0022-5347 /92/1483-0895$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, hie.
Ve;. 148, 895-898, September 1992 Printed in U.S.A.
Letters to the Editor RE: THE INCIDENCE OF MULTICENTRICITY IN RENAL CELL CARCINOMA W. S. Cheng, G. M. Farrow and H. Zincke
J. Urol., 146: 1221-1223, 1991
To the Editor. The authors of this article studied the frequency of multicentric tumors in kidneys removed for renal cell carcinoma. The incidence of small renal nodules in this series of kidneys was 13% and the incidence of small satellite renal carcinoma coexisting with a predominant tumor was 7%. Novick et al reported a 9% local recurrence rate in 100 partial nephrectomies for renal cell carcinoma. 1 The presence of multicentric tumors can explain the recurrence rates observed. For us it means that multicentricity poses a significant clinical problem when a nephron sparing operation is considered for patients with small tumors. To confirm this hypothesis we reviewed retrospectively our series of 759 malignant parenchymal kidney tumors. The overall rate of multicentric tumors was 70 of 759 (9.22%), including 1 sarcoma, 1 undifferentiated cancer, 1 epidermoid tumor and 67 renal cell carcinomas. We looked at the small tumors 5 cm. or less in diameter, which generally are the best candidates for conservative surgery (see table). The conclusion is that there is no safe limit to exclude multicentric tumors and that is a significant statement if we intend to propose nephron sparing surgery for renal cell carcinoma in patients with a normal contralateral kidney. Respectfully, D. Jacqmin and C. Saussine Hopitaux Universitaires de Strasbourg Centre Hospitalier Regional et Universitaire B.P. No. 426 67091 Strasbourg Cedex France 1. Novick, A. C., Streem, S., Montie, J. E., Pontes, J. E., Siegel, S., Montague, D. K. and Goormastic, M.: Conservative surgery for renal cell carcinoma: a single-center experience with 100 patients. J. Urol., 141: 835, 1989.
Reply by Authors. It is well established in the literature that local recurrence after renal conserving surgery for renal cell cancer ranges from 6 to 9% as reported in 2 major series. 1• 2 Our study did not address the question nor did it propose "nephron sparing for renal cell cancer to patients with a normal contralateral right kidney." Rather, ours was a histopathological study carefully performed by Doctor Farrow. In our study there was a 13% incidence of tumors but only a 7% incidence of true renal cell cancer in the 100 kidneys examined. Of those 7 renal cell cancers 3 were easily detectable at operation, and of the other 4, 3 were subcapsular and theoretically detectable with careful inspection at operation. Thus, the incidence of intraparenchymal nondetectable lesions at conservative surgery for lesser lesions seems to be small. However, the rather high local recurrence rate with large tumors 3 clearly shows a relationship between the size of the original tumor and the potential for local recurrence (namely, the larger the original tumor, the higher the local recurrence rate).
Frequency of multicentric kidney tumors according to the diameter of the biggest tumor Diameter (cm.) Less than Less than Less than Less than Less than Overall
5 4 3 2 1.5
No.
No. Multicentric Tumors(%)
274 166 86 21 8 759
29 (10.58) 22 (13.25) 15 (17.44) 5370 (9.22)
895
Doctors Jacqmin and Saussine have failed in their study to delineate the exact histopathological diagnosis of the tumors found; this is important because not every tumor represents renal cell cancer. This might explain the disproportionate relationships described in the table, where larger tumors were associated with a lower incidence of multicentricity than smaller tumors. It would be of interest if the authors could provide some clear histopathological information for their data. 1. Morgan, W. R. and Zincke, H.: Progression and survival after renal-conserving surgery for renal cell carcinoma: experience in 104 patients and extended followup. J. UroL, 144: 852, 1990. 2. Novick, A. C., Streem, S., Montie, J. E., Pontes, J. E., Siegel, S., Montague, D. K. and Goormastic, M.: Conservative surgery for renal cell carcinoma: a single-center experience with 100 patients. J. Urol., 141: 835, 1989. 3. Stormont, T. J., Bilhartz, D. L. and Zincke, H.: Pitfalls of bench surgery and autotransplantation for renal cell carcinoma. Mayo Clin. Proc., in press. RE: ENDOSCOPIC INJECTION OF GLUTARALDEHYDE CROSS-LINKED BOVINE DERMAL COLLAGEN FOR CORRECTION OF VESICOURETERAL REFLUX
M. P. Leonard, D. A. Canning, C. A. Peters, J. P. Gearhart and R. D. Jeffs J. Urol., 145: 115-119, 1991
