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Tumor regression and sirolimus-based therapy in lung transplantation
938
The Journal of Heart and Lung Transplantation, Vol 32, No 9, September 2013
By using these strategies and continuing to refine outcomes data, the integrity of transplant medicine should withstand media scrutiny.
Disclosure statement This author does not have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Katarsky C. Heart dropped on ground used in (successful) transplant. Healthcare, Business, and Technology. http://www.healthcarebusinesstech. com/heart-dropped-on-ground-used-in-successful-transplant/. 2012. Accessed July 2, 2013.
Radiofrequency perforation may increase the safety of transcatheter Potts shunt creation Keyhan Sayadpour Zanjani, MD From the Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
I appreciate the courage of Esch et al1 in creating transcatheter aortopulmonary shunts in humans for the first time. As a member of the group in Berlin, I had the chance to participate in making these shunts in piglets and in their postmortem gross examination.2 Although the objective of our study was to find a transcatheter substitute for surgical shunt creation in small infants, the procedure was quiet similar. Esch et al1 lost 1 of their patients due to fatal mediastinal hemorrhage during the procedure. Chigogidze et al3 reported massive bleeding in 2 dogs after successful transcatheter intervascular anastomosis creation. Contrary to these results, none of our animals died of this complication. Postmortem examination revealed no hemorrhage or only a small hematoma at the site of arterial punctures.2 This may be explained by our use of radiofrequency (RF) perforation for arterial puncture. In contrast to the mechanical force of the back (stiff) end of a guidewire
Tumor regression and sirolimus-based therapy in lung transplantation Uwe Hillen, MD,a Klaus Griewank, MD,a Urte Sommerwerck, MD,b Hideo A. Baba, MD,c and Dirk Schadendorf, MDa From the aDepartment of Dermatology; bDepartment of Pneumology, Ruhrlandklinik, West German Lung Center; and the c Department of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Organ transplant recipients (OTRs) are at high risk to develop nonmelanoma skin cancer, which accounts for 95% of all skin cancers.1 Metastatic cutaneous squamous cell carcinoma (cSCC) carries a poor prognosis, with 10-year
2. Petition by Family and Friends of Sarah Murnaghan. OPTN/UNOS: Change policy to allow pediatric transplants of adult lungs based on medical necessity. http://www.change.org/petitions/optn-unos-changepolicy-to-allow-pediatric-transplants-of-adult-lungs-based-on-medicalnecessity. Accessed July 2, 2013. 3. LaRosa C, Baluarte HJ, Meyers KE. Outcomes in pediatric solid-organ transplantation. Pediatr Transplant 2011;15:128-41. 4. Beauchamp TL, Childress JF. Principles of biomedical ethics. 6th ed. New York: Oxford University Press; 2008. 5. James IL. Victims of groupthink: a psychological study of foreignpolicy decisions and fiascoes. Boston, MA: Houghton Mifflin; 1972. 6. Park WW. A review of research on groupthink. J Behav Decis Making 1990;3:229-45. 7. Dudzinski DM. Ethics guidelines for destination therapy. Ann Thorac Surg 2006;81:1185-8.
by Esch et al1 and Chigogidze et al,3 RF has the potential to coagulate the tissue which may prevent extravasation of blood at the puncture sites and the created track.4 Use of RF may reduce the risk of bleeding and increase the safety of this promising procedure.
Disclosure statement This author does not have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Esch JJ, Shah PB, Cockrill BA, et al. Transcatheter Potts shunt creation in patients with severe pulmonary arterial hypertension: initial clinical experience. J Heart Lung Transplant 2013;32:381-7. 2. Sabi TM, Schmitt B, Sigler M, et al. Transcatheter creation of an aortopulmonary shunt in an animal model. Catheter Cardiovasc Interv 2010;75:563-9. 3. Chigogidze NA, Bilbao JI, Avaliani MV, et al. Intervascular anastomoses created by an endovascular approach: technical aspects and initial results in an animal study. J Vasc Interv Radiol 2006;17:521-31. 4. Justino H, Benson LN, Nykanen DG. Transcatheter creation of an atrial septal defect using radiofrequency perforation. Catheter Cardiovasc Interv 2001;54:83-7.
