Wednesday, March 31, 2010

Male Infertilty:Should we go for microsurgery wherever feasible rather than Assisted Reproductive Technology








There has been atleast 6 studies since 1973 which unambiguously show decrease in average sperm count as we are stepping into 21 st century.There has been estimated 5.2 million decrease in sperm count each year and the motilty has been reduced by 0.5% per year.This can be attributed to life style changes-smoking,substance abuse, increasing psychogenic stress,increasing prevalence of metabolic syndrome(obesity,hypertension),exposure to industrial/mutagenic pollutants and herbicides etc.This means more and more males will become infertiles and resort to medical/surgical or Assisted reproductive treatment.





Over the past 30 years,the treatment of infertility has seen the development of revolutionary new assisted reproduction technologies.First in 1978 Loius Brown - first baby to be concieved by In-Vitro Fertilisation and then it was micro-assisted Reproduction using techniques such as Intra-cytoplasmic sperm injection.




These highly complex technologies are used with increasing frequency in the treatment of couples around the globe;more than 1 million abies worldwide have been concieved by this manner.
These technologies bypass natural barriers so their is a risk of unwanted genetic traits being passed on to next generation .Researchers firmly believe that perhaps 75% of all infertility patients have a genetic basis.Then there is financial costs involved apart from mental agony if multiple cycles are required.
IVF and ICSI has been now routinely advised to all infertile males when medical management or Intra-Uterine Insemination fails.If evaluated properly the infertile males can be offered microsurgical treatment for allowing them to utilise a chance to parent their own biological children without or with a minimal aid of assisted reproduction.



Basically the infertile males can be grossly divided into two types of problems in sperm deficit in semen: Obstructive(defect in transport) or Non-Obstructive(defect in production).
In obstructive sperm problems, the bloackage can be treated in appropriate case by microsurgical reconstruction of the blocked passage(micro-surgical vaso-epididymostomy,microsurgical vasovasostomy).The chance of sperm reappearance rate can be as high as 80%.But unlike western populations; my observations about microsurgical success in India is less, probably because of the blockages here are more commonly due to infection.Infective blockages can be very difficult to treat even with microsurgery.
Microsurgery gives a magnification of 25-30 times.This magnification is highly necessary in reconstruction of vas/epididymis(male seminal pathway) as the naked eye cannot even visualise them properly so reconstructing them would be a remote possibility.


The advantage of microsurgical reconstruction is that once successful;natural conception is possible or minimal aid of Asssisted reproduction is necessary.I call it as one plus one free package as unlike IVF the couples donot have to resort to again same procedure for the second baby.
The multiple data have revealed cost effectiveness of microsurgical reconstruction over the routine sperm retrieval for IVF and ICSI.
For unobstructed oligospermia(problem with production); microsurgery has significant role in varicocecele(15-40% causative factor in male infertility).It can give success rate of almost 60%(pregnancy rate) in varicocele(although this issue is controversial- two randomised controlled trials have proven a role for surgery in varicocele related infertility).




One more area where it has a role is in some cases of male infertility that are advised donor insemination or adoption because of advanced testicular damage.In such cases microsurgical sperm retrieval(Micro-dissection TESE) can be utilised to find sperm in testis and this sperm can be used for Test Tube Baby process.The routine testicular sperm aspiration or biopsy may not yield sperms in grossly damaged testis but microsurgery can still offer a hope in such cases.


So I stress upon proper evaluation of male factor in infertility and offering them microsurgery in suitable cases before giving them an option for Assisted Reproduction Technology.

Tuesday, March 30, 2010

Pelvi-ureteric junction obstruction:overview

Ureteropelvic junction (UPJ) obstruction is defined as an obstruction of the flow of urine from the renal pelvis to the proximal ureter.





UPJ obstruction is the most common cause of neonatal and antenatal hydronephrosis, occurring in 1 per 1500 live births. 50% of patients diagnosed with antenatal hydronephrosis are eventually diagnosed with UPJ obstruction upon further workup.

PATHOPHYSIOLOGY:
Congenital UPJ obstruction most often results from intrinsic disease. A frequently found defect is the presence of an aperistaltic segment of the ureter, perhaps similar to that found in primary obstructive megaureter. In these cases, histopathologic studies reveal that the spiral musculature normally present has been replaced by abnormal longitudinal muscle bundles or fibrous tissue.
Other causes
A. An abnormal or high insertion of the ureter into the renal pelvis may affect drainage of urine. This may be an effect rather than a cause in some cases.
B. Crossing lower-pole renal vessel may result in pressure on the ureter by a vessel can prohibit urinary flow down the ureter.(cause and effect relationship not clear).
C. Rotation of the kidney and renal hypermobility can cause intermittent obstruction
D. Secondary UPJ obstruction can be caused by prior surgical intervention to treat other disorders (or failed repair of a primary UPJ obstruction (recurrent pelvi-ureteric junction obstruction). It is usually secondary to periureteral scar formation.


Problem
UPJ obstruction is defined as an obstruction of the flow of urine from the renal pelvis to the proximal ureter. The resultant back pressure within the renal pelvis may lead to progressive renal damage and deterioration.
UPJ obstruction presents most frequently in childhood, but adults and elderly individuals can also present
Frequency
• UPJ obstruction is found in approximately 50% of patients diagnosed with antenatal hydronephrosis.
• The male-to-female ratio of UPJ obstruction is 3-4:1.
• In general, the left kidney is more commonly affected than the right kidney.
• UPJ obstruction manifests bilaterally in 10% cases.
Presentation:

Neonates who present with hydronephrosis should be fully evaluated with voiding cystourethrography (VCUG; to rule out vesicoureteral reflux) and renal ultrasonography soon after birth.
If renal ultrasonography demonstrates hydronephrosis without reflux on VCUG, a diuretic renal scan should be performed to quantify relative renal function and to define the extent of obstruction.



Renal pelvic dilatation in a case of Pelvi-Ureteric Junction Obstruction



Micturating Cysto-Urethrography showing no reflux mandatory step before surgical therapy

Older children may present with UTI, a flank mass, or intermittent flank pain
Adults with UPJ obstruction can present with various symptoms, including back and flank pain, UTI, and/or pyelonephritis.
A detailed history may reveal that the pain correlates with periods of increased fluid intake or ingestion of a food with diuretic properties (ie, Dietl crisis, beer drinkers kidney).
Indications
The goals in treating patients with ureteropelvic junction (UPJ) obstruction are to improve renal drainage and to maintain or improve renal function.
As mentioned above, dilatation of the intrarenal collecting system or hydronephrosis does not necessarily imply obstruction. Specifically in children, renal pelvic dilatation should be monitored with serial imaging to assess for changes in dilatation, renal parenchymal thickness and/or the presence of scarring, and function(Renal ultrasonography and renal scintigraphy). Surgical repair is indicated upon a significant differential on serial imaging or progressive deterioration of renal function.
Similarly, in adults, repair is recommended if nuclear medicine renal scan(deteriorating on serial scan or deteriorated function on initial scan)or intravenous pyelography (IVP) reveals ureteral obstruction.
Relevant Anatomy

The evaluation of an obstructed ureteropelvic junction (UPJ) requires information about ureteral and surrounding anatomy, renal position and ectopy, associated vasculature, and renal function.
Prior to surgical intervention, the surgeon frequently evaluates for renal position/ectopy, mobility, and UPJ anatomy, such as high-insertion variants versus annular stricture variants.
The major vascular supply of the UPJ comes from branches of the renal artery. These vessels usually lie in an anteromedial location in relation to the proximal ureter. Aberrant polar vessels may also be associated with the renal pelvis, causing compression and obstruction of the collecting system. These vessels arise from either the renal artery from a position proximal to the main intrarenal branching site or directly from the aorta. They can surround the UPJ and can be associated with obstruction, or they may be aberrantly positioned secondary to increasing hydronephrosis.
The vascular anatomy at the UPJ becomes crucial during an endopyelotomy. The renal collecting system may be accessed percutaneously (antegrade) or in a retrograde fashion via passage of a ureteroscope through the urethra. While most associated UPJ vessels lie in the anteromedial plane, accessory vessels may lie posteriorly or laterally. If all endoscopic incisions are made in the posterior-lateral plane, intraoperative hemorrhage may occur. For this reason, a comprehensive vascular evaluation with complemented CT angiography is needed. CT scanning in combination with 3-phase and 3-dimensional contrast imaging yields a reported sensitivity of around 80% in revealing crossing vessels.



