- Email: [email protected]
RE: DOES PC-SPES INTERACT WITH WARFARIN?
294
LETTERS TO THE EDITOR
atives and digital rectal examination would be accurate enough in predicting the behavior of a biologically/molecularly diverse disease such as prostate cancer. Nonetheless, and as the authors conclude, this work is part of a continuing process of using the available data in improving decision making models. However, the answer to the aforementioned questions should help the readers to assess more accurately the value of the study. Respectfully, Magdi M. Kirollos Torbay Hospital 17 Shiphay Ave. Torquay, TQ2 7ED Devon United Kingdom
Reply by Authors. The use of quantitative nuclear grading for preoperative staging of prostate cancer was first reported in 1996, and included all stages of prostate cancer but used an earlier developed cell imaging system (CAS-200, Becton Dickinson, Sunnyvale, California).1 In contemporary prostate disease United States patient cohorts T1a and b are extremely rare diagnoses because of the rarity of transurethral prostatectomy procedures. We elected patients with T1c disease for this study not only because they are a diagnostic group that is disproportionately increasing in size, but also because once the disease is palpable the likelihood of nonorgan confined disease increases dramatically if the biopsy is positive. Other urological applications of quantitative nuclear grading in prostate cancer can be found in additional series of Veltri2 and Potter3 et al. Patients were excluded from the sample on the basis of microwave tissue processing (which destroys the ability to perform quantitative nuclear grading), preoperative hormone therapy, no cancer observed on biopsy or no history of radical prostatectomy. PSA density was performed based upon prostate weight. The Johns Hopkins Hospital has performed correlation analysis between the use of transurethral ultrasound volume and prostate weight, and determined that the correlation coefficient is 0.89. This is a correlation coefficient that we remain comfortable with and, therefore, we use prostate weight to determine density routinely. How reproducible are the results of nuclear grading? When the nuclei are captured from the same area dotted by an experienced pathologist (as was done in this study), the results are quite reproducible. Inter-operator variability is less than 10%. We successfully established the technology originally for a Clinical Laboratory Improvement Amendments approved reference laboratory in 1996, and have recently rendered it operational at Johns Hopkins University and successfully reproduced results from previous studies. Please note that once a quantitative nuclear grading solution is mathematically derived, it is always validated with cases not seen by the original training and testing sets. Is nuclear grading capable of replacing Gleason score? We have always compared our results with prostate cancer to Gleason score and have obtained results equal to or better than Gleason score. As Gleason scores continue to condense into 6 and 7, we believe that quantitative nuclear grading could replace Gleason grading/scoring. The definitive study to prove Kirollos’ point will require selection of biopsy cases with grading performed by uropathology experts and blinded to the AutoCyte (AutoCyte, Inc., Elon College, North Carolina) imaging machine to determine whether a quantitative nuclear grading solution can be derived to distinguish Gleason grades 3, 4 and 5. Such an experiment is in the planning stage. Quantitative nuclear grading and Gleason score assessed as independent variables contribute unique information multivariately when assessed by logistic regression. Conducting a correlation coefficient between a categorical (Gleason score 6 and 7) and a quantitative continuous independent variable is not mathematically acceptable. With regard to the ability of quantitative nuclear grading, Gleason score, PSA and its derivatives, quantitative pathology and so forth to predict disease outcomes, our group and several others have repeatedly demonstrated and validated these principles.4 – 6 1. Badalament, R. A., Miller, M. C., Peller, P. A., Young, D. C., Bahn, D. K., Kochie, P. et al: An algorithm for predicting nonorgan confined prostate cancer using the results obtained from sextant core biopsies and prostate specific antigen level. J Urol, 156: 1375, 1996 2. Veltri, R. W., Partin, A. W. and Miller, M. C.: Quantitative nuclear grade (QNG): a new image analysis-based biomarker of clinically relevant nuclear structure alterations. J Cell
