- •Preface and Acknowledgments
- •Contents
- •Contributors
- •1: Embryology for Urologists
- •Introduction
- •Renal Development
- •Pronephros
- •Mesonephros
- •Metanephros
- •Development of the Collecting System
- •Critical Steps in Further Development
- •Anomalies of the Kidney
- •Renal Agenesis
- •Renal Aplasia
- •Renal Hypoplasia
- •Renal Ectopia
- •Renal Fusion
- •Ureteral Development
- •Anomalies of Origin
- •Anomalies of Number
- •Incomplete Ureteral Duplication
- •Complete Ureteral Duplication
- •Ureteral Ectopia
- •Embryology of Ectopia
- •Clinical Correlation
- •Location of Ectopic Ureteral Orifices – Male (in Descending Order According to Incidence)
- •Symptoms
- •Ureteroceles
- •Congenital Ureteral Obstruction
- •Pipestem Ureter
- •Megaureter-Megacystis Syndrome
- •Prune Belly Syndrome
- •Vascular Ureteral Obstructions
- •Division of the Urogenital Sinus
- •Bladder Development
- •Urachal Anomalies
- •Cloacal Duct Anomalies
- •Other Bladder Anomalies
- •Bladder Diverticula
- •Bladder Extrophy
- •Gonadal Development
- •Testicular Differentiation
- •Ovarian Differentiation
- •Gonadal Anomalies
- •Genital Duct System
- •Disorders of Testicular Function
- •Female Ductal Development
- •Prostatic Urethral Valves
- •Gonadal Duct Anomalies
- •External Genital Development
- •Male External Genital Development
- •Female External Genital Development
- •Anomalies of the External Genitalia
- •References
- •2: Gross and Laparoscopic Anatomy of the Upper Urinary Tract and Retroperitoneum
- •Overview
- •The Kidneys
- •The Renal Vasculature
- •The Renal Collecting System
- •The Ureters
- •Retroperitoneal Lymphatics
- •Retroperitoneal Nerves
- •The Adrenal Glands
- •References
- •3: Gross and Laparoscopic Anatomy of the Lower Urinary Tract and Pelvis
- •Introduction
- •Female Pelvis
- •Male Pelvis
- •Pelvic Floor
- •Urinary Bladder
- •Urethra
- •Male Urethra
- •Female Urethra
- •Sphincter Mechanisms
- •The Bladder Neck Component
- •The Urethral Wall Component
- •The External Urethral Sphincter
- •Summary
- •References
- •4: Anatomy of the Male Reproductive System
- •Testis and Scrotum
- •Spermatogenesis
- •Hormonal Regulation of Spermatogenesis
- •Genetic Regulation of Spermatogenesis
- •Epididymis and Ductus Deferens
- •Accessory Sex Glands
- •Prostate
- •Seminal Vesicles
- •Bulbourethral Glands
- •Penis
- •Erection and Ejaculation
- •References
- •5: Imaging of the Upper Tracts
- •Anatomy of the Upper Tracts and Introduction to Imaging Modalities
- •Introduction
- •Renal Upper Tract Basic Anatomy
- •Modalities Used for Imaging the Upper Tracts
- •Ultrasound
- •Radiation Issues
- •Contrast Issues
- •Renal and Upper Tract Tumors
- •Benign Renal Tumors
- •Transitional Cell Carcinoma
- •Renal Mass Biopsy
- •Renal Stone Disease
- •Ultrasound
- •Plain Radiographs and IVU
- •Renal Cystic Disease
- •Benign Renal Cysts
- •Hereditary Renal Cystic Disease
- •Complex Renal Cysts
- •Renal Trauma
- •References
- •Introduction
- •Pathophysiology
- •Susceptibility and Resistance
- •Epidemiological Breakpoints
- •Clinical Breakpoints
- •Pharmacodynamic Parameters
- •Pharmacokinetic Parameters
- •Fosfomycin
- •Nitrofurantoin
- •Pivmecillinam
- •b-Lactam-Antibiotics
- •Penicillins
- •Cephalosporins
- •Carbapenems
- •Aminoglycosides
- •Fluoroquinolones
- •Trimethoprim, Cotrimoxazole
- •Glycopeptides
- •Linezolid
- •Conclusion
- •References
- •7: An Overview of Renal Physiology
- •Introduction
- •Body Fluid Compartments
- •Regulation of Potassium Balance
- •Regulation of Acid–Base Balance
- •Diuretics
- •Suggested Reading
- •8: Ureteral Physiology and Pharmacology
- •Ureteral Anatomy
- •Modulation of Peristalsis
- •Ureteral Pharmacology
- •Conclusion
- •References
- •Introduction
- •Afferent Signaling Pathways
- •Efferent Signaling
- •Parasympathetic Nerves
- •Sympathetic Nerves
- •Vesico-Spinal-Vesical Micturition Reflex
- •Peripheral Targets
- •Afferent Signaling Mechanisms
- •Urothelium
- •Myocytes
- •Cholinergic Receptors
- •Muscarinic Receptors
- •Nicotinic Receptors
- •Adrenergic Receptors (ARs)
- •a-Adrenoceptors
- •b-Adrenoceptors
- •Transient Receptor Potential (TRP) Receptors
- •Phosphodiesterases (PDEs)
- •CNS Targets
- •Opioid Receptors
- •Serotonin (5-HT) Mechanisms
- •g-Amino Butyric Acid (GABA) Mechanisms
- •Gabapentin
- •Neurokinin and Neurokinin Receptors
- •Summary
- •References
- •10: Pharmacology of Sexual Function
- •Introduction
- •Sexual Desire/Arousal
- •Endocrinology
- •Steroids in the Male
- •Steroids in the Female
- •Neurohormones
- •Neurotransmitters
- •Dopamine
- •Serotonin
- •Pharmacological Strategies
- •CNS Drugs
- •Enzyme-inducing Antiepileptic Drugs
- •Erectile Function
- •Ejaculatory Function
- •Premature Ejaculation
- •Abnormal Ejaculation
- •Conclusions
- •References
- •Epidemiology
- •Calcium-Based Urolithiasis
- •Uric Acid Urolithiasis
- •Infectious Urolithiasis
- •Cystine-Based Urolithiasis
- •Aims
- •Who Deserves Metabolic Evaluation?