When an open or laparoscopic pyeloplasty is performed, an accurate understanding of the vascular anatomy allows the surgeon to preserve the accessory renal vessels and to redirect them if the surgeon feels that they contribute to the obstruction. If an endopyelotomy is planned, this information can guide the surgeon in directing the endopyelotomy incision away from crossing vessels.
Retrograde pyelography at the time of surgery is often used to estimate the length of the stricture and the amount of pelvis/ureter that needs to be excised at the time of the pyeloplasty to create a dependent funnel
Laboratory Studies
• All patients with possible ureteropelvic junction (UPJ) obstruction should be evaluated routine hematological and biochemical tests along with urinalysis.
Imaging Studies
• Renal ultrasonography and VCUG are performed in children with suspected UPJ obstruction.
• IVP is used to evaluate patients with possible UPJ obstruction. However, in the evaluation of a child with a hydronephrotic kidney, diuretic renography has taken the place of IVP. The benefits of diuretic renography are that iodine-based intravenous contrast is not used, radiation exposure is minimal, and renal function can be better quantified. The disadvantage of the nuclear medicine scan is that insight into renal anatomy is not obtained(especially many urologists are used to IVP rather than even CT reconstructed images for taking decisions regarding renal surgery for example-percutaneous nephrolithotomy).





IVP showing right pelvi-ureteric junction obstruction

• Functionally significant obstruction is often diagnosed with diuretic renal scanning. The conventional renographic criteria include a flat or rising washout curve after diuretic with T 1/2 of greater than 20 minutes and differential function of less than 40. The differential function is important in determining the need for intervention, especially in asymptomatic patients, and in selecting the appropriate treatment (pyeloplasty vs nephrectomy). Poorly functioning kidneys (<10%) are often best treated with nephrectomy. Nuclear medicine scanning is also used to assess outcomes after surgical intervention. The scans are best interpreted by combination of nuclear consultant and urologist as sometimes the sheer size of the pelvis and kidney can overestimate the function of the kidney. Also after the surgery situation may arise that the kidney size will decrease because of removal of excess of pelvis and removal of obstruction resulting in decreasing in relative function(not representative) so patients attendants and the patient should be counseled pre-operatively.



Renal scan showing obstructed kidney

• Sometimes in a patient the scan may come up with the equivocal findings in such situations the scan can be repeated with different protocoal(prior loading with diuretic so called F- protocol)

Medical Therapy

In children with ureteropelvic junction (UPJ) obstruction, GOAL is focused on maintaining sterile urine and assessing renal function and the degree of hydronephrosis. Typically, when imaging studies reveal an incomplete obstruction, the patient is monitored with routine renal ultrasonography and nuclear medicine renography.
Currently, medical therapy is unavailable for the treatment of both adult and pediatric cases of UPJ obstruction.
Initially, most children are treated conservatively and monitored closely. Intervention is indicated in the event of significantly impaired renal drainage or poor renal growth. The accepted criteria for intervention in infants and children include T 1/2 greater than 20 minutes, differential function less than 40%, and ongoing parenchymal thinning with or without contralateral compensatory hypertrophy(indicating the ipsilateral kidney atrophy) . Intervention is also indicated in those with pain, hypertension, hematuria, secondary renal calculi, and recurrent UTIs.( a word of caution –pain may not always be alleviated in renal surgery .The patient will need counseling regarding this prior)
Surgical Therapy

Surgical intervention to treat an obstructed UPJ is warranted, especially upon deterioration of renal function.
The principles of surgical repair, as initially described by Foley, include the following:
• Formation of a funnel
• Dependent drainage
• Watertight anastomosis
• Tension-free anastomosis






In children, the procedure of choice is an Anderson-Hynes dismembered pyeloplasty. The approach may be performed through a flank, dorsal lumbotomy, or anterior extraperitoneal technique. Laparoscopy has gained increasing acceptance in pediatric surgery and is often used to perform pyeloplasties in children. In many cases, laparoscopic pyeloplasty is technically unfeasible in very small children and infants because of space constraints. Using this method, the obstructed segment is completely resected, with reanastomosis of the renal pelvis and ureter in a dependent funneled fashion. The decision of whether to use a ureteral stent transiently during the initial healing process is based on the personal preference of the surgeon. The success rate of dismembered pyeloplasty for treating an obstructed UPJ exceeds 95%.

Open pyeloplasty leaves behind scar.Increased hospitalisation ,pain and delay in recuperation are the other problems.


Laparoscopic pyeloplasty offers a minimally invasive treatment option that may be used in patients with either primary or secondary UPJ obstruction and is emerging as a new criterion standard in the treatment of UPJ obstruction. Success rates are comparable with those of open pyeloplasty procedures, and some studies have shown that laparoscopy offers the advantages of decreased morbidity, shorter hospital stay, and quicker recovery. Laparoscopic pyeloplasty is a technically demanding procedure that generally requires significant laparoscopic experience. Robotic-assisted laparoscopic pyeloplasty has become increasingly popular as the robots have become more prevalent. A small intrarenal pelvis is a relative contraindication to laparoscopic pyeloplasty as the intrarenal dissection would pose difficulty for the laparoscopic surgeon.
Endoscopic treatment alternatives include an antegrade or retrograde endopyelotomy, which is an endoscopic incision performed through the obstructing segment.
Prior to incising a UPJ obstruction, imaging study(CT angiography) is recommended to evaluate adjacent ureteral vasculature.An endopyelotomy incision is performed through the area of obstruction with a laser, electrocautery, or endoscopic scalpel. Most surgeons dilate the newly incised area with a balloon catheter to help ensure a complete incision. This is followed by prolonged ureteral stenting, for a period of 4-8 weeks. The stent acts as internal scaffolding during healing and maintains renal drainage. Success rates with the percutaneous and ureteroscopic endopyelotomy are 80-90%.
When open pyeloplasty fails, endopyelotomy is particularly useful, even in the pediatric population.
In patients who have a suboptimal result from endopyelotomy, repeat incision can be performed with success. Traditional open or laparoscopic pyeloplasty is also indicated after failed endopyelotomy.
Of the open surgical repairs used to treat UPJ obstruction, the Anderson-Hynes dismembered pyeloplasty is particularly useful for the high-insertion variant. The benefit of this procedure is complete excision of the diseased segment of ureter and reconstruction with healthy viable tissue.

Spiral and vertical flaps (eg, Culp and DeWeerd, Scardino and Prince) are useful when a long-strictured segment of diseased ureter is encountered. With these procedures, the proximal ureter is re-created with redundant renal pelvis that is tubularized.
Ureterocalicostomy, ie, anastomosis of the ureter to a lower-pole renal calyx, is usually reserved for failed open pyeloplasty when no extrarenal pelvis and significant hilar scarring are present.It also is convenient to perform the procedure in thinned out parenchyma.
Robotic-assisted laparoscopic pyeloplasty




This procedure is particularly helpful in the surgeon who is learning the laparoscopic technique. The da Vinci robotic surgical system has been used successfully for laparoscopic reconstruction. It offers several advantages to surgeons unskilled in laparoscopy, including increased degrees of suturing freedom(just like movement of the wrist), stereoscopic vision, tremor filtration, precision and maneuvreability. The results are similar to those of conventional laparoscopic pyeloplasty.
Follow-up

Prophylactic antibiotic therapy should be given postoperatively. Remove the endopyelotomy stent after 4-8 weeks.
Follow up with renal ultrasonography 1-3 months after surgery. In addition, follow up with IVP or nuclear medicine renal scan 3-6 months after surgery.
Serial renal imaging is recommended for the first year after surgery and should be continued less frequently thereafter if results have normalized.
Complications

Potential complications from open surgical pyeloplasty include UTI and pyelonephritis, urinary extravasation and leakage, recurrent ureteropelvic junction (UPJ) obstruction, or stricture formation. Treatment of urinary leakage is centered around catheter drainage, such as nephrostomy, ureteral stent, or perianastomotic drain, to direct urine away from the perianastomotic tissues and to decrease the risk of postoperative stricture disease.
Specific complications from endopyelotomy include significant intraoperative bleeding if the endoscopic incision is made inadvertently into a major polar vessel, postoperative infection, and recurrence of obstruction. If significant intraoperative bleeding is encountered with hypotension, emergency arteriography and embolization are indicated.

Monday, March 29, 2010

Erectile dysfunction:Overview

“Man survives earthquakes, experiences the horrors of illness, and all of the tortures of the soul. But the most tormenting tragedy of all time is, and will be, the tragedy of the bedroom.”

Tolstoy



ED is the inability to achieve and maintain an erection adequate for intercourse to the mutual satisfaction of the man and his partner.
Prevalence:
The Massachusetts Male Aging Study - 52% of men between the ages of 40 and 70. (1987-1997).Erectile dysfunction is classified as minimal, moderate, or complete. Of the 52% of men who suffer from erectile dysfunction 17% have minimal ED, 25% have moderate ED, and 10% have complete ED.
The worldwide incidence of erectile dysfunction estimated at over 152 million men, with a forecast of 322 million men by the year 2025. This may be because of change in life style-increasing population suffering from metabolic syndrome(syndrome with increased cholesterol,hypertension,cardiac disease,hyperuricemia and diabetes),smoking and substance abuse.It may also be because of increasing stress and change in interpersonal relationships.