To the Editor. The authors suggest that endoscopic injection of bovine dermal collagen is a safe and effective treatment of vesicoureteral reflux. I would like to express some concerns about the long-term safety of such a procedure. Zyderm collagen implant is a purified, reconstituted bovine dermal collagen dispersed in physiological saline at a concentration of 35 mg. (Zyderm I) or 65 mg, (Zyderm II) collagen per ml. Zyplast implant is identical to Zyderm collagen implant except that the fibrillar collagen has been cross-linked with 0.0075% glutaraldehyde to enhance the persistence of the implant. 1 Zyderm collagen implant was introduced in 1981 as a medical device (not as a drug) for percutaneous soft tissue augmentation. Food and Drug Administration approval was based on the assumption that bovine collagen, although metabolized, would not elicit any biological response in humans. However, although the immunogenicity of Zyderm collagen implant and Zyplast implant probably is modest compared with other proteins (that is y-globulins or various hemostatic collagens), animal collagen is still an immunogen that is capable of eliciting an immune response. From an immunological perspective this is not a surprising observation, given the extraordinary specificity of our immune system. Nevertheless, cutaneous reactions to commercially prepared collagen are reported to be uncommon and largely avoidable by preliminary skin testing. Published surveys of immunity to bovine collagen show a tendency to commingle observations of cellular immunity (cutaneous hypersensitivity) with those of humoral (antibody) immunity. 2 Actually, these are essentially independent biological phenomena and the absence of a perceived response might simply mean that a more sensitive assay is needed. Early reference to the antigenicity of collagen devices was made by Hopps, who demonstrated in 1944 that collagen sutures could elicit cutaneous hypersensitivity and humoral antibody reactions. 3 These biological responses to collagen sutures were believed to be a cause of early wound dehiscence in sensitized patients. In the literature there are numerous reports of Zyderm collagen implant injections resulting in cutaneous and humoral immune reactions.•-9 Frank 10 and Fishern et al focused on humoral antibody response to Zyderm collagen implant (instead of cell-mediated cutaneous hypersensitivity), using an enzyme-linked immunosorbent assay selected because of its extraordinary sensitivity to modest antigens. They demonstrated elevated anti-Zyderm antibody levels in patients treated with clinical doses of injectable bovine collagen, even in the absence of adverse cutaneous reactions. Increasing antibody titers were observed as repeated injections were given. The presence of humoral anti-Zyderm antibodies in patients without skin reactions has been reported previously.5· 9 The significance of anti-Zyderm antibody has been the subject
896
LETTERS TO THE EDITOR
of speculation ranging from simple curiosity to the possibility of severe disease. 4· 12- 15 Since some human autoimmune diseases can be associated with the presence of circulating antibodies against human collagen, it is reasonable to ask what the risk of cross-reaction is between human antibody produced in response to bovine collagen and native human collagen, In particular, what is the potential for cross-reactivity with type II collagen, known to be associated with a disease similar to rheumatoid arthritis? 16 Ellingsworth et al studied the specificity of human antibovine collagen antibodies from sera of patients with cutaneous reactions to Zyderm and found no cross-reactivity with human collagen. 2 They also found no significant species cross-reactivity against rat collagen type I or II or guinea pig collagen type I. Fisher et al also failed to show any cross-reactivity with human collagen types I to III and no patient had clinical evidence of autoimmune disease after Zyderm test doses or treatment injections. 11 Moreover, neither Zyderm I nor II contains type II collagen, since they are composed solely of bovine collagen type I (95%) and type III (5%), However, there has been expressed concern that an immune response to bovine collagen injected into a patient previously free of autoimmune disease might trigger the development of an immune reaction against the recipient's own collagen. 12• 15• 17 Castrow and Krull reported that systemic reactions that could be associated with autoimmune disease developed in 14 of 7,000 individuals (0.2%) injected with bovine collagen.4 Jarrett reported 1 instance in which a patient had polyarthritis after treatment with Zyderm collagen implant to fill acne scars. 