INTERSTITIAL CYSTITIS TREATED WITH INTRAVESICAL DOXORUBICIN OM P. KIIANNA, M .D . JEFFREY H . LOOSE, M .D . From the Department of Surgery (Division of Urology), and Department of Pathology and Laboratory Medicine, Hahnemann University, Philadelphia, Pennsylvania
CT-Three patients with interstitial cystitis diagnosed on the basis of clinical symptoms, doscopic findings, and a typical histologic picture were treated with intravesical doxorubi3 patients showed remarkable improvement, as manifested by complete clearance of irritadder symptoms and healing of ulceration . Doxorubicin therefore may be the breakthrough interstitial cystitis.
cystitis (IC) is a painful, chronic disthe bladder whose etiology is unknown . nically difficult to separate from other painful bladder disease,' partly because s do not agree on the definition, 2 and ecause of the wide spectrum of possible ins .' Diagnosis is based on the symptom , cystoscopic findings, and histology .' e of IC remains elusive, ,mptoms are some of the most disabling ced by urology patients ; they include e or persistent frequency, dysuria, nocematuria, abdominal and urethral pain . rstitial Cystitis Association reports that of IC patients arc unable to work, and patients harbor suicidal thoughts three imes as often as the general populaces s methods have been used to manage ging from oral and intravesical drugs to I stimulation, endoscopic fulguration ntion, neodymium-YAG laser treatd open surgery as a last resort .'' We eport 3 cases of "classic" ulcerative IC ith intravesical doxorubicin which is used to treat superficial bladder cancer not been used heretofore to manage IC . Material and Methods tidied patients (two men : Case 1, 64 and Case 2, 52 years old ; one woman,
AUGUS1 1090
Case 3, 30 years old), whose condition was classic IC with ulcerative disease . Their clinical symptoms, endoscopic patterns, and histologic findings supported the diagnosis . All had suffered from persistent frequency, urgency, painful urination, and hematuria for more than a year . The two men had sterile urine . The woman had superimposed urinary tract infections . After prolonged treatment with appropriate antibiotics, both oral and parenteral, her urine cultures were clear of pathogens . However, irritative symptoms and bladder lesions persisted . In all 3 cases, endoscopic examination revealed diffuse submucosal hemorrhage, diffuse surface bleeding, and ulcers and cracks in the mucosa (Fig . IA, B) . The biopsy specimens were reviewed by a pathologist who had no previous knowledge of treatment status or time of biopsy, and who assessed the lymphoplasmacytic, polymorphonuclear leukocyte, and eosinophilic inflammation ; granulation tissue formation ; reactive fibroblastic proliferation ; and subepithelial fibrosis (scarring), Any urothelial changes were also noted . A toluidine blue stain was used to assess mast cells on the fort alin-fixed, paraffinembedded biopsy specimens . Ilistopathologic features common to all pretreatment biopsy specimens were rnucosal and deep lymphoplasmacytic inflammation with lymphoid aggregates, granulation tissue and
VOLUME XXXVI, NUMBER 2
139
Case 1 . (A) Extensive submucosal hemorrhage and surface bleeding following bladder distention (arrows), and (B) large anucosa crack (arrows) . FieuRrw 1 .