Pathophysiology:
 The cGMP: The main mediator of penile erection causes smooth muscle relaxation and blood flows into the cavernous sinuses and the penis becomes erect.
 At the same time, the veins in the penis are squeezed almost completely shut due to this pressure. Since the veins are shut, blood can not drain from the penis, and it remains erect.
 Once the arousal has subsided, the cGMP is broken down and the penis again becomes flaccid.
 The main chemical responsible:phosphodiesterase-5 (PDE-5)sildenafil,Tadalafil are PDE-5 inhibitors :preventing the breakdown of cGMP, thus keeping blood in the penis to maintain the erection.







Causes
 Since an erection requires a precise sequence of events, ED can occur when any of the events is disrupted. The sequence includes nerve impulses in the brain, spinal column, and area around the penis, and response in muscles, fibrous tissues, veins, and arteries in and near the corpora cavernosa.

Damage to nerves, arteries, smooth muscles, and fibrous tissues, often as a result of disease, is the most common cause of ED. Erectile dysfunction is usually caused by one or more of the following pathologies::
 arterial vascular pathology: heart disease and vascular problems also raise the risk of erectile dysfunction.




 neurologic pathology
 Endocrine causes : Between 35 and 50 percent of men with diabetes experience ED. Also aging males can have dropping levels of testosterone which may lead to decreased libido,erectile dysfunction(Androgen Deficiency of Aging Male).Men with increased levels of prolactin will also experience erectile dysfunction because of decreased libido.
 Psychogenic causes Experts believe that psychological factors such as stress, anxiety(Performace anxiety), guilt(Previous sexual experiences), depression, low self-esteem, and fear of sexual failure cause 10 to 20 percent of ED cases.
 Post-Surgical: (especially radical prostate and bladder surgery for cancer) can injure nerves and arteries near the penis, causing ED.
 Local Pathology: Penile curvatures- Peyronies disease, corporal fibrosis-post trauma, surgery, post-priapism may also lead to impotence.
 Medications/substance abuse: many common medicines/drugs/substances-blood pressure drugs, antihistamines, antidepressants, tranquilizers, appetite suppressants,alcohol,tobacco and cimetidine (used for Acid Peptic Disease)-can produce ED




Evaluation:
 Somewhat subjective
 Doctor diagnosis
 Validated questionnaires like IIEF (International Index of Erectile Function)

Diagnosis
Patient History

Medical and sexual histories help define the degree and nature of ED. A medical history can disclose diseases that lead to ED, while a simple recounting of sexual activity might distinguish among problems with sexual desire,Painful sex,.dysfunction either difficulty in initiation or maintainance of erection, ejaculatory problems like-retrograde ejaculation or anejaculation, or problems with orgasm- anorgasmia.
Physical Examination
A physical examination can give clues to systemic problems. For example, if the penis is not sensitive to touching, Focal neurogical problems can pinpoint to neurological disorders.

• Abnormal secondary sex characteristics(defective androigenisation), such as hair pattern or breast enlargement, can point to hormonal problems, which would mean that the endocrine system is involved.
• The patient may have circulatory disturbances in the form of decreased pulsations in the ankle/popliteal region.
• Local pathologies: Penile curvatures, tender penile plaques will reveal local pathological cause for erectile dysfunction.

Practical Tips:
Psychogenic causes:

1. Younger patient (<40)
2. Preservation of morning erections and nocturnal erections
3. Achieve erection with masturbation
4. May be partner-specific(May achieve erection with specific person-quoad)
5. Often sudden onset(Related to sudden outburst of stress in life)
Organic ED:
1. Gradual deterioration over the period of months or years
2. Decrease in morning erections and nocturnal erections
3. No erections with masturbation
4. No loss of libido
5. Presence of co-morbid conditions like long standing hypertension,hyperlipidemia or diabetes.


Laboratory Tests

Several laboratory tests can help diagnose ED. Tests for systemic diseases include blood counts, urinalysis, lipid profile, and measurements of creatinine and liver enzymes. Measuring the amount of free and total testosterone, thyroid function or prolactin in the blood can yield information about problems with the endocrine system and is indicated especially in patients with decreased sexual desire.
Serum PSA is usually indicated in men over 50 years as if these men require testosterone replacement or supplementation they would need careful follow-up with Digital Rectal Examination and Serum PSA to rule out co-existing prostatic carcinoma which may flare up with the administration of testosterone.

Other Tests
Nocturnal Penile Tumuscence Tests:

Monitoring erections that occur during sleep (nocturnal penile tumescence) can help rule out certain psychological causes of ED. Healthy men have involuntary erections during sleep. If nocturnal erections do not occur, then ED is likely to have a physical rather than psychological cause.
In 1985, the RigiScan was introduced; it was the first device to provide automated, portable NPTR recording. The device combines the monitoring of radial rigidity, tumescence, number, and duration of erectile events with the convenience of a portable system that can be used at home. It consists of a recording unit that can collect data for three separate nights for a maximum of 10 hours each night. The mechanics consist of two loops: one is placed at the base of the penis and the other at the coronal sulcus. By constricting the loops, the device records penile tumescence (circumference) and radial rigidity at the penile base and tip. Measurement (initialization) is first done in the office for 15 to 20 minutes with the patient awake to establish an individual baseline. At home, penile rigidity is registered every 3 minutes by constriction of the loops, applying a radial compression.Radial rigidity above 70% represents a nonbuckling erection, and a rigidity of less than 40% represents a flaccid penis. The number of erections considered normal is three to six per 8-hour session, lasting an average of 10 to 15 minutes each
Cilurzo and colleagues (1992) recommend the following as normal NPTR criteria: four to five erectile episodes per night; mean duration longer than 30 minutes; an increase in circumference of more than 3 cm at the base and more than 2 cm at the tip; and maximal rigidity above 70% at both base and tip
The main advantages of NPT testing are its relative freedom from psychologic influences and its ability to detect sleep-related abnormalities. The documented presence of a full erection indicates that the neurovascular axis is functionally intact and that the cause of the ED is most likely psychogenic. Heaton and Morales (1997) have suggested indications for NPTR as follows: (1) suspected sleep disorder; (2) obscure cause of ED; (3) nonresponse to therapy; (4) planned surgical treatment; (5) legally sensitive case; (6) measurement of drug effects in placebo-controlled drug trials; and (7) suspected psychogenic cause.
Colour Doppler examination:
When vascular evaluation is indicated, intracavernous injection with color duplex Doppler ultrasound is the most informative diagnostic test. This may be all that is needed to define and determine severity. Color duplex ultrasound should be used before other tests are considered because it is the least invasive technology for evaluating vascular ED, distinguishing high-from low-flow priapism, and assessing Peyronie's plaque. Recently, the combination of oral sildenafil citrate with visual erotic stimulation has been shown to be an effective noninvasive pharmacologic induction method for penile blood flow evaluation rather than giving intracavernosal injection(which many patients find repulsive at first instance) PSV less than 25 cm/s after intracavernous injection and sexual stimulation has a 100% sensitivity and 95% specificity in selecting patients with abnormal penile arteriography, because it reflects severe cavernous arterial insufficiency. A PSV consistently greater than 35 cm/s is associated with normal arteriography and defines normal cavernous arterial inflow.
Penile arteriography:
Arteriography is most useful in providing anatomic information. The inferior epigastric vessels also need to be studied because they are most commonly used for penile revascularization. Because of the high cost and invasive nature of the study, only a small percentage of patients with complex ED are appropriate candidates- ED secondary to a traumatic arterial disruption or in a patient with a history of perineal compression injury. In these highly selected cases, a detailed “road map” of the arterial anatomy is essential to planning surgical reconstruction.
Dynamic Infusion Cavernosography and Cavernosometry:
This is a complex test done in special circumstances like young men who might be candidates for penile vascular operations, specifically those with a history of pelvic trauma.
Psychosocial Examination
A psychosocial examination, using an interview and a questionnaire, reveals psychological factors. A man's sexual partner may also be interviewed to determine expectations and perceptions during sexual intercourse.
Treatment
General Conservative measures:


Most physicians suggest that treatments proceed from least to most invasive. For some men, making a few healthy lifestyle changes may solve the problem. Quitting smoking, losing excess weight, and increasing physical activity may help some men regain sexual function. Avoiding drugs with harmful side effects is considered next. For example, drugs for high blood pressure like thiazides can be changed and alternative medications can be given.





Psychotherapy

Experts often treat psychologically based ED using techniques that decrease the anxiety associated with intercourse. The patient's partner can help with the techniques, which include gradual development of intimacy and stimulation.Master and Johnsons therapy involving couples can solve problems with performance anxiety /premature ejaculation
Drug Therapy
Drugs for treating ED can be taken orally, injected directly into the penis, or inserted into the urethra at the tip of the penis. In March 1998, the Food and Drug Administration (FDA) approved Viagra, the first pill to treat ED. Since that time, vardenafil hydrochloride (Levitra) and tadalafil (Cialis) have also been approved. Additional oral medicines are being tested for safety and effectiveness. Viagra, Levitra, and Cialis all belong to a class of drugs called phosphodiesterase (PDE) inhibitors. Taken an hour before sexual activity, these drugs work by enhancing the effects of nitric oxide, a chemical that relaxes smooth muscles in the penis during sexual stimulation and allows increased blood flow.