- •Metabolic Workup for Stone Producers
- •Medical History and Physical Examination
- •Stone Analysis
- •Serum Chemistry
- •Urine Evaluation
- •Urine Cultures
- •Urinalysis
- •Twenty-Four Hour Urine Collections
- •Radiologic Imaging
- •Medical Management
- •Conservative Management
- •Increased Fluid Intake
- •Citrus Juices
- •Dietary Restrictions
- •Restricted Oxalate Diet
- •Conservative Measures
- •Selective Medical Therapy
- •Absorptive Hypercalciuria
- •Thiazide
- •Orthophosphate
- •Renal Hypercalciuria
- •Primary Hyperparathyroidism
- •Hyperuricosuric Calcium Oxalate Nephrolithiasis
- •Enteric Hyperoxaluria
- •Hypocitraturic Calcium Oxalate Nephrolithiasis
- •Distal Renal Tubular Acidosis
- •Chronic Diarrheal States
- •Thiazide-Induced Hypocitraturia
- •Idiopathic Hypocitraturic Calcium Oxalate Nephrolithiasis
- •Hypomagnesiuric Calcium Nephrolithiasis
- •Gouty Diathesis
- •Cystinuria
- •Infection Lithiasis
- •Summary
- •References
- •12: Molecular Biology for Urologists
- •Introduction
- •Inherited Changes in Cancer Cells
- •VEGR and Cell Signaling
- •Targeting mTOR
- •Conclusion
- •References
- •13: Chemotherapeutic Agents for Urologic Oncology
- •Introduction
- •Bladder Cancer
- •Muscle Invasive Bladder Cancer
- •Metastatic Bladder Cancer
- •Conclusion
- •Prostate Cancer
- •Other Chemotherapeutic Drugs or Combinations for Treating HRPC
- •Conclusion
- •Renal Cell Carcinoma
- •Chemotherapy
- •Immunotherapy
- •Angiogenesis Inhibitor Drugs
- •Conclusion
- •Testicular Cancer
- •Stage I Seminoma
- •Stage I non-seminomatous Germ Cell Tumours (NSGCT)
- •Metastatic Germ Cell Tumours
- •Low-Volume Metastatic Disease (Stage II A/B)
- •Advanced Metastatic Disease
- •Salvage Chemotherapy for Relapsed or Refractory Disease
- •Conclusion
- •Penile Cancer
- •Side Effects of Chemotherapy
- •Conclusion
- •References
- •14: Tumor and Transplant Immunology
- •Antibodies
- •Cytotoxic and T-helper Cells
- •Immunosuppression
- •Induction Therapy
- •Maintenance Therapy
- •Rejection
- •Posttransplant Lymphoproliferative Disease
- •Summary
- •References
- •15: Pathophysiology of Renal Obstruction
- •Causes of Renal Obstruction
- •Effects on Prenatal Development
- •Prenatal Hydronephrosis
- •Spectrum of Renal Abnormalities
- •Renal Functional Changes
- •Renal Growth/Counterbalance
- •Vascular Changes
- •Inflammatory Mediators
- •Glomerular Development Changes
- •Mechanical Stretch of Renal Tubules
- •Unilateral Versus Bilateral
- •Limitations of Animal Models
- •Future Research
- •Issues in Patient Management
- •Diagnostic Imaging
- •Ultrasound
- •Intravenous Urography
- •Antegrade Urography and the Whitaker Test
- •Nuclear Renography
- •Computed Tomography
- •Magnetic Resonance Urography
- •Hypertension
- •Postobstructive Diuresis
- •References
- •Introduction
- •The Normal Lower Urinary Tract
- •Anatomy
- •Storage Function
- •Voiding Function
- •Neural Control
- •Symptoms
- •Flow Rate and Post-void Residual
- •Voiding Cystometry
- •Male
- •Female
- •Neurourology
- •Conclusions
- •References
- •17: Urologic Endocrinology
- •The Testis
- •Normal Androgen Metabolism
- •Epidemiological Aspects
- •Prostate
- •Brain
- •Muscle Mass and Adipose Tissue
- •Bones
- •Ematopoiesis
- •Metabolism
- •Cardiovascular System
- •Clinical Assessment
- •Biochemical Assessment
- •Treatment Modalities
- •Oral Preparations
- •Parenteral Preparations
- •Transdermal Preparations
- •Side Effects and Treatment Monitoring
- •Body Composition
- •Cognitive Decline
- •Bone Metabolism
- •The Kidneys
- •Endocrine Functions of the Kidney
- •Erythropoietin
- •Calcitriol
- •Renin
- •Paraneoplastic Syndromes
- •Hypercalcemia
- •Hypertension
- •Polycythemia
- •Other Endocrine Abnormalities
- •References
- •General Physiology
- •Prostate Innervation
- •Summary
- •References
- •Wound Healing
- •Inflammation
- •Proliferation
- •Remodeling
- •Principles of Plastic Surgery
- •Tissue Characteristics
- •Grafts
- •Flap
- •References
- •Lower Urinary Tract Symptoms
- •Storage Phase
- •Voiding Phase