Ficuiw 2 . Case 1 . (A) Pretreatment bladder biopsy specimen shows superficial lym-phoplas-macytic infiltrate present with granulation tissue and fibrin at surface (top), and absent epithelium . (B) Six months later lymphoplasrnacytic infiltrate present at surface (top) and focally in deep inuscle (lower left), and absent epi el m . (Hematoxylin id eosi vasodilatation, mucosal edema, focal to extensive loss of transitional epithelium, and focal squamous metaplasia of residual urothelium (Fig . 2A, B) . Polymorphonuclear leukocytes, a minor component of the inflammatory process, were seen predominantly intravascularly in the capillaries in granulation tissue . Eosinophils and mast cells were present in varying numbers . Active fibroblast proliferation was present in most pretreatment biopsy specimens, the amount of which correlated directly with increased severity of inflammation . One pretreatment biopsy (Case 3) had fully developed lymphoid follicles with germinal centers . A repeat biopsy specimen in thirteen months in Case 3 later showed inflammatory changes but without the lymphoid follicles . The following tests or procedures were performed before treatment : patient history, physical examination, urine analysis, urine culture and sensitivity, urine cytology, blood chemistry, electrolytes, intravenous pyclogram or ultrasound, chest x-ray study, electrocardiogram, cystoscopy, bladder distention, and bladder biopsy. Approximately two weeks after bladder biopsy and bladder distention, the patients were treated in the clinician's office with in-
140
Case 1 . Complete replacement areas and healing scar (arrows) . FJGLRE 3 .
travesical instillations of 50 mg of doxorub hydrochloride (Adriamycin) dissolved in of normal saline . The patient was catheterized sterilely an doxorubicin solution was instilled into the b der through the catheter, which was the moved . The patient remained in the office
UROLOGY
1
AUGUST 1990
/
VOLUME XXXVI, NUN
4 . Case 1 . (A) ) . Post-treatnment er biopsy specisu rface shows relialization, abo f superficia bnation, and subial scarring . Fobronic inflarnpresent in deep muscle (hematoxylin and eosin, original magnifications [A] x 40 and LB] ately turned from side to side every fifinutes for one hour. After this initial onerotation, the patient could leave the clinioffice, but was asked to retain the drug in adder for an additional hour, if possible, voiding . e ideal treatment schedule would be ly instillation for six weeks, followed by e monthly instillations . However, the inual treatment schedule is flexible . Patients arted on the weekly schedule until toleris reached . Tolerance is defined as the at which, in the patient's estimation, side s outweight symptomatic relief . Then the a-month schedule is started until complete ution of symptoms and complete healing chieved . ;general, when patients receive weekly inent, symptoms of persistent frequency, ey and painful urination become worse ing the second or third instillation . All nts are forewarned of this possibility and entally prepared. Suitable medications 'yen for pain and dysuria, along with sedarugs and antibiotics . When the irritating toms start to subside ; monthly instillations 1 stituted . Thus the regimen is different for patient . flow-up, in the form of cystoscopic exation, will be scheduled at three months the first instillation and then at six and e months, depending on the patient's ree o treatment . Results and Comment e female patient (Case 3) required 25 intions . Her irritating symptoms have comy resolved . Endoscopy revealed rnucosal dation and healing of all ulcer areas . This at has had one healthy child, and is now ant with another.
OG1
/
x
100) .
The two male patients (Cases 1 and 2) are still undergoing therapy. Each has had five instillation, and their symptoms have improved markedly. Endoscopy had revealed bladder capacities of more than 400 cc, few submucosal hemorrhages, healing ulcer areas, and absence of mucosal cracks (Fig . 3) . Post-treatment biopsy specimens in Case 1 showed decreased granulation tissue formation and decreased lymphoplasmacytic inflammation . There was focally increased subepithclial fibrosis (Fig . 