While oral medicines improve the response to sexual stimulation, they do not trigger an automatic erection as injections do. The recommended dose for Viagra is 50 mg, and the physician may adjust this dose to 100 mg or 25 mg, depending on the patient. The recommended dose for either Levitra or Cialis is 10 mg, and the physician may adjust this dose to 20 mg if 10 mg is insufficient. A lower dose of 5 mg is available for patients who take other medicines or have conditions that may decrease the body's ability to use the drug. Levitra is also available in a 2.5 mg dose.

None of these PDE inhibitors should be used more than once a day. Men who take nitrate-based drugs such as nitroglycerin for heart problems should not use either drug because the combination can cause a sudden drop in blood pressure. Also patients have severe cardiac diseases like recent Myocardial Infarction, reduced stress tolerance should avoid PDE-5 inhibitors.

Many men achieve stronger erections by injecting drugs into the penis, causing it to become engorged with blood. Drugs such as papaverine hydrochloride, phentolamine, and alprostadil (marketed as Caverject) widen blood vessels. These drugs may create unwanted side effects, however, including pain (36%) persistent erection (4%) and scarring. It gives a success rate of 70-90 % but these injections have a drop-out rate of 25-60% because of mainly pain or sometimes development of corporal fibrosis. A system for inserting a pellet of alprostadil into the urethra is marketed as Muse. The system uses a prefilled applicator to deliver the pellet about an inch deep into the urethra. An erection will begin within 8 to 10 minutes and may last 30 to 60 minutes. The most common side effects are aching in the penis, testicles, and area between the penis and rectum; warmth or burning sensation in the urethra; redness from increased blood flow to the penis; and minor urethral bleeding or spotting.




Vacuum Devices

Mechanical vacuum devices cause erection by creating a partial vacuum, which draws blood into the penis, engorging and expanding it. The devices have three components: a plastic cylinder, into which the penis is placed; a pump, which draws air out of the cylinder; and an elastic band, which is placed around the base of the penis to maintain the erection after the cylinder is removed and during intercourse by preventing blood from flowing back into the body The satisfaction rate varies from 35-80% but the problems with the Vacuum Erection devices are – cold penis, loosely hanging penis ,sometimes it can lead to bruises especially patient using it roughly and on aspirin or clopidogrel.



Surgery
Surgery usually has one of three goals:
•to implant a device that can cause the penis to become erect (Penile Implant surgery)
•to reconstruct arteries to increase flow of blood to the penis (Penile revascularization surgery for patient with focal arterial stenosis-post-trauma)
•to ligate veins that allow blood to leak from the penile tissues (penile venous leak-particularly detected on Doppler showing persistence end-diastolic velocity more than 5 cm/sec)

Implanted devices, known as prostheses, can restore erection in many men with ED. Possible problems with implants include mechanical breakdown and infection, although mechanical problems have diminished in recent years because of introduction of Viagra but there are a group of patients who fail with medications and refuse or fail with Vacuum Erection Device. Inflatable implants consist of paired cylinders, which are surgically inserted inside the penis and can be expanded using pressurized fluid Tubes connect the cylinders to a fluid reservoir and a pump, which are also surgically implanted. The patient inflates the cylinders by pressing on the small pump, located under the skin in the scrotum. Inflatable implants can expand the length and width of the penis. They also leave the penis in a more natural state when not inflated.



Advantages with the penile impants are:
 Good rigidity
 Freedom from medications
 Outpatient/24HR surgery
 Resume sexual activity 4-6 weeks
 No loss of ability to ejaculate or achieve orgasm








Surgery to repair arteries can reduce ED caused by obstructions that block the flow of blood. The best candidates for such surgery are young men with discrete blockage of an artery because of an injury to perineum or fracture of the pelvis.

Surgery to veins that allow blood to leave the penis usually involves an opposite procedure-intentional blockage. Blocking off veins (ligation) can reduce the leakage of blood that diminishes the rigidity of the penis during erection. However the results are not long lasting so the venous ligation surgery have diminished

Saturday, March 27, 2010

Seminal Vesiculoscopy with Ejaculatory Duct Obstruction

A 39 year old gentleman came with low volume ejaculate with oligospermia(documented on several semen analyseserum total tests) The semen volume was characteristically around 0.25-0.30 ml.His post-ejaculatory urine analysis for sperms was negative.His libido and orgasm was normal. He was evaluated with Hormone Profile(LH,FSH and Testosterone),Trans-Rectal Ultrasound for the seminal vesicles which showed grossly distended seminal vesicles and the ejaculatory duct. His seminal vesicular anatomy was further investigated with the MRI test which showed distended seminal vesicles. There was no midline or otherwise prostatic cysts. He was given option of Seminal vesiculoscopy. The surgery was performed under spinal anaesthesia.The verumontanum on cystourethroscopic examination was prominent. The bladder neck and the bladder were normal. With 6 Fr Ureteroscope the transutricular access was performed and bilateral seminal vesicles were fenestrated. The intra-operatively there was a lot of seminal clogged material pouring out from the seminal vesicles. The procedure was concluded with 14 Fr Foleys catheter kept in situ. The procedure was uneventful. Trans-utricular seminal vesiculoscopy has emerged as important diagnostic and therapeutic tool in seminal vesicle pathology. With conventional endoscopic instruments it is possible to do trans-utricular seminal vesiculoscopy. In our view this approach is better than routine trans-urethral resection of ejaculatory ducts as adequacy of deroofing is better in seminal vesiculoscopy and seminal vesicular toileting can be done at the same time. The deroofing in seminal vesiculoscopy is under direct vision and in controlled manner. In Trans Urethral Resection of Ejaculatory ducts the resection often is blind and adequacy is confirmed by methylene blue gushing out. The liberal TURED may sometime involve the risk of Bladder neck injury and even rectal injury in the hands of inexperienced resectionist. It is always stressed that the TURED should be performed by an experienced resectionist. But the seminal vesiculoscopy the possibility of such occurrences are remote. We feel the learning curve of this procedure is less and can be undertaken even in undilated seminal vesicles. This case was second in our Institute(Probably Third in India- as per personal communication with various urologists).This case was highlighted because in this there was no midline prostatic cyst so the technical question that would come in any urologists mind about the feasibility of the procedure in undilated utricle/seminal vesicles.This case shows the feasibility in cases where the utricle is not enlarged or there is no midline cyst.In a similar way the seminal vesiculoscopy can be carried out in undilated seminal vesicles.

Microsurgical Varicocelectomy with denervation for the varicocele and orchalgia.

We had a 22 year old gentleman who came with history of dragging pain in the left testis since 3 years. He did not have anyother complaints. The patient was was examined and found to have grade 3 varicocele on the left. There was no neurological deficit. His investigation profile (Urine and blood ) were unremarkable. He was subjected to Doppler Ultrasound examination which showed grade 3 varicocele with normal sized both testes with normal echotexture.
The patient was given all options including conservative management and the patient chose for the microsurgical varicocelectomy (Having gone through all modalities of the varicocecelectomy- embolisation,open and laparosocopic).He was of the opinion that embolisation would be a minimally invasive option for him(He thus read in the net).He was given the data about success,possible complication and failure rate of each surgical/non-surgical procedure and finally he opted for microsurgical varicocelectomy.(It is important to give best option available rather option suitable for the hospital/treating surgeon-if microsurgical facilities are not available the patient should be duly informed about it.)
The surgery was done with an aid of microscope with varying degrees of the magnification from 10-15X Keenly the lymphatics and the testicular artery was identified and veins of the spermatic cord, external spermatic vein and the gubernacular veins were ligated. The subinguinal approach was taken.The wound was closed after releasing cremasteric fascia and denuding the testicular artery ( as part of microsurgical denervation of the spermatic cord) and subcuticular stitches for the skin.
Surgical Approach to Varicocele:

Surgical repair may be accomplished by various surgical approaches like inguinal (Ivanissevich), subinguinal and retroperitoneal approaches (Palomo), Most experts perform inguinal or subinguinal surgical repair employing loupes or an operating microscope for optical magnification. Techniques using optical magnification help in reliable identification and preservation of the testicular artery or arteries, cremasteric artery and lymphatic channels and reliable identification of all internal spermatic veins and gubernacular veins reducing the risk of persistence or recurrence of varicocele. The introduction of microsurgical technique to varicocelectomy has resulted in a substantial reduction in the incidence of postoperative hydrocele formation and testicular atrophy. The use of magnification enhances the ability to identify and preserves the 0.5 - 1.5-mm testicular arteries, thus avoiding the complications of azoospermia.




Microsurgery only should be offered for varicocele patient
In general laparoscopy should not be assorted for varicocele treatment.
The Gold standard of varicocelectomy is Microsurgical Varicocele Ligation.



Varicocelectomy for pain:
The varicocelectomy for pain is little bit controversial topic while many urologist go for the surgery what we feel that the patient should be fully counseled for the chance that the orchalgia may not fully abate(20% chance).He may need certain other medicines in such cases like Pregabalin, Tegretol.
Our approach- in case of orchalgia with the varicocele has been microsurgical denervation and cremasteric release also which was done in the index case.

