everyday life is largely unknown. The aims of this study were to compare subjective morbidity of ileal neobladder to the urethra versus ileal conduit urinary diversion and to elucidate its influence on quality of life. A total of 102 patients who underwent cystectomy due to a bladder malignancy were included in the study. In 69 patients (67.6%) an orthotopic neobladder and in 33 patients (32.4%) an ileal conduit was performed as urinary diversion. The compliance was 99% and mean follow-up was 37 months. All patients completed two retrospective quality of life questionnaires, namely the QLQ-C30 and a questionnaire developed at our institution to ask for urinary diversion specific items. The questioning and assessment was performed by non-urologists. The results obtained from the validated (QLQ-C30) and our own specially compiled questionnaire clearly demonstrate that patients with an orthotopic neobladder are more able to adapt to the new situation than patients with an ileal conduit. In addition, neobladder to the urethra improves the quality of life because it improves self-confidence, causes better rehabilitation as well as the restoration of leisure, professional, travelling, and social activities, and reduced risk of inadvertent loss of urine. For example, 92.8% of neobladder patients did not feel handicapped at all, and 87% did not feel sick or ill, in contrast to 51.5% and 66.7% of ileal conduit patients, respectively. Of the neobladder patients, 74.6% felt absolutely safe with the urinary diversion in contrast to 33.3% in the ileal conduit group. Only 1.5% of neobladder patients had wet clothes caused by urine leakage during the day, versus 48.5% of ileal conduit patients. Moreover, 97% of our neobladder patients would recommend the same urinary diversion to a friend suffering from the same disease, but only 36% of ileal conduit patients would do so. These results demonstrate that the quality of life is preserved to a higher degree after orthotopic neobladder than after ileal conduit urinary diversion.

Aged↗
PubMed2000

Laparoscopic retroperitoneal lymph node dissection.

INTRODUCTION: Retroperitoneal lymph node dissection (RPLND) is the most accurate method for evaluating the presence of retroperitoneal metastases from clinical Stage I nonseminomatous testicular tumors. We have introduced laparoscopy to reduce the morbidity of open RPLND, which is too high for a diagnostic procedure. As the next step, we replaced open surgery with the laparoscopic approach for Stage IIb tumors to remove residual tumor after chemotherapy. TECHNICAL CONSIDERATIONS: One prerequisite for laparoscopic RPLND is free access to the retroperitoneum, which can be achieved by wide dissection of the colon and duodenum. The borders of the dissection are the same as with open surgery, and complete dissection can be achieved. Bipolar coagulation and the harmonic scalpel have proved very helpful in achieving adequate hemostasis, a crucial point. Venous lesions can be sealed with fibrin glue. CONCLUSIONS: Laparoscopic RPLND is superior to open surgery with regard to morbidity and complication rates, and operative times are equal once enough experience has been collected. The diagnostic accuracy is the same for both methods, and tumor control is not compromised by the laparoscopic approach. The only drawback of laparoscopy is the long and steep learning curve.

Humans↗
PubMed2000

Androgen receptor protein is down-regulated by basic fibroblast growth factor in prostate cancer cells.

Interactions between polypeptide growth factors and the androgen receptor (AR) are important for regulation of cellular events in carcinoma of the prostate. Basic fibroblast growth factor (bFGF), the prototype of heparin-binding growth factors, and the AR are commonly expressed in prostate cancer. bFGF diminished prostate-specific antigen protein in the supernatants of androgen-stimulated human prostate cancer cells LNCaP by 80%. In the present study, we asked whether the bFGF effect on prostate-specific antigen is preceded by action on AR expression. LNCaP cells were treated with bFGF and AR protein expression was determined by immunoblotting and ligand binding assay. bFGF down-regulated AR protein in a dose-dependent manner showing a maximal effect at 50 ng ml(-1) both in the presence or absence of dihydrotestosterone. Down-regulation of AR protein expression occurred already after 8 h of bFGF treatment and a maximal inhibition was observed 24 h after addition of bFGF to culture media. As AR expression can be reduced by an increase in intracellular calcium levels, we investigated whether the bFGF effect on AR protein is mediated by this mechanism. Calcium release from intracellular stores and store-operated calcium influx after treatment with either bFGF or calcium ionophore A 23187 were measured by single cell fluorescence technique. The ionophore A 23187 was able to induce calcium influx and an increase in cytoplasmic calcium concentration in LNCaP cells. In contrast, bFGF was incapable of eliciting a similar effect. In contrast to AR protein, AR mRNA levels were not affected by bFGF as shown by semiquantitative reverse transcription polymerase chain reaction. In summary, these studies show that bFGF is a potent negative regulator of AR protein expression in the human prostate cancer cell line LNCaP.