15 He speculated that there might be a relationship between the arthritis and the collagen injections. The variable response seen in cutaneous hypersensitivity reactions and serum antibody development may be due to individual genetic variation of susceptibility (in addition to low antigenicity, dose-related response and frequency of injections), A preliminary study in humans suggested that further investigations are needed before the significance of serum anti-Zyderm antibodies in patients with no apparent clinical symptoms can be established, 18 In conclusion, bovine collagen, despite its low antigenicity, is able to ellicit a cell-mediated and humoral antibody response in humans. The long-term significance of these antibodies is unknown. However, given the current wide use of Zyderm collagen implant it is presumable that for most patients biological exposure to collagen does not appear to pose any health hazard, Nevertheless, this immunological response could be potentially harmful for some patients and there is no proof that these antibodies will remain harmless in every individual for a lifetime. Until the nature of the immune response to bovine collagen implant is better understood we agree with McCoy et al that ",,. it would be advisable to err on the conservative side regarding contraindications of bovine collagen implant treatment." 17 Caution must be greater in patients with a long life expectancy and when other therapeutic modalities are available. Respectfully, Francesco Aragona Istituto di Urologia Universita di Padova Via Giustiniani, 2 35100 Padova, Italy 1. Kligman, A. M. and Armstrong, R. C.: Histologic response to intradermal Zyderm and Zyplast (glutaraldehyde cross-linked) collagen in humans. J. Dermatol. Surg. Oncol., 12: 351, 1986. 2. Ellingsworth, L. R., DeLustro, F., Brennan, J. E., Sawamura, S. and McPherson, J.: The human immune response to reconstituted bovine collagen. J. Immunol., 136: 877, 1986. 3. Hopps, H. C.: Role of allergy in delayed healing and in disruption of wounds. Arch. Surg., 48: 438, 1944. 4. Castrow, F. F., II and Krull, E. A.: Injectable collagen implantupdate. J. Amer. Acad. Dermatol., 9: 889, 1983. 5. McCoy, J. P., Jr., Schade, W. J., Siegle, R. J., Waldinger, T. P., Vanderveen, E. E. and Swanson, N. A.: Characterization of the humoral immune response to bovine collagen implants. Arch. Dermatol., 121: 990, 1985. 6. Swanson, N. A., Stoner, J. G., Siegle, R. J. and Solomon, A. R.: Treatment site reactions to Zyderm collagen implantation. J. Dermatol. Surg. Oncol., 9: 377, 1983. 7. Cooperman, L. and Michaeli, D.: The immunogenicity of injectable collagen. I. A 1-year prospective study. J. Amer. Acad. Dermatol., 10: 638, 1984. 8. Cooperman, L. and Michaeli, D.: The immunogenicity of injectable collagen. II. A retrospective review of 72 tested and treated patients. J. Amer. Acad. Dermatol., 10: 647, 1984. 9. Siegle, R. J., McCoy, J. P., Jr., Schade, W. and Swanson, N. A.: Intradermal implantation of bovine collagen. Humoral immune responses associated with clinical reactions. Arch. Dermatol.,
120: 183, 1984. 10. Frank, H. D., Ozkan, A. N. and Fisher, J.C.: Antibody responsiveness of injected bovine collagen. In: Plastic Surgery Forum, vol. IX, ASMS Meeting, October 31, 1986. 11. Fisher, J. C., Frank, H. D. and Ozkan, A. N.: Further study of humoral immune response to injectable bovine collagen. Surg. Forum, 38: 583, 1987. 12. Cohen, I. K., Peacock, E. E., Jr. and Chvapil, M.: Zyderm. Letter to the Editor. Plast. Reconstr. Surg., 73: 857, 1984. 13. Tarkowski, A., Klareskog, L., Carlsten, H., Herberts, P. and Koopman, W. J.: Secretion of antibodies to types I and II collagen by synovial tissue cells in patients with rheumatoid arthritis. Arth. Rheum., 32: 1087, 1989. 14. Trentham, D. E.: Adverse reactions to bovine collagen implants. Additional evidence for immune response gene control of collagen reactivity in humans. Arch. Dermatol., 122: 643, 1986. 15. Jarrett, M. P.: Collagen-induced arthritis in a human. Letter to the Editor. Arth. Rheum., 25: 1024, 1982. 16. Trentham, D. E.: Collagen arthritis as a relevant model for rheumatoid arthritis. Arth. Rheum., 25: 911, 1982. 17. McCoy, J. P., Jr., Waldinger, T. P., Cohen, K. A., Schade, W., Siegle, R., Hamilton, T. A. and Swanson, N. A.: Connective tissue diseases and bovine collagen implants. J. Amer. Acad. Dermatol., suppl. 2, pt. 1, 16: 315, 1987. 18. Vanderveen, E. E., McCoy, J. P., Jr., Schade, W., Kapur, J. J., Hamilton, T., Ragsdale, C., Grekin, R. C. and Swanson, N. A.: The association of HLA and immune responses to bovine collagen implants. Arch. Dermatol., 122: 650, 1986.