Thursday, March 25, 2010

Male infertility:An overview





CAUSES OF MALE INFERTILITY



Infertility is defined as the failure to conceive after one year of unprotected intercourse. The condition affects about 15% of couples within the reproductive age group and the male partner is contributory in about half the cases.
Basic clinical evaluation of the infertile male should include detailed reproductive history, physical examination and at least two semen samples must be obtained, preferably about a month apart with a 3-5 day abstinence period prior to each sample .According to abnormality in seminal parameters the following categories are made:
A. Oligo/astheno/teratospermia (OATs):
Abnormality in sperm density, motility or morphology.
B. Azoospermia:
Azoospermia refers to total absence of sperm. The presence of even a single mature sperm changes the diagnosis to extreme oligospermia or cryptozoospermia.


Hormonal evaluation(FSH and Testosterone)
An endocrine evaluation should be performed if:
1. Sperm concentration is less than 10 million/ml
2. Impaired sexual function such as decreased libido, volume of ejaculate
Semen culture
Persistent pyospermia despite an initial course of empirical antibiotics is an indication for seminal culture.Cultures are often negative since the infecting organisms: Chlamydia and Mycoplasma cannot be grown on routine bacterial cultures.

Scrotal ultrasound and Doppler
• Scrotal ultrasound should be done in case a suspicious mass lesion is found on clinical examination or the scrotum is difficult to evaluate clinically due to previous trauma/ surgery/ infection.


Genetic testing
Genetic abnormalities may be present in upto 10% men with severe OATs. These are primarily deletions in the long arm of the Y chromosome (Yq microdeletions) or karyotypic abnormalities such as Klinefelter’s syndrome or it’s variants.CFTR gene testing is done in obstructive azoospermia with vassal agenesis. Detecting these abnormalities identifies the etiology of the infertility and allows counseling of the patients if they choose to undergo ART
Management options for OATS (non-varicocele related)
Specific treatment must be offered to men with a demonstrable specific cause for OATs.








• Life-style changes, avoidance of heat exposure, toxin exposure should form the initial non-drug therapy for OATs.
• Hypogonadotropic hypogonadism requires hormone supplementation.
• Pyospermia should be initially treated with a short course of agents effective against Chlamydia and Mycoplasma.
• Empiric therapies should be avoided in couples with advanced age or where the fertility potential of the female partner is compromised.
• There is no role of empirical androgens including Testosterone, GnRH, FSH, hCG, hMG.
• Men with total asthenospermia with normal counts require ART.
Indications and techniques for correcting a varicocele





• A varicocelectomy should be advised only if all the following criteria are met:
1. Documented infertility
2. Clinically palpable varicocele
3. Presence of OATs
4. Fertile female partner
• Adolescent boys with a demonstrably smaller ipsilateral testis or unmarried men with documented decline in semen parameters may also be counseled for a varicocelectomy
• Azoospermic men with no other cause for azoospermia may rarely benefit from varicocelectomy, particularly if the varicocele is large or bilateral. Such men should be counseled well before surgery.
• Microsurgical procedures have the lowest risk of complications and should be preferred.
• Subinguinal approach is preferable as the pain is less because muscle cutting is not involved.



Laparoscopy for varicocelectomy:
Laparoscopy for varicocelectomy is challenging because of damage to testicular artery and higher recurrence rate however with the use of papavarine and meticulous dissection testicular artery can be preserved.This method can be probably used for bilateral varicocele.


Azoospermia

Etiologies of azoospermia can be categorized into pre-testicular, testicular and post testicular. Pre-testicular azoospermia occurs in men with hormonal abnormalities and are uncommon. Testicular causes result in poor spermatogenesis. These are usually not amenable to corrective therapy and require ART. Post testicular causes are due to ductal obstruction or ejaculatory dysfunction. These are often correctable and the aim of evaluation of azoospermic men is primarily to identify such patients.

Additional investigations
Hormone analysis
• Bilaterally small testis with FSH raised more than 2x normal is diagnostic for testicular impairment and these men may not need a diagnostic testicular biopsy/FNAC.
• Serum FSH estimation is optional in men with obstructive azoospermia..
Testicular biopsy
• Testicular biopsy is mandatory before diagnosing obstructive azoospermia in men with a normal volume ejaculate and at least one palpable vas deferens.
• Testicular FNAC/ needle biopsy provides diagnostic information as good as an open biopsy. Where feasible, FNAC/ needle biopsy should be used instead of an open biopsy.
Vasography
• Vas patency may be confirmed by saline infusion or similar tests that do not result in inflammation of the vas. This should usually be combined with a reconstructive procedure and should not be performed as a separate diagnostic test.
Trans rectal ultrasonography (TRUS)
• TRUS is indicated in men with low-volume ejaculate and a palpable vas deferens.
• TRUS with injection of dye into the seminal vesicles is performed immediately prior to a trans-urethral resection of ejaculatory ducts (TURED) in men with ejaculatory duct obstruction.
Post-ejaculate urine examination
• Post-ejaculate urine should be checked for sperms in men with low-volume azoospermia, normal TRUS and normal spermatogenesis.
• Urine should be alkalinized for 2 days prior to the test.
Abdominal ultrasound
• Ultrasound of the abdomen, particularly the kidneys should be obtained in men with CBAVD. These men have a higher incidence of renal agenesis.

Diagnosis and management
Vasoepididymal junction obstruction (VEJO)
• Most cases of VEJO are idiopathic.
• Diagnosis is to be made if all the following are present:
o At least one palpable vas deferens
o Normal volume ejaculate with positive fructose
o Normal spermatogenesis on FNAC
• Should be treated with a microsurgical vasoepididymal anastomosis
• The possible patency rates must be discussed with the patient before the surgery(30-50%)



Ejaculatory duct obstruction
1. Diagnosis is to be made if all the following are present:
• At least one palpable vas deferens
• Low volume ejaculate
• Absent of sperms on post-ejaculate urine examination
• Normal spermatogenesis on FNAC testis
2. Men with EDO and dilated ejaculatory ducts may benefit from Trans-urethral resection of the ejaculatory ducts (TURED) or seminal vesiculoscopy.
3. Results in the appearance of sperm in the ejaculate in about one-half to three-fourths of cases. The pregnancy rate achieved by this surgery is about 25 percent
4. Retrograde ejaculation and recurrent Urinary Tract Infections are complications usually encountered.
5. Seminal vesiculoscopy liberally,safely deroofs seminal vesicles and bypasses the ejaculatory duct that too under direct vision.So the chance of restenosis is less likely.







Vasectomy, vasal injury
• The diagnosis is usually evident from the history and examination.
• In patients with a long history of injury, spermatogenesis should be confirmed prior.
• Microsurgical reconstruction treatment of choice.
• The results in our setting is around 80-85%(patency rate).



Microsurgical vasectomy reversal with Goldstein technique
Testicular Sperm Retrieval:

1. For patients with nonobstructive azoospermia, recommend open testicular sperm extraction.
2. For cases of obstructive azoospermia, either open or percutaneous techniques may be used.
The modalities of sperm extraction:
Obstructive azoospermia:
Percutaneous epididymal sperm aspiration:The idea behind epididymal sperm acquisition is that higher yield of bankable sperms from the epididymis than the testis.As the percutaneous technique is unreliable the Microsurgical Epididymal Sperm Aspiration(MESA)has been method of choice for the sperm aqusition.It involves microsurgically exposing and incising epididymal tunic and aspirating epididymal fluid.MESA leads to extraction of large number of motile mature sperms which can be cryopreserved.

Non-obstructive azoospermia:

Two methods have been described:Percutaneous(Fine needle aspiration or percutaneous aspiration with 18 G needle)or testicular biopsyBut the yield is scanty or none in Sertoli cell only syndrome or early maturation arrest.In these cases either Random multiple biopsies or microdissection TESE have been employed with reasonable success rate.Microdissection technique employs inspection of individual seminiferous tubules under operating microscope and selcting opaque yellowish tubules and dissecting them out and examining them under microscope for spermatogenesis.The yield in this method more with very less testicular tissue damage.





Assisted reproduction

• Assisted reproduction should be the primary treatment modality in men with:
o Testicular failure with severe OATs or azoospermia
o CBAVD
o All immotile sperms
o Partners who have an indication for ART

Wednesday, March 24, 2010

Memocath stent insertion for a case of long segment urethral stricture disease

We had a 24-year-old gentleman - a case of recurrent stricture urethra.He had undergone multiple endoscopic interventions and was on regular dilatations.The ascending urethrogram has revealed long segment bulbar urethral stricture disease.The etiology of the stricture was most probably infective one with no history of prior instrumentation of surgery related to urinary tract.

He was given options of urethroplasty -substitution with the buccal mucosal graft and the Memocath- stent insertion.
The patient underwent stent insertion.The procedure took 45 minutes; it was done under spinal anaesthesia.The patient immediately resumed normal activities the very next day.
He started voiding immediately as no catheter kept after the procedure.