Calcium↗
PubMed2000

Renal cell carcinoma in a horseshoe kidney--superselective embolization of a vessel in a remaining calix after partial nephrectomy.

A 51-year-old patient underwent partial nephrectomy because of a renal cell carcinoma in a horseshoe kidney. Postoperatively a remaining calix led to persistent urinoma formation. By means of superselective embolization urine extravasation was stopped successfully. This demonstrates that superselective embolization can be an effective tool in the management of complications after open renal surgery.

Angiography↗
PubMed2000

Antagonist/agonist balance of the nonsteroidal antiandrogen bicalutamide (Casodex) in a new prostate cancer model.

Androgen ablation is standard therapy for advanced prostate carcinoma. It can be administered either as a monotherapy or as a combined androgen blockade. In the present study we have investigated molecular mechanisms which are responsible for the development of resistance to therapy in advanced prostate cancer. For this purpose, we have cultured LNCaP cells in steroid-depleted medium for 1 year. The newly generated subline LNCaP-abl was characterized. In early passages (<75) LNCaP-abl cells showed a biphasic hypersensitive response to androgenic stimulation. Passages later than 75 are inhibited by androgen. Proliferation of LNCaP-abl cells was stimulated by the pure nonsteroidal antiandrogen bicalutamide (Casodex). To improve our understanding of changes which occur during intermittent androgen ablation, we have generated the sublines LNCaP-R (reversal; cultured with fetal calf serum) and LNCaP-RA (reversal and androgen; cultured with fetal calf serum and androgen) from LNCaP-abl cells. In both cell lines an increase of the basal proliferation rate was observed. Androgen receptor expression in LNCaP-abl cells was 4-fold higher than that in parental LNCaP cells (4.7 vs. 1.2 fmol/microg protein). Androgen receptor content in LNCaP-R cells was 1.8 fmol/microg protein and in LNCaP-RA cells 1.0 fmol/microg protein. The basal androgen receptor activity was 30-fold higher in LNCaP-abl cells compared to that in parental LNCaP cells. This basal activity was reduced in LNCaP-RA cells. Both androgen and the nonsteroidal androgen receptor antagonist hydroxyflutamide induced a 2- to 4-fold higher activation of androgen receptor in LNCaP-abl than in LNCaP cells. There was a switch from an antagonist to an agonist of the nonsteroidal antiandrogen bicalutamide (Casodex) in LNCaP-abl cells. Antagonistic properties of this androgen receptor blocker were again observed in both sublines (LNCaP-R and LNCaP-RA) derived from LNCaP-abl cells. In concordance with proliferation data in vitro, growth of LNCaP-abl cells in nude mice was stimulated by bicalutamide. In contrast, supplementation of androgen led to inhibition of proliferation of these cells. The present study provides new information that is useful for a better understanding of therapy-refractory prostate cancer. It is also important for the development of new therapy strategies for advanced carcinoma of the prostate.

Androgen Antagonists↗
PubMed2000

Elevated levels of serum secretoneurin in patients with therapy resistant carcinoma of the prostate.