4A, B) . Mast cells also were decreased . Post-treament biopsy specimens in Case 2 showed increased granulation tissue and decreased lymphoplasmacytic inflammation . Subepithelial fibrosis was increased, but to a lesser degree than in Case 1 . Mast cells were decreased . No post-treatment biopsies were performed for Case 3 because of her pregnancy. The diagnosis of interstitial cystitis in these 3 patients was established on the basis of clinical symptoms, classic endoscopic findings, and Lypieal histologic pictures . Because of the limited number of cases in this preliminary report, we describe only changes seen relative to treatment . It is not our intention to address the problematic issue of the histologic diagnosis of interstitial cystitis . The microscopic findings in the present cases are consistent with the clinical diagnosis of IC . As specified by Messing,' all pretreatment biopsy specimens had submucosal vasodilatation, edema, and chronic inflammation with no evidence of other disease . The presence of granulation tissue in classic interstitial cystitis has recently been described .' In both cases where post-treatment biopsy specimens were obtained, there was decreased chronic inflammation . One patient (Case 1) showed evidence of scarring . Treatment with intravesical doxorubicin resulted in marked improvement or complete
AUGUST 1990 i VOI .OMV XXXVI, NUMBER 2
1
clearance of irritative bladder symptoms, as well as remarkable endoscopic changes in the form of complete healing of ulceration . The histologic changes of decreased granulation tissue formation (Case 1), decreased lymphoplasmacytic inflammation, and decreased number of mast cells all indicate the remarkable effects of doxorubicin . The subepithelial fibrosis remaining after the ulcerations healed was healthy scarring, not prone to cracking and bleeding . Available therapies for IC range from conservative treatment in the form of oral medications to a variety of surgical treatments . Several authors have detailed these treatments . 2 .4 a Oral drugs variously used for adjuvant therapy' are not yet backed by adequate long-term control studies or have shown disappointing results, 2 or have a high risk-to-benefit ratio with undesirable side effects, as with steroids .•° Sodium pentosan polysulfate, an investigational drug in the United States is among those showing promise . Current studiesso . ll have produced conflicting results, although Parsons and Mulholland" discuss
1
case of a chronic bladder
ulcer of longer than two years' duration, which was healed after three months' therapy. Of the intravesical drugs, only dimethyl sulfoxide (DMSO) can be instilled without anesthesia . Clorpactin (oxychlorosene sodium) and silver nitrate, which require regional or general anesthesia, are contraindicated in patients with 2,4 vesicoureteral reflux . Sant12 points out that the term "response" has been variously defined in studies of DMSO, making the results difficult to compare . Most of the improvement in classic
IC
cases treated with DMSO seems to involve
symptomatic 10 or urodynamic or bladder-capacity improvements' Reports of studies with DMSO often do not include cases of IC with uleers . 3 .u Parsons14 states that while a six-week course of DMSO may induce significant disease remission, patients gradually become refractory to this type of therapy . Transcutaneous electrical nerve stimulation
(TENS)
has produced good results in classic
IC
patients, as reported by Fall ." , " He reports the disappearance of lesions, but also comments that although the initial result is satisfactory, it is often not sufficient to sustain a patient's motivation to continue with long years of
TENS
therapy. He points out that this therapy demands considerable effort from the patient . YAC
laser therapy is effective in healing ul-
cers . 17 "s s However, it requires hospitalization for
142
one to two nights ; there have been cas,"
s'
small-bowel perforation and significant
ring, such as seen after transurethral resect" The main advantages of doxorubicin vesical therapy are that it falls within gory
in
e
the
of conservative
therapy ; can be earri in the office, carries a low risk, and does;, require anesthesia . On the basis of this lirninary study, we are certain that doxoru is effective in treating
IC
patients, altht
further study is needed to determine the tion of its effects .
d'"
Although this is a limited preliminary re the clinical response and the remarkable e scopic and histologic changes noted have vinced us that doxorubicin may be the br through drug for interstitial cystitis .