- •Return to Storage Phase
- •Urodynamic Parameters
- •Urodynamic Techniques
- •Volume Voided Charts
- •Pad Testing
- •Typical Test Schedule
- •Uroflowmetry
- •Post Voiding Residual
- •Further Diagnostic Evaluation of Patients
- •Cystometry with or Without Video
- •Cystometry
- •Videocystometrography (Cystometry + Cystourethrography)
- •Cystometric Findings
- •Comment:
- •Measurements During the Storage Phase:
- •Measurements During the Voiding Phase:
- •Abnormal Function
- •Disorders of Sensation
- •Causes of Hypersensitive Bladder Sensation
- •Causes of Hyposensitive Bladder Sensation
- •Disorders of Detrusor Motor Function
- •Bladder Outflow Tract Dysfunction
- •Detrusor–Urethral Dyssynergia
- •Detrusor–Bladder Neck Dyssynergia
- •Detrusor–Sphincter Dyssynergia
- •Complex Urodynamic Investigation
- •Urethral Pressure Measurement
- •Technique
- •Neurophysiological Evaluation
- •Conclusion
- •References
- •Endoscopy
- •Cystourethroscopy
- •Ureteroscopy and Ureteropyeloscopy
- •Nephroscopy
- •Virtual Reality Simulators
- •Lasers
- •Clinical Application of Lasers
- •Condylomata Acuminata
- •Urolithiasis
- •Benign Prostatic Hyperplasia
- •Ureteral and Urethral Strictures
- •Conclusion
- •References
- •Introduction
- •The Prostatitis Syndromes
- •The Scope of the Problem
- •Category III CP/CPPS
- •The Goal of Treatment
- •Conservative Management
- •Drug Therapy
- •Antibiotics
- •Anti-inflammatories
- •Alpha blockers
- •Hormone Therapies
- •Phytotherapies
- •Analgesics, muscle relaxants and neuromodulators
- •Surgery
- •A Practical Management Plan
- •References
- •Orchitis
- •Definition and Etiology
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation
- •Treatment of Infectious Orchitis
- •Epididymitis
- •Definition and Etiology
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation of Epididymitis
- •Treatment of Acute Epididymitis
- •Treatment of Chronic Epididymitis
- •Treatment of Spermatic Cord Torsion
- •Fournier’s Gangrene
- •Definition and Etiology
- •Risk Factors
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation
- •Treatment
- •References
- •Fungal Infections
- •Candidiasis
- •Aspergillosis
- •Cryptococcosis
- •Blastomycosis
- •Coccidioidomycosis
- •Histoplasmosis
- •Radiographic Findings
- •Treatment
- •Tuberculosis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Schistosomiasis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Filariasis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Onchocerciasis
- •References
- •25: Sexually Transmitted Infections
- •Introduction
- •STIs Associated with Genital Ulcers
- •Herpes Simplex Virus
- •Diagnosis
- •Treatment
- •Chancroid
- •Diagnosis
- •Treatment
- •Syphilis
- •Diagnosis
- •Treatment
- •Lymphogranuloma Venereum
- •Diagnosis
- •Treatment
- •Chlamydia
- •Diagnosis
- •Treatment
- •Gonorrhea
- •Diagnosis
- •Treatment
- •Trichomoniasis
- •Diagnosis
- •Treatment
- •Human Papilloma Virus
- •Diagnosis
- •Treatment
- •Scabies
- •Diagnosis
- •Treatment
- •References
- •26: Hematuria: Evaluation and Management
- •Introduction
- •Classification of Hematuria
- •Macroscopic Hematuria
- •Microscopic Hematuria
- •Dipstick Hematuria
- •Pseudohematuria
- •Factitious Hematuria
- •Menstruation
- •Aetiology
- •Malignancy
- •Urinary Calculi
- •Infection and Inflammation
- •Benign Prostatic Hyperplasia
- •Trauma
- •Drugs
- •Nephrological Causes
- •Assessment
- •History
- •Examination
- •Investigations
- •Dipstick Urinalysis
- •Cytology
- •Molecular Tests
- •Blood Tests
- •Flexible Cystoscopy
- •Upper Urinary Tract Evaluation
- •Renal USS
- •KUB Abdominal X-Ray
- •Intravenous Urography (IVU)
- •Computed Tomography (CT)
- •Retrograde Urogram Studies
- •Magnetic Resonance Imaging (MRI)
- •Additional Tests and Renal Biopsy
- •Intractable Hematuria
- •Loin Pain Hematuria Syndrome
- •References
- •27: Benign Prostatic Hyperplasia (BPH)
- •Historical Background
- •Pathophysiology
- •Patient Assessment
- •Treatment of BPH
- •Watchful Waiting
- •Drug Therapy
- •Interventional Therapies
