Tuesday, April 30, 2013

Application of Continuous Incisional Infusion of Local Anesthetic after Major Pediatric Urological Surgery Antoine E. Khoury

Introduction and Objective: To determine the efficacy of the newly developed locally infused anesthetic, ON-Q pain relief system (Kimberly-Clarke, Georgia), in improving postoperative pain, reducing narcotic requirement, and shortening recovery time after major pediatric urological surgery.
Material and Methods: A case-control analysis comparing 20 patients undergoing major urological  procedures who were treated postoperatively with the ON-Q system was compared to 20 patients treated with current hospital standard of care intravenous and oral analgesics. Pain was assessed in both groups  by staff nurses using the Visual Analog Scale (VAS) or the Face, Legs, Activity, Cry, Consolability Scale (FLACC) depending on the child’s age. Information regarding analgesic consumption along with recovery parameters such as temperature, start of oral nutrition, and length of hospitalization (LOH) were collected.
Results: The ON-Q group experienced significantly lower ratings of maximal pain on the first  postoperative day as compared to the control group (3 vs. 5.2, p=0.03) and a trend toward lower mean of  maximal pain score on post operative day two (1.8 vs. 3.5, p=0.055). Systemic intravenous and oral analgesics were significantly lower on the day of surgery and the first postoperative day for the ON-Q group (p=0.014; and p=0.046 respectively). No differences in frequency of fever, start of oral nutrition and LOH were found between study groups.
Conclusion: Continuous incisional infusion of local anesthetic with the ON-Q system is a viable option for postoperative pain management in children undergoing major urological surgeries. This technology significantly decreases the need for systemic analgesic consumption.

Saturday, April 27, 2013




Monday, April 22, 2013

Umbilical ligaments and folds

The median umbilical ligament is a structure in human anatomy. It is a shrivelled piece of tissue that represents the remnant of the embryonic urachus.
It extends from the apex of the bladder to the umbilicus, on the deep surface of the anterior abdominal wall. It is unpaired.
It is covered by the median umbilical fold
Lateral to this structure are the medial umbilical ligament (which is a different structure, not to be confused) and the lateral umbilical ligament.
It may be used as a landmark for surgeons who are performing laparoscopy, such as laparoscopic inguinal hernia repair. Other than this, it has no function in a born human and may be cut or removed with impunity الإفلات من العقاب.

2- Medial umbilical ligament
The medial umbilical ligament (or cord of umbilical artery) is a paired structure found in human anatomy. It is on the deep surface of the anterior abdominal wall, and is covered by the medial umbilical folds (plica umbilicalis medialis). It should not be confused with the median umbilical ligament, a different structure that represents the remnant of the embryonic urachus.


It represents the remnant of the fetal umbilical arteries, which serves no purpose in humans after birth, except for the part that becomes the adult umbilical artery.


It may be used as a landmark for surgeons exploring the medial inguinal fossa during laparoscopic inguinal hernia repair. Other than this, it has no purpose in an adult and it may be cut or damaged with impunity.


The supravesical fossa, and therefore a supravesical hernia, is medial to this structure. The medial inguinal fossa, and therefore a direct inguinal hernia, is lateral to it.

3- Lateral Umbilical Ligaments
The inferior epigastric artery is a medial branch of the distal segment of the external iliac artery. It ascends along the medial margin of the deep inguinal ring, continues between the rectus abdominis muscle and the posterior lamina of its sheath, and then abuts محاذياً on the anterior parietal peritoneum to create the lateral umbilical ligament. This ligament is the least pronounced of the three aforementioned peritoneal folds, and it is not always readily visualized. However, knowledge of its location is important to avoid injury to these vessels during either insertion of the lateral trocars or dissection of the space of Retzius.

Lateral umbilical fold

The lateral umbilical fold overlies the inferior epigastric artery (a branch of the external iliac artery) and its accompanying veins. Unlike the median and medial umbilical folds, the contents of the Lateral Umbilical fold remain functional after birth. It extends from inguinal ring to arcuate line.

Clinical significance

The lateral umbilical fold is an important reference site with regards to hernia classification. A direct hernia occurs medial to the lateral umbilical fold, whereas an indirect hernia originates lateral to the fold. This later case is due to the placement of the opening of the deep inguinal ring in the space lateral to the lateral umbilical fold, which allows the passage of the ductus deferens, testicular artery, and other components of the spermatic cord in men, or the round ligament of the uterus in women.

Posterior view of the anterior abdominal wall in its lower half. The peritoneum is in place, and the various cords are shining through.

