References

Khoo SK, Kahnoski K, Sugimura J, et al. Inacti-vation of BHD in sporadic renal tumors. Cancer Res 2003 63 4583-4587. 2. Walther MM, Enquist EG, Jennings SB, Gnarra JR, Zbar B, Linehan WM. Molecular genetics of renal cell carcinoma. In Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS, eds. Comprehensive Textbook of Genitourinary Oncology. Baltimore Williams & Wilkins, 1999 116-128. 3. Linehan WM, Zbar B, Klausner RD. Renal carcinoma. In Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B,...

Intravesical Immunotherapy and Recurrence Progression Rates

Intravesical immunotherapy using BCG was first proposed by Morales et al. 49 in 1976. Conventional prophylactic regimes of 6 weekly instillations, similar to those used for chemotherapy, resulted in complete response rates of 60 to 100 at 1 year, 55 to 75 after 2 years, and mean recurrence-free intervals of 10 to 22.5 months 50 . Although the long-term response rates with BCG are less enduring, the reduction in recurrence appears to be better than the rates achieved using most chemotherapy...

Von Hippel Lindau Disease

Von Hippel-Lindau (VHL) disease is a hereditary syndrome characterized by the development of multiple tumors, both benign and malignant, affecting several different organ systems 3 , including the eyes, spine, inner ear, pancreas, adrenal gland, and kidneys. Retinal angiomas, cerebellar and spinal hemangio-blastomas, and renal cell carcinomas are the hallmark lesions of this disease. Renal cysts, pancreatic cysts, pancreatic carcinomas, pheochromocytomas, epididymal or broad ligament cyst...

Treatment Resistance

Hsp Prostate

Androgen deprivation using luteinizing hormone-releasing hormone (LHRH) agonists is Urological Cancers Science and Treatment Fig. 1.2. The hypothalamic-pituitary gonadal axis and the intracellular action of the androgen receptor (AR). ACTH, adrenocorticotropic hormone AR, androgen receptor DHT, dihydrotestosterone HSP, heat shock protein LH, luteinizing hormone LHRH, luteinizing hormone-releasing hormone. Fig. 1.2. The hypothalamic-pituitary gonadal axis and the intracellular action of the...

Role of Transurethral Resection TUR and Tumor Surveillance Recurrence and New Occurrence

Cystoscopic visualization of the bladder remains the primary modality of diagnosis, surveillance, and treatment of superficial bladder tumors. Attention to and accurate documentation of the relevant clinical prognostic factors are essential components for future therapeutic decisions. This should include estimation of tumor number, size, position, and configuration as well as the intervals between recurrences. Tissue sampling by TUR is advocated from all the affected areas to document the worst...

Molecular Biology of Kidney Cancer

Brantley Thrasher Kidney cancer, more commonly known as renal cell carcinoma,is the sixth leading cause of cancer death in the United States 1 . It currently accounts for approximately 3 of all adult malignancies 1 .In 2001,32,000 cases of renal cell carcinoma in the United States were documented. Of these 32,000 cases, approximately 40 will die of the disease 1 . Renal cell carcinoma is more common in males than in females, with approximately a 2 1 ratio. It...

Testicular Prostheses

A testicular prosthesis can be inserted at the time of orchidectomy if the patient wishes. Testicular prostheses were previously manufactured using a solid shell containing a silicon gel core. Concerns were expressed in the early 1990s about such designs in breast prostheses, and a possible association with autoimmune diseases. No causal relationship has been established, although histological and serological evidence of silicone shedding has been identified 2,3 . Currently manufacturers employ...

DNA Repair Pathways Nucleotide Excision Repair

It has been suggested that embryonic stem cells are equipped with efficient defense mechanisms to cope with damaged DNA, either by removal of damage by repair mechanisms, or by elimination of irreparably damaged cells via apoptosis 118,119 . Similar importance of this control mechanism can be expected for germ cells, which share many properties of embryonic stem cells, in order to limit the risk that mutations are being passed on to the next generation. The role of DNA repair pathways in...

Twin Studies

Several twin studies show an increased RR in mono- compared with dizygotic twins of just over three- to sixfold 41 . In a study by Page et al. 42 on 15,924 male twin pairs, they found that pair-wise concordance (twins where both men had PCa) rates among monozygotic twins was 15.7 , while that of dizygotic twins was 3.7 (p < .001). Proband-wise concordance (number of concordant affected twins divided by total number of affected twins) was 27.1 Table 2.5. Estimated risk ratios for prostate...

Interleukin2

Interleukin-2 (IL-2) is the other cytokine that has shown significant activity against renal cell carcinoma. IL-2 is produced primarily by T cells it has no intrinsic antitumor activity, but it has a wide range of actions and plays a central role in immune regulation. Its primary action is to stimulate growth of activated T cells that bear the IL-2 receptor it also potentiates the activity of cytotoxic T cells and production of other cytokines. The initial work on IL-2 was carried out by...

Penile Conservative Therapy

Because amputative surgery for penile cancer may lead to major psychosexual dysfunction, various attempts have been made to devise conservative treatment modalities based on careful oncological, anatomical, and technical considerations. Judicious use of conventional or micrographic surgery, laser ablation, or radiotherapy can allow preservation of a functioning phallus in appropriately selected patients with early cancers. However, there are no comparative studies and no consensus regarding the...

Epidermal Growth Factor Receptor Inhibitors

The epidermal growth factor receptor (EGFR) superfamily of receptors, which comprises four distinct receptors known as EGFR, Human Epidermal growth Factor Receptor, HER2, HER3, and HER4, is a potential therapeutic target in prostate cancer where overexpression is seen in up to 80 of metastasis, and is generally associated with a poorer overall prognosis. Several EGFR targeting agents are now available, including tyrosine kinase inhibitors and monoclonal antibodies. To date, the tyrosine kinase...