- •Conclusions
- •References
- •28: Practical Guidelines for the Treatment of Erectile Dysfunction and Peyronie´s Disease
- •Erectile Dysfunction
- •Introduction
- •Diagnosis
- •Basic Evaluation
- •Cardiovascular System and Sexual Activity
- •Optional Tests
- •Treatment
- •Medical Treatment
- •Oral Agents
- •Phosphodiesterase Type 5 (PDE 5) Inhibitors
- •Nonresponders to PDE5 Inhibitors
- •Apomorphine SL
- •Yohimbine
- •Intracavernosal and Intraurethral Therapy
- •Intracavernosal Injection (ICI) Therapy
- •Intraurethral Therapy
- •Vacuum Constriction Devices
- •Surgical Therapy
- •Conclusion
- •Peyronie´s Disease (PD)
- •Introduction
- •Oral Drug Therapy
- •Intralesional Drug Therapy
- •Iontophoresis
- •Radiation Therapy
- •Surgical Therapy
- •References
- •29: Premature Ejaculation
- •Introduction
- •Epidemiology
- •Defining Premature Ejaculation
- •Voluntary Control
- •Sexual Satisfaction
- •Distress
- •Psychosexual Counseling
- •Pharmacological Treatment
- •On-Demand Treatment with Tramadol
- •Topical Anesthetics
- •Phosphodiesterase Inhibitors
- •Surgery
- •Conclusion
- •References
- •30: The Role of Interventional Management for Urinary Tract Calculi
- •Contraindications to ESWL
- •Complications of ESWL
- •PCNL Access
- •Instrumentation for PCNL
- •Nephrostomy Drains Post PCNL
- •Contraindications to PCNL
- •Complications of PCNL
- •Semirigid Ureteroscopy
- •Flexible Ureteroscopy
- •Electrohydraulic Lithotripsy (EHL)
- •Ultrasound
- •Ballistic Lithotripsy
- •Laser Lithotripsy
- •Ureteric Stents
- •Staghorn Calculi
- •Lower Pole Stones
- •Horseshoe Kidneys and Stones
- •Calyceal Diverticula Stones
- •Stones and PUJ Obstruction
- •Treatment of Ureteric Colic
- •Medical Expulsive Therapy (MET)
- •Intervention for Ureteric Stones
- •Stones in Pregnancy
- •Morbid Obesity
- •References
- •Anatomy and Function
- •Pathophysiology
- •Management
- •Optical Urethrotomy/Dilatation
- •Urethral Stents
- •Preoperative Assessment
- •Urethroplasty
- •Anastomotic Urethroplasty
- •Substitution Urethroplasty
- •Grafts Versus Flaps
- •Oral Mucosal Grafts
- •Tissue Engineering
- •Graft Position
- •Conclusion
- •References
- •32: Urinary Incontinence
- •Epidemiology and Risk Factors
- •Pathophysiology
- •Urge Incontinence
- •Conservative Treatments
- •Pharmacotherapy
- •Invasive/ Surgical Therapies
- •Stress Urinary Incontinence
- •Male SUI Therapies
- •Female SUI Therapies
- •Mixed Urinary Incontinence
- •Conclusions
- •References
- •33: Neurogenic Bladder
- •Introduction
- •Examination and Diagnostic Tests
- •History and Physical Examination
- •Imaging
- •Urodynamics (UDS)
- •Evoked Potentials
- •Classifications
- •Somatic Pathways
- •Brain Lesions
- •Cerebrovascular Accident (CVA)
- •Parkinson’s Disease (PD)
- •Multiple Sclerosis
- •Huntington’s Disease
- •Dementias
- •Normal Pressure Hydrocephalus (NPH)
- •Tumors
- •Psychiatric Disorders
- •Spinal Lesions and Pathology
- •Intervertebral Disk Prolapse
- •Spinal Cord Injury (SCI)
- •Transverse Myelitis
- •Peripheral Neuropathies
- •Metabolic Neuropathies
- •Pelvic Surgery
- •Treatment
- •Summary
- •References
- •34: Pelvic Prolapse
- •Introduction
- •Epidemiology
- •Anatomy and Pathophysiology
- •Evaluation and Diagnosis
- •Outcome Measures
- •Imaging
- •Urodynamics
- •Indications for Management
- •Biosynthetics
- •Surgical Management
- •Anterior Compartment Repair
- •Uterine/Apical Prolapse
- •Enterocele Repair
- •Conclusion
- •References
- •35: Urinary Tract Fistula
- •Introduction
- •Urogynecologic Fistula
- •Vesicovaginal Fistula
- •Etiology and Risk Factors
- •Clinical Factors
- •Evaluation and Diagnosis
- •Pelvic Examination
- •Cystoscopy
- •Imaging
- •Treatment
- •Conservative Management
- •Surgical Management
- •Urethrovaginal Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Ureterovaginal Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Vesicouterine Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Uro-Enteric Fistula
- •Vesicoenteric Fistula
- •Pyeloenteric Fistula