Friday, April 19, 2013


A term baby girl, who was born weighing 3 kg, is admitted to the pediatric
intensive care unit at 14 days of age. She is breastfeeding reasonably
and has continuous wet nappies. On examination, she weighs 2.4 kg and
appears dehydrated and unwell. Her observations reveal systolic blood pressure
of 40 mm Hg. Investigations show the following values: hemoglobin,
19 g/dl; WBC count, 12 × 109/l; platelet count, 246 × 109/l; sodium,
125 mmol/l; potassium, 6.5 mmol/l; urea, 10.4mmol/l; and plasma creatinine,
250μmol/l. Abdominal ultrasound shows a provisional diagnosis of
bilateral renal dysplasia and bilateral pelviureteric junction (PUJ) obstruction.

1 What immediate management would you institute?
2 What other urgent tests are required?
3 When she is better and tolerating enteral feeds, what further management
might she require?

1 Althoughinitiallytermbabiescanloseupto10%of their birth weight, they
usually regain this by day 10. However, this baby has lost 20% of her birth
weight at 2 weeks of age, and clinically this represents severe dehydration.
The immediate management would be confirmation of hypovolemic
shock looking for prolonged capillary refill time and other signs of poor
peripheral perfusion. She required urgent resuscitation with a bolus of
20 ml/kg of crystalloid (such as 0.9% sodium chloride) and commencement
of intravenous broad-spectrum antibiotics, ideally after samples of
urine, blood, and cerebrospinal fluid for culture and sensitivity.
2 Other urgent tests required are blood gas with tCO2, serum glucose, calcium,
and phosphate.
3 As she improves, the urinary tract ultrasound should be repeated, as initial
ultrasound when neonates are dehydrated may not show definitive
pathologies and true size of dilatation. Long-term prophylactic antibiotics
must also be considered. Many children with renal dysplasia are obligate
salt losers (with consistently high urinary sodium levels of6080mmol/l),
polyuric (even when dehydrated), and also usually quite acidotic. They
may require large quantities of both sodium chloride and sodium bicarbonate
to correct these losses, first intravenously and then enterally. Long term supplementation
with sodium chloride and sodium bicarbonate will
also be required, but take care not to overdo it when requirements fall as
the renal function deteriorates.


A male baby is born at 36 weeks gestation following a diagnosis of bilateral hydroureteronephrosis, thick-walled bladder, and oligohydramnios made at 21 weeks gestation.

1- What is the most likely underlying diagnosis?
2- What postnatal radiology investigations are required?
3-What investigations will give information about prognosis?

1 The most likely underlying diagnosis is posterior urethral valves, which
has an estimated incidence of 1 in 5000 to 1 in 8000.
2 The best postnatal radiology investigations are ultrasound of the kidneys
and urinary tract (whichmay showa thick-walled, poorly emptying bladder
with upper tract dilatation and possible aberrant kidney development)
and micturating cystourethrogram.
3 The best prognostic indicators are the size of kidneys, amount of renal
parenchyma, and corticomedullary differentiation. Other prognostic indicators
are plasma creatinine at 1 month of age, measured glomerular
filtration rate (e.g. using 51-labeled chromiumEDTA) at12months of age,
and later formal urodynamic assessment.

Consider the same case, but with placement of vesicoamniotic shunt at 31 weeks, which appeared to work initially (i.e. led to reduced dilatation) but was then lost and presumed to be dislodged. What is the likely cause of a rapidly rising urea and creatinine within a few days after birth?

This may reflect the underlying severe renal disease but might also represent occult internalization of shunt, which can drain into the peritoneal cavity generating urinary ascites, which is reabsorbed and exacerbates apparent renal dysfunction.

Michigan Manual of Plastic Surgery

Clinical Problems in Pediatric Urology

Operative Urology: At the Cleveland Clinic

Pocket Guide to the Operating Room Book

Wednesday, April 10, 2013

Modern management of stone disease

Prostate caner updates 2013

Tuesday, April 9, 2013

Surgical Suturing Videos

MR-Guided Biopsy of the Prostate Trumps Transrectal Approach Pam Harrison Mar 11, 2013