Pretreatment Evaluation and Pitfalls in Staging

For optimum management using the most appropriate treatment approach and ensuring best outcome, a simple but systematic pretreat-ment evaluation is mandatory. A careful history and interview should also include a history of sexual practices, sexually transmitted disease, chronic inflammatory penile conditions, and the likely psychosexual impact of a penectomy if recommended. The location, type, size, and extension of the tumor, presence of any prema-lignant or inflammatory condition, infection,...

Pathobiology of Human Germ Cell Tumors

Germ cell tumors can be found along the midline of the body, possibly related to the migration route of the primordial germ cells (PGCs) from the yolk sac to the genital ridge during intrauter-ine development 3 . In some of these tumors the germ cell origin is supported by their VASA staining 4 . This protein is specific for the germline 5 . Histologically, GCTs mimic intrauterine development to a certain extent, including both somatic and extraembryonic tissues 6, for review . Based on...

Genetic Counseling and Testing Research

Currently, genetic analysis (e.g., BRCA2 mutation analysis) should be performed only within the context of a research study that will determine penetrance and genotype-phenotype correlation of specific mutations. The criteria for the Cancer Research U.K. British Prostate Group British Association of Urological Surgeons' Section of Oncology Familial Prostate Cancer Study (principal investigator Dr. Eeles) are as follows Men with PCa diagnosed at < 60 years Affected relative pairs with PCa...

Small Cell Carcinoma of the Prostate

Small cell carcinoma is a rare variant of prosta-tic carcinoma, accounting for less than 1 of all tumors arising in the gland 106 . It behaves in Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis an aggressive manner, metastasizes early, and is unresponsive to some types of chemotherapeu-tic regimens 107 . Although pure small cell carcinoma is rare, the presence of neuroendocrine differentiation is not uncommonly seen to some extent in prostatic carcinoma and may take one of...

The Role of TP53 in Germ Cell Tumors

TP53 is known to play a dual role in stress response. On the one hand, it mediates a G1 S-phase cell cycle arrest via transactivation of p21, allowing time for DNA repair. Furthermore, TP53 can lead to apoptosis via the mitochondr-ial (intrinsic) pathway, for example, by induction of BAX 137, for review . In contrast to other solid tumors, p53 is hardly ever found to be mutated in GCTs, even though GCT cell lines do not have an overall lower frequency of mutations, both spontaneous and induced,...

Treatment and Outcome

As mentioned above, these tumors pursue an aggressive clinical course, with early lymphovas-cular and muscle invasion and are frequently metastatic at the time of presentation. The overall 5-year survival of patients with localized small cell carcinoma may be as low as 8 88,102 . Predictors of poor survival include age greater than 65 years, tumor stage, and presence of lymphovascular invasion 103 . Treatment options consist of cystectomy and adjuvant chemotherapy or radiotherapy, and a large...

Tumor Vaccines

Initial studies transfected tumor cell lines with cytokines in vitro and demonstrated that tumor formation was prevented when these cells were administered to experimental animals. This led to the development of so-called tumor vaccines. In this approach cancer cells transfected with a cytokine-producing gene are administered to animals with established tumors of the same cell line. By inducing specific immunity, an antitumor effect is seen. Connor et al. 54 studied the cytokines IL-2 and...

Growth Factors

A number of growth factor families have now been found to be involved in normal and cancerous growth of the prostate and are summarized in Table 1.2. Epidermal growth factor and transforming growth factor-a (TGF-a) are two related peptide growth factors that signal through the same EGF receptor (EGFR), a transmembrane tyrosine kinase. They are found in normal and cancerous prostate cells. In the nondiseased prostate, EGF appears to be an important regulator of growth 63 . Its expression is...

Teratomas with Malignant Transformation or Secondary Non Germ Cell Malignancies

This rare but clinically significant occurrence in GCTs refers to the transformation of a somatic teratomatous component in a nonseminoma to histologies resembling tumors of a primary somatic origin 162 . The clonal GCT origin of these lesions can be confirmed by the identification of iso chromosome 12p or excess 12p copy numbers, the genetic hallmark of type II GCTs 77,98 . Most frequently found histologies are rhabdomyosarcomas, primitive neurec-todermal tumors, enteric adenocarcinomas, and...

Inherited Genetic Changes

Unlike in breast and colon cancer, no major predisposition genes for prostate cancer have been detected. However, a number of susceptibility loci have been identified. As yet the susceptibility genes for most of these regions remain unknown 10 . This suggests that the predisposition to prostate cancer is heterogeneous and may involve multiple genes. Seven prostate cancer susceptibility loci have thus far been described and tested on independent data sets 5,11 HPC1 (hereditary prostate cancer)...

Targeted Therapies

Our current treatment approaches rely heavily on standard cytotoxic therapies however, greater insight at the molecular level into cell growth and proliferation has led to the development of targeted biological therapies that offer hope for improved efficacy with minimal toxicity. Table 9.4. Summary of neoadjuvant chemotherapy trials in prostate cancer Table 9.4. Summary of neoadjuvant chemotherapy trials in prostate cancer KAVE, ketoconazole, doxorubicin, vinblastine, estramustine, RP, radical...

Principles of Radical Prostatectomy

Radical prostatectomy is generally carried out with the intent of achieving long-term disease-free survival and thereby cure of early-stage prostate cancer 20 . Secondary, but nevertheless important, concerns are the maintenance of quality of life, in particular continence and erectile function. In some countries, interest is growing in a potentially palliative role in patients with more advanced and noncurable disease. Favorable long-term survival in patients with pathologically organ-confined...