Philadelphia, Pennsylvania 19 (DR . KHAN
References 1 . Lose G, et at : Urine cosinophil cationic protein in p bladder disease, Br J Urol 60 : 39 (1987) . 2 . Hanna PM, and Wein All! Medical treatment of inter cystitis (other than RimsoSO/Elmiron), Urology (Suppl) (1987) . 3 . niggers RD : Self-administration of dimethyl gulf (DM50) for interstitial cystitis, Urology 28 : 10 (198(3) . 4 . Parivar F, and Bradbrook BA : Interstitial cystitis, Br k 58 : 239 (1986) . 5 . Interstitial Cystitis Association : Intertitial cystitis : h the future (videotape), (1988) . P.O . Box 151323, San Die 0211 .5 . 8 . Sant GE, and Meares EM Jr: Interstitial cystitis : patho sis, diagnosis, and treatment, Infect Urol3 : 24 (1990) . 7 . Messing EM : The diagnosis of interstitial cystitis, Ur: (Suppl) 29 : 4 (1987) . ` 8 . Johansson SJ, and Fall M : The spectrum of light seopic changes in the bladders of patients with interstitial e (Abstr), Lab Invest 58:'13A (1988) . 9 . Walsh A : Interstitial cystitis, in ilarrison JH, et at ` Campbell's Urology, 4th ed, Philadelphia, WB Saunders . 1 693 . 10. rlolm-Bentzen M, et at : Prospective double-blind dig controlled multicenter trial of sodium pentosan polysulf, treatment of interstitial cystitis and related painful blad . ; cases, j Urol 138 : 503 (1987) . 11 . Parsons CL, and Mulholland SC : Successful therapy{' terstitial cystitis with pentosan polysulfate, j Prof 138 : 513 ( ;' 12 . Sant GR : Intravesical 50% dimethyl sulfoxide (Rise_ in treatment of interstitial cystitis, Urology (Suppl) 29 : 17 13 . Perez-Marrero R, et at : A controlled study of dimetli'foxide in interstitial cystitis, j Urol 140 :38 (1988) . 14. Parsons Cl . : Interstitial cystitis, Urol Grand Rounds (1987) . 15 . Fall M : Conservative management of chronic inter:a cystitis : transcutaneous electrical nerve stimulation and tra . .thral resection, j Urol 133 : 774 (1985) . 16 . Fall M : Transcutaneous electrical nerve stimulauo terstitial cystitis, Urology (Suppl) 29 : 40 (1987) . 17 . Shanberg AM, and Malloy T: Treatment of interstitia this with neodymium-YAG laser, Urology (Suppl) 29: 31 (L 18 . Shanberg AM, et at : Treatment of interstitial cystitis,the ncodymium-YAG laser, j Urol 134 : 885 (1985) .
UROLOGY
AUGUST 1990 / VOLUME XXXVI, NUMB,
CT-Three patients with interstitial cystitis diagnosed on the basis of clinical symptoms, doscopic findings, and a typical histologic picture were treated with intravesical doxorubi3 patients showed remarkable improvement, as manifested by complete clearance of irritadder symptoms and healing of ulceration . Doxorubicin therefore may be the breakthrough interstitial cystitis.
cystitis (IC) is a painful, chronic disthe bladder whose etiology is unknown . nically difficult to separate from other painful bladder disease,' partly because s do not agree on the definition, 2 and ecause of the wide spectrum of possible ins .' Diagnosis is based on the symptom , cystoscopic findings, and histology .' e of IC remains elusive, ,mptoms are some of the most disabling ced by urology patients ; they include e or persistent frequency, dysuria, nocematuria, abdominal and urethral pain . rstitial Cystitis Association reports that of IC patients arc unable to work, and patients harbor suicidal thoughts three imes as often as the general populaces s methods have been used to manage ging from oral and intravesical drugs to I stimulation, endoscopic fulguration ntion, neodymium-YAG laser treatd open surgery as a last resort .'' We eport 3 cases of "classic" ulcerative IC ith intravesical doxorubicin which is used to treat superficial bladder cancer not been used heretofore to manage IC . Material and Methods tidied patients (two men : Case 1, 64 and Case 2, 52 years old ; one woman,
AUGUS1 1090
Case 3, 30 years old), whose condition was classic IC with ulcerative disease . Their clinical symptoms, endoscopic patterns, and histologic findings supported the diagnosis . All had suffered from persistent frequency, urgency, painful urination, and hematuria for more than a year . The two men had sterile urine . The woman had superimposed urinary tract infections . After prolonged treatment with appropriate antibiotics, both oral and parenteral, her urine cultures were clear of pathogens . However, irritative symptoms and bladder lesions persisted . In all 3 cases, endoscopic examination revealed diffuse submucosal hemorrhage, diffuse surface bleeding, and ulcers and cracks in the mucosa (Fig . IA, B) . The biopsy specimens were reviewed by a pathologist who had no previous knowledge of treatment status or time of biopsy, and who assessed the lymphoplasmacytic, polymorphonuclear leukocyte, and eosinophilic inflammation ; granulation tissue formation ; reactive fibroblastic proliferation ; and subepithelial fibrosis (scarring), Any urothelial changes were also noted . A toluidine blue stain was used to assess mast cells on the fort alin-fixed, paraffinembedded biopsy specimens . Ilistopathologic features common to all pretreatment biopsy specimens were rnucosal and deep lymphoplasmacytic inflammation with lymphoid aggregates, granulation tissue and
VOLUME XXXVI, NUMBER 2
139
Case 1 . (A) Extensive submucosal hemorrhage and surface bleeding following bladder distention (arrows), and (B) large anucosa crack (arrows) . FieuRrw 1 .
