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TGFβ is a known driver of epithelial-mesenchymal transition (EMT) which is associated with tumor aggressiveness and metastasis. However, EMT has not been fully explored in clinical specimens of castration-resistant prostate cancer (CRPC) metastases. To assess EMT in CRPC, gene expression analysis was performed on 149 visceral and bone metastases from 62 CRPC patients and immunohistochemical analysis was performed on 185 CRPC bone and visceral metastases from 42 CRPC patients. In addition, to assess the potential of metastases to seed further metastases the mitochondrial genome was sequenced at different metastatic sites in one patient. TGFβ was increased in bone versus visceral metastases. While primarily cytoplasmic; nuclear and cytoplasmic Twist were significantly higher in bone than in visceral metastases. Slug and Zeb1 were unchanged, with the exception of nuclear Zeb1 being significantly higher in visceral metastases. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype. Underscoring the relevance of EMT-like cells, mitochondrial sequencing revealed that metastases could seed additional metastases in the same patient. In conclusion, while TGFβ expression and EMT-associated protein expression is present in a considerable number of CRPC visceral and bone metastases, nuclear Twist, Slug, and Zeb1 localization and an EMT-like phenotype (elongated nuclei and cytoplasmic compartment) was only present in a small subset of CRPC bone metastases. Mitochondrial sequencing from different metastases in a CRPC patient provided evidence for the seeding of metastases from previously established metastases, highlighting the biological relevance of EMT-like behavior in CRPC metastases.

Disseminated tumor cells (DTCs) are detected early in the disease process in prostate cancer (PCa) patients and can persist after radical prostatectomy. DTCs can remain dormant in patients with no evidence of disease for a prolonged period of time only to recur 10 or more years later. Recent advances in single-cell genomics and transcriptomics have provided much needed insight into DTC biology and cancer dormancy in patients. With the development of new in vitro and preclinical models, researchers recapitulate the clinical events in patients and therefore allow further elucidation of the molecular mechanisms underlying cancer dormancy and escape. In this review, we explore novel ideas on the detection, heterogeneous transcriptomic profiles, molecular and cellular mechanisms of dormancy, and potential mechanisms underlying dormancy escape by DTCs. As such, there is hope that identifying and targeting novel dormancy-associated pathways in patients with residual disease will have significant clinical implications for the treatment of PCa patients in the future.

Our objective was to elucidate phenotypic differences between prostate cancer (PCa) liver, lymph node, and bone metastases. PCa metastases were obtained through a rapid tissue acquisition necropsy protocol. We grossly dissected metastatic foci from frozen samples and performed expression analyses using cDNA microarrays. Immunohistochemical analyses using a tissue microarray from thirty individuals with PCa metastases to lymph nodes, liver, and bone was used to confirm the gene expression changes associated with each metastatic site. Transcript alterations statistically-associated with bone metastases included increased expression of IBSP (Bone sialoprotein), F13A1 (factor XIII), and decreased expression of EFNA1 (ephrin-A1) and ANGPT2 (angiopoietin-2) when compared to liver and lymph node metastases. The metastasis-associated changes in proteins involved in coagulation and angiogenesis prompted further analysis of additional factors known to participate in the clotting cascade and blood vessel formation (angiopoitein-1, PAI-1, uPA, PAI-RBP-1 and hepsin). We also assessed tumor-associated microvessel density and distribution in liver, lymph node, and bone metastasis. Intense fibrin(ogen) and fibulin-1 staining was localized to epithelial cells at the periphery of metastatic tumors possibly to facilitate angiogenesis. The expression of hepsin, uPA, PAI-RBP1, PAI-1, and factor XIII may influence fibrinolysis and are regulated by the tumor microenvironment. The expression of angiopoietin-2 and apparent silencing of angiopoietin-1 in PCa bone, liver, and lymph node metastases may be critical for angiogenesis in this tumor type. In addition, the resulting tumor-associated microvessel density and distribution was significantly different between liver and bone metastasis possibly in response to the protein expression changes detailed above.

The morbidity and mortality associated with prostate cancer can almost universally be attributed to the consequences of metastases to the bone. While clinically there have been descriptive reports of these lesions and their detection by bone scan, there is an embrrassing paucity of reports as to the mechanisms of prostate cancer cell trafficking to the bone, adaptation to the bone environment, pertubation of the normal bone reformation process and the events leading to cachexia and death. In recent years, there have been numerous in vitro studies suggesting that PSA and hK2 may play a significant biological role in these events. Also, recent data generated form reverse transcription polymerase chain reaction assays reveal that metastasis to the bone may be an early event which further underscores the need to better understand this complex and critically important process. This commentary highlights several general concepts and a few specific issues related to CaP bone metastasis with the intent of revealing numerous opportunities for further investigation and inquiry.

Is prediagnosis PSA velocity predictive of the risk of death from prostate cancer following radical prostatectomy?

The development of immunoassays for prostate-specific antigen (PSA) and their clinical utility are summarized. Because of the complexity of the PSA molecule and anti-PSA antibodies, there is currently no standard in PSA measurement [1, 2]. Evaluating various immunoassays requires the knowledge of the lower limit of detection as well as the biological and clinical thresholds of a given assay [1]. There have been recent reports demonstrating earlier detection of residual prostate cancer after radical prostatectomy by ultrasensitive assays for PSA [3, 4]. Because of the recent evidence for non-prostatic sources of PSA such as the male urethra [5–7], the possibility of their contaminating PSA levels must be evaluated when more sensitive assays for PSA are under consideration.

