Natural Cures For Prostate Cancer

The 21 Day Prostate Fix

21 Day Prostate Fix written by Radu Belasco is a healthier alternative to drugs and invasive medical procedures. Radu Belasco is an early prostate problem sufferer, with a family history of prostate pain, problems and cancer. Using a unique system of natural remedies, he fixed his prostate problems and wrote them in his smash hit eBook The 21 Day Prostate Fix. It is about miraculous herbs and fruits from all over the world. These unique foods have the power to cure your prostates inflammation in record time and shrink it to a healthier size. Also, you will learn how to concoct the miracle elixir that will not just cleanse your prostate, but also burn body fat. Aside from these, youll get topnotch information on nutrition, so you can keep your prostate healthy and your sex drive at its peak. Plus, youll learn other health conditions that might be contributing to your prostate issues, so you can also remedy them and get your body in its best shape ever.

The 21 Day Prostate Fix Overview


4.6 stars out of 11 votes

Contents: Ebook
Author: Radu Belasco

Download Now

MRI of Prostate Cancer Introduction

Prostate cancer continues to be the leading cancer among American men, with 184,500 new cases annually 1 . It has been estimated that 39,200 men died of prostate cancer in the U.S.A. in 1998. This makes prostate cancer the second cause of cancer-related death in men 2, 3 . Furthermore, the probability of developing prostate cancer from birth to death is 20 3 . Treatment selection is dependent on patient age and health, cancer stage and grade, morbidity and mortality of treatment, as well as patient and physician preference. The mainstay for organ-confined disease is either radical surgery or curative radiotherapy 4, 5 . This is only considered an option in the absence of seminal vesicle infiltration (SVI), extension through the prostatic capsule (extracapsular extension, ECE) or metastatic disease. Therefore, the purpose of staging is the possible detection of extraprostatic disease. Clinical staging by digital rectal examination (DRE) and prostate specific antigen (PSA) remains as...

Introduction to the Prostate

The prostate is a fibromuscular glandular organ involved in the male reproductive system. It is located between the bladder and pelvic floor, and surrounds the prostatic urethra. It is comprised of a large, nonglandular region and a smaller, glandular region that consists of epithelium and stroma, and can be further subdivided into three main zones the peripheral zone, which constitutes about 70 of the gland the central zone, comprising 25 of the gland and the transitional zone, which represents about 5-10 of the gland (see Figure 1). These zones have histological differences, mainly relating to secretory cell structure and the ratio of epithelium-to-stroma, which indicates that they have different functions.1 Figure 1 A sagittal section of the prostate, which shows anatomic subdivisions. (Reproduced with kind permission from Dixon, J. S. Gosling, J. A. Textbook of Benign Prostatic Hyperplasia, 2nd ed. Taylor & Francis London, 2005, pp 3-10 Taylor & Francis.) Figure 1 A sagittal...

The Definition of Benign Prostatic Hyperplasia

BPH is a progressive disease characterized by prostate stromal and epithelial cell hyperplasia, which usually begins in the periurethral zone of the prostate. This process can be asymptomatic or associated with lower urinary tract symptoms (LUTS), typified by urinary frequency and urgency, nocturia, decreased and or intermittent force of stream, and incomplete bladder emptying.9 BPH is extremely common one European survey of 80 774 subjects estimated that the prevalence of symptomatic BPH was 2.7 in men aged 45-49 years and 24 in men aged 80 years and over. Similar age-related trends have been observed in the USA, with an incidence of 34 100000 in 20- to 39-year-olds compared with a peak incidence of 1803 100 000 in 60- to 69-year-olds10 (see Table 1). Histopathologic evidence of BPH places the burden much higher, with a prevalence around 50 in men aged 60 years and 85 in men aged

The Pathophysiology of Benign Prostatic Hyperplasia

The prostate of aging males can be stimulated to undergo excessive growth. This is characterized by a number of cellular and molecular alterations leading to increased cell proliferation and reduced apoptosis in the prostate epithelium and stroma. The 'remodeling' that occurs as a result of these processes can permanently alter the appearance of the prostate, and may result in symptoms, long-term damage, and prostate cancer. It is not clear why these changes occur in some males, although it has been suggested that they are linked to a number of risk factors such as smoking, racial differences, obesity, liver cirrhosis, cardiovascular risks, and genetic predisposition. The pathogenesis of BPH is discussed in this section. A genetic involvement in the development and progression of BPH has been established. Molecular profiling using realtime quantitative reverse transcriptase-polymerase chain reaction on prostate tissue samples from BPH patients and normal controls has shown that at...

Surgical Transurethral Prostatectomy with CC

Prostate cancer is the most common type of cancer in men and the second leading cause of death among men in the United States. The American Cancer Society estimated that, in 2005, there would be 232,090 new cases and 30,350 men would die from prostate cancer. Overall, 1 in 6 men are diagnosed with prostate cancer and 1 in 33 die from this disease. The 5-year survival rate is 99 . Prostate cancer may begin with a condition called prostatic intraepithelial neoplasia (PIN), which can develop in men in their 20s. In this condition, there are microscopic changes in the size and shape of the prostate gland cells. The more abnormal the cells look, the more likely that cancer is present. It has been noted that 50 of men have PIN by the time they are 50 years old. Adenocarcinomas compose 99 of the prostate cancers. They most frequently begin in the outer portion of the posterior lobe in the glandular cells of the prostate gland. Local spread occurs to the seminal vesicles, bladder, and...

Reproductive System DRG Category 336 Mean LOS 40 days Description Surgical Transurethral Prostatectomy with CC

Prostatitis, an inflammation of the prostate gland, is classified in four categories. Acute bacterial prostatitis is an acute, usually gram-negative, bacterial infection of the prostate gland, generally in conjunction with acute bacterial cystitis. Chronic bacterial prostatitis is a subclinical chronic infection of the prostate by bacteria that can be localized in prostatic secretions and is the most common recurrent urinary tract infection in men. Nonbacterial prostatitis is a chronic prostatitis for which there is no identifiable organism. Prostatodynia is a condition in which the patient experiences irritation and pelvic pain on voiding the symptoms suggest an acute inflammatory process, but there is no evidence of inflammatory cells in the prostatic secretions. The most common complication of prostatitis is a urinary tract infection. If it is left untreated, a urinary tract infection can progress to prostatic edema, urinary retention, pyelonephritis, epi-didymitis, and prostatic...

The Tramp Mouse as a Model for Prostate Cancer

Prostate cancer ranks as one of the most common cancers among men. Consistent with this, prostate cancer is also one of the most frequent causes of male cancer-related death. Adenocarcinoma represents the predominant histologic type of prostate cancer, typically arising from malignant transformation of lumenal epithelial cells within glands comprising the peripheral zone of the prostate. Somewhat unique to this cancer are a number of key features. Androgens play an essential role not only in normal prostate development but also the pathogenesis of prostate cancer. Related to this, most prostate tumors are androgen-sensitive i.e., demonstrate initial regression following androgen removal or blockade, and then subsequent progression due to proliferation of androgen-inde-pendent or androgen-suppressed tumor cells. Human prostate cancer encompasses a wide spectrum of histologic grades ranging from the putative precursor lesion, prostate intraepithelial neoplasia (PIN), to...

Microdissection Of The Mouse Prostate

In contrast to the human prostate, which is a single organ that can be histologically segregated into several zones (i.e., anterior, peripheral, and transitional), the mouse prostate represents an organ complex composed of four paired-sets of lobes ventral, dorsal, lateral, and anterior (coagulating). Microsurgical isolation of the individual murine prostate lobes ensures adequate representation of all four, facilitating valid histologic comparison of similar glandular tissues from different mice after experimental treatment. Isolation and recovery of the individual glands of the murine prostate, however, is challenging given the extremely small size of these glands within the murine prostate complex. In fact, experienced urologic surgeons have encountered difficulty with even locating the prostate in a male mouse. In addition to their minute size, the individual lobes of the murine prostate are spatially separated along the urethra, intimately invested within fat and connective...

Prostate Surgery and Incontinence

Prostate surgery can contribute to transient, short- or long-term incontinence. Radical retropubic prostatectomy is a surgical procedure used in prostate cancer, which involves the removal of adenomatous tissue via an incision in the surgical capsule of the prostate. However, this technique can result in refractory incontinence. One study of 146 prostate cancer patients showed that stress urinary incontinence was evident in the majority of patients (95 ) after surgery, with the main cause of incontinence being intrinsic sphincter deficiency.65 Another study in 120 prostate cancer patients showed that radical prostatectomy had a significant impact on nocturia and voiding frequency in a small proportion of patients.66

The Diagnosis of Benign Prostatic Hyperplasia

Animal Models

Several guidelines have been published to aid in the diagnosis of BPH the most prominent ones are those published by the American Urological Association (AUA)9 and by the European Association of Urology (EAU).29 Both of these guidelines recommend that the diagnosis of BPH is based on a medical history, symptomatic assessment using a validated instrument such as the International Prostate Symptom Score (IPSS), which uses eight items to categorize BPH 'urinary' symptoms as mild (IPSS 0-7), moderate (IPSS 8-19) and severe (IPSS 20-30), and a physical examination consisting of a digital rectal examination (DRE) to evaluate the prostate size. The AUA guidelines have produced a diagnostic algorithm, which is illustrated in Figure 10. The prostate-specific antigen (PSA) test is used to distinguish between BPH and prostate cancer. PSA, an endogenous serine protease secreted by the epithelium, is a key malignant tumor marker. At present, a number of methods are used to assess PSA (e.g., PSA...