Epidemiology and Etiology

Penile malignancies are uncommon in most parts of the world, but there is a striking geographical variation around the world. While the age-adjusted incidence rate is less than 1 per 100,000 in Europe and North America, in parts of South America, Africa, and India, the incidence is as high as 12 per 100,000 men 1 . Even within a country, there are marked regional variations. In Brazil the incidence of penile cancer is as high as 28 and 50 per 100,000 men in the cities of Sao Paulo and Recife,...

Conclusion

This chapter has summarized the large amount of experimental work exploring the potential for gene therapy in bladder cancer. Several phase I trials have now been reported, and the next decade holds out the hope of successful transfer of these therapies to the clinical situation. The future must lie with multimodality treatment, and the studies that have described synergy between chemotherapy and gene therapy are extremely encouraging. However, there is a long way to go, and, unfortunately,...

Hormone Therapy for Prostate Cancer

Dancey and Jonathan Waxman Prostate cancer is now the most prevalent of all male malignancies and the second most common cause of male cancer deaths. Death rates have trebled over the last 30 years, and changes in mortality during this period are shown in Table 8.1 1 . Prostate cancer is initially an androgen-dependent tumor, and treatment aims to reduce androgen supply to it. It is over a century since the first treatment for prostate cancer was introduced by an English surgeon, who...

Tissue Culture Studies

Tissue from prostate cancers is often difficult to obtain, and tissue from normal prostate even more so, meaning that only small amounts of Urological Cancers Science and Treatment protein are available for study. In contrast, cell-culture studies allow the production of large amounts of protein, and for this reason some studies have concentrated on the differences between prostate cancer cell lines 5,6 . Many studies have been carried out on the LNCaP cell line, due to its retaining a...

Why Defer Treatment

Prostate cancer is perhaps unique among soft tissue malignancies in that it is accepted that there are many patients for whom treatment is not needed, at least on first diagnosis. Indeed, it would be considered unusual not to defer treatment in a man of 85 in whom a well-differentiated tumor is identified in the chips from a transurethral resection of the prostate (TURP) done for apparently benign disease. Although a poorly differentiated tumor in a man of 50 is clearly likely to be life...

Second Line Therapies

It is well known that the treatment of advanced prostate cancer with antiandrogens and other hormone therapies is successful only for a limited time. The cancer inevitably progresses to hormone independence, in which treatment by antiandrogens is no longer effective, or at worst stimulates cancer growth. Growth-related proteins, downstream from the androgen receptor, may be targets of therapy themselves, so that when antiandrogen treatment fails, therapy aimed at these downstream targets can...

Relative Risk of Clinical Prognostic Factors

The factors that predict the biological potential of superficial lesions must be correctly weighted before deciding on cystoscopic surveillance protocols and adjuvant therapy. The relative importance of the prognostic factors was measured by multivariate analyses of two Medical Research Council (MRC) trials 26 and two EORTC-GU trials 20 . In the MRC analyses, tumor number at presentation and tumor recurrence at the first follow-up cystoscopy at 3 months were statistically better at predicting...

How Can We Study Screening

As mentioned above, screening for prostate cancer can be studied by randomized controlled trials such as the ones currently underway in Europe and the U.S. These involve randomizing a population of men at risk of harboring the disease, with good life expectancy, to either an intensive screening program or to no screening. The outcome is measured by analyzing differences in mortality between the two groups, on the assumption that the screened group would have received early aggressive...

Biological Aggressiveness

The biologic aggressiveness of FPC has been the focus of interest of several investigators. Walsh 111 first noted that there was no significant difference between phenotypes of hereditary, familial, and sporadic prostate cancer among those who underwent radical prostatectomy with respect to preoperative PSA, PSA density, Gleason score, tumor histology, pathological stage, or clinical stage. Kupelian et al. 112 later observed that men with localized PCa with a positive family history may have a...

Genome Searches in Prostate Cancer

A genome-wide search (GWS) involves the process of running a large (typically in the region of 400) number of microsatellite markers throughout the genome to locate disease- predisposing genes by looking for co-segregation of markers with the disease in families. The attempt to identify prostate cancer susceptibility loci has been undertaken across the genome by numerous groups. The Union Biomed (ACTANE) group has defined age at onset and number of cases and focused on the collection of...

Combined Radiotherapy and Hormone Therapy

The use of combined modality treatment, with hormone therapy and radiotherapy, for the treatment of prostate cancer may be beneficial for two reasons. First, by combining two effective modalities, there is hope that the anticancer effects will be additive. Second, the use of hormone therapy to shrink a large prostate before irradiation may improve efficacy by reducing the tumor burden and also may reduce rectal toxicity by reducing the volume irradiated to high dose 24 . The LHRH agonists...

Gene Therapy for Prostate Cancer

Danish Mazhar and Roopinder Gillmore Prostate cancer has recently become the most commonly diagnosed male malignancy in industrialized countries and the second leading cause of cancer-related mortality in men. Over the last 30 years death rates from prostate cancer have more than doubled in England and Wales 1 . It is argued that disease confined to the prostate can be successfully treated by radiation or surgery, with adjuvant hormonal therapy. However, up to half of men with clinically...

Immediate or Deferred Treatment in 2005

Studies in rat prostate cancer models support the use of immediate hormone therapy, which is most effective in terms of survival when initiated at the time of, or early after, tumour implantation 29,30 . For patients with locally advanced prostate cancer who receive radiotherapy, several prospective randomized controlled multicenter trials have indicated that adjuvant hormone therapy (goserelin or orchiectomy) extends progression-free survival and may also improve overall survival in some...