VIENNA, Austria — Magnetic resonance (MR)-guided biopsy of the prostate is a safe and effective alternative to the standard transrectal ultrasound-guided biopsy, and patients prefer it, according to 2 new studies.
"The problem with the transrectal approach is that significant cancers are missed, insignificant cancers are detected by chance, and there's a high percentage of undergrading of the lesions," lead researcher of one of the studies, Stephan Polanec, MD, from the Medical University of Vienna in Austria, told Medscape Medical News.
"MR-guided biopsy is a targeted biopsy with pinpoint accuracy and a higher detection rate. It also detects cancer in the anterior part of the prostate, which the transrectal approach isn't able to do," he explained here at the European Congress of Radiology 2013.
In the first study, Dr. Polanec and colleagues analyzed 44 biopsies from 41 patients that were initially identified as suspicious on multiparametric magnetic resonance imaging (MRI), which combines several different MRI techniques to render a complex image of the prostate.
Mean patient age was 65 years and mean prostate-specific antigen (PSA) level was 8.17 ng/mL. All patients had at least 1 previous negative transrectal ultrasound-guided biopsy.
Dr. Polanec explained that for MR-guided biopsy, patients are placed in the prone position with the head forward and an 18-gauge needle is inserted transrectally. Approximately 3 or 4 biopsy cores are extracted during the procedure.
On MR-guided biopsy, conducted in a 1.5 Tesla MR unit, lesions were identified as malignant in 11 patients. In the remaining 30 patients, no prostate cancer was detected on MR-guided biopsy and no prostate cancer was subsequently identified during active monitoring (mean follow-up, 36 months).
Of the 11 patients in whom prostate cancer was identified, 5 had a Gleason score of 6, 4 had a Gleason score of 7, 1 had a Gleason score of 8, and 1 had a Gleason score of 9.
In 9 patients, the cancer was identified in the peripheral zone of the prostate, in 1 patient it was in the transition zone, and in 1 it was in the central zone.
"It's very important to mention that no new prostate cancer was detected during our follow-up of the benign lesions, so the sensitivity of MR-guided biopsy was therefore 100%," Dr. Polanec said.
"While I don't think MR-guided biopsy will replace the transrectal approach, if I were a patient, I would prefer doing the multiparametric MRI in combination with MR-guided biopsy because you reduce the number of cores you need and it's just more comfortable," he said.
More Comfortable for Patients
In the second study, lead researcher Tobias Franiel, MD, from Charité Medical University in Berlin, Germany, and colleagues compared acceptance, adverse effects, and complications between MR-guided biopsy and transrectal ultrasound-guided biopsy.
The researchers looked at 54 patients with a median PSA of 12.1 ng/mL. All patients had at least 1 previous negative result on transrectal ultrasound-guided biopsy, during which 10 to 12 biopsy cores were harvested.
Patients subsequently underwent MR-guided biopsy, and were then questioned about pain duration and intensity, adverse events, and their preferred procedure.
"Sixty-five percent of patients indicated they preferred the MR-guided biopsy because there were fewer side effects and they expected better results than with the transrectal approach," Dr. Franiel explained.
Patients rated pain duration and intensity significantly lower with MR-guided biopsy, and 82% said they would prefer the MR-guided approach for any subsequent biopsies.
Both approaches had a low complication rate (6% each).
However, "our study had several limitations," Dr. Franiel acknowledged.
First, the median interval between the initial procedure and subsequent MR-guided biopsy was 13 months, which is admittedly "quite long," he said.
Second, patients were questioned only after the MR-guided biopsy, not after the transrectal approach.
It is quite possible that these 2 issues could "have led to a recall bias," he pointed out.
In addition, because all patients had at least 1 negative ultrasound biopsy, it could be that they were negatively biased against that approach and favorably predisposed to think positively about MR-guided biopsy.
"Nevertheless, we think it's justified to conclude that patients prefer targeted MR-guided biopsy of the prostate...due to lower pain intensity and fewer side effects, Dr. Franiel said. "Targeted MR-guided biopsy is a suitable option for patients with persistent suspicion of prostate cancer," he added.
Jurgen Fütterer, MD, from Radboud University Nijmegen Medical Centre in the Netherlands, who was asked by Medscape Medical News to comment on these studies, agrees that ultrasound-guided biopsy has a poor yield for cancer detection (range, ~40% to 45%).
He also agrees that the multiparametric MR-guided approach is a far more targeted option and requires far fewer biopsies for histopathologic analysis.
"With the MR-guided technique, you use imaging to guide the needle to the exact spot identified on multiparametric MRI, so you need far fewer biopsies and you are sure you're right on target," Dr. Fütterer said.
In addition, in patients with a negative biopsy, the likelihood of picking up a subsequent cancer on an additional ultrasound biopsy is only about 12% to 14%.
The detection rate found by Dr. Polanec's team was approximately 27%, which is low compared with the reported 40% to 50% detection rate for MR-guided biopsy in patients with negative ultrasound-guided biopsy results, but better than an additional ultrasound biopsy would have yielded, Dr. Fütterer noted.
Dr. Polanec, Dr. Franiel, and Dr. Fütterer have disclosed no relevant financial relationships.
European Congress of Radiology (ECR) 2013: Abstracts B171 and B172. Presented March 7, 2013.