Ficuiw 2 . Case 1 . (A) Pretreatment bladder biopsy specimen shows superficial lym-phoplas-macytic infiltrate present with granulation tissue and fibrin at surface (top), and absent epithelium . (B) Six months later lymphoplasrnacytic infiltrate present at surface (top) and focally in deep inuscle (lower left), and absent epi el m . (Hematoxylin id eosi vasodilatation, mucosal edema, focal to extensive loss of transitional epithelium, and focal squamous metaplasia of residual urothelium (Fig . 2A, B) . Polymorphonuclear leukocytes, a minor component of the inflammatory process, were seen predominantly intravascularly in the capillaries in granulation tissue . Eosinophils and mast cells were present in varying numbers . Active fibroblast proliferation was present in most pretreatment biopsy specimens, the amount of which correlated directly with increased severity of inflammation . One pretreatment biopsy (Case 3) had fully developed lymphoid follicles with germinal centers . A repeat biopsy specimen in thirteen months in Case 3 later showed inflammatory changes but without the lymphoid follicles . The following tests or procedures were performed before treatment : patient history, physical examination, urine analysis, urine culture and sensitivity, urine cytology, blood chemistry, electrolytes, intravenous pyclogram or ultrasound, chest x-ray study, electrocardiogram, cystoscopy, bladder distention, and bladder biopsy. Approximately two weeks after bladder biopsy and bladder distention, the patients were treated in the clinician's office with in-
140
Case 1 . Complete replacement areas and healing scar (arrows) . FJGLRE 3 .
travesical instillations of 50 mg of doxorub hydrochloride (Adriamycin) dissolved in of normal saline . The patient was catheterized sterilely an doxorubicin solution was instilled into the b der through the catheter, which was the moved . The patient remained in the office
UROLOGY
1
AUGUST 1990
/
VOLUME XXXVI, NUN
4 . Case 1 . (A) ) . Post-treatnment er biopsy specisu rface shows relialization, abo f superficia bnation, and subial scarring . Fobronic inflarnpresent in deep muscle (hematoxylin and eosin, original magnifications [A] x 40 and LB] ately turned from side to side every fifinutes for one hour. After this initial onerotation, the patient could leave the clinioffice, but was asked to retain the drug in adder for an additional hour, if possible, voiding . e ideal treatment schedule would be ly instillation for six weeks, followed by e monthly instillations . However, the inual treatment schedule is flexible . Patients arted on the weekly schedule until toleris reached . Tolerance is defined as the at which, in the patient's estimation, side s outweight symptomatic relief . Then the a-month schedule is started until complete ution of symptoms and complete healing chieved . ;general, when patients receive weekly inent, symptoms of persistent frequency, ey and painful urination become worse ing the second or third instillation . All nts are forewarned of this possibility and entally prepared. Suitable medications 'yen for pain and dysuria, along with sedarugs and antibiotics . When the irritating toms start to subside ; monthly instillations 1 stituted . Thus the regimen is different for patient . flow-up, in the form of cystoscopic exation, will be scheduled at three months the first instillation and then at six and e months, depending on the patient's ree o treatment . Results and Comment e female patient (Case 3) required 25 intions . Her irritating symptoms have comy resolved . Endoscopy revealed rnucosal dation and healing of all ulcer areas . This at has had one healthy child, and is now ant with another.