Is the Case for Immediate Treatment Proved

Confirmation of definite advantages from immediate treatment is reflected in the improved survival seen in the EORTC study of adjuvant treatment with radiotherapy 18 , although in the study of the RTOG, this was noted only in those with high-grade disease 19 . Hormone treatment also reduces the risk of complications from local progression. The increased risk of spinal cord compression seems to transcend the start of deferred treatment, warning that disease progression occurring during the...

Laparoscopic Prostatectomy

Laparoscopic radical prostatectomy has developed within the past 10 years, recognizing the many potential benefits of laparoscopic surgery. It was first described by Schuessler et al. 10 in 1992, and at that time presented significant challenges 11 . Reduction in the extent of surgical incisions, postoperative pain, and analgesic requirement, and shorter convalescence including reduced hospital stay contribute to its potential advantages. Disadvantages relate to the considerable specific skills...

Other Significant Loci

PCaP (1q42.2-43 65 ) was a locus identified in the German French population, but not confirmed by other groups. CAPB (1p36 67 ) is a locus associated with primary brain tumor and PCa, which on further analysis was probably more associated with young-onset PCa rather than brain tumor 95 . Suarez et al. 66 described a locus on chromosome 16q in sibling pairs. Berry et al. 71 described another one on 20q (HPC20). These are still to be confirmed. It is likely that the HPC20 locus is not real, as...

Proteins Differing Between Normal and Cancerous Prostate

One of the most appealing studies that one can carry out with proteomics technology is the investigation of proteins with differing expression levels between normal and cancerous prostate. The first directly prostate-cancer related proteomics paper appeared in 1997, in which Partin et al. 4 identified a protein, PC-1, that was present in prostate cancer but not in normal or hyperplastic prostate. The protein, to which an antibody was subsequently raised, was then used in experiments to...

The Androgen Receptor and Androgen Synthesis

Testosterone is the main circulating androgen and is primarily produced by the Leydig cells in the testes. Its release is influenced by the pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Fig. 1.2). Once reaching the prostate, 90 of the testosterone is converted intracellularly by the enzyme 5a-reductase to dihydrotestosterone (DHT). Both DHT and testosterone bind to the androgen receptor (AR) and DHT has 100 times more relative androgenicity than...

The Disease Should Be an Important Health Problem

As the most common male cancer in Europe and the United States, and second only to lung cancer in terms of male cancer deaths, there is little doubt that prostate cancer represents a significant public health burden in Western countries 2 . In the U.S. alone, an estimated 220,900 new prostate cancer cases were diagnosed in 2003, with 28,900 deaths attributable to the disease 3 .Although a dramatic increase has been observed in the number of men diagnosed with localized disease as a consequence...

The PTENPI3KAkt Pathway

PTEN is located on 10q23 and is mutated in up to a third of hormone refractory prostate cancer 9 . Homozygous deletions and mutations have also been identified in a subset of primary prostate cancers 18 . The loss of PTEN expression in primary prostate cancer has been found to correlate with a high Gleason score and an advanced stage 19 . PTEN phosphatase functions as a tumor suppressor, via its ability to indirectly reverse phosphatidylinositol-3 kinase (PI3K)-mediated phosphorylation and...

What Do Men with Prostate Cancer Think of Screening for the Disease

Public perception of screening for the disease varies. There is widespread pressure for the establishment of national screening programs, with resistance to this pressure often misinterpreted as attempts to save money, deceive the public, or even as sex discrimination. A recent interesting and elegant qualitative research study by Chapple et al. 35 highlighted these feelings, interviewing 52 men with prostate cancer from various geographical areas of the U.K. Although some factual conceptions...

Management of Ilioinguinal Nodes

Lymph node metastasis in patients with penile cancer is the main determinant of survival, and optimal management of regional nodes is challenging as well as controversial. Superficial and deep inguinal nodes are the first-echelon nodes, with skip metastasis in the pelvic lymph nodes being very rare. The diagnostic and therapeutic approach for the ilioinguinal nodes depends on the index of suspicion for nodal metastasis in a clinically negative groin, and the laterality, size, and mobility of...

Renal Oncocytoma

Renal oncocytoma is a neoplasm that occurs in approximately 3 to 5 of renal cell carcinomas 74,100 . It typically has a more benign course, although metastases have been reported 101 . In a large number of tumors there are no chromosomal losses associated with oncocytomas. However, in some tumors genetic changes, including losses at chromosomes 1p, 14q, X, and Y or translocations involving 5q35 and 11q13, have been reported 1,74,102-108 . There is a familial syndrome known as familial renal...

Prostate Cancer Immediate vs Deferred Treatment

There continues to be controversy about the timing of treatment for localized, for locally advanced, and for metastatic prostate cancer. The decision for early radical treatments in localized disease has been based on the patient's age, general health, and preference. However, an increased understanding of the natural history of this cancer may allow us to select patients at risk for whom treatment might possibly improve survival while reducing the risk of treatment-related morbidity in those...

Intensity Modulated Radiotherapy

Intensity-modulated radiotherapy (IMRT) is an advanced form of 3D-CRT that allows tighter conformation to the target volume and sparing of normal tissues in the vicinity of and even within the target volume to an extent that was not previously possible. In general, IMRT uses inverse treatment planning systems that work backward from a desired dose distribution to generate treatment fields with varying intensities across the cross section of the beam. Treatment delivery utilizes MLCs where each...

Radical Radiotherapy for Prostate Cancer

The incidence of prostate cancer is rising worldwide due to the ageing of the population and the increasing availability of prostate-specific antigen (PSA) screening. Prostate-specific antigen testing has led specifically to an increase in the proportion of patients diagnosed with early-stage (localized) prostate cancer. Radical radiotherapy is one of the curative treatment options for localized prostate cancer and it also has a role to play in locally advanced and even metastatic disease. This...