National Comprehensive Cancer Network (NCCN) Issues New Treatment Guidelines for Penile Cancer Roxanne Nelson Mar 22, 2013

Hollywood, Florida — The National Comprehensive Cancer Network (NCCN) has issued new treatment guidelines for penile cancer.
"The first thing people ask me is why develop guidelines for such a rare cancer," said Philippe  E. Spiess, MD, genitourinary oncologist at the H. Lee Moffitt Cancer Center in Tampa, Florida.
In 2010, an estimated 1250 new cases of penile cancer were diagnosed in the United States and there were about 310 related deaths. Penile cancer accounts for 0.4% to 0.6% of all malignant neoplasms in the United States and Europe.
Dr. Spiess presented highlights of the guidelines here at the NCCN 18th Annual Conference.
There is a high degree of heterogeneity in the way penile cancer is treated in North America and globally, he explained. "The standard of care remains complete tumor excision and eradication of negative margins."
However, there has been increasing consideration of less or noninvasive management of primary penile tumors, based on stage and grade, he added.
Less and Noninvasive Therapy
For carcinoma in situ and superficial verrucous carcinoma, a British study showed that 5-fluorouracil or imiquimod produced response rates of 60% to 70% at 5 years (World J Urol. 2009;27:179-187). In this setting, CO2 and Nd:YAG laser ablation can also be used, although retreatment rates are quite high (about 20% to 30%), explained Dr. Spiess.
Total gland resurfacing and wide local excision with circumcision are also options.
There is some evidence for the use of topical therapies. In a recent retrospective review of all primary and recurrent cases of penile carcinoma in situ treated with topical 5-fluorouracil and imiquimod over a 10-year period (Eur Urol. 2012;62:923-928), "the response rates were excellent," said Dr. Spiess. "A complete response was seen in 57% of the patients, with a partial response in 14%."
No response was seen in the remaining 29.5% of patients, but none of the patients recurred or progressed. Toxicity was also low; 10% of patients reported local toxicity and 12% reported an adverse event.
Another study, looking at penile-preserving surgery for patients with penile Tis and PT1 tumors, found that there was a recurrence rate of 21.4% in both subgroups (J Urol. 2011;186:1303-1307). At 5 years, 13.8% of patients had a late recurrence, but none of the patients with pTis tumors had progressed to invasive or metastatic disease.
"These patients can recur fairly late, so it is important to follow them for at least 10 years," Dr. Spiess pointed out.
"As far as penile-preserving therapy, the take-home message is that clinical stage is everything," Dr. Spiess explained. However, he went on to emphasize that "it has to be a patient with a small superficial lesion, where you can obtain negative margins. If you can't, then you need to look at more radical options in surgery."
Another treatment option is brachytherapy. A recent French study found a 10-year penile recurrence rate of 20% and a 10-year inguinal recurrence rate of 11% (Int J Radiat Oncol Biol Phys. 2009;74:1150-1156). However, "centers of excellence that have experience with penile brachytherapy are few and far between," he cautioned. "That's why the guidelines...are somewhat cautious in making recommendations until we see a wider experience using penile brachytherapy."
He emphasized the importance of stringent surveillance after radiotherapy to the penis; up to 40% of patients who receive radical radiotherapy will eventually need surgery for disease recurrence. Surgery in this population can be challenging because irradiated tissues are brittle and poorly vascularized, making them less than ideal for grafting.
Sentinel Node Biopsy
Dr. Spiess discussed the concept of sentinel lymph node biopsy in penile cancer, which was proposed more than 30 years ago. One study reported a false-negative rate of 18% using a combined preoperative injection of technetium-99m labeled sulfur colloid and isosulfan blue dye (J Urol. 2002;168:76-80).
A more recent prospective study found a sensitivity of only 71%, with 2 false-negative results reported (J Urol. 2007;177:2157-2161). But a review found that false-positive results can be minimized with preoperative ultrasound and fine-needle aspiration cytology on suspicious nodes (World J Urol. 2009;27:197-203).
However, this technique has not yet been embraced in this setting. "We are somewhat cautious about promoting this technique, although clearly it is something very interesting and something that can be used at a center that has high expertise in sentinel lymph node biopsy," said Dr. Spiess. "At this point, it is not being widely used in North American centers."
National Comprehensive Cancer Network (NCCN) 18th Annual Conference.

Bladder Cancer: Current Optimal Intravesical Treatment Donald L. Lamm, William R. McGee, Kaye Hale Disclosures Urol Nurs. 2005;25(5):323-332.