- •Urethrorectal Fistula
- •References
- •36: Urologic Trauma
- •Introduction
- •Kidney
- •Expectant Management
- •Endovascular Therapy
- •Operative Intervention
- •Operative Management: Follow-up
- •Reno-Vascular Injuries
- •Pediatric Renal Injuries
- •Adrenal
- •Ureter
- •Diagnosis
- •Treatment
- •Delayed Diagnosis
- •Bladder and Posterior Urethra
- •Bladder Injuries: Initial Management
- •Bladder Injuries: Formal Repair
- •Anterior Urethral Trauma
- •Fractured Penis
- •Penile Amputation
- •Scrotal and Testicular Trauma
- •Imaging
- •CT-IVP (CT with Delayed Images)
- •Technique
- •Cystogram
- •Technique
- •Retrograde Urethrogram (RUG)
- •Technique
- •Retrograde Pyelogram (RPG)
- •Technique
- •One-Shot IVP
- •Technique
- •References
- •37: Bladder Cancer
- •Who Should Be Investigated?
- •Epidemiology
- •Risk Factors
- •Role of Screening
- •Signs and Symptoms
- •Imaging
- •Cystoscopy
- •Urine Tests
- •PDD-Assisted TUR
- •Pathology
- •NMIBC and Risk Groups
- •Intravesical Chemotherapy
- •Intravesical Immunotherapy
- •Immediate Cystectomy and CIS
- •Radical Cystectomy with Pelvic Lymph Node Dissection
- •sexual function-preserving techniques
- •Bladder-Preservation Treatments
- •Neoadjuvant Chemotherapy
- •Adjuvant Chemotherapy
- •Preoperative Radiotherapy
- •Follow-up After TUR in NMIBC
- •References
- •38: Prostate Cancer
- •Introduction
- •Epidemiology
- •Race
- •Geographic Variation
- •Risk Factors and Prevention
- •Family History
- •Diet and Lifestyle
- •Prevention
- •Screening and Diagnosis
- •Current Screening Recommendations
- •Biopsy
- •Pathology
- •Prognosis
- •Treatment of Prostate Cancer
- •Treatment for Localized Prostate Cancer (T1, T2)
- •Radical Prostatectomy
- •EBRT
- •IMRT
- •Brachytherapy
- •Treatment for Locally Advanced Prostate Cancer (T3, T4)
- •EBRT with ADT
- •Radical Prostatectomy
- •Androgen-Deprivation Therapy
- •Summary
- •References
- •39: The Management of Testis Cancer
- •Presentation and Diagnosis
- •Serum Tumor Markers
- •Primary Surgery
- •Testis Preserving Surgery
- •Risk Stratification
- •Surveillance Versus Primary RPLND
- •Primary RPLND
- •Adjuvant Treatment for High Risk
- •Clinical Stage 1 Seminoma
- •Risk-Stratified Adjuvant Treatment
- •Adjuvant Radiotherapy
- •Adjuvant Low Dose Chemotherapy
- •Primary Combination Chemotherapy
- •Late Toxicity
- •Salvage Strategies
- •Conclusion
- •References
- •Index
168
Practical Urology: EssEntial PrinciPlEs and PracticE
Cytoplasm
mRNA
HIFβ HIFα
Rb
HRE
HIF target genes
Nucleus
BNIP3
EPO
VEGF |
|
GLUT1 |
|
PDGF |
TGFα |
|
|
|
|
|
CA-IX |
Figure 12.3. Hypoxia responsive genes: binding of the HiFaHiFb heterodimer to the HrE in the promoter region at HrE’s turns on gene transcription resulting in upregulation of messenger rna (mrna) of genes that are responsive to hypoxia and controlled/regulated by HiF. these include vascular endothelial growth factor (VEgF), platelet-derived growth factor (PdgF), transforming growth factor alpha (tgFa), carbonic anhydrase iX (ca-iX), erythropoietin, glucose transporter 1 (glUt-1), and others. the mrna translocates from the nucleus to the cytoplasm where it associates with ribosomes, trna, and the translational
VEGR and Cell Signaling
VEGF has stimulated particular interest given its central role in the process of angiogenesis (the process of developing new blood vessels), the growing recognition that angiogenesis is a critical component of malignant tumor progression, combined with the clinical observation that clear cell RCCs are often hypervascular tumors.47–49 The VEGF protein family includes multiple subtypes; VEGF-A, -B, -C, -D, -E, and placenta growth factor-1 (PIGF-1).50–53 The majority of these are regulated by VHL and HIF using the regulatory system discussed previously. These proteins can in turn bind to