Prostate Cancer

Age (not seen in men < 40 years old incidence increases with age 60 of men > .80 have prostate cancer) Patients present late, because early prostate cancer is asymptomatic. Look, for symptoms suggestive of benign prostatic hypertrophy (hesitancy, dysuria, frequency) with hematuria and or elevated prostate-specific antigen (PSA) or acid phosphatase. Acid phosphatase is elevated only when the cancer has broken through the capsule for this reason, it was replaced with the more sensitive PSA as a screening tool. Look for prostate irregularities (nodule) on rectal exam. Patients also commonly present with back pain from vertebral metastases (osteoblastic). Local prostate cancer is treated with surgery (prostatectomy). Patients with metastases have several options for hormonal therapy orchiectomy, gonadotropin-releasing hormone agonist (leuprolide), androgen-receptor antagonist (flutamide), estrogen (diethyistilbestrol), and others (e.g., cyproterone). Chemotherapy does not work, and...


Prostatitis is an extremely common condition, which is classified into several subgroups. Acute bacterial prostatitis is the result of an acute pathogenic infection and can lead to chronic bacterial prostatitis. Chronic nonbacterial prostatitis, or chronic pelvic pain syndrome (CPPS), is a multifactorial condition that may be linked to other conditions such as bladder neck obstruction, urethral stricture, detrusor sphincter, dyssynergia, or dysfunctional voiding. Nonculturable organisms and sexually transmitted infections (e.g., Chlamydia trachomonas) are also possible causes. Given the multiple etiologies, prostatitis can be extremely difficult to diagnose and treat. Acute bacterial prostatitis is usually diagnosed via dipstick testing of midstream urine, together with bacterial cultures. If bacteria are present, then it is typically treated by hydration and intravenous antibiotics such as cephalosporins followed by oral antibiotics such as quinolones or co-trimoxazole. For those...

Prostate Gland

This figure shows the epithelium of the prostate gland at higher magnification. The lining of the branched tubuloalveolar glands consists in part of 2 single-layered, in part of two-layered or multilayered epithelium. The shapes o of the epithelial cells range from flat to cuboidal to columnar. Dependent on the secretory activity and the presence of hormones, epithelial cells appear in different configurations. Age also influences the appearance of the epithe- lium. The apical regions of the gland cells contain secretory granules, which bind variable amounts of stain. The apical regions also contain lipid granules, glycogen granules and vacuoles. Occasionally, cytoplasmic protrusions are pinched off from the secretory cell and sequestered into the lumen. Undif-g ferentiated, flattened basal cells are found between the secretory epithelium and the basal membrane. They are considered progenitor cells of the gland cells. The connective tissue fibers are stained red and the muscle tissue...

The Prostate Gland

Your prostate is a walnut-shaped gland that lies immediately beneath your bladder surrounding the urethra, the tube inside the penis that carries urine out of your body. It secretes a fluid that becomes part of semen. The gland can easily become inflamed during an infection, causing soreness, swelling, frequent urination, and a burning sensation while urinating. The prostate gland also can become enlarged, a condition called benign prostatic hyperplasia, which is a common problem in older men. An enlarged prostate gland can cause a number of bothersome problems when urinating, including hesitancy or straining to urinate a weak stream of urine dribbling retention of urine or the inability to control urination, also called incontinence. Other common symptoms include frequent urination, feeling an urgent need to urinate, and excessive urination at night. If you have any of the symptoms of prostate enlargement, you should not feel embarrassed about talking them over with your doctor. You...

Risk Factors and Cancer

Diet and obesity in adults account for 30 of all cancer deaths in the USA. Diet has been shown to play a significant role in the causation of cancer but little is known about how it plays its role as a carcinogen.15,18 Excessive fat in the diet raises the risk of colorectal and breast cancer and possibly prostate cancer. Adult obesity is associated with endometrial cancer, postmenopausal breast cancer, and cancers of the colon, rectum, and kidney.15,18 Obesity in concert with other risk factors such as low activity level, menopausal status, and predisposition to insulin resistance significantly increase the risk of cancer. While some methods of food preparation and preservation have been shown to increase the risk of various forms of cancers, certain classes of foods appear to contain protective substances against cancer including vegetables, whole grain products (fiber), and citrus fruits.12,15,18,20 Salt intake has been associated with risk of stomach cancer, but no other food...

Cancer Screening Diagnosis and Prevention

Thus far, biological markers (biomarkers) have been used to diagnose cancer, and to monitor disease progression and recurrence after therapy.59-62 Biomarkers have substantially improved the understanding of the molecular mechanism of action of carcinogenesis and risk, although they are more useful for monitoring the consequences of the disease and therapy rather than assessing the effects of risk factors on the onset of the disease. For example the serum-based markers calcitonin, prostate-specific antigen, and CA-125 are all elevated in medullary thyroid, prostate cancer, and a small subset of ovarian cancers, respectively.63-65 Urine-based biomarkers like bladder tumor antigen, survivin, and calreticulin have been recently used as diagnostic marker for bladder cancer.66 life-threatening cancer types. This is best exemplified for prostate and breast cancers which are diagnosed relatively early. Using biomarker analysis performed on the primary tumor recommendations can be made as to...

NCI directors consumer liaison group

This goal was achieved in August 1998 when the first Directors Consumer Liaison Group (DCLG) was selected, with a remit to provide input to the planning of programmes and future directions of research of the NCI. Setting up the initial DCLG involved careful planning by a group of NCI staff undertaken in collaboration with key cancer advocacy groups. Following response to an NCI call for nominations, fifteen members were selected by the NCI director. Nominees had to meet a series of eligibility requirements (summarised in Box 2.3) and were subject to an objective and pre-defined screening and evaluation process. The planning group recommended that the DCLG should reflect the breadth and depth of the cancer advocacy community and should therefore be multi-culturally diverse and include representation from a range of organizations and a broad mix of cancer sites. The initial membership, which was selected from 136 nominations, comprised mostly cancer survivors, but family...

Treatment Options for Major Cancers and Future Directions

According to the most recent statistics, one in three people will be diagnosed with cancer during their lifetime. Increased life expectancy (cancer can be considered a disease of advanced years), environmental factors (e.g., exposure to carcinogens), and social habits (e.g., diet and or smoking) have dramatically increased the risk of cancer in Western populations. Breast, lung, colorectal, and prostate are the four major types of cancer in adults, and they account for over half of all cases diagnosed. The treatments of these major cancers depend upon a variety of factors, but the most common ones involved surgery combined with radiation and or chemotherapy. These treatments are briefly discussed in this section. Table 1 shows representative examples of anticancer agents and their mechanism of action.

Biomarkers and Molecular Diagnostics

Besides sampling only a subset of the proteome, these methods have in common the notion that a diagnosis can be based on a consistent pattern of protein expression changes, a proteomic signature. For diagnostic purposes the underlying identities of the proteins contributing to the signature are not absolutely required, and are in fact, particularly in the case of SELDI, not always easy to obtain.85 The idea of using proteomic signatures has been around for a while. Spot patterns on 2D gels were considered a potential diagnostic tool soon after the first reports on 2D-PAGE,117 but were never truly brought to bear for a long time, because of the variability associated with 2D gels. Only the advent of more robust profiling methods based on MS has revived the interest in proteomic signatures. Especially in the oncology field, several reports claim better performance of such multiparameter biomarkers, compared to the traditional individual proteins, such as prostate-specific antigen for...

FSee 708 Kinase Inhibitors for Cancer

Treatment options for prostate cancer include surgery and radiotherapy (e.g., external beam or radioactive seed implants, called brachytherapy see above).78 Hormonal treatment, chemotherapy, and radiation (or a combination of them) are used for metastatic diseases and as supplemental additional therapies for early stage tumors. Hormonal treatment, which controls the progression of the disease by shrinking the size of the primary tumor and reduces symptoms (e.g., pain), involves the use of antiandrogens to block production of testosterone, a hormone that prostate cancer cells use to grow. Examples of drugs used for this specific treatment include flutamide, leuprolide acetate, bicalutamide, and goserelin acetate. Bone metastasis is often associated with prostate cancer. The secondary tumor causes the breakdown of bone tissue releasing substantial amounts of calcium into the bloodstream. In order to treat the excess calcium in the blood (hypercalcemia), bisphosphonates (e.g., zoledronic...

Dehydroepiandrosterone DHEA

DHEA is the major C-19 sex steroid produced by the zona reticularis of the adrenal cortex that acts as a weak androgen which promotes virilization in women. During fetal life, contributes to development of the male external genitalia, vas deferens, epididymis, seminal vesicles, and prostate.