survival rates of less than 20% with regional lymph node involvement and less than 10% with distant metastases. The course of cSCC disease appears to be more aggressive in OTRs than in non-OTRs.1,2 Systemic therapy for sSCC traditionally consists of platinum-based chemotherapy regimens; however, recently promising results with targeted therapies, such as antiepithelial growth factor receptor therapies, have been reported. Controlled trials supporting these findings are still lacking. New treatment strategies for modified immunosuppression in OTRs in the setting of advanced cSCC are urgently needed. A 64-year-old man received a lung transplant in 2009 and was initially treated with basiliximab 20 mg on Days 1 and 4 after transplantation and prednisolone, tacrolimus,
Case Anecdotes, Comments and Opinions
939 Histopathologic examination showed a dedifferentiated tumor (Figure 1C–F) with activation of the mammalian target of rapamycin (mTOR) signal transduction pathway (Figure 1G and H). Immunosuppressive therapy consisted of once daily doses of prednisone (7.5 mg), tacrolimus (2.5 mg), and mycophenolate mofetil (500 mg). The patient refused any tumor-specific therapy but accepted the substitution of tacrolimus by sirolimus (SRL; 3 mg once daily). Three months later, the tumor nearly completely regressed (Figure 1B). Efficacy of mTOR inhibitors has been shown in clinical trials for different tumor types and resulted in an approval of this drug class for cancer treatment (eg, renal cell cancer, breast cancer). A recent study showed that OTRs who had developed at least 1 cSCC while receiving a calcineurin inhibitor (CNI) had a higher probability of cSCC-free survival when switched to SRL than patients maintained on a CNI.3 A previous study showed that shifting immunosuppressive therapy from a CNI-based therapy to a CNI-free, SRL-based regimen inhibited progression of dermal Kaposi’s sarcoma.4 Here we report that switching from a CNI-based to an SRL-based treatment regimen was able to induce tumor regression in cSCC. Activation of the mTOR pathway appears to be common in cSCC and not restricted to those developing in OTRs.5 Incorporating mTOR inhibitors in anti-neoplastic treatment regimens could prove valuable in the treatment of patients with advanced cSCC.
Disclosure statement Figure 1 Clinical, microscopic, and immunohistochemical features of the squamous cell carcinoma. (A) Clinical features at admission showed multiple confluent indurated nodules on the border of the skin graft, which were 6.5 cm in diameter. (B) No tumor is visible 3 months after the switch to a sirolimus-based immunosuppressive therapy. (C) Microscopically, the tumor was dedifferentiated showing no keratinization. (D) Only some tumor cells expressed cytokeratin. (E and F) Epithelial growth factor receptor was expressed by most of the tumor cells and p63 by nearly all tumor cells. (G and H) Phosphoprotein analysis by immunohistochemistry demonstrated phosphorylation of S6 ribosomal protein, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and 70 S6 kinase (not shown), indicating activation of the mammalian target of rapamycin signal transduction pathway.
mycophenolate mofetil. He presented in June 2012 with a cSCC on the scalp, which recurred on the border of the skin graft 3 months after primary excision of the tumor. The tumor evolved within 20 days into confluent large nodules (Figure 1A).
None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Ulrich C, Kanitakis J, Stockfleth E, Euvrard S. Skin cancer in organ transplant recipients—where do we stand today? Am J Transplant 2008; 8:2192-8. 2. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344:975-83. 3. Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skincancer prevention in kidney transplantation. N Engl J Med 2012;367: 329-39. 4. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 2005;352:1317-23. 5. Gutiérrez-Dalmau A, Revuelta I, Ferrer B, et al. Distinct immunohistochemical phenotype of nonmelanoma skin cancers between renal transplant and immunocompetent populations. Transplantation 2010;90: 986-92.