The insertion of the stent has a very few and only minor side effects.It has immediate effect on voiding.The stent does not interfere with normal bladder control.
As such there no contra-indications for the stent insertion but stone disease,need for urological intervention in future for some other problem like prostatomegaly or recurrent Urinary Tract Infections can be a relative contra-indication for the procedure.
We inserted The Memocath 044 stent which expands from CH 24 TO CH 44 after warm saline irrigation.The stent comes under various sizes 3 cm,4 cm, 5cm, 6 cm amd 7 cm .We used 7 cm stent for this patient.

The patient voided with superflow 60 ml/sec and continues to void with the good stream 4 days pos-operatively.
He is planned for Retrograde Urethrogram after a period of 1 month along with uroflowmetry.

Monday, March 22, 2010

Long segment urethral stricture caused by Balanitis Xerotica Obliterans treated in single stage

A 57 –year old gentleman came WITH PAN URETHRAL STRICTURE. He underwent multiple endoscopic interventions and dilatations over a period of 5 years.He had history of recurrent UTIs because of stricture.
The Ascending urethrogram revealed long segment anterior urethral stricture with meatal involvement. Clinically he had Balanitis Xerotica Obliterans and indurated urethra in the penile region.







He was taken up for endo-assessment which revealed stricture involving meatus and extending into the penile urethra till the mid-bulbar region with diverticuli in bulbar region.
The Pan-urethral stricture is a challenging situation for a urologist. Furethermore, the BXO causing pan-urethral stricture is even more complex because it has wide spread involvement in the penile skin/prepuce urethra and also proximal urethral involvement as in our case where he had bulbar stricture also
Clinically in Lichen sclerosis there are hypo-pigmented patches on the glans and the prepuce, obliteration of the coronal sulcus, deformed glans and meatal stenosis.
Various tissues have been used for the repair of long urethral strictures either in form of free grafts or pedicled flaps. The tissues used for substitution are skin either genital or extra genital, or mucosa from the oral cavity. The methods for substitution have been in form of free grafts, pedicled flaps, and tubularised flaps and graft, which are, used either in a single stage or two stage surgical reconstructions.

Johanson described the most common 2-stage repairs. The majority of failures of the Johanson technique were secondary to hair growth in the urethra, which caused infection and stone formation. This led to recurrence of the stricture. Strictures complicated by a lack of sufficient penile skin has generally consisted of 2-stage scrotal inlay urethroplasty. Scrotal skin has shortcomings, most notably hair formation, diverticula and stricture recurrence from urine-induced dermatitis.
We did single stage urethroplasty – with Kulkarni´s single stage penile invagination technique and dorsal onlay with Buccal Mucosal Graft.
The procedure was done as follows: A midline perineal incision was given and the left sided dissection of the bulbar urethra was done. One sided dissection helps to maintain the blood supply of the urethra coming from the right side. The penis in invaginated through the perineal wound and the process of the dissection is carried out further. After the full dissection the urethra is opened dorso-laterally along the whole length of the urethra (till mid-bulbar region)
The meatus is then cut dorsally widely and the BMG harvested ( we had to harvest two Buccal mucosal grafts from each side of the mouth)








was sutured to the cut edges of the meatotomy.






Then the BMG was pushed through the meatus in the urethra which is invaginated in the perineal wound. The BMG was quilted through-out the length to the underlying corpora and sutured to the cut edge of the opened urethra.







The neo-urethra combined with the BMG now quilted and the original narrowed urethra was confirmed to be adequate on the scale.






Then a 16 Fr SILICON catheter was kept in situ and the two edges of the urethra were sutured so the neo-urethra is completely re-tubularised in the entire length. The perineal wound was then closed in layers.
The plan is now to keep catheter for 4 weeks followed by Micturating cystourethrography.

HIFU:NEW HOPE FOR EARLY PROSTATE CANCER

We had a 71 year old gentleman coming from Bengal who had organ confined carcinoma prostate. He was a known case of asthma on regular nebuliser and steroid inhalation. He had very poor Pulmonary Function Tests parameters. The prostate was 40 cc and digital rectal examination revealed no nodularity or lateral wall spread.The biopsy revealed 3+3 Gleason score. So this gentleman was considered for the HIFU (High Intensity Focussed Ultrasound) for the prostate carcinoma. This is a new option for men with well differentiated organ confined Prostate Cancer. (This means a single tumour inside the prostate or several tumours but all on the same side of the prostate gland).The patient usually selected are Serum PSA less than 10 ng/ml, Gleason score less than or equal to 6 and the clinical stage of T1 or T2 a. As there is no such thing likes perfect prostate cancer treatment the physician has to do perfect balancing act in between cancer control and the quality of life. The radical surgery and the radiotherapy can sometimes cause impotence and incontinence and seriously damage the quality of life of the patient. HIFU: It uses a high energy focused ultrasound beam, which is directed across the wall of the back passage into the prostate to heat and destroy a very precise volume of tissue. HIFU MACHINE High Intensity Focused Ultrasound, or HIFU, is a therapy that destroys tissue with rapid heat elevation, which essentially "cooks" the tissue. Ultrasound energy, or sound waves, is focused at a specific location and at that "focal point" the temperature raises to 90 degrees Celsius in a matter of seconds. Over 7000 men, in nearly 100 HIFU centers worldwide, have already chosen HIFU with the Sonablate® 500, because it is the most advanced HIFU therapy available. The good part of HIFU is that; it avoids or reduces the damage to surrounded structures such as the muscle controlling urine flow and the nerves controlling erections whilst still suffering cancer control (which is a possibility after radical prostatectomy or radical radiotherapy-other two main options to cure prostate cancer). This means the patient can have a treatment for your prostate cancer without all of the associated side-effects with other treatments. The benefits of HIFU: - Rapid return to normal life after treatment - Almost 100% of patients maintain sexual potency - No incision is required which avoids the risk of surgical infection - The procedure can be repeated as necessary All men are followed up after HIFU with PSA tests every three months. If the PSA rises then further diagnosis is undertaken, but for approximately 90% of men treated, HIFU should be the only treatment required. If further treatment is required this is usually a further HIFU treatment, though any of the traditional treatments including surgery and radiotherapy are possible after . Contra-indications for HIFU:  Patients with Prostate Cysts more than 10 mm  Patients with calcifications greater than 10mm  Prostate Stents  Active Bacterial prostatitis  brachytherapy seeds  Patients on anticoagulation therapy  Rectum cannot accommodate 2 fingers dilatation Procedure: The patient was anesthesized with an epidural anaesthesia to prevent pain and movement. The patient was taken up for LASER prostatectomy to to evaporate the prostate basically to downsize the prostate so that HIFU can treat the whole prostate effectively in two zones only. Then HIFU probe was introduced in the rectum and the prostate anatomy was mapped .The prostatic tissue was divided in two zones and HIFU treatment was carried out. It took 3 hours for whole treatment including the LASER vaporization of the prostate. At the commencement of the procedure a suprapubic catheter was inserted through the patient´s lower abdomen and into the bladder. This catheter, which was kept as precautionary measure to prevent urinary retention because sloughed prostatic tissue blocking the prostatic urethra. The suprapubic catheter was clamped on day 3 to see whether the patient can void and the patient voided very well. The next plan to observe his urinary stream for 2 more days and then remove the suprapubic catheter if everything goes on well. OUTCOME OF HIFU: 94% BIOCHEMICAL FREE DISEASE RATE AT THE END OF 4 YEARS AND 87% BIOPSY NEGATIVE RATE AT THE END OF 6 MONTHS. Scientific background for HIFU: Uchida et al conducted a study on 63 patients (published in British Journal of Urology (2006) who underwent HIFU for organ confined prostate cancer. The mean follow-up was for 23 months (3 – 63 months), and all patients had biopsy at 6 months. The 3 year biochemical disease free rate (ASTRO) in all patients was 75% after 3 years. The Biopsy after 6 months was negative in 87% of patients. The Incontinence rate was 1% , Fistula rate 1, Stricture rate 24 % ( managed by office dilatation )

Thursday, March 18, 2010

Advanced carcinoma prostate:Management options

Prostate cancer is one of the most common cancer which attributes significantly to the morbidity and mortality among elderly male population. With the introduction of screening programmes for prostate cancer detection, improved modalities of staging, improvements in surgical techniques and monitoring led to early detection and better survival rates compared to that in the past. In countries where screening programmes are not routine, a considerable number of people present with advanced disease (Like in India). Advanced prostate cancer results from any combination of lymphatic, blood, or contiguous local spread. We are coming out with this information as many cancers detected in India are advanced in initial presentation unlike in Western population where majority are locally confined. So routine screening is necessary for early detection of the cancer and also it has been proved to reduce the mortality(as per studies)albeit not dramatically.