Clusterin Expression Induced at Pathological Boundaries

Two notable examples of clusterin induction in response to hormonal withdrawal are in prostate gland subjected to the loss of testosterone and in the lactating mammary gland subjected to weaning. There is some evidence that clusterin activation is a response to the loss of repression by hormone, but this is less clear in the mammary gland, as occasional tubules in the actively lactating gland are intensely positive for clusterin expression. This occurs in the exact same pattern as in the bulk of the mammary epithelial cells that become high expressers at day 3 to day 5 post weaning. Thus, an interesting question is the extent to which induction is primarily the result of stasis or obstruction, rather than the loss of trophic

Roles of Transporters in Pharmacokinetics

Hepatocyte Sinusoidal Membrane Apical

Transporters are now recognized to be as important as the metabolizing enzymes in the modulation of the main steps controlling the fate and action of xenobiotics in the body. They affect all the main pharmacokinetic events, such as the oral bioavailability, distribution, and clearance of any substrates. As most drugs, toxicants, and carcinogens are taken orally, we focus here on their impact on the enterocytes, as these are the main intestinal cells involved in the passage of compounds from the intestine to the blood. The absorbed compounds are then cleared by the liver, where the hepatocytes may produce, like the enterocytes, coordinated transporter-enzyme systems that influence the overall availability of compounds taken via the mouth before they can be distributed throughout the body. Tissue distribution depends on many factors, such as the degree to which a drug is bound to plasma proteins, the organ perfusion rate, and the rate at which the drug permeates biological membranes....

Gender Ethnicracial And Life Span Considerations

By the age of 50, 50 of men have some degree of prostate enlargement. Many of these men do not manifest any clinical symptoms in the early stages of hypertrophic changes. As men become older, the incidence of symptoms increases to more than 75 for those over 80 years of age. Of Benign Prostatic Hyperplasia (Hypertrophy) 123

Primary Nursing Diagnosis

Those patients with the most severe cases, in which there is total urinary obstruction, chronic urinary retention, and recurrent urinary tract infection, usually require surgery. Transurethral resection of the prostate (TURP) is the most common surgical intervention. The procedure is performed by inserting a resectoscope through the urethra. Hypertrophic tissue is cut away, thereby relieving pressure on the urethra. Prostatectomy can be performed, in which the portion of the prostate gland causing the obstruction is removed. The relatively newer surgical procedure called TUIP involves making an incision in the portion of the prostate attached to the bladder. The gland is split, reducing pressure on the Benign Prostatic Hyperplasia (Hypertrophy) 125 urethra. TUIP is more helpful in men with smaller prostate glands that cause obstruction. Other minimally invasive treatments for BPH rely on heat to cause destruction of the prostate gland. The heat is delivered in a controlled...

Discharge And Home Healthcare Guidelines

Provide instructions about all medications used to relax the smooth muscles of the bladder or to shrink the prostate gland. Provide instructions on the correct dosage, route, action, side effects, and potential drug interactions and when to notify these to the physician. Cancer of the urinary bladder is the second most common genitourinary (GU) cancer after prostate cancer. It accounts for approximately 4 of all cancers and 2 of deaths from cancer in the United States. The American Cancer Society estimates that, in 2005, there will be over 63,000 new cases of bladder cancer diagnosed, and over 13,000 deaths in the United States. The majority of bladder tumors (> 90 ) are urothelial or transitional cell carcinomas arising in the epithelial layer of the bladder, although squamous cell (4 ), adenocarcinoma (1 to 2 ), and small cell (1 ) may occur. Urothelial tumors are classified as invasive or noninvasive, and according to their shape, papillary or flat. Noninvasive...

Plasminogen Activation and Cancer

Plasmin are inhibited by the action of specific inhibitors, plasminogen activator inhibitor (PAI-1) and a2-antiplasmin, respectively uPA is secreted as a proenzyme that is reciprocally activated by the action of plasmin. Activation of the cascade is locally confined by the high-affinity binding between uPA or pro-uPA and the cell surface receptor uPAR. Mice lacking uPA display defects in extravascular fibrin degradation while cooperation is observed in transgenic animals that coexpress uPA and uPAR.192 In a similar manner to MMPs, stromal cells appear to be the major sources of plasminogen activity in most tumors. The stromal cell type producing uPA depends on the origin of the tumor, myofibroblasts being responsible in breast and colon and macrophages in prostate cancer. Elevated levels of uPA and uPAR in the blood and tissue are associated with poor prognosis in many types of cancer, regardless of their respective sources.193,194 Manipulation of uPA levels by overexpression,...

Tumor Necrosis Family Apoptosis and Immune Surveillance

Upon entering the vasculature, mechanical forces contribute to the delivery of tumor cells to specific target organs. The relatively large size of solid tumor cells will tend to lead to their arrest in the first capillary bed they encounter. However, it apparent that tumors arising in particular organs have preferential secondary sites of metastasis, indicating that interaction between the cancer cells (seed) and the organ microenvironment (soil) can influence the fate of the cells.228 In addition to negative regulators, such as TNF ligand expression as described above, diverse factors that can promote the formation of tissue-specific metastasis have been postulated. Chemokines have been identified as key regulators of this process. Chemokines are soluble ligands that are involved in recognition and homing of multiple cell types, including hematopoietic cells, lymphocytes, and germ cells.229 Breast cancer cell lines, as well as carcinomas and metastasis, express high levels of the...

Preventive Healthcare

The most common tests performed in men over 40 include the PSA (prostate-specific antigen) test for prostate cancer, the fecal occult blood test for colon cancer, and a series of tests that screen for the presence of heart disease or your risk of having it. Such tests may include measuring your blood pressure and the levels of cholesterol in your blood an electrocardiogram, which measures the electrical activity in your heart and a stress test, which evaluates the heart's response to physical exercise. If you have a family history of a certain disease that has a strong hereditary component, such as diabetes (see page 365), you also may undergo a screening for that disorder. For example, in the case of diabetes, the doctor would perform a test known as a glucose tolerance test (see page 367).

Periodic Health Checkups for

To look for signs of cancer of the colon, rectum, and prostate. Includes rectal examination performed by hand by a doctor, fecal occult blood test that checks for blood in the stool, sigmoidoscopy (see page 284), and possibly a PSA (prostate-specific antigen) test. Those at risk Men with a family history of colon or rectal cancer men who have intestinal polyps or ulcerative colitis men over age 50. African American men have an increased risk of prostate cancer. Prostate Not needed Once a year beginning at age 45 if you are African American or if you are a white male with a family history of prostate cancer Prostate Physical

Tissue distribution

Most of the drug-conjugating UGT isoforms are expressed in the liver, but are also present at variable levels in extrahepatic tissues, particularly tissues that are responsible for the absorption or excretion of drugs, such as intestine, lung, and kidney. Human hepatic UGTenzymes include UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B11, and UGT2B17.102 The gastrointestinal tract contains UGT1A1, UGT1A8 (restricted to the colon) and UGT1A10, whereas UGT1A7 seems to be localized to in the esophagus, stomach, and lung. Human kidney UGTenzymes include UGT1A8, UGT1A9, UGT1A10, and UGT2B7. In fact, UGT2B7 levels in the kidney are similar to those found in the liver. UGT2B transcripts are found in steroid-sensitive tissues, including the prostate (UGT2B17) and mammary tissues (UGT2B11 and UGT2B28).99 Glucuronidation reactions are also readily detectable in the brain and placenta.102

Biomarker as Surrogates for Clinical Activity

As briefly referred to earlier in this chapter, the greatest historical value of biomarkers in drug development has been in the clinic as markers of disease status and response to therapy. Biomarkers that have been strongly linked to improvement in a particular disease are often referred to as surrogate endpoints or surrogate markers. Surrogate endpoints have been defined as a biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.1 After extensive testing, often requiring years of large and well-controlled clinical studies, well-correlated surrogate endpoints can sometimes be used as the basis of regulatory approval in the absence of a large body of evidence based on actual clinical endpoints, which are defined as characteristics or variables that reflect how a patient feels, functions, or...

QOL Assessment Instruments

One example from the prostate cancer literature shows that with longer follow-up, persistent incontinence may dampen early enthusiasm over having had a successful operation.26 An analogy in the area of HNC might be that patients who require delayed or have long-term tracheotomies and difficulty swallowing may become depressed, whereas they were initially happy to have their larynx preserved. These conditions may not develop for years after nonsurgical organ preservation treatments, as a result of progressive soft tissue fibrosis in the head and neck, and may not be recognized if cancer follow-up terminates at 5 years, the traditional cure endpoint. Additional surveillance of HNC patients for second primaries should continue indefinitely with yearly chest radiographs that can detect early, operable second primary lung cancers.

The Discovery of ICI46474

Although the discovery of ICI46,474 (tamoxifen) (Figure 4), the antiestrogenic, pure trans isomer of a substituted triphenylethylene, was made by Harper, Richardson, and Walpole45-47 as part of the Fertility Control Program at ICI Pharmaceuticals (now AstraZeneca), Cheshire, UK, the study of cancer therapies was Walpole's long-term interest.48 In the late 1940s Walpole was a member of staff at ICI's Dyestuffs Division Biological Laboratory in Wilmslow, Cheshire. This establishment was the fledgling predecessor of the Pharmaceuticals Division Research Laboratories built in 1956-57 at Alderley Park near Macclesfield, Cheshire. Walpole was asked to establish animal models for the bioassay of potential alkylating agents49-54 to evaluate compounds as bladder carcinogens55 and to assess the potential health hazards for workers in the dyestuffs industry.56 Walpole made the important discovery that tris-ethyleneimino-S-triazine (M9500) was an active anticancer agent in the Walker rat...