Biochem, suppl., 35: 151, 2000 3. Potter, S. R., Miller, M. C., Mangold, L. A., Jones, K. A., Epstein, J. I., Veltri, R. W. et al: Genetically engineered neural networks for predicting prostate cancer progression after radical prostatectomy. Urology, 54: 791, 1999 4. Ross, P. L., Scardino, P. T. and Kattan, M. W.: A catalog of prostate cancer nomograms. J Urol, 165: 1562, 2001 5. Veltri, R. W., Miller, M. C., Partin, A. W., Poole, E. C. and O’Dowd, G. J.: Prediction of prostate carcinoma stage by quantitative biopsy pathology. Cancer, 91: 2322, 2001 6. Narayan, P., Gajendran, V., Taylor, S. P., Tewari, A., Presti, J. C., Jr., Leidich, R. et al: The role of transrectal ultrasoundguided biopsy-based staging, preoperative serum prostatespecific antigen, and biopsy Gleason score in prediction of final pathologic diagnosis in prostate cancer. Urology, 46: 205, 1995 DOI: 10.1097/01.ju.0000040524.79139.5d
RE: COMPARISON OF INTUSSUSCEPTION PULL-THROUGH END-TO-SIDE AND CONVENTIONAL END-TO-SIDE MICROSURGICAL VASOEPIDIDYMOSTOMY: PROSPECTIVE RANDOMIZED CONTROLLED STUDY IN MALE WISTAR RATS S. McCallum, P. S. Li, Y. Sheynkin, L.-M. Su, P. Chan M. Goldstein
AND
J Urol, 167: 2284 –2288, 2002 To the Editor. The authors describe a study comparing the intussusception and standard end-to-side anastomosis techniques for microsurgical vasoepididymostomy, and conclude that intussusception is superior. Although they cite the original report describing this technique, they fail to acknowledge the basic principle.1 We first developed the invagination technique for vasoepididymostomy in 1988 in Germany, and described the technique in an animal model in 1991.1 The basic principle and innovation was invaginating a loop of the epididymis into the lumen of the vas deferens. During the last few years several articles have described modifications of our technique under various names, including intussusception and triangulation.2 In the original technique 1 suture was used for invaginating, the loop of epididymis. The only modification in subsequent reports has been the use of additional sutures to perform the invagination. We believe that invagination of a loop of epididymis into the lumen of the vas deferens was the innovative principle, which was first described by us and which deserves to be acknowledged as such. Triangulation and other names given represent modifications of the original procedure. Respectfully, Bijan Shekarriz Department of Urology SUNY, Upstate Medical University Syracuse, New York 13120 and Sigmund Pomer Department of Urology University of Heidelberg Heidelberg, Germany 1. Shekarriz, M. and Pomer, S.: Microsurgical vasoepididymostomy: a comparison between the end-to-side anastomosis and the invagination technique. Urol Res, 19: 285, 1991 2. Berger, R. E.: Triangulation and end-to-side vasoepididymostomy. J Urol, 159: 1951, 1998 DOI: 10.1097/01.ju.0000040681.90702.f4
RE: DOES PC-SPES INTERACT WITH WARFARIN? N. B. Davis, L. Nahlik and N. J. Vogelzang J Urol, 167: 1793, 2002 To the Editor. The authors report the difficulty of maintaining therapeutic international normalized ratios with warfarin in a patient taking PC-SPES. They also cite the case of disseminated intravascular coagulation reported by Lock et al.1 In the latter case disseminated intravascular coagulation increased during PC-SPES
295
LETTERS TO THE EDITOR therapy and continued to be increased for some time after medication was discontinued. The patient was treated in British Columbia after moving here for terminal care. It is noteworthy that a dramatic decrease in prostate specific antigen was observed in this patient in the setting of advanced hormone refractory disease. Was this a response to PC-SPES? Did disseminated intravascular coagulation produce an “adjunct” response similar to that seen with febrile episodes?2 Did rapid tumor lysis lead to the disseminated intravascular coagulation and prostate specific antigen responses? Although not the mechanism in this patient, disseminated intravascular coagulation can also occur rarely in advanced prostate cancer.3 Davis et al state that “there are no other reports of PC-SPES interacting with warfarin.” However, in February 2002 (after their case report had been accepted for publication) United States Food and Drug Administration and Health Canada alerts were issued as warfarin had been found in PC-SPES.4, 5 The product was placed under investigation in both countries. One might expect to see interference with international normalized ratio in the case of low levels of diethylstilbestrol contamination that led to Small et al stopping a trial of PC-SPES at the University of California, San Francisco.6 The same group also noted concerns