The Journal of Heart and Lung Transplantation, Vol 32, No 9, September 2013
By using these strategies and continuing to refine outcomes data, the integrity of transplant medicine should withstand media scrutiny.
Disclosure statement This author does not have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Katarsky C. Heart dropped on ground used in (successful) transplant. Healthcare, Business, and Technology. http://www.healthcarebusinesstech. com/heart-dropped-on-ground-used-in-successful-transplant/. 2012. Accessed July 2, 2013.
Radiofrequency perforation may increase the safety of transcatheter Potts shunt creation Keyhan Sayadpour Zanjani, MD From the Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
I appreciate the courage of Esch et al1 in creating transcatheter aortopulmonary shunts in humans for the first time. As a member of the group in Berlin, I had the chance to participate in making these shunts in piglets and in their postmortem gross examination.2 Although the objective of our study was to find a transcatheter substitute for surgical shunt creation in small infants, the procedure was quiet similar. Esch et al1 lost 1 of their patients due to fatal mediastinal hemorrhage during the procedure. Chigogidze et al3 reported massive bleeding in 2 dogs after successful transcatheter intervascular anastomosis creation. Contrary to these results, none of our animals died of this complication. Postmortem examination revealed no hemorrhage or only a small hematoma at the site of arterial punctures.2 This may be explained by our use of radiofrequency (RF) perforation for arterial puncture. In contrast to the mechanical force of the back (stiff) end of a guidewire
Tumor regression and sirolimus-based therapy in lung transplantation Uwe Hillen, MD,a Klaus Griewank, MD,a Urte Sommerwerck, MD,b Hideo A. Baba, MD,c and Dirk Schadendorf, MDa From the aDepartment of Dermatology; bDepartment of Pneumology, Ruhrlandklinik, West German Lung Center; and the c Department of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Organ transplant recipients (OTRs) are at high risk to develop nonmelanoma skin cancer, which accounts for 95% of all skin cancers.1 Metastatic cutaneous squamous cell carcinoma (cSCC) carries a poor prognosis, with 10-year
2. Petition by Family and Friends of Sarah Murnaghan. OPTN/UNOS: Change policy to allow pediatric transplants of adult lungs based on medical necessity. http://www.change.org/petitions/optn-unos-changepolicy-to-allow-pediatric-transplants-of-adult-lungs-based-on-medicalnecessity. Accessed July 2, 2013. 3. LaRosa C, Baluarte HJ, Meyers KE. Outcomes in pediatric solid-organ transplantation. Pediatr Transplant 2011;15:128-41. 4. Beauchamp TL, Childress JF. Principles of biomedical ethics. 6th ed. New York: Oxford University Press; 2008. 5. James IL. Victims of groupthink: a psychological study of foreignpolicy decisions and fiascoes. Boston, MA: Houghton Mifflin; 1972. 6. Park WW. A review of research on groupthink. J Behav Decis Making 1990;3:229-45. 7. Dudzinski DM. Ethics guidelines for destination therapy. Ann Thorac Surg 2006;81:1185-8.
by Esch et al1 and Chigogidze et al,3 RF has the potential to coagulate the tissue which may prevent extravasation of blood at the puncture sites and the created track.4 Use of RF may reduce the risk of bleeding and increase the safety of this promising procedure.
Disclosure statement This author does not have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Esch JJ, Shah PB, Cockrill BA, et al. Transcatheter Potts shunt creation in patients with severe pulmonary arterial hypertension: initial clinical experience. J Heart Lung Transplant 2013;32:381-7. 2. Sabi TM, Schmitt B, Sigler M, et al. Transcatheter creation of an aortopulmonary shunt in an animal model. Catheter Cardiovasc Interv 2010;75:563-9. 3. Chigogidze NA, Bilbao JI, Avaliani MV, et al. Intervascular anastomoses created by an endovascular approach: technical aspects and initial results in an animal study. J Vasc Interv Radiol 2006;17:521-31. 4. Justino H, Benson LN, Nykanen DG. Transcatheter creation of an atrial septal defect using radiofrequency perforation. Catheter Cardiovasc Interv 2001;54:83-7.