Does Screening for Prostate Cancer Reduce Mortality from the Disease

Since the introduction of the PSA test, screening for early prostate cancer has become prevalent in the United States, with, as expected, a sharp rise in the incidence of the disease in the early 1990s. This was contrasted by a static incidence rate in countries where screening was not widely practiced, such as the United Kingdom. However, by 1996 the U.S. started to experience a slow but constant decrease in the prostate cancer mortality rate, which was advocated by some as resulting from...

Serum Markers for Prostate Cancer

The discovery and development of PSA in the 1980s revolutionized the diagnosis of prostate cancer. The marker, which is simple to detect, easy to access, and relatively noninvasive for the patient, is an ideal find. It is now firmly established that PSA is one of the most reliable cancer markers currently in use. It is also true, however, that there are a very high number of false-positive and false-negative diagnoses obtained via PSA testing, and for this reason the use of PSA as a screening...

The Role of Radical Radiotherapy

The optimum management of patients with localized prostate cancer remains controversial. Three major treatment options are available radical prostatectomy, radical radiotherapy (external beam radiotherapy EBRT or brachytherapy), and active surveillance (also known as active monitoring and watchful waiting). Each treatment involves its own risk. Radical treatments can cause harmful side effects including incontinence, erectile dysfunc tion, and even death, whereas watchful waiting causes anxiety...

Lymphoma of the Prostate

Primary lymphoma of the prostate is very rare, representing only approximately 0.2 to 0.8 of extranodal lymphomas and 0.1 of all prostate neoplasms 1,64,65 . Secondary involvement of the prostate by lymphoma or leukemia is more frequent,being found at postmortem in up to 8 of non-Hodgkin lymphomas and up to 20 of cases of CLL 66 . However, in most cases this involvement is not clinically apparent. In a series of 62 prostatic lymphomas, Bostwick et al. 67 found 35 to be primary (defined by...

Screening for Prostate Cancer

Hamdy Prostate cancer screening is one of the most controversial public health issues in urology. The natural aging of the population and the continued and widespread use of improved diagnostic tests, such as serum prostate-specific antigen (PSA), are resulting in an increase in the numbers of men diagnosed with localized prostate cancer. The issue of screening to identify organ-confined prostate cancer has provoked much public and scientific attention, and there...

Viral Delivery Systems

Viral vectors are used in the vast majority of gene therapy trials owing to their relatively high gene transfer efficiency. They may be either RNA or DNA virus based. The DNA viruses include adenovirus, vaccinia, and herpes simplex viruses. The RNA viruses include retroviruses and lentiviruses. To improve their safety, viral vectors may be designed to be replication-deficient, with no further virus particles generated following infection of the target cells. Alternatively, they may be...

The Natural History of the Disease Should Be Known

The natural history of prostate cancer in the PSA era is uncertain, because men are far more likely to die with, rather than from, the disease. The lifetime risk of having microscopic prostate cancer for a man aged 50 years is 42 , although his risk of dying from the disease is about 3 10 . There is little published long-term outcome data for prostate cancer in the PSA era, which makes any previous data difficult to translate in contemporary terms. In clinical practice, it has become customary...

Cancer Control

Cancer-specific outcomes observed after radical prostatectomy have improved substantially within the past 20 years owing to the possibility of detection of earlier stage disease 23 . This is almost entirely attributable to the discovery of prostate-specific antigen (PSA), its increasing availability and clinical use, together with the increasingly prevalent proactive approach toward men's health. Though dependent on patient selection, 10 year biochemical recurrence rates less than 30 can be...

Recommendations for Treatment of Metastatic Transitional Cell Carcinoma

Over the past two decades, multiple chemother-apeutic regimens with activity in TCC have been introduced. Additionally, the importance of baseline prognostic factors, comorbidities, and postchemotherapy surgery has been recognized. Integrating this information allows the development of a rational approach to the treatment of individual patients (Fig. 14.1). Based on phase III data, GC or MVAC is recommended for patients with metastatic TCC who can tolerate cisplatin-based therapy and who have...

Diet and Prostate Cancer Biology

Although prostate cancer is primarily a disease of older men, neoplastic changes may occur in the prostatic epithelium as early as in the third decade. The time required for some of these early neoplastic transformations is likely to be long. Some dietary compounds display antioxi-dant properties, thus preventing peroxidation and generation of free radicals with potential DNA-damaging effects. Others are inhibitors of cell proliferation, apoptosis inducers, or enhancers of cellular...

Vascular Targeting

Vascular targeting drugs employ a different strategy. A transient direct attack on the tumor Novel Therapies for Renal Cell Cancer endothelium may result in tumor infarction. Combretastatin is one member of this group that targets endothelial cell microtubules, for which phase I trials have been completed 81,82 . Measurement of tumor blood flow, for example by dynamic contrast magnetic resonance imaging (DC-MRI), may provide a method to identify the occurrence of vascular blockade by this class...

Mixed Epithelial and Stromal Renal Tumors

The new WHO classification of tumors includes the entity of mixed epithelial and stromal tumors. This is a complex renal neoplasm composed of a mixture of stromal and epithelial elements. some of these cases have been reported under different names, including cystic hamar-toma of the renal pelvis or adult mesoblastic nephroma 9-11 . The new WHO classification accepts the term mixed epithelial and stromal tumor 1 . Importantly, there is a 6 1 predominance of women over men, and all of the women...

Clinically Significant or Cytologically Confirmed Groin Nodes

In patients with operable nodes, surgery is the mainstay of treatment and often curative, especially for those with limited nodal metastasis. In planning the most appropriate treatment, these patients should be evaluated clinically for oper-ability and with a contrast-enhanced CT scan, especially for pelvic nodes. Various authors have reported that 20 to 67 of patients with clinically palpable metastatic inguinal lymph node metastasis will be disease free at 5 years after lymphadenectomy...