OG1
/
x
100) .
The two male patients (Cases 1 and 2) are still undergoing therapy. Each has had five instillation, and their symptoms have improved markedly. Endoscopy had revealed bladder capacities of more than 400 cc, few submucosal hemorrhages, healing ulcer areas, and absence of mucosal cracks (Fig . 3) . Post-treatment biopsy specimens in Case 1 showed decreased granulation tissue formation and decreased lymphoplasmacytic inflammation . There was focally increased subepithclial fibrosis (Fig . 4A, B) . Mast cells also were decreased . Post-treament biopsy specimens in Case 2 showed increased granulation tissue and decreased lymphoplasmacytic inflammation . Subepithelial fibrosis was increased, but to a lesser degree than in Case 1 . Mast cells were decreased . No post-treatment biopsies were performed for Case 3 because of her pregnancy. The diagnosis of interstitial cystitis in these 3 patients was established on the basis of clinical symptoms, classic endoscopic findings, and Lypieal histologic pictures . Because of the limited number of cases in this preliminary report, we describe only changes seen relative to treatment . It is not our intention to address the problematic issue of the histologic diagnosis of interstitial cystitis . The microscopic findings in the present cases are consistent with the clinical diagnosis of IC . As specified by Messing,' all pretreatment biopsy specimens had submucosal vasodilatation, edema, and chronic inflammation with no evidence of other disease . The presence of granulation tissue in classic interstitial cystitis has recently been described .' In both cases where post-treatment biopsy specimens were obtained, there was decreased chronic inflammation . One patient (Case 1) showed evidence of scarring . Treatment with intravesical doxorubicin resulted in marked improvement or complete
AUGUST 1990 i VOI .OMV XXXVI, NUMBER 2
1
clearance of irritative bladder symptoms, as well as remarkable endoscopic changes in the form of complete healing of ulceration . The histologic changes of decreased granulation tissue formation (Case 1), decreased lymphoplasmacytic inflammation, and decreased number of mast cells all indicate the remarkable effects of doxorubicin . The subepithelial fibrosis remaining after the ulcerations healed was healthy scarring, not prone to cracking and bleeding . Available therapies for IC range from conservative treatment in the form of oral medications to a variety of surgical treatments . Several authors have detailed these treatments . 2 .4 a Oral drugs variously used for adjuvant therapy' are not yet backed by adequate long-term control studies or have shown disappointing results, 2 or have a high risk-to-benefit ratio with undesirable side effects, as with steroids .•° Sodium pentosan polysulfate, an investigational drug in the United States is among those showing promise . Current studiesso . ll have produced conflicting results, although Parsons and Mulholland" discuss
1
case of a chronic bladder
ulcer of longer than two years' duration, which was healed after three months' therapy. Of the intravesical drugs, only dimethyl sulfoxide (DMSO) can be instilled without anesthesia . Clorpactin (oxychlorosene sodium) and silver nitrate, which require regional or general anesthesia, are contraindicated in patients with 2,4 vesicoureteral reflux . Sant12 points out that the term "response" has been variously defined in studies of DMSO, making the results difficult to compare . Most of the improvement in classic
IC
cases treated with DMSO seems to involve
symptomatic 10 or urodynamic or bladder-capacity improvements' Reports of studies with DMSO often do not include cases of IC with uleers . 3 .u Parsons14 states that while a six-week course of DMSO may induce significant disease remission, patients gradually become refractory to this type of therapy . Transcutaneous electrical nerve stimulation
(TENS)
has produced good results in classic
IC
patients, as reported by Fall ." , " He reports the disappearance of lesions, but also comments that although the initial result is satisfactory, it is often not sufficient to sustain a patient's motivation to continue with long years of
TENS
therapy. He points out that this therapy demands considerable effort from the patient . YAC
laser therapy is effective in healing ul-
cers . 17 "s s However, it requires hospitalization for
142
one to two nights ; there have been cas,"
s'
small-bowel perforation and significant
ring, such as seen after transurethral resect" The main advantages of doxorubicin vesical therapy are that it falls within gory
in
e
the
of conservative
therapy ; can be earri in the office, carries a low risk, and does;, require anesthesia . On the basis of this lirninary study, we are certain that doxoru is effective in treating
IC
patients, altht
further study is needed to determine the tion of its effects .