Superficial bladder cancer can be treated surgically, but patients are at high risk for recurrence. Tumors are categorized as low, intermediate, and high-risk based on grade, stage, and pattern of recurrence. Low-risk tumors are best treated with a single instillation of chemotherapy (thiotepa, doxorubicin, or mitomycin) (Lamm, 2002). Though effective, the toxicity of bacillus Calmette-Guerin immunotherapy (BCG) restricts its use to treat higher-grade tumors. Intermediate risk tumors can be treated with chemotherapy as well, but will often require immunotherapy. High-risk tumors are best treated with intravesical BCG using a 3-week maintenance schedule. Side effects of BCG immunotherapy can be decreased by logarithmic reductions in dose. Patients who fail BCG may be rescued with BCG plus interferon alfa or radical cystectomy.
Bladder cancer is more common than generally appreciated; 62,240 new cases and 12,710 deaths were expected in the United States in 2004 (Jemal et al., 2004). Patients typically present with either microscopic or gross hematuria. Bleeding from a bladder tumor is generally intermittent. Therefore resolution, either spontaneously or after antibiotic treatment for presumed bladder infection, does not reduce the need for urologic evaluation. Diagnostic studies most commonly used are intravenous urography, urine cytology, and cystoscopy. Fortunately, about 80% of patients present with superficial disease that can be successfully treated surgically (Lamm, Griffith, Pettit, & Nseyo, 1992). Effective treatment plans can lead to high survival rates. The goals of treatment are (a) reduce tumor recurrence, (b) lower the risk of disease progression, and (c) improve survival. Preventing progression to muscle-invasive disease is key, because only 50% of these patients will survive 5 years even with aggressive surgery (cystectomy) (Dalbagni et al., 2001). Prognosis, as noted later, is also highly dependent on grade.
Historically, two-thirds of patients have tumor recurrence within 5 years, and nearly 90% have recurrence by 15 years (Lamm & Griffith, 1992). Two factors best predict recurrence: (a) history of previous recurrence, particularly if within 3 months, and (b) the presence of multiple tumors. Solitary tumors recurred in 51% of patients, while those with recurrent tumors or multiple tumors had recurrence rates of 91% (Heney, 1992). As few as 20% of patients who are disease-free at 3 months will have tumor recurrence within 5 years. Invasion of the stroma (lamina propria) increases the risk of invasion into the bladder muscle from 4% to 30% (Vicente, Laguna, Duarte, Algaba, & Chechile, 1991). High-grade tumors have a significantly worse prognosis. In the National Bladder Cancer Group study, only 2% of patients with low-grade (grade I Stage Ta) tumors had progression to muscle invasion, compared with 48% of patients with high-grade (grade III Stage T1) tumors. The presence of carcinoma in situ (CIS) significantly worsens the prognosis of high-grade disease, increasing progression risk from 10% to 65% in one study (Bostwick, 1992). The best predictor of death from superficial bladder cancer is the presence of high-grade disease. Mortality for low-grade tumors was 6% compared with 21% for high-grade tumors (Heney, 1992).
The European Organization for Research and Treatment of Cancer (EORTC) divided superficial bladder cancer patients into low, intermediate, and high-risk groups based on their experience with thousands of patients enrolled in prospective studies. The authors' experience corroborates that – low-risk patients are those with solitary grade I Stage Ta tumors; intermediate-risk patients are those with multiple or recurrent grade I Stage Ta tumors, or grade II Ta tumor(s) (single or multiple); high-risk patients are those with one or more of the following: grade III disease (high-grade, in the new terminology), lamina propria (T1) invasive disease, CIS, or recurrence at 3 months.
Smoking has long been recognized as an important risk factor for bladder cancer, but only recently has the importance of smoking cessation been demonstrated. One study reviewed 286 patients, including ex-smokers, patients who quit smoking at the time of diagnosis, and patients who continued to smoke. Ex-smokers presented at a later age, had an improved recurrence-free survival compared to quitters and current smokers (p < 0.03), and most importantly, had a higher progression-free survival (p < 0.01) (Fleshner et al., 1999). Therefore, early smoking cessation is not only effective at preventing recurrence of superficial bladder cancer, it is also the least toxic and most cost effective option (Chen, Su, Guo, Houseman, & Christiani, 2005).
Genetic predisposition is clearly a factor in the development of bladder cancer, but familial occurrence is rare. Environmental factors impact DNA to modify tumor suppressor genes (p53), genes controlling cell proliferation (Rb), growth factor genes (erbB-2), and others (p15, p16). Chemical carcinogens are thought to account for 20% of bladder cancers in the United States.
Dietary factors are also potentially important in bladder cancer. Diets low in vitamin A and low serum carotene levels are associated with increased risk of bladder cancer. Multiple animal studies and two clinical trials demonstrated that vitamin A derivatives reduce the development and recurrence of bladder cancer. Pyridoxine (vitamin B6) is reported to enhance tumor immunity in animals. B6 was as effective as thiotepa (discussed later) in reducing bladder cancer recurrence after 1 year, but subsequent studies failed to confirm its benefit (Byar & Blackard, 1977). Vitamins C and E may reduce patient's risk of developing bladder cancer but studies are inconsistent. Evidence for anti-tumor activity also exists for folic acid and vitamin D (Kamat & Lamm, 1999). Finally, a vitamin preparation containing high doses of vitamins A, B6, C, and E demonstrated in a randomized clinical trial to reduce tumor recurrence significantly, and is commercially available as Oncovite® from Mission Pharmacal (Lamm et al., 1994).
Increased intake of dietary fat, particularly cholesterol, is linked to increased risk of bladder cancer. Soy proteins appear to inhibit bladder carcinogenesis, and garlic extract has been confirmed, in the murine bladder cancer model, to inhibit the growth of transplanted bladder cancer.
Additional agents associated with reduced risk of bladder cancer or anti-tumor effect in animals include selenium, green tea, and nonsteroidal anti-inflammatory drugs including ketoprofen, sulindac, and piroxicam. Clinical studies are evaluating Celebrex® and the anti-schistosomal agent, Oltipraz,® which inhibits nitrosamine carcinogenesis (Lamm et al., 1994).
Four intravesical drugs are available and commonly used as chemotherapy in the United States with one more that has been studied and used, but is currently not available. Randomized trials have failed to demonstrate that any of the chemotherapies — thiotepa, doxorubicin, mitomycin C, epirubicin, or the previously available valrubicin — is superior to the others. Randomized trials also failed to show that chemotherapy reduces progression or reduces mortality. The EORTC/MRC meta analysis showed a long-term reduction in tumor recurrence of 6%, but no reduction in disease progression or mortality (Pawinski et al., 1996).