Reply by Authors. Doctor Aragona has raised an issue of some concern to all physicians involved with the implantation of prosthetic materials in patients, that of long-term safety. We acknowledge that bovine collagen may elicit cellular and humoral immune responses in humans. As noted in our article, patients who have positive skin tests produce antibodies that react with bovine collagen but do not crossreact with human collagen (reference 2 in Letter). Moreover, those few patients (0.2%) who have limited systemic reactions to collagen injection (nausea, rash, arthralgia, myalgia and headache) do not have detectable serum antibodies to either bovine or human collagen (reference 8 in Letter). Reports of autoimmune diseases due to collagen injection remain purely speculative and do not prove or disprove the assumption (reference 15 in Letter). We believe that we are being cautious in studying a defined group of patients who will have longterm followup. Although it is much easier to prove the hazards of a product than to prove its safety, it is only through legitimately approved studies that we can take ourselves from the realm of conjecture to that of science.
RE: COMPUTERIZED ANALYSIS OF SMOOTH MUSCLE FIBERS IN POTENT AND IMPOTENT PATIENTS J. E. Wespes, P. M. Goes, S. Schiffmann, M. Depierreux, J. J. Vanderhaeghen and C. C. Schulman
J. Urol., 146: 1015-1017, 1991 To the Editor. This interesting study on the quantification of the amount of smooth muscle in the cavernous bodies deserves some comments on our results with a similar methodology in 43 patients from whom 51 samples of cavernous tissue were taken during various surgical procedures.'· 2 The samples were obtained from 4 patients with congenital penile curvature, 1 undergoing withdrawal of a penile implant for psychogenic impotence, 9 undergoing deep dorsal vein arterialization, 11 undergoing venous resection and 18 undergoing penile implantation. We found a statistically significant {p
Ve;. 148, 895-898, September 1992 Printed in U.S.A.
Letters to the Editor RE: THE INCIDENCE OF MULTICENTRICITY IN RENAL CELL CARCINOMA W. S. Cheng, G. M. Farrow and H. Zincke
J. Urol., 146: 1221-1223, 1991
To the Editor. The authors of this article studied the frequency of multicentric tumors in kidneys removed for renal cell carcinoma. The incidence of small renal nodules in this series of kidneys was 13% and the incidence of small satellite renal carcinoma coexisting with a predominant tumor was 7%. Novick et al reported a 9% local recurrence rate in 100 partial nephrectomies for renal cell carcinoma. 1 The presence of multicentric tumors can explain the recurrence rates observed. For us it means that multicentricity poses a significant clinical problem when a nephron sparing operation is considered for patients with small tumors. To confirm this hypothesis we reviewed retrospectively our series of 759 malignant parenchymal kidney tumors. The overall rate of multicentric tumors was 70 of 759 (9.22%), including 1 sarcoma, 1 undifferentiated cancer, 1 epidermoid tumor and 67 renal cell carcinomas. We looked at the small tumors 5 cm. or less in diameter, which generally are the best candidates for conservative surgery (see table). The conclusion is that there is no safe limit to exclude multicentric tumors and that is a significant statement if we intend to propose nephron sparing surgery for renal cell carcinoma in patients with a normal contralateral kidney. Respectfully, D. Jacqmin and C. Saussine Hopitaux Universitaires de Strasbourg Centre Hospitalier Regional et Universitaire B.P. No. 426 67091 Strasbourg Cedex France 1. Novick, A. C., Streem, S., Montie, J. E., Pontes, J. E., Siegel, S., Montague, D. K. and Goormastic, M.: Conservative surgery for renal cell carcinoma: a single-center experience with 100 patients. J. Urol., 141: 835, 1989.