Two Dimensional Gel Electrophoresis 2DGE

Proteins in a biological mixture, whether it be a fluid such as urine, blood serum, or cell lysates, are separated first according to their charge, by isoelectric focusing (IEF), and then second according to their molecular weight, using standard sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) techniques. Isoelec-tric focusing relies on the charges of the various amino acids in an individual protein sequence, resulting in an overall charge for that protein. Proteins of the...

Stromal Tumors

Stromal tumors of the testis (e.g., Leydig, Sertoli, and granulosa cell tumors) are uncommon, accounting for about 2 of adult testicular tumors. Most do not behave in a malignant fashion and can be cured by orchidectomy, but approximately 10 have metastatic potential. In contrast with treatment for germ cell tumors, treatment for metastatic stromal tumors is not very effective. Patients with a malignant stromal tumor that metastasizes survive on average only 3 years from diagnosis. In addition,...

Triplet Combinations

Triplet combinations of estramustine, paclitaxel, and carboplatin in a small study have shown a 67 PSA response rate but lacked palliative benefit. Other three-drug regimens estramustine, etoposide, and paclitaxel paclitaxel, estramustine, and carboplatin and estramustine, etoposide, and vinorelbine have shown PSA responses but yet no palliative improvements 34-37 . The value of these three-drug regimens at this time remains largely unknown. Urological Cancers Science and Treatment Table 9.3....

New Cisplatin Doublets

The combinations of paclitaxel or docetaxel plus cisplatin have been explored in multiple phase II studies. In an Eastern Cooperative Oncology Group (ECOG) study, 52 patients were treated with paclitaxel 175mg m2 and cisplatin 75mg m2 every 21 days 15 . Twenty-six patients achieved an objective response (50 95 CI, 36-64 ) with four (8 ) complete responses. The toxicity of this regimen was considered moderate, with neutropenia (without fever) and neuro-toxicity being most common. Trials...

Other Cytokines

Several other interleukins (for example IL-1, -4, and -6) have been tested in phase I and II trials in renal cell carcinoma, but antitumor activity has been low,with response rates of less than 5 . One of the more promising new agents is IL-12, which promotes cell-mediated immunity through its regulatory effects on T and natural killer (NK) cells. In a randomized phase II trial of IL-12 versus IFN-a in advanced renal cell carcinoma, 30 patients were treated with IL-12 and 2 (7 ) achieved a...

New Carboplatin Triplets

Several carboplatin triplets have been studied including paclitaxel plus carboplatin plus methotrexate 33 , paclitaxel plus carboplatin plus gemcitabine 34 , and methotrexate plus carboplatin plus vinblastine (M-CAV) 35 . In general, these regimens have been associated with slightly higher response proportions and slightly increased toxicity compared with historical trials of carboplatin doublets. No phase III trials have explored the activity of these triplets relative to standard therapy.

Pathology and Immunohistochemical Profile

Rhabdomyosarcomas are usually composed of a mixture of small round cells with hyperchro-matic nuclei and scant cytoplasm, and variable numbers of larger elongated cells with abundant eosinophilic cytoplasm (rhabdomyoblasts). The tumor cells contain intracytoplasmic cross-striations that may be visible on routine hema-toxylin and eosin (H& E)-stained sections, but are more clearly identified using special staining techniques. Although classically exophytic, forming papillary structures with a...

Pathology

Studies have shown that almost all low-grade primary lymphomas of the bladder, although rare, are MALT lymphomas 53,55,56 . These tend to remain localized to the bladder (stage 1) 53,56 . A smaller subset of primary bladder lymphomas are DLBCLs, perhaps arising by transformation of MALT lymphoma in some cases 53,55 .Very occasional cases of T-cell lymphoma, plasmacytoma, and Burkitt lymphoma in an HIV-positive person have been reported. Secondary involvement of the bladder is usually by DLBCL,...

Androgen Receptor and Prostate Cancer Etiology

The reason for the varying incidence of prostate cancer between racial groups is undoubtedly multifactorial, with the contribution of both genetic and environmental factors. African-American men have the highest risk of prostate cancer and Asian populations have the lowest 38 . 5a-Reductase, which converts testosterone into the more active androgen DHT activity, correlates with race, with low levels of activity in Japanese men and higher levels in African Americans and Caucasian 57 . Racial...

Scientific Understanding of the Development of Penile Tumors

Kilian Mellon Penile cancer is a relatively rare disease in developed countries. The incidence in Europe is 1 per 100,000 men per year with a mean age at diagnosis of 60 years. Higher incidence rates have been reported in Africa, Asia, and in parts of South America 1-3 . Approximately 95 of all penile cancers in developed countries are squamous cell carcinomas (SCCs) the remaining 5 are nonsquamous primary neoplasms such as sarcomas, melanomas, basal cell...

Molecular Analysis Evidence Linkage Studies

In contrast to other common cancers such as breast and colon cancer, in which a small number of high-risk genes account for a percentage of the high-risk multiple case families, familial PCa is likely to be caused by numerous different genes. Linkage analysis is performed by using a gene-hunting technique that identifies co-segregation of the disease in large, high-risk families, with disease-causing genetic mutations. Linkage analysis has been used to map many familial cancer loci, for...

Familial Prostate Cancer

Eeles Prostate cancer (PCa) is the most common cancer diagnosed in North American men, excluding skin cancers. It is estimated that, in 2004, approximately 230,110 new cases and 29,900 prostate cancer-related deaths will occur in the United States 1 . In Australia, one in 11 men will develop the disease during their lifetime 2 . The annual number of new cases registered in England and Wales increased by over threefold between 1971 and 2004, from 6174 to over...