Since the side effects of chemotherapy are generally less than bacillus Calmette-Guerin (BCG) immunotherapy, chemotherapy is the treatment of choice for low-risk patients (see Table 1 ). Patients who fail to respond to alkylating agents (thiotepa or mitomycin C) may be best treated with an intercalating agent (doxorubicin, epirubicin, or valrubicin) and vice versa.
Data now clearly show that the greatest benefit of intravesical chemotherapy occurs when treatment is given to prevent seeding and initiated within 6 hours of tumor resection. Continued treatment for 4 to 8 weeks is appropriate for patients with residual disease until complete response is obtained, but "maintenance" chemotherapy or "prophylactic" chemotherapy has not been demonstrated to be effective. The use of chemotherapy in the absence of existing malignancy should be avoided. Animal studies have demonstrated that repeated instillation of thiotepa, doxorubicin, or mitomycin C can induce hyperplasia, dysplasia, carcinoma in situ, and even, in the case of mitomycin C, invasive transitional cell carcinoma (Friedman, Mooppan, Rosen, & Kim, 1991).
In contrast to systemic chemotherapy, where the administered dose is of primary importance, with topical intravesical chemotherapy, response is proportional to drug concentration and duration of exposure. Since duration of exposure is limited by bladder capacity, and increased urine output reduces drug concentration, overnight dehydration is recommended prior to drug instillation. Patients are generally asked to retain the instilled drug for 2 hours. Care must be taken to completely empty the bladder prior to instilling chemotherapy. An ultrasound of the bladder after insertion of a catheter is useful in confirming complete emptying, since, surprisingly, catheterization does not reliably empty. This was objectively determined by Au et al. (2001). It resulted in a protocol that required confirmation of bladder emptying with a bladder scan prior to intravesical mitomycin instillation into the bladder for all patients. We recommend that patients lie prone for 15 minutes to displace the air bubble introduced with the catheter, thereby ensuring contact at the bladder dome.
Available Intravesical Chemotherapies: Thiotepa. The standard dosage of thiotepa is 30 mg in 15 cc sterile water. When given as a single instillation at the time of tumor resection, an exposure of 30 minutes is used. When not given in conjunction with tumor resection, doses of 30 mg to 60 mg are used in 15 cc to 30 cc of sterile water and held for 2 hours. Treatment is given weekly for 4 to 8 weeks, depending on volume of residual disease. When repeated treatments are used, blood counts should be obtained, since thiotepa has a molecular weight of 188 and drugs with molecular weight less than 300 are more readily absorbed from the bladder. Liver function studies are not required, since the primary toxicity of thiotepa is due to myelosuppression. The intravenous dose of thiotepa is 0.5 mg/kg, so a single treatment is safe even if, as is common with large tumors and recent resection, 100% absorption occurs.
Thiotepa has been used in many body cavities, including the peritoneum. Unlike most other chemotherapies, which are caustic, thiotepa can be instilled safely in the bladder even if perforation has occurred. Thiotepa can also be instilled in the bladder in patients who are undergoing cystectomy or partial cystectomy to reduce the risk of wound seeding. Thiotepa generally causes little or no symptoms of cystitis. For these reasons, this is the chemotherapy of choice at the authors' facility. Studies suggest that a single instillation reduces the risk of tumor recurrence by about 20%.
Doxorubicin. The standard dosage of doxorubicin is 50 mg in 25 cc of sterile water. As with other chemotherapies, optimal response occurs when given as a single instillation at the time of tumor resection. An exposure of 30 minutes is used when given at the time of surgery. When given to treat existing disease rather than prevent recurrence, treatment is held for 2 hours, and given weekly for 4 to 8 weeks, depending on volume of residual disease. Side effects include irritative bladder symptoms and, very infrequently, decreased bladder capacity.
Mitomycin C. The standard dosage of mitomycin C is 40 mg in 20 cc sterile water. Contraindications include hypersensitivity, bladder perforation, myelosuppression, and thrombocytopenia. The main side effects are skin rash, irritative bladder symptoms, bladder calcifications, and myelosuppression.
While mitomycin C is highly effective, like doxorubicin it should never be given if bladder perforation is suspected. In a randomized study, recurrence was nearly cut in half by using an optimized schedule: 40 mg/20 cc (compared with 20 mg/20 cc), overnight dehydration, ultrasound-confirmed complete bladder emptying, alkalinization using 1.3 g of sodium bicarbonate the night before, morning of, and 30 minutes prior to treatment. Mitomycin C is inactivated by acid urine (Au et al. 2001).
Recent studies also suggest that local hyperthermia, which can be obtained with a microwave applicator inserted into the bladder with a special catheter (not available in the United States), can also enhance the efficacy of mitomycin C, albeit with a significant increase in systemic absorption. Myelosuppression is the primary systemic toxicity of mitomycin.
Epirubicin. Epirubicin is a very popular intravesical drug in Europe. Standard dosage is 80 mg in 40 cc sterile water. The main side effects are irritative bladder symptoms. Systemic absorption is minimal, but systemic administration is associated with myelosuppression, cardiomyopathy, congestive heart failure, and arrythmias. Like doxorubicin, mitomycin C, and valrubicin, epirubicin is a vesicant and will result in necrosis with extravasation. Best Results occur with immediate postoperative instillation, but instillation should not be done if bladder perforation or any risk for extravasation is present, since this would put the patient at risk for peritonitis.
Valrubicin. Valrubicin was specifically approved for BCG-refractory carcinoma in situ of the bladder, where it is effective in about 20% of patients. The standard dose is 800 mg in 75 mL normal saline weekly for 6 weeks. However, valrubicin is currently not available in the United States.
Like chemotherapy, immunotherapy for superficial bladder cancer is instilled in the bladder with the goal of eradicating existing disease, reducing disease recurrence and progression, and improving patient survival. Immunotherapy has very little else in common with chemotherapy. It is important, therefore, to keep the anticipated treatment schedules, side effects, and Results separate (see Table 1 ). Cytotoxic chemotherapy directly kills cancer cells, while immunotherapy generally stimulates the patient's immune response. Increasing the dose of chemotherapy Results in increased cancer cell killing. However, increasing immunotherapy beyond the effective dose will begin to suppress the patient's immune response.