machinery.the code in the mrna is now translated into the corresponding amino acid sequence forming the relevant proteins. these proteins accumulate and help the cell respond to the hypoxic conditions or,in the case of rcc,may go on to contribute to malignant transformation.HIFa Hypoxia inducible Factor alpha, HIFb Hypoxia inducible Factor beta, HrE hypoxia response element,Rb ribosome,EPO erythropoietin,VEGF vascular endothelial growth factor, PDGF platelet derived growth factor, CA-IX carbonic anhydrase iX, TGFa transforming growth factor alpha, GLUT1 glucose transporter 1.
one of three different receptors located at the cell surface, VEGFR-1 (Flt-1), VEGFR-2 (KDR/ Flk-1), and VEGFR-3 (Flt-4).50–53 Of these, VEGFR-1 and -2 are thought to be more important for angiogenesis whereas VEGFR-3 is thought to be more important for lymphangiogenesis.53 Thus, VEGF is termed a ligand, the molecule that is soluble or “mobile,” which will bind to its receptor, which is less mobile and soluble, in this case positioned in the cell surface membrane. The binding of a ligand to its receptor leads to signaling that affects a cells behavior.
The members of the VEGF receptor family are cell membrane associated tyrosine kinases. What this means, is that when VEGF binds to
169
MolEcUlar Biology For Urologists
one of these receptors at the cell surface, it |
on the cell, through a process yet to be fully |
induces a change in the receptor that gets passed |
explained in all its complexity, ultimately lead |
along to its intracellular (or cytoplasmic) por- |
to carcinogenesis. |
tion. In that cytoplasmic portion of the recep- |
A key point for both the Raf-Mek-Erk and |
tor, specific tyrosine amino acid residues in the |
PI3K-AKT-mTOR pathways is that they also |
protein become phosphorylated, a reaction that |
involve kinases, that is, enzymes that phospho- |
is generally carried out by a class of enzymes |
rylate other proteins to regulate their activity. |
termed kinases. Therefore, a tyrosine kinase |
Another important observation relates to the |
membrane receptor is one that phosphorylates |
mammalian target of rapamycin (mTOR), which |
tyrosines (in this case on itself) when it becomes |
is downstream of VEGF but can also act to |
activated by binding to its ligand (in this case |
increase the cellular levels of HIFa.55 In princi- |
VEGF). Once the receptor is activated and its |
ple, the abnormal function of VHL in clear cell |
cytoplasmic tyrosine residue(s) is phosphory- |
RCC can set up a vicious, positive feedback loop |
lated, this then leads to a downstream cascade |
in which HIFa levels rise, leading to high levels |
of signaling events (see Fig. 12.4). There are |
of VEGF, which binds to its receptor VEGFR |
thought to be at least two main pathways these |
resulting in its activation, that in turn signals |
cascades follow. One is via the Raf-Mek-Erk |
through the phosphatidylinositol-3 kinase-AKT |
series of kinases and the other is via the phos- |
pathway to activate mTOR (by phosphorylation |
phatidylinositol-3 kinase-AKT-mTOR pathway. |
as with many of these proteins), which can in |
The activation of these pathways in turn leads |
turn lead to even higher levels of HIFa. This |
to endothelial cell activation, proliferation, |
positive feedback loop can accelerate and ramp |
migration, and cell survival.50–54 These effects |
up signaling via the oncogene HIF. |
Figure 12.4. ligand-receptor interaction and downstream signaling: increased expression of proteins such as VEgF (the ligand) allows them to diffuse and bind to their receptor (in this case VEgFr).the VEgF receptor is a tyrosine kinase. When VEgF binds its receptor, a tyrosine is phosphorylated which in turns leads to downstream signaling through a series of other kinases. note that activation of the Pi3K-akt-mtor pathway leads to increased HiFain the cell, which can contribute to a positive feedback loop as HiFain turn leads to increased signaling along this pathway. shown within these pathways are some of the known target sites for the monoclonal antibody to VEgF (Bevacizumab), the tyrosine kinase inhibitors (or tKi’s, sorafenib and sunitinib), and the mtor inhibitors (temsirolimus and everolimus).