Case Control Studies

Case-control studies can be grouped into two main types. The first type compares PCa incidence in first-degree relatives of affected patients (cases) with the incidence in the relatives of cancer free men (controls). The second type compares the fraction of PCa cases vs. controls with a positive family history of the disease 15-17,19-34 . These studies are summarized in Table 2.1. These studies indicate that the relative risks (RR) in first-degree relatives of PCa patients range from 0.64 to...

Locally Advanced Disease

The results of the VACURG studies were considered inconclusive, but more recent studies have not fully answered these questions. The study sponsored by the British Medical Research Council (MRC) 17 ,which finished recruitment in 1993,provided evidence in favor of early treatment, as has the outcome of studies of adjuvant hormone treatment in patients receiving radiotherapy, reported from the European Organization for Research and Treatment of Cancer (EORTC) 18 and Radiation Therapy Oncology...

Diet and Prostate Cancer

Prostate cancer is the most commonly diagnosed malignancy in men in industrialized countries and the second leading cause of male cancer-related death. Given the trebling of death rates in the last 30 years and the relative lack of a survival benefit from the treatment of advanced disease, it is critical that we look at preventative stratagems to reduce death rates. Although aging is the most significant risk factor for prostate cancer with a virtually exponential increase in age-related...

The Molecular Biology of Prostate Cancer

Prostate cancer is the most frequently diagnosed malignancy among men in industrialized countries. In the United States, one in eight men will develop prostate cancer during their lifetime 1 , and in 1999 approximately 37,000 died from the disease 2 . In England and Wales, 17,000 cases are diagnosed and there are nearly 9000 deaths annually from prostate cancer 3 . Advances in our understanding of the molecular basis of cancer have led to the characterization of critical pathways regulating...

Sporadic and Familial Prostate Cancer Biochemical Failure and Differences in Survival

Gronberg et al. 122 tried to estimate the survival of men with FPC and compare them with prostate cancer cases unselected for family history. No significant differences in either overall or prostate cancer-specific survival between familial and sporadic cases were found. Tumor grade at diagnosis in familial cases did not differ from that in a population with prostate cancer unselected for family history. The conclusion, based on the result from this study, was that no differences in treatment...

Biology and Genetics

MALT lymphoma is thought to arise from the marginal zone B cells of MALT, acquired as a Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis Small Cell Tumors and Tumors of the Bladder, Prostate, and Testis Fig. 26.2. A mucosa-associated lymphoid tissue (MALT) lymphoma of the bladder (A, H& E) showing characteristic plasma cell differentiation (top right of each panel). Tumor cells express CD20 (B) and immunoglobulin M (IgM) (C), but not IgD (D). Original magnification each...

Prostate Brachytherapy

Prostate brachytherapy involves placement of radioactive sources directly into the parenchyma of the prostate. It is a highly conformal form of therapy, permitting dose escalation to the target volume far exceeding that of other radiation modalities. The surrounding normal tissues are spared because of the rapid dose falloff with distance from the source (inverse square law). The evolution of TRUS imaging, a closed transper-ineal approach, and the increasing sophistication of computerized...

Factors Involved in Drug Sensitivity

Cisplatin (CDDP) exerts its effect by damaging DNA. In principle, different processes leading to binding of a drug to DNA can be distinguished whereas mechanisms such as influx and efflux of a drug across the cell membrane can affect intra-cellular concentration, other factors influence drug activation, detoxification, or DNA binding itself. Most findings, however, suggest that crucial determinators of drug sensitivity in GCTs lie downstream of DNA binding, for example, in the intrinsic or...

Activation of Telomerase

The E6 protein has been implicated in the activation of the enzyme telomerase a potential mechanism for HPV-induced immortalization 43 . Mammalian telomeres are structures at the chromosomal tips consisting of multiple repeats of TTAGG, which shorten as a function of division in vivo as a consequence of an intrinsic inability to replicate the 3' end of DNA. Telom-erase replaces the telomeric repeats and is not normally expressed in somatic cells. Activation of telomerase enables cells to escape...

Attempts to Improve MVAC

In an attempt to decrease the toxicity and enhance the efficacy of MVAC, several investigators evaluated the use of altered doses and schedules with granulocyte colony-stimulating factor (GCSF) support. Based on the potential for enhanced survival conferred by greater drug delivery, the European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial comparing MVAC administered every 2 weeks (with GCSF) with MVAC administered every 4 weeks 8 . Although this...

Angiogenic Targeting

Renal cancer specimens are often observed to be densely vascularized reports of difficult-to-control bleeding during surgery on metastases (as opposed to nephrectomy, where the renal vascular stalk is a point of control) are common. The concept of targeting the blood vessels of the cancer is appealing for several reasons low toxicity, conversion of the disease to a chronic pattern, and an independent attack at a fundamental vulnerability of the growing tumor. The genotype of the targeted cell...

Background

The term proteomics was coined to parallel the term genomics however, proteomics encompasses more that just the study of the protein equivalent of the genome. The proteome, that is, all the proteins and their multiple isoforms and modified forms expressed in any one cell type or biological fluid, is responsible for the active work undertaken by a cell, and even reflective of the status of the entire organism, where fluids such as urine and blood serum are studied. The pro-teome is therefore...

Bcl2

The BCL2 protein is an antiapoptotic factor. Changes in the bcl-2 proto-oncogene were initially described in association with the t (14 18) translocation found in follicular lymphoma. The BCL2 protein is expressed mostly in basal cells in healthy prostate tissue. It is overexpressed within the luminal epithelium in a subset of high-grade prostatic intraepithelial neoplasia lesions and in many androgen-independent prostate cancers however, it is absent in most low- to intermediate-grade...