Symptoms and signs:
Manifestations of metastatic and advanced prostate cancer may include anemia, bone marrow suppression, weight loss, pathologic fractures, spinal cord compression, pain, hematuria, ureteral and/or bladder outlet obstruction, urinary retention, chronic renal failure, urinary incontinence, and symptoms related to bony or soft-tissue metastases causing bony pain, sometimes disseminated intravascular co-agulation because of bone marrow metastases.
Treatment-related symptoms, such as rectal bleeding, gross hematuria, and urethrorectal fistula, can occur after brachy or systemic radiotherapy.
Physical examination:
• On Per-Rectal Examination grossly hard nodular prostate can be felt reaching pelvic walls.
• Physical examination findings of iliac adenopathy, lower-extremity edema and scrotal oedema, and bony tenderness may indicate metastatic disease. The patient may have paraplegia because of spinal compression, urinary incontinence because of either prostatic obstruction of neurogenic in origin because of spinal cord compression.
• Anemia and systemic symptoms of loss of weight and appetite can be present.
• Chronic renal derangement either because of trigonal infiltration or because of retroperitoneal lymphnodal enlargement.
Work up:
• Hematological workup should include a complete Blood picture and a chemistry profile, including serum creatinine, liver function tests, serum PSA, and acid and alkaline phosphatase.
• Urinalysis should be performed and if necessary complemented with a urine culture, especially if the patient is symptomatic.
• Note that not all patients with a relatively high-grade prostate cancer have elevated PSA levels, nor do elevated PSA levels always signify disease progression. Some anaplastic prostate carcinoma especially with neuronal differentiation.
Imaging Studies
Bone scan: A bone scan may be performed as a baseline for treatment response in patients with recurrent metastatic disease at high risk of having bony metastatic disease. Regardless of these guidelines, a bone scan is indicated in patients with prostate cancer who have symptoms suggesting bony metastases.
• Chest radiography is usually done to reveal rare pulmonary metastases in select cases.
MRI/CT SCAN: May be needed for the evaluation of organ where metastases are suspected. For example; MRI spine for the spinal metastases.
Procedures
• Transrectal ultrasound-guided needle biopsy of the prostate is indicated for tissue diagnosis in patients who present with elevated PSA levels or abnormal digital rectal examination findings or findings suggestive of advanced prostate carcinoma with bony metastases.
• Those patients who progress after radical radiotherapy/radical prostatectomy will show PSA level rising.
(Staging
The Whitmore-Jewett classification of stages A-D is no longer widely used. Prostate cancer does not necessarily progress in a sequential manner.
• Currently, the accepted international tumor, node, metastasis (TNM) staging system pertaining to prostate cancer includes the extent of local disease (T), status of regional lymph nodes (N), and distant metastasis (M).
o Stage T1-2c - Organ-confined disease
o Stage T3a - Extracapsular extension of the tumor
o Stage T3b - Invasion of the seminal vesicle(s)
o Stage T4 - Tumor fixed or tumor invading adjacent structures other than seminal vesicles (eg, bladder neck, external sphincter, rectum, levator muscles, and/or pelvic floor)
o Stage NX - Regional lymph nodes cannot be assessed
o Stage N0 - No regional lymph node metastasis
o Stage N1 - Regional lymph node(s) metastasis
o Stage MX - Distant metastasis cannot be assessed.
o Stage M0 - No distant metastasis
o Stage M1 - Distant metastasis
o Stage M1a - Distant metastasis other than regional lymph nodes
o Stage M1b - Metastasis to bone(s)
o Stage M1c - Other site(s)
o Stage pM1c - Metastasis to more than 1 site
• The definition of stage D by Whitmore-Jewett has been further stratified by Crawford and Blumenstein. The additional stratification is thought to improve classification and understanding of a subset of patients who have hormone-insensitive prostate cancer. The staging is as follows:
o Stage D1 - Involvement of pelvic lymph nodes
o Stage D1.5 - Rising PSA level after failure of local therapy (ie, biochemical failure)
o Stage D2 - Metastatic disease to bone and other organs
o Stage D2.5 - Rising PSA after nadir level
o Stage D3 - Hormone-refractory prostate cancer
o Stage D3.5 - Sensitive to hormones
o Stage D4 - Insensitive to hormones)
Management:

o Bilateral orchidectomy as a treatment modality for carcinoma prostate, introduced by Hodges and Huggins in 1941 has revolutionized the treatment of carcinoma prostate and fetched them Nobel prize. The treatment modalities available for advanced carcinoma prostrate are mainly based on androgen deprivation (hormonal manipulation). The initial response rate of androgen deprivation therapy is more than 80%. This response is usually temporary and palliative. The 5 year survival rate is around 10-20%. The median time to progression and survival for metastatic disease is 12-18 months and 24-36 months respectively. Androgen deprivation has many side effects like: osteopenia, anemia, asthenia, hot flashes and sarcopenia.
o A study by Saad et al (2008) found that the risk of osteopenia, osteoporosis, and bone fractures caused by ADT can be mitigated by appropriate bisphosphonate therapy. The decision to institute bisphosphonate therapy should be based on the risk of these complications on a case-by-case basis. Patients determined to be at risk for such complications should be educated about measured to reduce the risk, including lifestyle modifications that may benefit their general and bone health.
o Different forms of androgen deprivation has been in vogue for ex:o Continuous androgen blockage(CAB) recognizes the 10% contribution of adrenal androgens to the total body testosterone. A GnRH antagonist with a nonsteroidal antiandrogen is used concurrently for what was thought to be complete ADT. However, multiple randomized trials have shown conflicting findings regarding significant improvement in survival.
o Labrie and colleagues described the concept of CAB, in which LHRH accomplished medical castration and antiandrogens achieved peripheral blockade. Initially, they reported improved response and survival rates. Additional studies supported these findings.
o A recent meta-analysis by the Prostate Cancer Trialists' Collaborative Group included 22 trials with a total of 5710 patients with advanced prostate cancer. Both medical castration and bilateral orchiectomy were included. The overall mortality rate was 56.3% in those receiving CAB versus 58.4% receiving medical or surgical castration alone. Estimated 5-year survival rates were 26.2% with CAB and 22.8% with castration alone. No statistically significant survival advantage was found with CAB. The current American Society of Clinical Oncology (ASCO) guidelines recommend castration alone with either an orchiectomy or GnRH agonist.
o Intermittent androgen suppression is a well-established treatment offered to patients with advanced prostate cancer; however, it is not considered standard of care. Some indications for androgen withdrawal therapy include newly diagnosed metastatic disease, localized disease with high risk of systemic relapse, PSA level rise during treatment, lack of tolerance for side effects, and biochemical failure after local therapy. Intermittent androgen suppression may delay androgen-independent cancer and increase quality of life (i.e., fewer issues regarding potency and libido). Ongoing research is investigating the utility of intermittent treatment.
Early versus delayed treatment
o In the years following the introduction of hormone therapy for prostate cancer by Huggins and Hodges, early institution of such treatment was recommended based on comparison with historical controls.
o Later, the Veterans Administration Cooperative Urology Research Group (VACURG) studies reversed the recommendation of early hormone therapy; instead, hormone therapy was deferred until symptomatic progression. Thus allowing patient to have quality of life avoiding ADT. The Medical Research Council study published in 1997 was a randomized study of 938 patients with locally advanced or asymptomatic metastatic prostate cancer. Patients received treatment with orchiectomy or LHRH agonist, either immediately or after symptoms occurred. Development of extraskeletal metastases, pathologic bone fractures, spinal cord compression, and ureteral obstruction was twice as common in the deferred-treatment group. Overall survival was significantly prolonged in those who were treated early.
o However, virtually all patients develop hormone-refractory disease. Although hormone therapy is associated with significant responses, its curative potential is limited because of the inherent heterogeneity of prostate cancer and the inability of hormones to eradicate all prostate cancer clones, both the androgen-dependent and androgen-independent components.
Many theories were proposed to explain this hormone independent stage:
1. Androgen independent cell line reaching critical proportion.
2. Phenotypic changes
i) Morphologic transformation
ii) Growth pattern and differentiation change
iii) Cellular antigenic expression modification
3. Biological change
a) Mutation
b) Oncogenes
c) Enhanced tumour angiogenesis
d) Altered expression of androgen receptors (AR)
Rising PSA level is usually the first manifestation of disease progression after androgen deprivation. This rise in serum PSA precedes approximately 6 months before clinical evidence of the disease. Progression of the disease is suspected if there is a rise in PSA level or worsening symptoms and the progression can be seen in imaging studies most of the times.
The biological mechanism of the failure of hormonal therapies is not completely understood but many factors are likely to contribute. Throughout the progression of prostate cancer AR continues to be the primary effector of tumor growth and progression despite castrate testosterone, even in the presence of anti-androgens. Amplification of the AR gene is present in HRPC and it has been shown to correlate with increased AR protein expression. AR mutations are most common in patients with progressive disease despite treatment with antiandrogen, reflecting the strong selection pressure induced by these agents. A practical implication of this data is that each antiandrogen may interact uniquely with AR. Therefore, it is reasonable that a patient progressing while receiving antiandrogen may still respond to another member of this class of agents.
After hormonal therapy alternative signaling mechanisms through AR maintain cellular proliferation and survival despite castrate testosterone. They consist of mechanisms that occur in a ligand dependent or a ligand independent manner. The former includes AR mutations, which lead to receptor promiscuity and activation by a range of steroid hormones, and amplification of the AR gene. The latter includes AR activation by nonclassic factors, such as certain growth factors (epidermal growth factor, insulin-like growth factor-1 and keratinocyte growth factor), receptor tyrosine kinases, activation of the AKT (protein kinase B) and mitogen-activated protein kinase pathways, recruitment of coactivators such as ARA70 and alternative signaling pathways. The recent finding that an increase in AR expression is associated with resistance to antiandrogen therapy may provide insight into the development of new diagnostic and treatment strategies for advanced prostate cancer. A provocative thought is that AR over expression may allow the continued growth of prostate cancer cells due to minute amounts of testosterone undetectable by conventional assays.
An increasing body of data on second-line endocrine manipulations in patients with evidence of disease progression after initial androgen deprivation suggests that there may be a role for this approach before institution of other therapies. Although response rates between 20% and 80% have been reported in various studies, the median duration of response in the patients treated in the reported experience is short, ranging between 2 and 4 months. Of castrate patients with HRPC treated with high doses (150 to 200 mg) of bicalutamide 20% to 24% have PSA decreases of 50% or greater with most responses seen in those who received prior flutamide therapy.