Risk Factors and Genetics

Familial breast cancer has been associated with certain genes. The two main genes are BRCA I and BRCA II.1 BRCA I is found on chromosome 17 and is also associated with an increased risk of colon, ovarian, and prostate cancer. BRCA I is thought to function as a tumor suppressor gene in DNA repair. BRCA II, located on chromosome 13, is associated with male breast cancer. BRCA II is also thought to function as a tumor suppressor gene. Both of the above genes are inherited in an autosomal dominant pattern with incomplete penetrance. Prophylactic bilateral mastectomy has been shown to decrease breast cancer in women with the previous listed mutations in early studies.2 Other syndromes have increased risk of breast cancer include Li-Fraumini syndrome and p53 mutations. The most common abnormally expressed gene in any breast cancer is p53 on chromosome 17. The risk of breast cancer is especially increased with exposure to radiation. Male breast cancer is increased in BRCA II and in...

Figure 2 Contemporary preclinical drug development process

On the organ or stromal environment of the growing tumor and this can be helpful when working with targeted agents. In addition, the PK PD relationships in different tumor-containing organs can be evaluated. However, relative to flank models, orthotopic and metastatic model systems often have increased complications associated with staging of trials and, without sensitive imaging technologies and or genetic alteration of tumors cells, the inability to monitor tumor sizes remains a drawback. Furthermore, without tumor staging, these models can require large cohorts of tumor-bearing animals for convincing statistical analysis. These models also often require a high degree of technical skill and can be quite time-consuming, thus potentially restricting the size of trials that can be conducted. However, the evaluation of biomarkers in selected orthotopic or metastatic models, such as prostate-specific antigen (PSA) in the LuCap 23.1 (human prostrate carcinoma) or CA15-3 in the MDA-MB-231...

Analysis of Cytotoxic Agents in Xenograft Models

The data include several examples of cytotoxic agents that show significant xenograft activity that is reflective of clinical activity irinotecan is highly active in several models of colon cancer, temozolomide is efficacious in a model of glioma and one of two models of melanoma, paclitaxel is active in models of bladder, breast, lung, and prostate cancer, rituximab is highly active in two models of B-cell lymphoma, and gemcitabine is active in a model of pancreatic cancer. Note, however, that this activity can be quite dependent on the dose and schedule employed (note irinotecan in colon cancer models). Correlating dose and schedule with PK (e.g., efficacy driven by Cmax, area under the curve (AUC), time over threshold, etc.) is a vital aspect of preclinical evaluation in order to help define the optimum clinical schedule (once- versus twice-daily administration, continuous versus intermittent therapy, etc.). Table 1 also highlights some of the differences in activity that can be...

Table 13 Some of the common terms used to describe clinical studies

Endpoints is acute rejection, and creatinine serves as a straightforward surrogate endpoint. In prostate cancer, the definitive endpoints are mortality and disease progression, but prostate-specific antigen (PSA) levels have been used as a surrogate endpoint (though not without controversy).126 In targeted cancer therapies, a number of changes have been made to the standard clinical protocols. For instance, instead of looking for a maximum tolerated dose and dose-limiting toxicities in Phase I, the desired outcome might instead be the optimal biological dose with no toxicity.127'128 Ultimately, substantial evidence of efficacy must be demonstrated to gain approval of an NCE, which may require multiple adequate and well-controlled clinical trials, using prospectively determined assessment variables for major outcomes and both a global clinical improvement rating and a specific quantitative assessment related to the disease that is accepted to be valid and reliable.129

Disclaimer Not for patient use To be used as a research guide only

CEA, carcinoembryonic antigen CA-125, cancer antigen-125 PSA, prostate-specific antigen SNPs, single nucleotide polymorphisms EGFR, epidermal growth factor receptor kinase-P, kinase phosphorylation PARP inhibition, poly(ADP-ribose) polymerase inhibition. Figure 3 Types of biomarkers. CEA, carcinoembryonic antigen CA-125, cancer antigen-125 PSA, prostate-specific antigen SNPs, single nucleotide polymorphisms EGFR, epidermal growth factor receptor kinase-P, kinase phosphorylation PARP inhibition, poly(ADP-ribose) polymerase inhibition.

Epidemiology And Routes Of Transmission

The virus has not yet been found in fecal matter, but viral DNA can be detected in the semen by the polymerase chain reaction (PCR) technique. It has been reported that HHV-8 can be detected in the PBMCs in between 12 and 25 of homosexual men with KS but has not been consistently detected in semen samples of HIV-infected men without KS or from HIV-negative men (26-28). HHV-8 infections of the urogenital and prostate tissue of healthy men also do not appear to occur frequently. Therefore, the role of HHV-8 transmission via semen is still not clear. Apart from the implication of a linkage between HHV-8 infection and sexual activity suggested by the strong correlation between HHV-8 infection and homosexuality in North America and northern Europe, convincing evidence of heterosexual transmission of HHV-8 has not as yet been found. There are studies suggesting that commercial sex workers are more likely to be

Disorders of the Reproductive System

The vas deferens is a long duct that carries sperm from the epididymis past the prostate gland and into the seminal vesicle. The prostate gland and seminal vesicle produce fluids that support the sperm and make up 98 percent of the semen that is ejaculated through the urethra during orgasm. The urethra is also part of the urinary tract and transports urine from the bladder. Prostate gland Prostate gland

Identifying key symptoms

Sometimes more than one symptom may be important. For instance, patients may present with a complex mixture of symptoms which the treatment should palliate. In this situation a combination score or an algorithm maybe considered. In a trial assessing the value of mitoxantrone and prednisone in twenty-seven patients with hormonally resistant prostate cancer, Moore etal. 40 pre-defined a palliative response as a decrease in analgesic score by > 50 per cent or a decrease in 'present pain intensity' by > 2 points without an increase in analgesic score. In this phase II study nine patients were considered 'palliated' using this trial-specific definition, compared with only one who showed a traditional partial response. In an MRC Lung Cancer Working Party trial 41 comparing oral chemotherapy versus standard intravenous chemotherapy in patients with small cell lung cancer, QL was considered to be a primary outcome. In order to be considered 'equivalent' the oral treatment was required 'to...

The antiandrogen cyproterone

Finasteride inhibits 5a-reductase, the enzyme converting T. into dihydro-testosterone (DHT). Thus, the androgen-ic stimulus is reduced in those tissues in which DHT is the active species (e.g., prostate). T.-dependent tissues or functions are not or hardly affected (e.g., skeletal muscle, negative feedback inhibition of gonadotropin secretion, and libido). Finasteride can be used in benign prostate hyperplasia to shrink the gland and, possibly, to improve micturition.

Rac1 Protein Protein Interaction

Rac GTPase is involved in one of several signaling pathways mediated by Rho family GTPases. The 3D structure of a Rac1-Tiam1 complex was used to specify the binding pocket for inhibitors, and a flexible 3D search was performed in 140,000 compounds of the NCI database with the program Unity. The hits of this search were flexibly docked with the program FlexX and ranked by the consensus scoring function CScore. By visual inspection, 58 of the 100 highest-scoring hits were eliminated because they did not show an interaction of the ligand with Trp56. Considering solubility and availability of the remaining compounds, finally 15 compounds were tested for their ability to inhibit the Rac1-binding interaction with its guanine nucleotide exchange factor (GEF) TrioN. Compound 82 (IC50 50 M Fig. 16.10) was the only active and selective compound, significantly inhibiting TrioN binding to Rac1 but not interfering with Cdc42 binding to Intersectin. Also in cells it effectively inhibited Rac1...

Background Information

Initial experiments should use a general phosphatase such as potato acid phosphatase or calf intestine alkaline phosphatase which can successfully dephosphorylate a wide variety of phosphoproteins modified on several different amino acids. It should be noted that acid phos-phatases from animal tissues (e.g., bone, prostate, liver, and heart) represent a class of low-molecular-weight (18,000- to 25,000-kDa) protein tyrosine phosphatases that selectively dephosphorylate phosphotyrosine residues. These enzymes were defined as acid phos-phatases because they hydrolyzed p-ni-trophenyl phosphate (PNPP) at a pH optimum between 4.0 and 5.0. However, at physiological pH, these enzymes appear to specifically de-phosphorylate proteins and peptides containing phosphotyrosine residues. The mammalian acid phosphatases show no significant activity against proteins.

Ordered Categorical Data

In clinical trials it is not uncommon to have more discrete efficacy and safety endpoints with more than two categories. For example, although an adverse event can be classified into dichotomous groups, such as serious or nonserious adverse event, as a binary response, the intensity of an adverse event is evaluated according to the categories mild, moderate, or severe. Similar examples are seen in laboratory safety assessments. For example, we can assess the safety of a drug based on a particular laboratory parameter such as aspartate transaminase (AST) or alanine transaminase (ALT). Using the observed value of this particular parameter, subjects are usually classified into three categories below, within, and above the referenced laboratory normal range. For another example, each individual symptom score in the composite AUA symptom index for benign prostatic hyperplasia (BPH) presented in Table 9.1.3 consists of six categories. These six categories evaluate individual symptoms in an...

Fat Intake And Disease

Official recommendations are based on the evidence that reduced fat, particularly saturated fat, leads to a reduction in serum cholesterol, a known risk factor for coronary heart disease. Some investigators have also postulated that a reduction in fat intake may decrease mortality from breast, colon, and prostate cancers (4-6). Browner and colleagues have estimated that if the population were to follow the current dietary recommendations for fat intake, coronary heart disease mortality rates could decrease as much as 20 depending on age (7). Based on their assumptions of the relationship between fat intake and heart disease and

Epidemiology 1521 Introduction

The yearly cancer incidence rate can be expressed in terms of the number of new cancer cases during a year per 100,000 inhabitants. For example, if the incidence of cancer in country A is the same as that in country B, and country A has more inhabitants (persons at risk), the incidence rate is lower in country A. If a disease only affects a particular subpopulation, e.g., men, in the case of prostate cancer, the incidence is related to that subpopulation.