Chemotherapy penetrates the bladder by diffusion down a concentration gradient, while BCG immunotherapy attaches by means of specific receptors. Such differences have important clinical consequences. While chemotherapy is best given immediately at the time of tumor resection, immediate immunotherapy does not reduce tumor recurrence, and in the case of BCG, can result in life-threatening toxicity. Maintenance chemotherapy has not improved Results, but maintenance BCG immunotherapy not only reduces recurrence, but also appears to be required to reduce disease progression. Surprisingly, low-grade urothelial carcinoma is relatively more responsive to chemotherapy than high-grade carcinoma. In contrast, with BCG immunotherapy, low-grade tumors appear to be relatively less responsive. Therefore, chemotherapy is used initially in low-grade disease, where the risk of progression is very low and the side effects and cost of a single postoperative treatment are also appropriately low.
Available intravesical immunotherapies: BCG immunotherapy. BCG, or bacillus Calmette-Guerin, is an attenuated form of the bacterium Mycobacterium tuberculosis, used to prevent tuberculosis. It is a potent immune stimulant. The standard dose of BCG is 81 mg for TheraCys® and 50 mg for TICE,®both in 50 cc physiologic saline. Treatment should be postponed for at least 1 to 2 weeks following tumor resection or bladder biopsy. A purified protein derivative (PPD) test may be performed as the response and side effects vary according to PPD status. Those with a positive PPD will have a more vigorous and accelerated response, with more hypersensitivity. Treatments are repeated weekly for 6 weeks, with dose reductions to 1/3, 1/10, 1/30, or 1/100 as needed to prevent increasing or severe symptoms of bladder irritation. Three additional instillations, given at 3 months (6 weeks after completion of the initial 6-week course) increase the complete response in CIS from 56% to 84%. Maintenance BCG, using up to 3 weekly instillations in disease-free patients given at 3, 6, 12, 18, 24, 30, and 36 months, decreased 7-year recurrence in high-risk patients from 52% to 25% and significantly reduced disease worsening. However, since only 16% of patients received treatment at each scheduled interval, it is clear that a reduced treatment regimen may be appropriate, and in our hands, the 30-month maintenance dose is now omitted in many patients. It is also clear that the risk for recurrence and progression lasts for decades. Therefore, based on what is known of the long-term risk of disease progression with CIS or high-grade disease, we continue 3-week maintenance at years (counting from the start of treatment) 4, 5, 6, 8, 10, and 12 forpatients with CIS or high-grade disease.
The primary side effects of BCG are increased urinary frequency, dysuria, hematuria, and flu-like symptoms. Systemic symptoms can include arthralgia/arthritis, rash, fatigue, fever, and systemic BCG infection, which can present as pneumonitis, hepatitis, epididymitis, prostatitis, renal abscess, or sepsis. BCG is sensitive to ciprofloxacin and other fluoroquinolones as well as most antitubercular antibiotics, such as isoniazid, ethambutol, etc. Septic reactions should be treated with combination antibiotics including isoniazid and rifampicin as well as steroids. Steroids should be tapered gradually to prevent relapse.
BCG induces an anti-tumor response in bladder cancer by drawing lymphocytes and macrophages to the bladder and stimulating a cellular (TH1) immune response. Cytokines associate with this response result in symptoms of bladder inflammation and even flu-like symptoms. Patients who have a fever associated with BCG have a lower risk of tumor recurrence, but fever and increasing local symptoms can also herald a severe BCG reaction. Therefore, we have adopted the policy of reducing the dose of BCG in patients with increasing side effects.
The primary effect of BCG is local, at the site of administration. Patients with high-grade bladder cancer or CIS are at risk of developing malignancy within the prostatic urethra and upper urinary tracts. These patients require long-term followup with prostatic urethral biopsies and upper-tract ureteral washes, imaging studies, or ureteroscopy to prevent silent progression from disease in those sites.
Interferon Alfa 2b. Though not specifically approved for superficial bladder cancer, interferon alfa 2b has a response rate of 47% in CIS and 25% in papillary tumors. These Results compare favorably with those of intravesical chemotherapy. The Results in prophylaxis have been less favorable, but a recent study reported a reduction in recurrence from 68% to 28% (Papatsoris, Deliveliotis, Giannopoulos, & Dimopoulos, 2004). The primary advantage of interferon treatment is the absence of significant side effects. Doses as high as 1 billion units have been given intravesically without dose-limiting side effects (Turti et al., 1988). The standard dose is 50 to 100 million units weekly for 6 weeks. Additional maintenance treatments may be beneficial, but the ideal regimen is unknown. Based on the favorable experience with 3-week maintenance BCG, we have used this regimen for patients treated with interferon as well.
Interferon is remarkably non-toxic. Many patients who have major BCG reactions have long-term persistence of the organism within their systems. Interferon in combination with BCG appears to potentiate the effect of BCG. Therefore later use of interferon as a single agent may be very useful in potentiation of these residual levels in BCG-intolerant patients. TB transmission is only a risk for immunosuppressed patients or those with open wounds. No other special precautions are required.
BCG immunotherapy has been combined with chemotherapy, primarily mitomycin C. These studies demonstrate no improvement in efficacy compared with BCG alone. Combination chemotherapy is now standard for patients with metastatic transitional cell carcinoma but has not been adequately studied in patients with superficial disease. Combination immunotherapy, specifically the use of BCG plus interferon alfa 2b, is highly effective. About 60% of patients who fail to respond to BCG can be rescued with BCG plus interferon (O'Donnell, Krohn, & DeWolf, 2001). The standard dose is 50 mg to 81 mg of BCG plus 50 million units of interferon alfa 2b. Treatments are given weekly for 6 weeks, with maintenance using up to 3 weekly instillations at 3 or 6 months, and then every 6 to 12 months. The dose of BCG is reduced to 1/3, 1/10, 1/100 as needed to prevent increased side effects. While we try to avoid giving a second 6-week course of BCG to patients who have previously received BCG because they are at risk of immunosuppression, the addition of interferon appears to reduce this risk.