regarding thrombotic events in patients receiving PC-SPES.6, 7 PC-SPES was obtainable by mail, telephone and Internet order, as well as through stores and health care professionals. The producers, BotanicLab (Brea, California), closed to business on June 1, 2002. PC-SPES is no longer available. Respectfully, Graeme G. Duncan Department of Radiation Oncology BC Cancer Agency 600 W. 10th Ave. Vancouver, British Columbia Canada V5Z 4E6 1. Lock, M., Loblaw, D. A., Choo, R. and Imrie, K.: Disseminated intravascular coagulation and PC-SPES: a case report and literature review. Can J Urol, 8: 1326, 2001 2. Kleef, R., Jonas, W. B., Knogler, W. and Stenzinger, W.: Fever, cancer incidence and spontaneous remissions. Neuroimmunomodulation, 9: 55, 2001 3. Cooper, D. L., Sandler, A. B., Wilson, L. D. and Duffy, T. P.: Disseminated intravascular coagulation and excessive fibrinolysis in a patient with metastatic prostate cancer. Response to
epsilon-aminocaproic acid. Cancer, 70: 656, 1992 4. FDA Warning: Stop taking PC-SPES immediately. http://www. thecancer.info/prostate/news/FDA_SPEC.htm 5. Health Canada is warning Canadians not to use the herbal supplements PC SPES and SPES. Health Canada Online. http:// www. hc-sc. gc. ca / english / protection /warnings/2002/2002_ 06e.htm 6. Small, E. J., Kantoff, P., Weinberg, W. K., Nguyen, S., Smith, M., Bubley, G. J. et al: A prospective multicenter randomized trial of the herbal supplement, PC-SPES vs. diethylstilbestrol (DES) in patients with advanced, androgen independent prostate cancer (AiPCa). Presented at annual meeting of American Society of Clinical Oncology, Orlando, Florida, May 18 –21, 2002 7. Schiff, J. D., Ziecheck, W. S. and Choi, B.: Pulmonary embolus related to PC-SPES use in a patient with PSA recurrence after radical prostatectomy. Urology, 59: 444, 2002 DOI: 10.1097/01.ju.0000039604.77579.0c
ERRATA DIETHYLSTILBESTROL REVISITED Volume 168, No. 4, page 1506: The last sentence is . . . (prevention of osteoporosis, anti-angiogenesis, cardiovascular . . . . INTACT PSA IN DETECTION OF PROSTATIC CARCINOMA Volume 168, No. 5, page 1920, table 2: The correct values for AUC, 95% CI and p Value of Total PSA 2-10 Ng./Ml. are Free PSA 0.574, 0.51-0.64, 0.8249; Intact PSA 0.510, 0.44-0.58, 0.1197; and Nicked PSA 0.628, 0.56-0.69, 0.3680. Free PSA in column 1, line 5 should be Total PSA.
LETTERS TO THE EDITOR
atives and digital rectal examination would be accurate enough in predicting the behavior of a biologically/molecularly diverse disease such as prostate cancer. Nonetheless, and as the authors conclude, this work is part of a continuing process of using the available data in improving decision making models. However, the answer to the aforementioned questions should help the readers to assess more accurately the value of the study. Respectfully, Magdi M. Kirollos Torbay Hospital 17 Shiphay Ave. Torquay, TQ2 7ED Devon United Kingdom
Reply by Authors. The use of quantitative nuclear grading for preoperative staging of prostate cancer was first reported in 1996, and included all stages of prostate cancer but used an earlier developed cell imaging system (CAS-200, Becton Dickinson, Sunnyvale, California).1 In contemporary prostate disease United States patient cohorts T1a and b are extremely rare diagnoses because of the rarity of transurethral prostatectomy procedures. We elected patients with T1c disease for this study not only because they are a diagnostic group that is disproportionately increasing in size, but also because once the disease is palpable the likelihood of nonorgan confined disease increases dramatically if the biopsy is positive. Other urological applications of quantitative nuclear grading in prostate cancer can be found in additional series of Veltri2 and Potter3 et al. Patients were excluded from the sample on the basis of microwave tissue processing (which destroys the ability to perform quantitative nuclear grading), preoperative hormone therapy, no cancer observed on biopsy or no history of radical prostatectomy. PSA density was performed based upon prostate weight. The Johns Hopkins Hospital has performed correlation analysis between the use of transurethral ultrasound volume and prostate weight, and determined that the correlation coefficient is 0.89. This is a correlation coefficient that we remain comfortable with and, therefore, we use prostate weight to determine density routinely. How reproducible are the results of nuclear grading? When the nuclei are captured from the same area dotted by an experienced pathologist (as was done in this study), the results are quite reproducible. Inter-operator variability