Disorders of the Bladder and Urethra

Surgery is the most common treatment for bladder cancer. Superficial bladder cancer can be treated with transurethral resection, in which the tumor is surgically removed through a cystoscope. With invasive bladder cancer, all or part of the bladder is removed using a surgical procedure called cystectomy. Often, surrounding lymph nodes, the prostate gland, and the seminal vesicles also are removed. Additional treatment may include radiation therapy, chemotherapy (treatment with powerful anticancer drugs), or immunotherapy (treatment in which the body's immune system is stimulated to destroy cancer cells), depending on where the cancer has spread and how advanced it is. Until recently, nearly all men experienced erectile dysfunction after bladder removal surgery, but surgical improvements have reduced the likelihood of this side effect. However, men who have had their prostate gland and seminal vesicles removed no longer produce semen, so they do not ejaculate when they have an orgasm,...

Normal Urothelial Histology and Cytology

Urine Cytology Umbrella Cell

The majority of the collecting system is lined by urothelium (transitional epithelium). Variable areas of the bladder and urethra may be lined by glandular epithelium (simple columnar), especially in the trigone and the dome of the bladder (the vestigial urachus) pa-raurethral glands, which provide lubrication for the urethra, might also be a source of glandular epithelium from that area. Cystitis cystica or glandularis, arising in Brunn's nests in the bladder mucosa, may shed groups of atypical glandular cells not to be confused with those cells of an adenocarcinoma of the bladder or prostate. In addition, the prostate and accessory sex glands are lined by

Histopathologic Diagnosis

The histopathology of the metastasis provides information that can aid in the search for a primary site and that is used for appropriate management decisions. Adenocarcinoma in low cervical lymph nodes only is strongly suggestive of an infraclavicular primary lesion. In such cases, further exhaustive evaluation of the upper aerodigestive tract is not warranted. The diagnostic evaluation would shift to focus on the organs being the most likely sources of the metastasis. The potential primary sites in decreasing order of frequency for an infraclavicular adenocarcinoma are lung, gastrointestinal tract, breast, pancreas, prostate, and ovary. Adenocarcinoma from an infraclavicular site manifesting as cervical adenopathy represents distant metastatic disease and, as might be expected, has a very poor prognosis.7 By contrast, metastatic adenocarcinomas presenting in the upper neck often arise from salivary tissue in the major or minor salivary glands. Metastatic differentiated or medullary...

Cadherins and epithelialmesenchymal transition EMT

Changes in expression of other cadherins accompanies downregulation of E-cadherin, in a situation reminiscent of the epithelial-mesenchymal transition that occurs during embryonic development. This transition is characterized by a loss of epithelial cell polarity and cell-cell contact, gain of mesenchymal markers such as N-cadherin, and an increased migratory phenotype.154 Increased levels of N-cadherin, normally expressed in neuronal cells and fibroblasts in adults, are observed in breast and prostate cancer and invasive melanoma.155 N-cadherin is thought to mediate a less stable and more dynamic form of cell-cell adhesion, and its overexpression enhances invasion and formation of metastasis. These changes occurred despite the presence of E-cadherin, suggesting that N-cadherin may play a dominant role. N-cadherin invasive activity occurs, at least partly, via association with the fibroblast growth factor receptor-1 (FGFR-1). Interaction results in stabilization of FGFR-1 leading to...

Finding Your Glomerular Filtration Rate

The urinary clearance technique cannot be used if complete urine collections cannot be obtained. Many persons do not empty their bladders completely when they void, for a variety of reasons. For example, people with diabetes may have some degenerative changes in the nerves that supply the bladder. Older men often have some degree of prostate enlargement that causes residual urine to remain in the bladder after voiding. Patients whose kidney failure is the late result of congenital defects in the urinary system, many of whom develop enlarged bladders, often continue to have substantial residual urine in the bladder after voiding.

Anspor Velosef [Rx Classification Cephalosporin firstgeneration

Uses Infections of the respiratory tract (including lobar pneumonia, tonsillitis, pharyngitis), urinary tract (including prostatitis and enterococcal infections), skin, skin structures, and bone. Otitis media, septicemia, prophylaxis in surgery, following cesar-ean section to prevent infection. In severe infections, therapy is usually initiated parenterally. Contraindications Hypersensitiv-ity to cephalosporins. Special Concerns Safe use during pregnancy, of the parenteral form in infants under 1 month of age, and of the PO form in children less than 9 months of age have not been established. Hypersensitivity to penicillins. Use in renal impairment. Side Effects See also Cephalosporins. Drug Interactions See also Cepha-losporins.

Eventfree survival eventfree interval and cancerspecific survival

Study, may plausibly dilute and hence obscure any difference between treatments and in some situations, through the play of chance, may enhance the difference. For example, in trials of men with early prostate cancer, progression-free interval is widely used as an outcome measure because many of the men with this disease will die from causes other than prostate cancer. As a safeguard against too much misclassification for this outcome measure, the information on cause of death is often examined so that patients who are reported as dying from this disease are included as 'event' even though they may previously have had no reported evidence of progressive disease. Although this maybe helpful, it is widely known that in nearly all countries cause of death is poorly classified.

Clinical manifestation

Papules or pustules evolve into purulent, verrucous, or ulcerative nodules or plaques, characterized by sharp and heaped-up borders with centrally located granulation tissue and exudate pulmonary findings signs of acute pneumonia, including fever, night sweats, wheezing and dyspnea signs and symptoms of chronic pneumonia last for 26 months, including weight loss, night sweats, fever, cough, and chest pain osteo-lytic bone lesions prostatitis or epididymi-tis

Unmet Medical Needs

Androgen replacement therapy has been reported to cause water retention, polycythemia, hepatotoxicity, sleep apnea, prostate enlargement, and to reduce HDL cholesterol.3 Hepatic toxicity is associated with derivatives of testosterone rather than pure testosterone. Polycythemia is observed more commonly in males receiving injectable testosterone. Thus, hematocrit should be measured periodically to minimize the risk of polycythemia. HDL cholesterol lowering is more profound with oral methyltestosterone than transdermal or injectable testosterone, but this effect is dose dependent, with higher doses causing more profound lowering of HDL cholesterol. Although testosterone is associated with prostate enlargement and prostate cancer, testosterone replacement therapy is rarely associated with an increase in urinary tract voiding symptoms, leading to cessation of therapy. In addition, prostate cancer surveillance can be done by measurement of PSA during the first 6-month interval after...

New Research Areas

Large, long-term clinical trials are needed in males over the age of 50 years to determine the benefits and risks of androgen replacement therapy. These studies could determine if cardiovascular risk, prostate cancer, frailty, fractures, osteoporosis, cognitive function, and life expectancy are influenced by androgen replacement therapy. A critical area of uncertainty is what testosterone concentration is needed to provide adequate androgenic effects. This is an important question because it relates to the concentration of testosterone where benefits might or might not be expected. Should free, bioavailable, or total testosterone concentrations be used

Biofilm and Medical Devices

Biofilm, as a matter of fact, is involved in acute and chronic infectious diseases and has been described in human and experimental pathology such as native valve endocarditis, otitis media, bacterial chronic rhinosinusitis, COPD, chronic urinary infections, bacterial prostatitis, osteomyelitis, dental caries, biliary tract infections, Legionnaire's disease and amyloidosis.

Selective Androgen Receptor Modulators

The development of selective androgen receptor modulators (SARMs) that have anabolic effects on the muscle but that do not have adverse effects on the prostate and cardiovascular system has been of considerable interest for the treatment of older men with testosterone deficiency.51-54 The nonsteroidal SARMs differ from testosterone in that they are not converted to active metabolites, such as estradiol and DHT, but they act as agonists in muscle and bone and only partial agonists in prostate and seminal vesicles. More favorable pharmacokinetics and androgen receptor specificity of nonsteroidal SARMs compared to testosterone provide promise for unique pharmacological interactions with the androgen receptor and actions that may allow more specific indications for their clinical use. The proposed mechanisms to explain the tissue selectivity of SARMs as nuclear receptor modulators include ligand binding specific conformational changes in the ligand-binding domain and modulation of surface...

Red stinkwood Prunus africana Rosaceae

The bark of Prunus africana is obtained from a tree that grows in the high (at elevations of 1000-2500 m) mountain forests of Africa and Madagascar). It has been developed into a phy-tomedicine and used to treat benign prostate enlargement, with good clinical evidence pointing to the extract's efficacy. Within Africa, different decoctions of the plant are used to treat various conditions, including fevers, urinary tract infections, and inflammation (bark tea), and to prepare wound dressings (leaves), and the leaf sap is drunk for insanity. In the regions of origin a high-quality extract is produced from the botanical drug, which is mostly exported to Italy, France, and Spain. This extract could provide a sustainable and valuable income for many of the African countries, especially for Cameroon and Madagascar. However, the bark is currently harvested from this slow-growing tree in an unsustainable manner. Overharvesting has resulted in serious damage to plant populations and it is now...