Reply by Authors. It is well established in the literature that local recurrence after renal conserving surgery for renal cell cancer ranges from 6 to 9% as reported in 2 major series. 1• 2 Our study did not address the question nor did it propose "nephron sparing for renal cell cancer to patients with a normal contralateral right kidney." Rather, ours was a histopathological study carefully performed by Doctor Farrow. In our study there was a 13% incidence of tumors but only a 7% incidence of true renal cell cancer in the 100 kidneys examined. Of those 7 renal cell cancers 3 were easily detectable at operation, and of the other 4, 3 were subcapsular and theoretically detectable with careful inspection at operation. Thus, the incidence of intraparenchymal nondetectable lesions at conservative surgery for lesser lesions seems to be small. However, the rather high local recurrence rate with large tumors 3 clearly shows a relationship between the size of the original tumor and the potential for local recurrence (namely, the larger the original tumor, the higher the local recurrence rate).
Frequency of multicentric kidney tumors according to the diameter of the biggest tumor Diameter (cm.) Less than Less than Less than Less than Less than Overall
5 4 3 2 1.5
No.
No. Multicentric Tumors(%)
274 166 86 21 8 759
29 (10.58) 22 (13.25) 15 (17.44) 5370 (9.22)
895
Doctors Jacqmin and Saussine have failed in their study to delineate the exact histopathological diagnosis of the tumors found; this is important because not every tumor represents renal cell cancer. This might explain the disproportionate relationships described in the table, where larger tumors were associated with a lower incidence of multicentricity than smaller tumors. It would be of interest if the authors could provide some clear histopathological information for their data. 1. Morgan, W. R. and Zincke, H.: Progression and survival after renal-conserving surgery for renal cell carcinoma: experience in 104 patients and extended followup. J. UroL, 144: 852, 1990. 2. Novick, A. C., Streem, S., Montie, J. E., Pontes, J. E., Siegel, S., Montague, D. K. and Goormastic, M.: Conservative surgery for renal cell carcinoma: a single-center experience with 100 patients. J. Urol., 141: 835, 1989. 3. Stormont, T. J., Bilhartz, D. L. and Zincke, H.: Pitfalls of bench surgery and autotransplantation for renal cell carcinoma. Mayo Clin. Proc., in press. RE: ENDOSCOPIC INJECTION OF GLUTARALDEHYDE CROSS-LINKED BOVINE DERMAL COLLAGEN FOR CORRECTION OF VESICOURETERAL REFLUX
M. P. Leonard, D. A. Canning, C. A. Peters, J. P. Gearhart and R. D. Jeffs J. Urol., 145: 115-119, 1991
To the Editor. The authors suggest that endoscopic injection of bovine dermal collagen is a safe and effective treatment of vesicoureteral reflux. I would like to express some concerns about the long-term safety of such a procedure. Zyderm collagen implant is a purified, reconstituted bovine dermal collagen dispersed in physiological saline at a concentration of 35 mg. (Zyderm I) or 65 mg, (Zyderm II) collagen per ml. Zyplast implant is identical to Zyderm collagen implant except that the fibrillar collagen has been cross-linked with 0.0075% glutaraldehyde to enhance the persistence of the implant. 1 Zyderm collagen implant was introduced in 1981 as a medical device (not as a drug) for percutaneous soft tissue augmentation. Food and Drug Administration approval was based on the assumption that bovine collagen, although metabolized, would not elicit any biological response in humans. However, although the immunogenicity of Zyderm collagen implant and Zyplast implant probably is modest compared with other proteins (that is y-globulins or various hemostatic collagens), animal collagen is still an immunogen that is capable of eliciting an immune response. From an immunological perspective this is not a surprising observation, given the extraordinary specificity of our immune system. Nevertheless, cutaneous reactions to commercially prepared collagen are reported to be uncommon and largely avoidable by preliminary skin testing. Published surveys of immunity to bovine collagen show a tendency to commingle observations of cellular immunity (cutaneous hypersensitivity) with those of humoral (antibody) immunity. 2 Actually, these are essentially independent biological phenomena and the absence of a perceived response might simply mean that a more sensitive assay is needed. Early reference to the antigenicity of collagen devices was made by Hopps, who demonstrated in 1944 that collagen sutures could elicit cutaneous hypersensitivity and humoral antibody reactions. 