Nurses are key to vital patient communication for optimal intravesical therapy. This is particularly critical with BCG where increasing symptoms need to be noted so that dosage can be reduced before major side effects occur. Patients need to know that BCG requires special antibiotic treatment, and symptoms such as night sweats, fever, and chills can present months and even years after BCG administration. This information should be communicated directly to the urologist, since physicians in other specialties, even infectious disease, may not be aware of this consideration. A nurse should be able to explain the procedure selected by the physician, understand, discuss, and interview for possible complications, and be able to assist as directed in the administration of intravesical treatment.
Superficial bladder cancer is a heterogeneous disease that requires a variety of treatments. Low-risk patients typically have a benign course and can be effectively treated with transurethral resection followed by a single instillation of cytotoxic chemotherapy. Intermediate and high-risk patients require, in general, the addition of BCG immunotherapy due to the risk of disease progression. BCG, and presumably BCG plus interferon-alfa, can significantly reduce the risk of progression when used in a maintenance schedule. Nurses provide a vital role in patient communication, and can help reduce potential complications. Cystectomy is used when topical therapies fail, and is associated with an excellent survival rate with local disease.
The print version of this article was originally certified for CE credit. For accreditation details, please contact the publisher, the Society of Urologic Nurses and Associates, Inc., East Holly Avenue Box 56, Pitman, NJ 08071-0056

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