Future Directions

The incidence of disorders and dysfunctions of the urogenital tract including the kidney are increasing with the aging of the population. Drug treatments for both bona fide organic disorders (endometriosis, prostatitis, BPH, incontinence, BOO) and those more psychologically related (sexual dysfunction) are limited in their efficacy and side effect liabilities and perhaps with new insights into potential genetic causes of these disorders, may be treated via newer targets that have a lesser impact on cardiovascular system function. 3. Speakman, M. Batista, J. Berges, R. Chartier-Kastler, E. Conti, G. Desgrandchamps, F Dreikorn, K. Lowe, F O'Leary, M. Perez, M. et al. Prostate Cancer Prostatic Dis. 2005, 8, 369-374.

Management Approaches

The overall aim of therapy is to improve both symptoms and quality of life. Both the EAU and AUA guidelines9'29 list a number of recommended treatments for LUTS associated with BPH. Those listed by the EAU are outlined in Table 4 watchful waiting (i.e., no intervention) is advised if patients have minimal symptoms, 5a-reductase inhibitors or aj-adrenoceptor antagonists are recommended in patients with moderate-to-severe LUTS, with combination therapy being an option for those with large prostate volumes, at risk of developing complications or progressing, and surgery is advised for those who do not improve after medical therapy, do not want medication, or have complications such as acute urinary retention (AUR), bladder stones, recurrent infections, or recurrent hematuria refractory to medication. The type of surgery undertaken is usually based on prostate size, surgeon's judgment, and the presence of comorbidities. Open prostatectomy Transurethral holmium laser enucleation...

Treatment Complications and Progression

BPH is considered a progressive condition. Longitudinal data from a large-scale trial known as the Proscar Long-Term Efficacy and Safety Study (PLESS) in which 3040 men were randomized to treatment with finasteride (Proscar) or placebo for 4 years, with an additional 2-year follow-up period showed that finasteride prevented progression.59 However, baseline PSA and prostate volume could predict those patients at greater risk of symptom and quality of life deterioration, and those at risk for the development of AUR or BPH-related surgery. Those patients with a prostate size greater than 40 cm3 and PSA of 1.4 ng mL or above were at the greatest risk for developing AUR, and serum PSA was a strong predictor of prostate growth the annual growth ranged from 0.7 mL year_ 1 for patients with a PSA 0.2-1.3 ngmL _ 1 to 3.3 mLyear _ 1 for PSA range of 3.3 to 9.9 ngmL _ 1.60 In the MTOPS study, which also assessed the impact of medical treatment of BPH progression, baseline PSA, Qmax, PVR, and...

Other Prostatitic Conditions Causing Incontinence

There is evidence to suggest that prostatitis may be pathologically linked to interstitial cystitis in men as both of these conditions share common symptoms. In a survey of 92 men with interstitial cystitis confirmed by the National Institute for Diabetes and Digestive and Kidney Diseases criteria, the most commonly reported initial symptoms were mild suprapubic discomfort (33 ), nocturia (15 ), urgency (15 ), dysuria (11 ), and frequency (11 ) however, after 2.5 years these symptoms had become more severe and 89 reported dysuria, 85 had urinary frequency, 82 had severe suprapubic discomfort and or urgency, and 56 had sexual dysfunction.67 The overlap between prostatitis and interstitial cystitis has led researchers to consider that they have underlying causes. In a recent study of 50 patients with prostatitis, the majority of patients were also symptomatic on an interstitial cystitis questionnaire known as the pelvic pain and urgency frequency questionnaire, and 77 with a score more...

Ampulla of the Ductus Deferens

Immediately before entering the prostate gland, the ductus deferens widens and forms the ampulla of the ductus deferens. The muscular layer is thinner in this ampulla than in the vas deferens. The typical three-layer structure is re- placed by a meshwork of muscles 0. The smooth muscles are predominantly EJi circular. Copious connective tissue 0 exists between the smooth muscles. O The structure of the mucosa is especially remarkable. It reminds of the semi-15 nal gland structure (cf. Figs. 536, 537). The mucous membrane forms many shallow, sometimes branched invaginations. They appear as isolated alveolar glands in cross-sections. Occasionally, they extend into the muscular layer. The epithelium is two-layered and shows secretory activity. Human ampulla of the ductus deferens.

New MRI Techniques Uspio Mri

In Boston 91 , in 80 patients with histologically proven prostate cancer, using high-resolution techniques (at 1.5 T using a body phased-array coil), on post USPIO MRI the rate of detection of small nodal metastases in normal 5-8 mm sized nodes was significantly improved. Sensitivity, accuracy and negative predictive value showed a significant improvement using post-USPIO to 100 , 98 and 100 , respectively. This was due to the detection of small 3-4 mm metastases in normal-sized nodes. In addition, MRI nodes were found outside of the surgical field in 9 out of 80 patients thanks to post USPIO. Similar post USPIO results - sensitivity, accuracy and negative predictive value, respectively 96 , 95 and 98 - were acquired recently in urinary bladder cancer 93 .

When should the first results be published

For time-to-event data, the number of events (and associated number of patients) required to provide the desired power should have been specified up front, and when this is the case it provides a simple guide as to the 'right time' to publish. This will depend both on the event rate and the accrual rate the slower the rate of accrual, the longer the median follow-up at the closure of the trial and the shorter the time required after closure for the required number of events to accrue. It is necessary to bear in mind that those running trials have an obligation to the patients who agree to enter trials that they should contribute to the final results. Therefore presentation of results should not generally take place until all patients have at least completed their treatment. Exceptions to this may occur, firstly when the trial treatment is very long-term - for example ten years of hormone therapy for prostate cancer - and secondly when a trial stops early because of unequivocal...

Example The Estrogen Receptor

This section describes examples of usage of the methods that were introduced above. Molecular dynamics simulations have proven useful for drug design purposes on many different targets.88-103 Here, we will focus on the ligand-binding domain of the estrogen receptor. The estrogen receptor is a member of the nuclear hormone receptors and plays a key role in the growth, development, and maintenance of a diverse range of tissues. It consists of an N-terminal DNA-binding domain, a ligand-binding domain, and a C-terminal activation domain. Upon binding of an agonist to the ligand-binding domain a conformational change in the estrogen receptor takes place, allowing it to homodimerize and subsequently to translocate to the nucleus. Here, the DNA-binding domain directly interacts with response elements on the DNA, thereby activating or repressing transcription.104 Apart from the physiological effects, the estrogen receptor is involved in a range of diseases such as breast cancer, osteoporosis,...

The Breeding And Screening Of C57BL6 H2b OR C57BL6 X Fvbn H2q F1 Tramp Mice

Greenberg et al. (1995) introduced the murine TRAMP model which was originally generated from a single transgenic founder ( 8247) in the C57BL 6 background. Heterozygous postpubertal male progeny from this line develop adenocarcinoma, predominantly affecting the paired dorsal and lateral lobes of the murine prostate. Tumor progression in heterozygous TRAMP mice is slow and insidious, often becoming apparent as a soft mass in the lower abdomen of an 18 to 24 week-old mouse. This mass typically results from carcinomatous invasion, consequent dilation of the seminal vesicles, and to a lesser extent obstruction of the bladder. In contrast, male offspring of TRAMP mice back-crossed one generation onto the FVB N background (TRAMPF1) exhibit a somewhat accelerated pattern of tumorigenesis and tend to form firm spherical and vascular tumors arising from the dorsolateral prostate without significant seminal vesicle invasion (Gingrich et al., 1999). While rates and patterns of metastasis...

Scoring Tumors In The Autochthonous Tramp Mouse

Four separate parameters can be assessed and used, either alone or together, to score tumors in TRAMP mice. These include genitourinary (GU) weight (Gingrich et al., 1997), primary tumor incidence (Hurwitz et al., 2000), metastases (Gingrich et al., 1996), and tumor grade (Hurwitz et al., 2000 Gingrich et al., 1999). Prior to microdissection and processing of tissues, the en bloc GU complex (including the prostate lobes, seminal vesicles, and drained bladder) can be weighed as one index of primary tumor burden in these mice (see Support Protocol 1, steps 1 to 5). Alternatively, to determine primary tumor incidence, one can record the presence or absence of tumors, first appearing as whitish nodules emanating from one or several lobes of the prostate during microscopic dissection. This procedure is relatively simple and particularly useful when treated and untreated TRAMP mice are being compared at 16 to 18 weeks of age i.e., when established but relatively small (2 to 10 mm) tumors...

Global And Targeted Proteomics

And diagnostic markers, provide mechanistic insights, or define critical signaling pathways. For example, protein expression profiling has resulted in the annotation of some of the proteins that are differentially regulated in normal human luminal and myoepithelial breast cells (Page et al., 1999). Such studies are also contributing to the compilation of databases for the study of bladder cancer (Celis et al., 1999) and the human prostate (Nelson et al., 2000), while a number of potential cancer biomarkers have been identified by similar means (Srinivas et al., 2001). Although the value of successfully elucidating cellular and pathological processes on a proteome-wide level is indisputable, the scale of the undertaking is not trivial and becomes more challenging as the complexity of the organism increases, as discussed above. Thus, the ability to effectively analyze proteins on a global scale is subject to the capacities of proteomic technologies for the resolution of a large number...

AProlonged renal hypoperfusion is the most common cause of ATN

Postrenal insult results from obstruction of urine flow. Postrenal insult is the least common cause of acute renal failure, accounting for 10 . Postrenal insult may be caused by obstruction secondary to prostate cancer, benign prostatic hypertrophy, or renal calculi. Postrenal insult may be caused by amyloidosis, uric acid crystals, multiple myeloma, methotrexate, or acyclovir.