Bevacizumab
VEGF
VEGFR
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p38MAPK |
RAS |
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Temsirolimus |
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Everolimus |
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ERK |
HIFα
HIFα
HIFα
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170 |
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Practical Urology: EssEntial PrinciPlEs and PracticE |
Moving from Biology |
humanized, meaning it has been modified to |
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to Targeted Therapy |
resemble antibodies normally produced by |
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humans (as opposed to rabbits, mice, or other |
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mammals). This modification is what permits |
The basic biology of the VHL-HIF cascade |
the antibody to be used repeatedly in the same |
|
described above is an elegant example of how |
patient without the body automatically recog- |
|
years of work by many talented investigators has |
nizing it as foreign and eliminating it from cir- |
|
shed light on the inner workings of a particular |
culation. This novel, targeted agent was first |
|
cancer. Had the story ended there, however, one |
tested in a randomized phase II trial and found |
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might argue what the relevance is to modern |
to increase the time to progression of advanced |
|
medicine. How does this impact on health care |
RCC when compared to placebo.59 It has now |
|
and our patient’s well being? The real beauty of |
been tested in a large scale phase III trial in |
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this story lies in the movement in the last several |
combination with IFNafor men with previously |
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years from the “bench top” to the bedside of |
untreated advanced renal cell carcinoma.60 The |
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patients with clear cell RCC. For several decades |
combination regimen improved the progression |
|
the management of metastatic RCC was based |
free survival from 5.4 months to 10.2 months |
|
on the use of immunotherapy including inter- |
when compared to interferon alone. Based on |
|
feron a(IFNa) and interleukin 2 (IL-2).56 These |
these studies, Bevacizumab in combination with |
|
agents produced response rates on the order of |
IFNais now one of the frequently utilized thera- |
|
only 10–20%, only a minority of which were |
pies for advanced RCC. |
|
durable complete responses. For the remainder |
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the responses were temporary such that the 5 |
The Tyrosine Kinase |
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and 23%.57,58 Essentially, this meant that 80–90% |
||
year survival of metastatic RCC was between 0% |
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of patients with advanced RCC did not respond |
Inhibitors (TKIs) |
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to any appreciable degree to therapy, a situation |
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that cried out for new and innovative agents. |
An alternate approach to blocking VEGF is to |
|
A look again at the VHL-HIF-VEGF pathway |
abrogate the downstream signaling after it binds |
|
we have described so far suggests that if one can |
to its receptor (see Fig. 12.4). As we discussed, |
|
interfere with the cascade of events, then in the- |
the receptor for VEGF (as well as PDGF and |
|
ory one ought to be able to treat clear cell RCC. |
TNFa) are tyrosine kinases. When the ligand |
|
Stated another way, if one targeted components |
(VEGF) binds to the receptor (VEGFR) a |
|
of the pathway, then the process of carcinogen- |
tyrosine in the receptor is phosphorylated, |
|
esis and tumor progression should be reversible. |
allowing further downstream signaling to take |
|
This concept of so called “Targeted Therapies,” |
place via at least one of the two pathways, the |
|
in which specific components of the tumor’s |
Raf-MEK-ERK and the PI3-kinase-AKT-mTOR |
|
biology are attacked and interrupted, forms the |
pathways. Many of the members of these down- |
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basis for many of the therapies that have become |
stream signaling cascades also rely on kinase |
|
the standard of care for advanced clear cell RCC. |
activity. It would seem logical, then, to look for |
|
Given the connection between aberrations in |
agents that can block this signaling cascade and |
|
VHL protein function, leading to accumulation |
thereby interrupt the oncogenic signaling down- |
|
of HIF, and subsequent upregulation of VEGF, it |
stream of VHL and HIF. The early attempts |
|
was logical to explore the use of an inhibitor of |
developing these tyrosine kinase inhibitors |
|
VEGF as one of these novel approaches. |
(TKIs) were relatively specific for the VEGF |
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Conceptually the easiest way to block the |
receptors’ tyrosine kinase activity.61,62 The |
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action of elevated VEGF would be to directly |
results were generally disappointing and these |
|
inhibit the molecule itself (see Fig. 12.4). One |
agents have largely been abandoned. In the |
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such approach utilizes a humanized monoclonal |