Ketoconazole (200 or 400 mg 3 times daily) is an antifungal that interferes with cytochrome 3A4 and inhibits steroidogenesis in the testes and adrenal glands. The most common side effects are weakness or lack of strength, gastrointestinal complaints such as nausea or vomiting, hepatotoxicity, skin reactions and a potential risk of adrenal suppression. The principal side effects of ketoconazole are related to gastric irritation, leading to nausea and anorexia in at least 10% of patients. Glucocorticoid repletion is a standard supportive therapy in patients treated with agents that inhibit adrenal function. These agents may also have modest anticancer activity. Diethylstilbestrol is an inexpensive synthetic estrogen that decreases testosterone by decreasing LHRH secretion as well as directly inhibiting LH secretion by the pituitary gland. DES at a dose of 3 mg daily results in castrate testosterone in 1 to 2 weeks by the inhibition of LHRH production from the hypothalamus. Several studies have demonstrated the modest efficacy of estrogens in the context of HRPC with PSA responses of 26% to 66% at 1 to 3 mg DES. DES is associated with significant cardiovascular toxicities, including myocardial infarction, stroke and pulmonary embolism, especially at moderate to high doses. Anticoagulation with Coumadin is recommended to prevent these side effects. Nonstandard secondary hormonal manipulations, such as estrogens, antiestrogens and progestins, are associated with low response rates In patients with castrate serum testosterone levels, hormone-refractory prostate cancer is defined as 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from CT scan and/or bone scan, bone pain, or obstructive voiding symptoms. In a subgroup of patients, the PSA level does not rise at diagnosis or throughout the entire course of the disease.


Nonhormonal approaches are required for the treatment of HRPC. The options available are:
1. Chemotherapy
2. Radiotherapy
3. Gene therapy
4. Newer systemic approaches




The options for the treatment of HRPC are limited; many chemotherapy regimes have been shown to be ineffective and associated with significant toxicity. More recently, alternative chemotherapy regimens, such as those based on mitoxantrone, estramustine and taxanes, have been identified and are increasingly used to control the cancer. Docetaxel belongs to the taxane class of chemotherapy drugs. It works by inhibiting tubulin, a protein essential to cell division, thus preventing cancer cells from dividing and growing in number. Most of the studies with docetaxel are done in combination with other drugs like thalidomide, etramustine and prednisolone. The results are encouraging. Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. Docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer was compared in one of the trials where 770 men were randomized to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. In the sudy result was out Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02.The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers, nausea and vomiting, and cardiovascular events were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. This study shows improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

Radiotherapy:HRPC responds poorly to radiotherapy. Role of radiotherapy in these cases is limited to palliation of bone pain and in treating spinal cord compression due to metastases. Adverse effects of EBRT include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence.

Gene therapy:
Molecular medicine has resulted in the identification of numerous antigens associated with several cancers, including adenocarcinoma of the prostate. Induction of antitumor immune responses after immunization has been demonstrated in preclinical studies. Specific immune cells responsible for tumor killing in the laboratory have been shown to detect target cells by recognizing major histocompatibility complex proteins in the membrane of these cells, and evidence of antitumor activity has been detected in vivo. Among the most potent antigen-presenting cells are dendritic cells, which have been used as vehicles for tumor-specific antigens such as prostate-specific membrane antibody, and this constitutes the background for immunostimulatory strategies against prostate cancer. Initial phase I and phase II studies with a dendritic cell vaccine have demonstrated safety in patients with advanced hormone refractory disease, and additional trials are in process to evaluate the efficacy of this approach. Cytoreductive approaches include the use of granulocyte-macrophage colony-stimulating growth factor transduced allogeneic prostate cancer cells. Tumor-specific immune responses have been reported, along with evidence of safety in patients with advanced disease; clinical trials are in process to further define the efficacy in prostate cancer. Other approaches include the transduction of suicide genes, such as the thymidine kinase gene, that can be activated by agents such as gancyclovir; use of toxins such as diphtheria and Pseudomonas; and targeting against critical cellular promoters, such as adhesion molecules and various other mechanisms involved in tumor cell–specific cell kill.
Newer systemic therapy:
Newer systemic approaches include antiangiogenic drugs like thalidomide. Angiogenesis is a process of new blood vessel development from pre-existing vasculature. It plays an essential role in embryonic development, normal growth of tissues, wound healing, female reproductive cycle (i.e., ovulation, menstruation and placental development) and also is central to several pathological processes such as tumour growth and metastasis. Particular interest has been focused on cancer, since tumours cannot grow beyond a few millimeters in size without developing a new blood supply. Angiogenesis therefore is necessary for the spread and growth of tumour cell metastasis.
Bevacizumab blocks the activity of a protein called vascular endothelial growth factor (VEGF). Many cancers use VEGF to help form the new blood vessels they need for continued growth. Furthermore, high levels of VEGF in the blood and urine of patients with hormone-refractory prostate cancer have been found to indicate a reduced likelihood of survival.
A previous phase II clinical trial that combined docetaxel and bevacizumab resulted in improved outcomes over historical controls.
Other novel agents: Suramin acts via growth factor inhibition. It remains active in patients with hormone-refractory cancer and may be used in combination with other agents. Adverse effects include edema, leukopenia, infection, hyperglycemia, anemia, anorexia, dyspnea, platelet abnormalities, elevated creatinine levels, malaise, arrhythmias, and coagulopathy.

Radio-Isotope therapy:

More than two-thirds of the patients with osseous metastases experience debilitating bone pain, requiring some form of pain relief. Analgesics are limited in their efficacy. Palliative application of hemi-body external beam radiation therapy in the treatment of multiple osseous metastases also is limited due to toxicity associated with large treatment ports. Intravenous injections of bone seeking radioisotopes (Phosphorus 32 /strontium) are effective in the palliation of pain with fewer side effects.
Surgery:

Surgical intervention of weight-bearing bones involved in pathologic fractures is mandatory.
Consultations

• Consultation with a radiation oncologist should be obtained for palliative radiation therapy for bone metastases, locally extensive tumors, and on an emergent basis for spinal cord compression.
• Consultations with a neurosurgeon for spinal cord compression and an orthopedic surgeon for pathologic fractures are appropriate.
• Consultation with a medical oncologist may also be considered for chemotherapy.
Diet
• Because a high-fat diet is linked with a higher incidence of prostate cancer, a low-fat diet may be beneficial for patients at high risk of developing prostate cancer (namely those with positive family history, African American males) and for patients undergoing treatment for advanced prostate cancer.
• Tomatoes, broccoli, green tea, soy, lycopenes, licorice root, selenium, and antioxidants have all been hypothesized to be beneficial.




• The Physicians' Health Study II, a long-term randomized controlled trial involving male physicians, recently found that neither vitamin E nor C supplementation reduced the risk of cancer—prostate or otherwise.
• Similarly, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized placebo-controlled trial involving 35,533 relatively healthy study participants from 427 US sites, found that neither selenium nor vitamin E (alone or in combination), at the doses and formulations used, prevented prostate cancer.
Activity

• Patients diagnosed with impending paralysis due to spinal cord compression or patients with pathologic fractures should be immediately immobilized until appropriate consultations are obtained. They should be immediately given methyl prednisolone injection to reduce the oedema so as to further prevent the damage to spinal cord.
• A study conducted by Agarwal et al has shown the bone mineral density of Indian men is low even before androgen supplementation; so careful follow-up with BMD measurement with calcium, alpha –D3, zoledronic acid supplementation and daily atleast 30-45 minutes of activity –like walking would help Indian men with advanced prostate cancer to cope with the effects of loss of Bone Mineral Density .