survival rates of less than 20% with regional lymph node involvement and less than 10% with distant metastases. The course of cSCC disease appears to be more aggressive in OTRs than in non-OTRs.1,2 Systemic therapy for sSCC traditionally consists of platinum-based chemotherapy regimens; however, recently promising results with targeted therapies, such as antiepithelial growth factor receptor therapies, have been reported. Controlled trials supporting these findings are still lacking. New treatment strategies for modified immunosuppression in OTRs in the setting of advanced cSCC are urgently needed. A 64-year-old man received a lung transplant in 2009 and was initially treated with basiliximab 20 mg on Days 1 and 4 after transplantation and prednisolone, tacrolimus,
Case Anecdotes, Comments and Opinions
939 Histopathologic examination showed a dedifferentiated tumor (Figure 1C–F) with activation of the mammalian target of rapamycin (mTOR) signal transduction pathway (Figure 1G and H). Immunosuppressive therapy consisted of once daily doses of prednisone (7.5 mg), tacrolimus (2.5 mg), and mycophenolate mofetil (500 mg). The patient refused any tumor-specific therapy but accepted the substitution of tacrolimus by sirolimus (SRL; 3 mg once daily). Three months later, the tumor nearly completely regressed (Figure 1B). Efficacy of mTOR inhibitors has been shown in clinical trials for different tumor types and resulted in an approval of this drug class for cancer treatment (eg, renal cell cancer, breast cancer). A recent study showed that OTRs who had developed at least 1 cSCC while receiving a calcineurin inhibitor (CNI) had a higher probability of cSCC-free survival when switched to SRL than patients maintained on a CNI.3 A previous study showed that shifting immunosuppressive therapy from a CNI-based therapy to a CNI-free, SRL-based regimen inhibited progression of dermal Kaposi’s sarcoma.4 Here we report that switching from a CNI-based to an SRL-based treatment regimen was able to induce tumor regression in cSCC. Activation of the mTOR pathway appears to be common in cSCC and not restricted to those developing in OTRs.5 Incorporating mTOR inhibitors in anti-neoplastic treatment regimens could prove valuable in the treatment of patients with advanced cSCC.
Disclosure statement Figure 1 Clinical, microscopic, and immunohistochemical features of the squamous cell carcinoma. (A) Clinical features at admission showed multiple confluent indurated nodules on the border of the skin graft, which were 6.5 cm in diameter. (B) No tumor is visible 3 months after the switch to a sirolimus-based immunosuppressive therapy. (C) Microscopically, the tumor was dedifferentiated showing no keratinization. (D) Only some tumor cells expressed cytokeratin. (E and F) Epithelial growth factor receptor was expressed by most of the tumor cells and p63 by nearly all tumor cells. (G and H) Phosphoprotein analysis by immunohistochemistry demonstrated phosphorylation of S6 ribosomal protein, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and 70 S6 kinase (not shown), indicating activation of the mammalian target of rapamycin signal transduction pathway.
mycophenolate mofetil. He presented in June 2012 with a cSCC on the scalp, which recurred on the border of the skin graft 3 months after primary excision of the tumor. The tumor evolved within 20 days into confluent large nodules (Figure 1A).
None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Ulrich C, Kanitakis J, Stockfleth E, Euvrard S. Skin cancer in organ transplant recipients—where do we stand today? Am J Transplant 2008; 8:2192-8. 2. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344:975-83. 3. Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skincancer prevention in kidney transplantation. N Engl J Med 2012;367: 329-39. 4. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 2005;352:1317-23. 5. Gutiérrez-Dalmau A, Revuelta I, Ferrer B, et al. Distinct immunohistochemical phenotype of nonmelanoma skin cancers between renal transplant and immunocompetent populations. Transplantation 2010;90: 986-92.