course of these studies,though,it rapidly became |
|
antibody to bind and sequester VEGF, Beva- |
apparent that less specific tyrosine kinase inhib- |
|
cizumab (Avastin, Genentech, Inc.).59 The anti- |
itors, ones that could affect several different sig- |
|
body has been designed so that each antibody |
naling molecules simultaneously, were more |
|
molecule is identical (monoclonal or originat- |
effective. This is presumably due to the ability to |
|
ing from the same cell clone). It has also been |
interrupt the signaling cascade at multiple levels |
171
MolEcUlar Biology For Urologists
simultaneously utilizing one agent. This concep- |
Sorafenib is also an orally bioavailable, multi- |
tual framework has resulted in the development, |
targeted tyrosine kinase inhibitor, which was |
testing, and now approval of several agents in |
originally developed as a specific inhibitor of |
this drug class. There is a rapidly expanding |
Raf-1, a member of the Raf/MEK/ERK pathway |
pool of potentially active drugs of this type (eq. |
downstream of receptors important in the VHL/ |
AG-013736, GW572016, PTK787/ZK222584, plus |
HIF axis (see Fig. 12.4) such as VEGFR and |
others) but for the purpose of this chapter we |
PDGFR and the same (in principle) to the path- |
discuss the two with large scale, published phase |
ways targeted by Sunitinib.71 Subsequently, stud- |
three trial data confirming their clinical utility |
ies showed it could also block the downstream |
and which are now both approved for use in |
signaling of a variety of other tyrosine kinases, |
metastatic RCC (for a more in depth review of |
including VEGFR, PDGFR, as well as others. As |
the other agents see Lane et al.,54 Shaheen and |
was the case with Sunitinib, the initial phase II |
Bukowski,63 and Amato64). |
studies with Sorafenib showed promise, with |
Sunitinib is an orally bioavailable multitar- |
substantial improvements in progression free |
geted tyrosine kinase inhibitor. It has been |
survival.39,72 These in turn lead to a large-scale, |
shown to block the downstream signaling from |
multicenter, international, randomized, pro- |
several tyrosine kinase receptors important in |
spective trial of 903 patients with clear cell RCC |
RCC, including the receptors for VEGF and |
who had failed at least one prior systemic ther- |
PDGF.65,66 Phase I studies showed promising |
apy.73 Patients were randomized to either oral |
results in the setting of advanced RCC67 prompt- |
Sorafenib versus placebo. Sorafenib was supe- |
ing investigators to initiate two phase II studies |
rior to placebo with respect to progression free |
in patients who had failed prior systemic |
survival and it was generally well tolerated, |
cytokine therapy followed by a large, prospec- |
though there were rare cases of significant |
tive, randomized phase III trial in patients who |
hypertension and cardiac ischemia. As with |
had not received prior systemic therapy.68–70 In |
Sunitinib, the salient point is that the success of |
the phase II trials, both designed to test the effi- |
this oral, small molecule agent lies in its devel- |
cacy of Sunitinib in the setting of patients with |
opment to specifically target a pathway involved |
metastatic RCC who had failed prior systemic |
in the disease. |
cytokine therapy (with either interferon or |
|
interleukin-2) the partial response rates were |
Targeting mTOR |
34–40% and the median time to progression was |
|
8.3–8.7 months.69,70 Based on these promising |
|
results, a large scale, international, multicenter, |
As we have discussed,aberrations inVHL under- |
prospective, randomized, phase III trial was |
lies the process of carcinogenesis in clear cell |
completed that enrolled 750 patients with clear |
RCC, which in turn leads to accumulation and |
cell RCC who had not received prior systemic |
build up of HIFa in RCC cells. Conceptually, |
therapy.68 Patients were randomized to either |
another way to block the buildup of HIFa in the |
Sunitinib or IFNa with the primary endpoint of |
cell is to interrupt its initial or starting levels. |
the trial being progression free survival (PFS). |
There are a number of important pathways that |
The partial response rate for Sunitinib was 31%, |
impact on the expression of HIFa, but one of the |
significantly better than the 6% for patients ran- |
most important is the Akt/mTOR pathway. |
domized to IFNa. The median progression free |
Signaling from the mTOR pathway leads to |
survival was significantly better in patients who |
increased expression of HIFa mRNA and then |
received Sunitinib (11 months) compared to |
to increased starting levels of the protein. In |
5 months for those in the IFNa arm. Toxicity |
RCC, buildup of HIFa leads to increased signal- |
was generally manageable. These results dem- |
ing along the Akt-mTOR pathway, which leads |
onstrated the superiority of the oral TKI |
to upregulation and increased levels of HIFa, |
Sunitinib over IFNa in the front line setting for |
which cannot be targeted for degradation by |
advanced RCC. The critical point to note is the |
association with VHL since it is abnormal in |
development and testing of this tyrosine kinase |
clear cell RCC. This vicious cycle, or positive |
inhibitor flowed directly from an understanding |
feedback loop, as reviewed already, is thought to |
of the molecular biology that underlies the dis- |
be important in RCC. Strategies to interrupt this |
ease it is treating (advanced RCC). |
cycle presumably would be effective in treating |