Unmet Medical Needs and New Research Areas

The advent of endocrine therapy has led to significant advances in the treatment of cancer. In particular, modulation of the estrogen receptor and the proteins that regulate estrogen synthesis have led to improved treatments for breast cancer. The clinical manifestation of tissue-selective compounds such as tamoxifen has led to the identification of SERMs as viable treatments for therapies ranging from breast cancer to osteoporosis. Moreover, this discovery has laid the groundwork for the identification of tissue-selective agents for other steroid receptors such as the androgen, glucocorticoid, and progesterone receptors, i.e., SARMs, SGRMs, and SPRMs, respectively. Future research will lie in obtaining the appropriate tissue selectivity for the disease state in question. An in depth understanding of ligand-protein interactions, including co-regulators, will be important for fine-tuning tissue-selective pharmacology. In the area of the regulation of estrogen synthesis, small-molecule,...

Clues from Localization Studies

In the prostate, clusterin (TRPM-2) is implicated to play a role in apoptosis, as clusterin mRNA is found to be induced during regression of the rat ventral prostate after castration.40 Since clusterin mRNA is also increased in neurodegenerative diseases (AD, scrapie, epilepsy) where apoptosis may occur, it has been hypothesized that clusterin may be a marker of apoptosis. This hypothesis has been challenged because not all apoptotic neurons contain increased levels of clusterin mRNA41 and many normal neurons contain clusterin mRNA without evidence of apoptosis.10,41 More direct evidence comes from two recent studies using rodent models of neuronal apoptosis.42,43 In the rd mice (model of retinitis pigmentosa, where photoreceptors die by apoptosis) the clusterin mRNA increase is associated with surviving, not apoptotic, motor neuron cells.42 Removal of the olfactory bulb (only synaptic target for sensory neurons of olfactory nasal mucosa) causes massive degeneration of sensory neurons...

Patients with Hypertensive Kidney Disease

Chester Land, a black retired postal supervisor, was referred at age 61 with a 20-year history of hypertension. By age 59 his serum creatinine level was elevated, though he had no symptoms of kidney disease. Physical exam showed only hypertension, but kidney function was severely reduced. He was prescribed a very-low-protein diet supplemented by essential amino acids or ketoacids (in addition to his antihypertensive drugs and diuretics). A few years later a routine lab report raised the spectre of severe intestinal bleeding, until the lab error was discovered. At age 66 a blood test for prostate cancer was reported as abnormal and confirmed by prostate biopsy. He underwent a course of radiotherapy. During eight years of dietary treatment, kidney function did not worsen nevertheless, he eventually started dialysis. Despite some complications, he is still doing fairly well, having received a transplant. In retrospect, dietary treatment probably deferred dialysis for about four years.

Adrenoceptor Antagonists

Since a1-adrenoceptors are present in the bladder musculature, a-adrenoceptor antagonists have been tested and found effective in improving urine flow in patients with benign prostatic hypertrophy (BPH) (see 6.24 Incontinence (Benign Prostatic Hyperplasia Prostate Dysfunction)). Excellent results have been obtained in BPH with doxazosin, 4 mgday_ for periods up to 10 years.31 Terazosin has also been reported to inhibit growth and to induce apoptosis of prostate cancer cells,32 so that a-adrenoceptor antagonists are likely to have an additional therapeutic indication, not only in BPH, but also in the therapy of prostate cancer.

Clues from Genetic Manipulation of Clusterin Expression

For example, overexpression of clusterin has been shown to protect clonal prostate cancer cells from tumor necrosis factor-(TNF-)alpha-induced cytotoxicity.68 Additionally, Sensibar determined that antisense depletion of clusterin caused an increase in cell death. Similarly, Humphreys et al69 showed that clusterin transfected L929 (murine fibrosarcoma) cells are protected from TNF-alpha-mediated cytotoxicity. Overexpressed clusterin did not protect these cells from other death-inducing agents such as colchicine, staurosporine or azide. In this system, clusterin's protective activity may be an intracellular property as protection was no observed with addition of exogenous clusterin or from secreted proteins.69 An intracellular role for clusterin has also been implicated in other cell systems where a truncated form of clusterin interacts with TGF-p receptors and may target them to the cell nucleus.5,70 Therefore, clusterin may be involved in TGF-p's...

Points To Be Considered And Common Pitfalls During Development And Preparation Of A Protocol

Development and preparation of a clinical trial protocol begin with scientific medical questions and end with a comprehensive and complete investigational plan that is doable and feasible to test and verify clinical hypothesis. A good and well-written protocol can not only achieve its goal by answering the scientific medical questions if it is executed according to the plan, but also prepare different contingency plans to handle and resolve various unforeseen or unexpected situations and issues during the implementation of the trial protocol. Therefore, it is a challenging and complicated process that requires careful and thoughtful planning. The Women's Health Initiative Clinical Trial (1998) and the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial (2000) provide two excellent examples of

Other Tumors of the Jugular Foramen

The most common malignant tumor of the jugular foramen is a secondary metastasis of the temporal bone. The most common site of the primary tumor in order of frequency is breast, kidney, lung, stomach, larynx, prostate, and thyroid gland.69 Hematologic neoplasm of the temporal bone, including leukemia, lymphoma, and multiple myeloma, may all present with jugular foramen syndrome.

Glandular Cells In Ureteral Washing

Urothelial Cells Urine

Metastatic lesions to the urinary bladder and into ureters must be considered when history is consistent or when an unexpected cell population is found. Rectum, uterus, vagina, and prostate are contiguous and may be sources of direct spread (Figs. 5.4-5.6). Voided urines from women with occult gynecologic lesions may contain diagnostic cells in the urine (Figs. 5.7-5.11). Therefore, any woman presenting with hematuria should be catheterized to avoid vaginal contamination and to localize the source of bleeding. Drop metastases into the pouch of Douglas, or onto the dome of the bladder occur from distant sites. A complete and accurate history obviously is necessary to include such lesions in the differential diagnosis (Tables 8 and 9). -Menstrual endometrium -Endometriosis -Normal endocervical cells -Malignancies Retrograde ejaculation Prostate, benign and malignant Adenocarcinoma -Bladder

Trampc2 Subcutaneous Tumor Resectionmetastasis Model

To facilitate studies more closely focused on prostate tumor metastasis, we recently introduced an immunocompetent murine model that nominally recapitulates clinical metastatic cancer relapse after primary tumor resection (Kwon et al., 1999). The establishment of this model is significant because, in general, the development of adjunctive cancer therapies has been hindered by the absence of such models. This model capitalizes on the capacity of TRAMP-C2 cells to metastasize to regional lymph nodes and other organs following an interval of chronic primary tumor growth. Following primary tumor resection in this model, metastatic recurrence occurs at a high rate (i.e., > 95 of mice) and in a predictable pattern, typically within the axillary and anterior cervical lymph nodes draining the primary tumor site (Kwon et al., 1999). Metastatic failure in this model can be readily quantified by measuring overtly appreciable tumor-bearing nodes. These tumor-bearing nodes can be assessed...

Cytology of Organ Biopsies and Exudates

In principle, all parenchymatous organs can be accessed for material for cytological analysis. Of particular importance are thyroid biopsy (especially in the region of scintigraphically cold nodules), liver and spleen biopsy (under laparascopic guidance) in the region of lumps lying close to the surface, and breast and prostate biopsy. Again, the cytological analysis is usually made by a specialist cytologist or pathologist.

Bladder Cancer Staging

Muscle wall invasion is separated into superficial (stage T2a) and deep (stage T2b). In stages T2b, the low signal intensity layer of the bladder wall is disrupted on T2-weighted images by the higher signal tumor (Fig. 11b). Stage T2b cannot be separated on MRI from stage T3a (microscopic fat infiltration). Macroscopic tumor extension through the bladder wall into the perivesical fat (stage T3b) will cause a focal irregular decrease of signal intensity of the fat on standard T1- or T2-weighted images (Fig. 18a). Contrast-enhanced images with fat saturation also show tumor (enhancement) in the perivesical fat. Invasion of adjacent organs may be inferred from the extension of abnormal tumor signal intensity through fat planes into adjacent structures (Fig. 18b). This is well demonstrated with contrast-enhanced images. Invasion of the seminal vesicles can be demonstrated by an increase in vesicular size, decrease in signal intensity on T2-weighted images and obliteration of angle between...

Biomarkers And Signatures

Carcinogenic potential is conventionally measured using a two-year study, incurring significant expense in both animals and human resources. It is therefore of great interest to identify biomarkers of carcinogenicity that can be detected in acute, short-term studies, and efforts toward this have been reported 36,40,58-60,88 . Biomarkers with clinical relevance have also been found using toxicogenomics approaches. For example, Petricoin et al. 89 found a set of protein markers that distinguished patients with high levels of prostate-specific antigen (PSA), a clinical marker correlated with prostate cancer, from those with low PSA levels and thus presumed to be healthy. In addition the marker set also correctly predicted 71 of patients with intermediate PSA levels. In a second example 90 , three plasma biomarkers were discovered and then independently validated to detect early stage invasive epithelial ovarian cancer from healthy controls with high sensitivity and specificity compared...