3 These biological responses to collagen sutures were believed to be a cause of early wound dehiscence in sensitized patients. In the literature there are numerous reports of Zyderm collagen implant injections resulting in cutaneous and humoral immune reactions.•-9 Frank 10 and Fishern et al focused on humoral antibody response to Zyderm collagen implant (instead of cell-mediated cutaneous hypersensitivity), using an enzyme-linked immunosorbent assay selected because of its extraordinary sensitivity to modest antigens. They demonstrated elevated anti-Zyderm antibody levels in patients treated with clinical doses of injectable bovine collagen, even in the absence of adverse cutaneous reactions. Increasing antibody titers were observed as repeated injections were given. The presence of humoral anti-Zyderm antibodies in patients without skin reactions has been reported previously.5· 9 The significance of anti-Zyderm antibody has been the subject
896
LETTERS TO THE EDITOR
of speculation ranging from simple curiosity to the possibility of severe disease. 4· 12- 15 Since some human autoimmune diseases can be associated with the presence of circulating antibodies against human collagen, it is reasonable to ask what the risk of cross-reaction is between human antibody produced in response to bovine collagen and native human collagen, In particular, what is the potential for cross-reactivity with type II collagen, known to be associated with a disease similar to rheumatoid arthritis? 16 Ellingsworth et al studied the specificity of human antibovine collagen antibodies from sera of patients with cutaneous reactions to Zyderm and found no cross-reactivity with human collagen. 2 They also found no significant species cross-reactivity against rat collagen type I or II or guinea pig collagen type I. Fisher et al also failed to show any cross-reactivity with human collagen types I to III and no patient had clinical evidence of autoimmune disease after Zyderm test doses or treatment injections. 11 Moreover, neither Zyderm I nor II contains type II collagen, since they are composed solely of bovine collagen type I (95%) and type III (5%), However, there has been expressed concern that an immune response to bovine collagen injected into a patient previously free of autoimmune disease might trigger the development of an immune reaction against the recipient's own collagen. 12• 15• 17 Castrow and Krull reported that systemic reactions that could be associated with autoimmune disease developed in 14 of 7,000 individuals (0.2%) injected with bovine collagen.4 Jarrett reported 1 instance in which a patient had polyarthritis after treatment with Zyderm collagen implant to fill acne scars. 15 He speculated that there might be a relationship between the arthritis and the collagen injections. The variable response seen in cutaneous hypersensitivity reactions and serum antibody development may be due to individual genetic variation of susceptibility (in addition to low antigenicity, dose-related response and frequency of injections), A preliminary study in humans suggested that further investigations are needed before the significance of serum anti-Zyderm antibodies in patients with no apparent clinical symptoms can be established, 18 In conclusion, bovine collagen, despite its low antigenicity, is able to ellicit a cell-mediated and humoral antibody response in humans. The long-term significance of these antibodies is unknown. However, given the current wide use of Zyderm collagen implant it is presumable that for most patients biological exposure to collagen does not appear to pose any health hazard, Nevertheless, this immunological response could be potentially harmful for some patients and there is no proof that these antibodies will remain harmless in every individual for a lifetime. Until the nature of the immune response to bovine collagen implant is better understood we agree with McCoy et al that ",,. it would be advisable to err on the conservative side regarding contraindications of bovine collagen implant treatment." 17 Caution must be greater in patients with a long life expectancy and when other therapeutic modalities are available. Respectfully, Francesco Aragona Istituto di Urologia Universita di Padova Via Giustiniani, 2 35100 Padova, Italy 1. Kligman, A. M. and Armstrong, R. C.: Histologic response to intradermal Zyderm and Zyplast (glutaraldehyde cross-linked) collagen in humans. J. Dermatol. Surg. Oncol., 12: 351, 1986. 2. Ellingsworth, L. R., DeLustro, F., Brennan, J. E., Sawamura, S. and McPherson, J.: The human immune response to reconstituted bovine collagen. J. Immunol., 136: 877, 1986. 