Biology

The histogenesis of these tumors is unclear. One hypothesis is that they originate from a multipotential stem cell in the prostatic epithelium, whereas others favor either malignant transformation of normal prostatic neuroendocrine cells or metaplastic change in a conventional acinar adenocarcinoma 107 . There is also evidence to suggest that prostatic tumors with a significant neuroendocrine component may be largely androgen-independent and are thus resistant to conventional forms of...

Biopsy Studies

Despite the difficulties in obtaining prostate tissue, several studies have already been published comparing either normal or BPH tissue to malignant prostate. Alaiya et al. 10 used 19 benign and malignant radical prostatectomy samples to carry out 2DGE and obtained 23 identities of differentially expressed proteins, including heat shock 70 and cytochrome P-450 7A1. Meehan et al. 11 used 2DGE of matched normal and malignant tissue from 34 radical prostatectomy specimens to identify 20 proteins...

Biopsy

Histological confirmation of malignancy is mandatory before planning definitive treatment. Patients with small lesions restricted to the prepuce or the penile skin may undergo wide excision of the same with a healthy margin all around, which will be both diagnostic and therapeutic in some cases. Lesions involving the glans, however, require a deep punch or incision biopsy to confirm malignancy and its histologi-cal subtype, grade, and invasiveness. In case of a phimotic preputial sac, a dorsal...

Chromosome

Chromosome 9 LOH is found in more than 50 of all bladder tumors regardless of grade and stage 8,12,13 . The finding that many TCCs have loss of the entire chromosome, commonly with reduplication of the other homologue, implies that loss of function of tumor-suppressor genes on both chromosome arms contributes to tumor development. Identification of these target genes is considered pivotal to understanding the pathogenesis of the disease and to providing useful clinical markers and targets. Some...

Chromosomal Alterations

Up to 54 of primary cancers and 100 of metastatic tumors have LOH occurring in at least one chromosome. The technique of comparative genomic hybridization (CGH) has helped to identify the most commonly altered chromosomal regions in prostate cancer. Chromosomal losses are far more common that gains in primary tumors however, they are found at equal frequencies in hormone-refractory tumors 10 . This suggests that tumor suppressor inacti-vation may be an early event in prostate cancer The...

Clinical Features

Almost all patients diagnosed with prostatic lymphoma, whether primary or secondary, present with symptoms of lower urinary tract obstruction 64,65,67 . Occasional patients present with pain or hematuria, and some with systemic disease have B symptoms. Serum prostate-specific antigen is raised in approximately 20 of patients. On digital rectal examination the prostate appears diffusely enlarged or nodular, and firm. A tissue diagnosis is usually obtained by examination of needle biopsies or...

Collecting Duct and Medullary Carcinoma of the Kidney

Collecting duct carcinoma, also known as Bellini's tumor, is a rare form of kidney cancer accounting for approximately 0.4 to 2 of renal cancers 110 . Typically these tumors are very aggressive, with many patients presenting with metastases. Median survival has been reported to be around 11.5 months across all stages 111 . Structurally and histologically these tumors resemble papillary renal cell carcinoma (Fig. 16.5) 110 . Collecting ducts carcinomas are typically characterized by hypodiploid...

Combination Chemotherapy and the Development of MVAC

Multiagent chemotherapeutic regimens were developed during the 1980s in an attempt to improve upon the results with single-agent therapy. A landmark trial reported in 1985 used the combination of methotrexate, vinblastine, Adriamycin (doxorubicin), and cisplatin (MVAC). In this trial, 24 patients with advanced or unresectable urothelial TCC were treated with MVAC 3 . Remarkably, responses were observed in 71 of those treated (95 confidence interval CI , 53-89 ), with complete clinical responses...

Contralateral Testicular Biopsy

Carcinoma in situ (intratubular germ cell neoplasia ITGCN ) consists of atypical cells located in a single row at the basement membrane of seminiferous tubules. It is universally detected in the tissue surrounding germ cell tumors 7 . These cells are the uniform precursor of all germ cell neoplasms of the testis (other than sperma-tocytic seminoma) and develop during embryogenesis. Cellular proliferation then probably occurs during and after puberty 8 . Usually all spermatogenic cells are...

Corrective Strategies in Gene Therapy of Bladder Cancer

The development of bladder cancer is known to involve activation of a variety of oncogenes combined with loss of vital tumor-suppressor genes. These genes have crucial roles in control of cell proliferation, adhesion, and apoptosis, and are responsible for changes in the cancer cell phe-notype from benign to malignant. The rationale of gene therapy in this situation is to restore gene expression in the cell to normal either by replacing lost genes or by inhibiting destroying those that are...

CpG Island Promoter Methylation

The most common genomic change in prostate cancer is silencing of the gene encoding the pi class of glutathione-S transferase (GSTP1) by hypermethylation of the promoter region. This change has been found in 90 to 95 of prostate cancers and 70 of high-grade prostatic intraepithelial neoplasia lesions 9 . The GSTP1 enzyme has a cell-detoxifying function, and therefore may protect cells from environmental carcinogens and DNA damage. Detection of the methylated GSTP1 promoter in urine and semen is...

Current Issues in Superficial Bladder Cancer Classification

The current system of bladder tumor classification is based on the International Union Against Cancer (UICC) revision of 1997 4 . Superficial bladder cancer is the term used to describe transitional cell carcinomas with histopathological categories pTa and pT1 as well as carcinoma in situ (CIS) pTa tumors are confined to the urothelium bordered by the basement membrane, whereas pT1 tumors have penetrated into the lamina propria. Much debate has been concerned with the inclusion of pT1 tumors as...