Advanced renal cell carcinoma (RCC) is refractory to all traditional therapies and has been the subject of intense investigation using newer therapeutic modalities, including monoclonal antibodies, lymphokine-activated killer cells and vaccines. We review these newer immunotherapies and summarize our results with radioimmune imaging and radioimmunotherapy using mouse xenografts of human RCC and one of our RCC-preferential monoclonal antibodies (A6H). We have consistently been able to image RCC xenografts without background subtraction. Radioimmunotherapy caused tumor shrinkage, and dosimetry results were consistent with xenograft “cure.” Phase I clinical trials are now underway at this institution.

Prostate-specific antigen (PSA) represents a major advance in our tumor marker armamentarium. Although not cancer-specific, it is specific for prostatic epithelium. Sophisticated serum assays have been developed for the detection of the analyte, and serum PSA has been used in the staging, monitoring, and screening of patients. The greastest utility of PSA appears to be in the monitoring of patients with carcinoma of the prostate, most significantly following radical prostatectomy. The role of serum PSA involving patients undergoing radiation therapy and hormonal manipulation is less clear; however, there also appears to be potential in these areas. The usefulness of PSA in screening is hampered by the observation that benign hyperplasia may be associated with elevated serum levels. PSA is a significantly better tumor marker for prostatic disease than prostatic acid phosphatase and should be used by all physicians managing these patients.

A comparison of the Small-Carrion and Scott-Bradley penile prostheses, based on our experience with their use over the last three years, is presented. Nearly all patients given either device were satisfied with the results. Selection of the type of prostheses to be used must be made on an individual basis, taking into consideration which choice will best suit the requirements of each patient. In the majority of cases, however, the patient may make the final choice himself.

The necessity for monitoring serum levels of alphafetoprotein (AFP) and human chorionic gonadotropin (hCG) in patients with testicular cancer is widely known, but a few questions remain unanswered. Cross-reactivity of commercial hCG assays with luteinizing hormone remains a problem; and as patients apparently cured of testicular cancer age, they become subject to other diseases that can elevated AFP or hCG levels, creating confusion. There still are no adequate studies of the role of markers in staging, a problem that has become acute with the introduction of expectant treatment for metastases in clinical stage A disease. Calculation of the metabolic half-life of markers can be helpful in staging postoperatively, but calculations of the actual half-life of markers during induction chemotherapy is less useful than had once been hoped. Attempts to capitalize on the molecular heterogeneity of AFP have had little success, although newer analytic methods may change this; but ultrasensitive assays for urinary hCG are beginning to show promise. Studies of radioimmunodetection with anti-marker antibodies have been both encouraging and frustrating; the newly available monoclonal anti-marker antibodies may improve the results and also offer a possible means of improving chemotherapy. Placental alkaline phosphatase continues to look like a useful marker for seminoma, and lactic dehydrogenase is often helpful in all types of testicular cancer, especially in high-stage disease.

Lymphadenectomy-based treatment for low-stage nonseminomatous testicular cancer is a proven therapy. The operation is difficult, but the mortality rate has been low, less than 1% in most major centers. Patients need careful psychological preparation before surgery. Patients with persistent aspermia despite limitation of the dissection distally sometimes can be treated with various sympathomimetic drug combinations. It is important to know that there is more than one way to do the operation, but the result should be the same; namely, a thorough removal of all potentially tumor-bearing tissues in the retroperitoneum. Although there is debate as to what the limits of this operation should be, we have advanced a rationale to support suprahilar dissections in most cases. Nuances in technique will determine the adequacy of exposure, the completeness of the operation, and the incidence of complications.

The outlook for fertility among patients who are treated for testicular cancer is one of guarded optimism. Although some of these men are subfertile before the onset of their disease, it is probable that the majority, although temporarily subfertile because of their tumors, have a potential for normal fertility. Lymphadenectomy probably can be performed effectively while preserving ejaculation in most patients. Likewise, the effects of platinum-based chemotherapy appear to be reversible in many patients, and there is hope that spermatogenesis can be protected during chemotherapy by endocrine manipulation. During the next decade, the preservation of fertility will become an increasingly important issue in the management of testicular cancer as investigators consolidate therapeutic gains.

Percutaneous nephrolithotomy has become an established procedure for urologic surgery. For the stone which is poorly accessible or of large volume, special approaches and techniques are essential for success. For example, exact anatomical conceptualization and pinpoint puncture are vital. These requirements are aided by retrograde hyperinflation with contrast medium and C-arm fluoroscopy. Sometimes multiple percutaneous nephrostomy tracts are required or the tract must be directed so that it courses transpleurally. Among the large number of instruments available for percutaneous nephrostomy, flexible endoscopy becomes increasingly important for the difficult stone. Intrarenal electrosurgery is also important. Finally, for ureteral stones, retrograde flushing with CO2 or saline through a percutaneous sheath may be useful. These additional approaches when judiciously applied can result in a stone-free status for virtually 100% of patients.