d'"
Although this is a limited preliminary re the clinical response and the remarkable e scopic and histologic changes noted have vinced us that doxorubicin may be the br through drug for interstitial cystitis .
Philadelphia, Pennsylvania 19 (DR . KHAN
References 1 . Lose G, et at : Urine cosinophil cationic protein in p bladder disease, Br J Urol 60 : 39 (1987) . 2 . Hanna PM, and Wein All! Medical treatment of inter cystitis (other than RimsoSO/Elmiron), Urology (Suppl) (1987) . 3 . niggers RD : Self-administration of dimethyl gulf (DM50) for interstitial cystitis, Urology 28 : 10 (198(3) . 4 . Parivar F, and Bradbrook BA : Interstitial cystitis, Br k 58 : 239 (1986) . 5 . Interstitial Cystitis Association : Intertitial cystitis : h the future (videotape), (1988) . P.O . Box 151323, San Die 0211 .5 . 8 . Sant GE, and Meares EM Jr: Interstitial cystitis : patho sis, diagnosis, and treatment, Infect Urol3 : 24 (1990) . 7 . Messing EM : The diagnosis of interstitial cystitis, Ur: (Suppl) 29 : 4 (1987) . ` 8 . Johansson SJ, and Fall M : The spectrum of light seopic changes in the bladders of patients with interstitial e (Abstr), Lab Invest 58:'13A (1988) . 9 . Walsh A : Interstitial cystitis, in ilarrison JH, et at ` Campbell's Urology, 4th ed, Philadelphia, WB Saunders . 1 693 . 10. rlolm-Bentzen M, et at : Prospective double-blind dig controlled multicenter trial of sodium pentosan polysulf, treatment of interstitial cystitis and related painful blad . ; cases, j Urol 138 : 503 (1987) . 11 . Parsons CL, and Mulholland SC : Successful therapy{' terstitial cystitis with pentosan polysulfate, j Prof 138 : 513 ( ;' 12 . Sant GR : Intravesical 50% dimethyl sulfoxide (Rise_ in treatment of interstitial cystitis, Urology (Suppl) 29 : 17 13 . Perez-Marrero R, et at : A controlled study of dimetli'foxide in interstitial cystitis, j Urol 140 :38 (1988) . 14. Parsons Cl . : Interstitial cystitis, Urol Grand Rounds (1987) . 15 . Fall M : Conservative management of chronic inter:a cystitis : transcutaneous electrical nerve stimulation and tra . .thral resection, j Urol 133 : 774 (1985) . 16 . Fall M : Transcutaneous electrical nerve stimulauo terstitial cystitis, Urology (Suppl) 29 : 40 (1987) . 17 . Shanberg AM, and Malloy T: Treatment of interstitia this with neodymium-YAG laser, Urology (Suppl) 29: 31 (L 18 . Shanberg AM, et at : Treatment of interstitial cystitis,the ncodymium-YAG laser, j Urol 134 : 885 (1985) .
UROLOGY
AUGUST 1990 / VOLUME XXXVI, NUMB,