Urinary Tract Infection Acute Pyelonephritis

In males with a urinary tract infection (UTI) and or suspected pyelonephritis, US is valuable to identify common causes of UTI such as epididymitis, orchitis and prostatitis. Patients with a neurogenic bladder secondary to a spinal cord injury pose a difficult problem as the urine is usually colonized. Development of systemic symptoms should prompt rapid imaging as these patients may not be sensate to pain and a devastating abscess can develop quickly 21 . Finally, in order to diminish radiation dose to pregnant patients, US with power Doppler may be at

Syngeneic Trampc1 And C2 Subcutaneous Tumor Model

Previously, two prostate cancer cell lines, TRAMP-C1 and -C2, were established from a tumor harvested from a 32-week-old C57BL 6 TRAMP male (Foster et al., 1997). These lines retain expression of androgen receptor (AR), E-cadherin, and cytokeratin supporting their tissue-specific origin from prostate epithelial cells following malignant transformation. Interestingly, unlike autochthonous TRAMP tumor cells, these lines no longer express TAg (Foster et al., 1997 Kwon et al., 1997). Nevertheless, and perhaps owing to this absence, TRAMP-C1 and -C2 are reliably tumorigenic following subcutaneous injection into the nontransgenic C57BL 6 male mouse. Morphologically, TRAMP-C1 and -C2 form tumors that are histologically similar to advanced tumors in TRAMP mice. These cell lines also provide a convenient reagent for the creation of cell-based vaccines (Kwon et al., 1997 Hurwitz et al., 2000) and facilitate the derivation of potential prostate-specific and nonTAg-related antigens that can be...

Clinical Trial Issues

A safe general principle in androgen replacement therapy is to approach normal physiology with concentrations of testosterone (350-1050 ngdL_ 1) and its active metabolites3 and this should not have untoward health hazards on the prostate, serum lipids, and cardiovascular, liver, and lung function. Thus, unphysiologically high or low serum testosterone concentrations should be avoided. Normal physiological responses to androgen replacement therapy allow virilization in prepubertal males and restoration or preservation of virilization in postpubertal males. Self-administration that is convenient, causes minimal discomfort, and results in reproducible daily pharmacokinetics at a reasonable cost is preferred. None of the currently available androgen replacement therapies achieves the ideal, but improvements have been made in achieving these goals. A dose of 600 mg testosterone buccilate injected IM in hypogonadal males produced serum testosterone concentrations within the normal range for...

Urinary Tract Infections Urethritis Cystitis and Pyelonephritis

The structure of the urinary tract reduces the likelihood of infection by preventing urine from flowing backward toward the kidneys and by washing bacteria out of the body with the normal flow of urine. In men, the prostate gland also produces secretions that slow bacterial growth. Urine is normally sterile. obstruction of the urinary tract (such as a kidney stone or an enlarged prostate Urinary gland) also increases the risk of infection. People with diabetes, immune disor- Tract

Concluding remarks

Chung, L.Y., Cheung, T.C., Kong, S.K., Fung, K.P., Choy, Y.M., Chan, Z.Y. et al. (2001) Induction of apoptosis by green tea catechins in human prostate cancer DU145 cells. Life Sci., 68, 1207-1214. Shidaifat, F., Canatan, H., Kulp, S.K., Sugimoto, Y., Chang, W.Y., Zhang, Y. et al. (1996) Inhibition of human prostate cancer cells growth by gossypol is associated with stimulation of transforming growth factor- Cancer Lett. (Shannon, Irel.), 107, 37-44.

Behaviors and Medical History That May Lead to Kidney Failure

When the outflow of urine from the body is partially obstructed, either as the urine flows from the kidneys to the bladder or out from the bladder via the urethra, back pressure may build up in the kidneys. This back pressure may distort the shape of the kidneys and diminish their function. This condition is called hydronephrosis. In some cases, complete urinary tract obstruction can develop and acute renal failure may occur. More commonly renal failure is only partial. By far the most common cause of urinary tract obstruction is enlargement of the prostate in men, but there are many other causes in women as well. When the obstruction is relieved, in most cases the kidneys have an amazing ability to recover from this damage, but the obstruction must first be recognized. A sono-gram of the kidneys and bladder will quickly reveal any obstruction. Surgery may be needed to relieve the obstruction. Urologists treat this type of kidney failure.

Cancer Epidemiology

Cancer comprises over 200 distinct entities differing in their genetic basis, etiology, clinical characteristics, patterns of progression, and final outcome. In broad terms cancer can be classified into carcinomas and sarcomas according to the fetal germ layer from which tumors arise. Carcinomas arise within tissues derived from the fetal ectoderm or endoderm and include most of the common cancers in adults. Sarcomas are seen more frequently in children and arise from tissues originating from the fetal mesoderm which generate tumors of the bone, muscle, connective tissues, and blood vessels. In developed countries, about 50 of all cancer cases are carcinomas of the lung, colon, prostate, and breast while hematological cancers (leukemias and lymphomas) account for about 8-10 of all cancer cases.1,2

Cfr 202

A treatment for a single illness might consist of a combination of drugs, biological products, and or medical devices. If a treatment consists of a number of drugs, then it is called a combined therapy. For example, leuprolide and flutamide are for treatment of disseminated, previously untreated D2 stage prostate cancer. However, if a treatment consists of a combination of drugs, biologics, and or devices such as drug with device, biologic with device, drug with biologic, drug with biologic in conjunction with device, then it is defined as a combined product. For a combined product consisting of different pharmaceutical entities, FDA requires that each of entities should be reviewed separately by appropriate centers at the FDA. In order to avoid confusion of jurisdiction over a combination product and to improve efficiency of approval process, the principle of primary mode of action of a combination product was established in the Safe Medical Devices Act (SMDA) in 1990 (21 U.S.C....


Radiotherapy (also called radiation therapy) uses high-energy radiation, e.g., photon or particle radiation, to eliminate or shrink localized tumors.71 The radiation damages the DNA of cancer cells, blocking their ability to divide and proliferate. Unfortunately, the surrounding normal cells are also affected and, to protect them, radiation treatments are spread over time. This strategy (termed fractionation) tries to minimize the damage to normal tissue by allowing cells to be repaired during the time between treatments. The different repair rate between normal and cancer cells means that only a small fraction of malignant cells, which have a lower recovery rate, will have been repaired by the time of the next treatment. Ideally the vast majority of (or indeed all) cancer cells will be dead after the last treatment session. As an alternative to external beam therapy, until now the most traditional way to deliver radiation, radioisotopes (e.g., cesium-137 or iodine-125) can be...


He is treated for prostate cancer. After his last consultation with the urologist he feels upset. The urologist told him, According to the statistics of prostate cancer, you still have 13 years to live. According to the statistics for the healthy population you have, 15 years to live


Perhaps the most recognized role of selenium in human nutrition is its ability to serve as a cancer-preventive agent. Recent doubleblind clinical trials have demonstrated that supplementation of the human diet with a daily dose of 200 g of selenium resulted in 63 , 53 , and 48 reduction in the incidence of prostate, colon, and lung cancers, respectively (Clark et al., 1996). The majority of these biological and biomedical effects of selenium are most certainly mediated by selenium-containing proteins.

Randomization Models

As discussed above, for current practice, although the study site selection and patient selection are not random, the assignment of treatments to patients is usually performed based on some random mechanism. Thus, treatment comparisons can be made based on the so-called randomization or permutation tests introduced in the mid-1930s (Fisher, 1935). To illustrate the concept of permutation tests, we consider the following hypothetical data set concerning endpoint changes from baselines in peak urinary flow rate (mL s) after three months of treatment for patients with benign prostate hyperplasia


The human SLC 29 family contains four members. These equilibrative nucleoside transporters (ENTs) include the well-characterized, low-affinity facilitators ENT1 (SLC29A1) and ENT2 (SLC29A2), but the cation-dependence, and the tissue and subcellular distribution of ENT3 have not yet been fully evaluated. The ENT proteins have 11 TMDs, in which the amino-terminus is in the cytoplasm and the carboxyl-terminus is extracellular. ENT1 and ENT2 can both transport adenosine, but differ in their abilities to transport other nucleosides and nucleobases.109 ENT1 is almost ubiquitously distributed in human and rodent tissues and transports purine and pyrimidine nucleosides with Km values of 50 mM (adenoside) to 680 mM (cytidine). The antiviral drugs ddC and ddl are also poorly transported.110 ENT2 is present in a wide range of tissues, including the brain, heart, pancreas, prostate, and kidney, and is particularly abundant in skeletal muscle. ENT2 differs from ENT1 in that it can also transport...


The time necessary for skeletonization of a body is also variable. In areas where the body is exposed to the elements and scavengers, it can proceed quite rapidly, occurring in 9-10 days. In rare instances, it may be even faster than this. The uterus and prostate are two of the last organs to decompose.

Types of Biomarkers

The concept of biological markers of disease is both old and new. Historically, markers for disease have been used to diagnose and monitor disease risk, progression, improvement, and severity.67 Examples are clinical chemistry for many disease states, histological markers such as Papanicolaou smears for cervical cancer, magnetic resonance imaging (MRI) for multiple sclerosis, as well as serum markers associated with cancer states, i.e., prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), and cancer antigen-125 (CA-125).29,65,68-73 Markers that can be assessed from blood and or urine samples are very reliable in determining the clinical status of the disease. In most references, the definitions of biomarkers and its categories are often used interchangeably, but for clarity, the functional categories of biomarkers will be used in this discussion (Figure 3).64,65,67,74 Biomarkers can be categorized as disease biomarkers