is less than 10%. We successfully established the technology originally for a Clinical Laboratory Improvement Amendments approved reference laboratory in 1996, and have recently rendered it operational at Johns Hopkins University and successfully reproduced results from previous studies. Please note that once a quantitative nuclear grading solution is mathematically derived, it is always validated with cases not seen by the original training and testing sets. Is nuclear grading capable of replacing Gleason score? We have always compared our results with prostate cancer to Gleason score and have obtained results equal to or better than Gleason score. As Gleason scores continue to condense into 6 and 7, we believe that quantitative nuclear grading could replace Gleason grading/scoring. The definitive study to prove Kirollos’ point will require selection of biopsy cases with grading performed by uropathology experts and blinded to the AutoCyte (AutoCyte, Inc., Elon College, North Carolina) imaging machine to determine whether a quantitative nuclear grading solution can be derived to distinguish Gleason grades 3, 4 and 5. Such an experiment is in the planning stage. Quantitative nuclear grading and Gleason score assessed as independent variables contribute unique information multivariately when assessed by logistic regression. Conducting a correlation coefficient between a categorical (Gleason score 6 and 7) and a quantitative continuous independent variable is not mathematically acceptable. With regard to the ability of quantitative nuclear grading, Gleason score, PSA and its derivatives, quantitative pathology and so forth to predict disease outcomes, our group and several others have repeatedly demonstrated and validated these principles.4 – 6 1. Badalament, R. A., Miller, M. C., Peller, P. A., Young, D. C., Bahn, D. K., Kochie, P. et al: An algorithm for predicting nonorgan confined prostate cancer using the results obtained from sextant core biopsies and prostate specific antigen level. J Urol, 156: 1375, 1996 2. Veltri, R. W., Partin, A. W. and Miller, M. C.: Quantitative nuclear grade (QNG): a new image analysis-based biomarker of clinically relevant nuclear structure alterations. J Cell
Biochem, suppl., 35: 151, 2000 3. Potter, S. R., Miller, M. C., Mangold, L. A., Jones, K. A., Epstein, J. I., Veltri, R. W. et al: Genetically engineered neural networks for predicting prostate cancer progression after radical prostatectomy. Urology, 54: 791, 1999 4. Ross, P. L., Scardino, P. T. and Kattan, M. W.: A catalog of prostate cancer nomograms. J Urol, 165: 1562, 2001 5. Veltri, R. W., Miller, M. C., Partin, A. W., Poole, E. C. and O’Dowd, G. J.: Prediction of prostate carcinoma stage by quantitative biopsy pathology. Cancer, 91: 2322, 2001 6. Narayan, P., Gajendran, V., Taylor, S. P., Tewari, A., Presti, J. C., Jr., Leidich, R. et al: The role of transrectal ultrasoundguided biopsy-based staging, preoperative serum prostatespecific antigen, and biopsy Gleason score in prediction of final pathologic diagnosis in prostate cancer. Urology, 46: 205, 1995 DOI: 10.1097/01.ju.0000040524.79139.5d
RE: COMPARISON OF INTUSSUSCEPTION PULL-THROUGH END-TO-SIDE AND CONVENTIONAL END-TO-SIDE MICROSURGICAL VASOEPIDIDYMOSTOMY: PROSPECTIVE RANDOMIZED CONTROLLED STUDY IN MALE WISTAR RATS S. McCallum, P. S. Li, Y. Sheynkin, L.-M. Su, P. Chan M. Goldstein
AND
J Urol, 167: 2284 –2288, 2002 To the Editor. The authors describe a study comparing the intussusception and standard end-to-side anastomosis techniques for microsurgical vasoepididymostomy, and conclude that intussusception is superior. Although they cite the original report describing this technique, they fail to acknowledge the basic principle.1 We first developed the invagination technique for vasoepididymostomy in 1988 in Germany, and described the technique in an animal model in 1991.1 The basic principle and innovation was invaginating a loop of the epididymis into the lumen of the vas deferens. During the last few years several articles have described modifications of our technique under various names, including intussusception and triangulation.2 In the original technique 1 suture was used for invaginating, the loop of epididymis. The only modification in subsequent reports has been the use of additional sutures to perform the invagination. We believe that invagination of a loop of epididymis into the lumen of the vas deferens was the innovative principle, which was first described by us and which deserves to be acknowledged as such. Triangulation and other names given represent modifications of the original procedure. Respectfully, Bijan Shekarriz Department of Urology SUNY, Upstate Medical University Syracuse, New York 13120 and Sigmund Pomer Department of Urology University of Heidelberg Heidelberg, Germany 1. Shekarriz, M. and Pomer, S.: Microsurgical vasoepididymostomy: a comparison between the end-to-side anastomosis and the invagination technique. Urol Res, 19: 285, 1991 2. Berger, R. E.: Triangulation and end-to-side vasoepididymostomy. J Urol, 159: 1951, 1998 DOI: 10.1097/01.ju.0000040681.90702.f4