PURPOSE: The majority of prostate cancers show some degree of neuroendocrine differentiation. It was previously demonstrated that chromogranin A, a constituent of large dense core vesicles of neuroendocrine cells, is frequently elevated in patients with metastatic prostate cancer. We evaluate the expression of secretoneurin, which is generated by proteolytic processing of secretogranin II (chromogranin C), in patients with prostate disease. MATERIALS AND METHODS: Secretoneurin was measured in sera of 16 healthy men whose blood was drawn for prostate cancer screening (controls), and in 9 patients with prostatitis, 19 with benign prostate hyperplasia and 54 with prostate cancer detected by radioimmunoassay. Therapy resistant disease (clinical stage D3) was noted in 20 prostate cancer cases. Serum prostate specific antigen was measured in all patients and controls. In addition, chromogranin A, prostate acid phosphatase and interleukin-6 were determined in patients with D3 prostate cancer. Molecular properties of secretoneurin immunoreactivity were analyzed by gel filtration chromatography followed by radioimmunoassay. RESULTS: Mean secretoneurin was 58.9+/-8 fmol./ml. in patients with therapy resistant prostate cancer. Levels were significantly higher than those measured in sera from controls and patients with prostatitis, benign prostatic hyperplasia and pT2 or pT3 prostate cancer. There was a statistically significant correlation between secretoneurin and chromogranin A in patients with endocrine therapy failure (r = 0.543, p<0.05). There was no correlation between serum secretoneurin and prostate specific antigen, prostate acid phosphatase or interleukin-6. Gel filtration chromatography analysis of sera of 3 patients with D3 prostate cancer revealed a peak of secretoneurin immunoreactivity where intact secretoneurin elutes, thus showing that the processed peptide is circulating in the blood. CONCLUSIONS: Secretoneurin is elevated in sera of patients with endocrine therapy refractory prostate cancer. Our results support the concept that neuroendocrine differentiation is associated with prostate cancer progression.

Adult↗
PubMed2000

Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous testicular carcinoma: long-term outcome.

PURPOSE: We report the long-term oncological efficacy and morbidity of laparoscopic retroperitoneal lymph node dissection for testicular carcinoma. MATERIALS AND METHODS: From August 1992 to September 1999, 73 consecutive patients underwent laparoscopic retroperitoneal lymph node dissection with modified unilateral template dissection. All lumbar vessels within the template were routinely transected in the initial 29 cases only. Patients with positive lymph nodes received 2 cycles of chemotherapy. RESULTS: Operative time ranged from 150 to 630 minutes (mean 221) in our most recent 28 cases. All but 2 operations were completed as planned for a conversion rate of 2.7%. Minor intraoperative complications developed in only 6.8% of cases. In our last 44 patients there was no major and only 1 minor (2.3%) postoperative complication. Mean postoperative hospitalization was 3.3 days. Ejaculation was preserved in all patients. Lymph nodes were positive in 19 cases (26%). Mean followup in 47 patients with pathological stage I disease was 43.3 months (range 7 to 84). We noted 1 retroperitoneal recurrence due to false-negative histological findings but there were no other relapses. At a mean followup of 42.7 months (range 6 to 86) 17 patients with pathological stage II carcinoma treated with 2 cycles of adjuvant chemotherapy were also free of disease. CONCLUSIONS: In our hands laparoscopic retroperitoneal lymph node dissection has not only proved its surgical efficiency, but also its oncological efficacy. Patient satisfaction is high. During long-term followup of more than 3 years not a single recurrence developed due to surgical failure.

Adolescent↗
PubMed1999

Correlation between preoperative predictors and pathologic features in radical prostatectomy specimens in PSA-based screening.

BACKGROUND: Measurement of percent free prostate-specific antigen (PSA), PSA density, and PSA-transition zone density (PSA-TZ density) in addition to total PSA is known to improve the specificity of PSA-based prostate cancer screening. We evaluated the ability of total PSA, percent free PSA, PSA density, and PSA-TZ density to predict pathologic features in radical prostatectomy specimens. METHODS: The levels of total PSA, percent free PSA, PSA density, and PSA-TZ density assessed prior to the diagnosis of prostate cancer were correlated with the pathologic findings in 102 prostate glands with cancer obtained at radical prostatectomy. The entire organs were examined histologically; Pearson correlation coefficients were used for statistical analysis. RESULTS: High levels of total PSA, PSA density, and PSA-TZ density correlated significantly with capsular penetration, high Gleason scores, and large cancer volumes in the prostatectomy specimens. Free PSA was found to correlate well with high Gleason scores, high percentages of cancer, and large cancer volumes, but not with capsular penetration. The four parameters were evaluated by means of logistic regression, which showed that only percent free PSA and total PSA were significant predictors of Gleason scores > or =7 and cancer volumes > or =0.5 cc. With regard to clinically insignificant cancers, only percent free PSA and the Gleason score obtained at biopsy were significant predictors. CONCLUSIONS: In men whose prostate cancers are detected by PSA-based screening, high total PSA levels in combination with low percent free PSA levels are suggestive of a potentially more aggressive type of prostate cancer. This may help both patient and clinician in selecting the most appropriate therapeutic approach.

Adult↗