3. Hopps, H. C.: Role of allergy in delayed healing and in disruption of wounds. Arch. Surg., 48: 438, 1944. 4. Castrow, F. F., II and Krull, E. A.: Injectable collagen implantupdate. J. Amer. Acad. Dermatol., 9: 889, 1983. 5. McCoy, J. P., Jr., Schade, W. J., Siegle, R. J., Waldinger, T. P., Vanderveen, E. E. and Swanson, N. A.: Characterization of the humoral immune response to bovine collagen implants. Arch. Dermatol., 121: 990, 1985. 6. Swanson, N. A., Stoner, J. G., Siegle, R. J. and Solomon, A. R.: Treatment site reactions to Zyderm collagen implantation. J. Dermatol. Surg. Oncol., 9: 377, 1983. 7. Cooperman, L. and Michaeli, D.: The immunogenicity of injectable collagen. I. A 1-year prospective study. J. Amer. Acad. Dermatol., 10: 638, 1984. 8. Cooperman, L. and Michaeli, D.: The immunogenicity of injectable collagen. II. A retrospective review of 72 tested and treated patients. J. Amer. Acad. Dermatol., 10: 647, 1984. 9. Siegle, R. J., McCoy, J. P., Jr., Schade, W. and Swanson, N. A.: Intradermal implantation of bovine collagen. Humoral immune responses associated with clinical reactions. Arch. Dermatol.,
120: 183, 1984. 10. Frank, H. D., Ozkan, A. N. and Fisher, J.C.: Antibody responsiveness of injected bovine collagen. In: Plastic Surgery Forum, vol. IX, ASMS Meeting, October 31, 1986. 11. Fisher, J. C., Frank, H. D. and Ozkan, A. N.: Further study of humoral immune response to injectable bovine collagen. Surg. Forum, 38: 583, 1987. 12. Cohen, I. K., Peacock, E. E., Jr. and Chvapil, M.: Zyderm. Letter to the Editor. Plast. Reconstr. Surg., 73: 857, 1984. 13. Tarkowski, A., Klareskog, L., Carlsten, H., Herberts, P. and Koopman, W. J.: Secretion of antibodies to types I and II collagen by synovial tissue cells in patients with rheumatoid arthritis. Arth. Rheum., 32: 1087, 1989. 14. Trentham, D. E.: Adverse reactions to bovine collagen implants. Additional evidence for immune response gene control of collagen reactivity in humans. Arch. Dermatol., 122: 643, 1986. 15. Jarrett, M. P.: Collagen-induced arthritis in a human. Letter to the Editor. Arth. Rheum., 25: 1024, 1982. 16. Trentham, D. E.: Collagen arthritis as a relevant model for rheumatoid arthritis. Arth. Rheum., 25: 911, 1982. 17. McCoy, J. P., Jr., Waldinger, T. P., Cohen, K. A., Schade, W., Siegle, R., Hamilton, T. A. and Swanson, N. A.: Connective tissue diseases and bovine collagen implants. J. Amer. Acad. Dermatol., suppl. 2, pt. 1, 16: 315, 1987. 18. Vanderveen, E. E., McCoy, J. P., Jr., Schade, W., Kapur, J. J., Hamilton, T., Ragsdale, C., Grekin, R. C. and Swanson, N. A.: The association of HLA and immune responses to bovine collagen implants. Arch. Dermatol., 122: 650, 1986.
Reply by Authors. Doctor Aragona has raised an issue of some concern to all physicians involved with the implantation of prosthetic materials in patients, that of long-term safety. We acknowledge that bovine collagen may elicit cellular and humoral immune responses in humans. As noted in our article, patients who have positive skin tests produce antibodies that react with bovine collagen but do not crossreact with human collagen (reference 2 in Letter). Moreover, those few patients (0.2%) who have limited systemic reactions to collagen injection (nausea, rash, arthralgia, myalgia and headache) do not have detectable serum antibodies to either bovine or human collagen (reference 8 in Letter). Reports of autoimmune diseases due to collagen injection remain purely speculative and do not prove or disprove the assumption (reference 15 in Letter). We believe that we are being cautious in studying a defined group of patients who will have longterm followup. Although it is much easier to prove the hazards of a product than to prove its safety, it is only through legitimately approved studies that we can take ourselves from the realm of conjecture to that of science.
RE: COMPUTERIZED ANALYSIS OF SMOOTH MUSCLE FIBERS IN POTENT AND IMPOTENT PATIENTS J. E. Wespes, P. M. Goes, S. Schiffmann, M. Depierreux, J. J. Vanderhaeghen and C. C. Schulman
J. Urol., 146: 1015-1017, 1991 To the Editor. This interesting study on the quantification of the amount of smooth muscle in the cavernous bodies deserves some comments on our results with a similar methodology in 43 patients from whom 51 samples of cavernous tissue were taken during various surgical procedures.'· 2 The samples were obtained from 4 patients with congenital penile curvature, 1 undergoing withdrawal of a penile implant for psychogenic impotence, 9 undergoing deep dorsal vein arterialization, 11 undergoing venous resection and 18 undergoing penile implantation. We found a statistically significant {p