RE: DOES PC-SPES INTERACT WITH WARFARIN? N. B. Davis, L. Nahlik and N. J. Vogelzang J Urol, 167: 1793, 2002 To the Editor. The authors report the difficulty of maintaining therapeutic international normalized ratios with warfarin in a patient taking PC-SPES. They also cite the case of disseminated intravascular coagulation reported by Lock et al.1 In the latter case disseminated intravascular coagulation increased during PC-SPES
295
LETTERS TO THE EDITOR therapy and continued to be increased for some time after medication was discontinued. The patient was treated in British Columbia after moving here for terminal care. It is noteworthy that a dramatic decrease in prostate specific antigen was observed in this patient in the setting of advanced hormone refractory disease. Was this a response to PC-SPES? Did disseminated intravascular coagulation produce an “adjunct” response similar to that seen with febrile episodes?2 Did rapid tumor lysis lead to the disseminated intravascular coagulation and prostate specific antigen responses? Although not the mechanism in this patient, disseminated intravascular coagulation can also occur rarely in advanced prostate cancer.3 Davis et al state that “there are no other reports of PC-SPES interacting with warfarin.” However, in February 2002 (after their case report had been accepted for publication) United States Food and Drug Administration and Health Canada alerts were issued as warfarin had been found in PC-SPES.4, 5 The product was placed under investigation in both countries. One might expect to see interference with international normalized ratio in the case of low levels of diethylstilbestrol contamination that led to Small et al stopping a trial of PC-SPES at the University of California, San Francisco.6 The same group also noted concerns regarding thrombotic events in patients receiving PC-SPES.6, 7 PC-SPES was obtainable by mail, telephone and Internet order, as well as through stores and health care professionals. The producers, BotanicLab (Brea, California), closed to business on June 1, 2002. PC-SPES is no longer available. Respectfully, Graeme G. Duncan Department of Radiation Oncology BC Cancer Agency 600 W. 10th Ave. Vancouver, British Columbia Canada V5Z 4E6 1. Lock, M., Loblaw, D. A., Choo, R. and Imrie, K.: Disseminated intravascular coagulation and PC-SPES: a case report and literature review. Can J Urol, 8: 1326, 2001 2. Kleef, R., Jonas, W. B., Knogler, W. and Stenzinger, W.: Fever, cancer incidence and spontaneous remissions. Neuroimmunomodulation, 9: 55, 2001 3. Cooper, D. L., Sandler, A. B., Wilson, L. D. and Duffy, T. P.: Disseminated intravascular coagulation and excessive fibrinolysis in a patient with metastatic prostate cancer. Response to
epsilon-aminocaproic acid. Cancer, 70: 656, 1992 4. FDA Warning: Stop taking PC-SPES immediately. http://www. thecancer.info/prostate/news/FDA_SPEC.htm 5. Health Canada is warning Canadians not to use the herbal supplements PC SPES and SPES. Health Canada Online. http:// www. hc-sc. gc. ca / english / protection /warnings/2002/2002_ 06e.htm 6. Small, E. J., Kantoff, P., Weinberg, W. K., Nguyen, S., Smith, M., Bubley, G. J. et al: A prospective multicenter randomized trial of the herbal supplement, PC-SPES vs. diethylstilbestrol (DES) in patients with advanced, androgen independent prostate cancer (AiPCa). Presented at annual meeting of American Society of Clinical Oncology, Orlando, Florida, May 18 –21, 2002 7. Schiff, J. D., Ziecheck, W. S. and Choi, B.: Pulmonary embolus related to PC-SPES use in a patient with PSA recurrence after radical prostatectomy. Urology, 59: 444, 2002 DOI: 10.1097/01.ju.0000039604.77579.0c
ERRATA DIETHYLSTILBESTROL REVISITED Volume 168, No. 4, page 1506: The last sentence is . . . (prevention of osteoporosis, anti-angiogenesis, cardiovascular . . . . INTACT PSA IN DETECTION OF PROSTATIC CARCINOMA Volume 168, No. 5, page 1920, table 2: The correct values for AUC, 95% CI and p Value of Total PSA 2-10 Ng./Ml. are Free PSA 0.574, 0.51-0.64, 0.8249; Intact PSA 0.510, 0.44-0.58, 0.1197; and Nicked PSA 0.628, 0.56-0.69, 0.3680. Free PSA in column 1, line 5 should be Total PSA.