Pediatr Transplantation 2015: 19: E15–E18
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12398
The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman’s disease Thomas TO, Chandrakasan S, O’Brien M, Jefferies JL, Ryan TD, Wilmot I, Baker ML, Madueme PC, Morales D, Lorts A. (2015) The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman’s disease. Pediatr Transplant, 19: E15–E18. DOI: 10.1111/petr.12398.
Tamara O. Thomas1, Shanmuganathan Chandrakasan2, Maureen O’Brien2, John L. Jefferies1, Thomas D. Ryan1, Ivan Wilmot1, Michael L. Baker1, Peace C. Madueme1, David Morales1 and Angela Lorts1
Abstract: We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four-yr-old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non-malignant lymphoproliferative disorder fueled by excessive IL-6 production. Treatment with IL-6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti-coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anticoagulation regimen to coincide with changes in the inflammatory state.
1
CD is a rare non-malignant lymphoproliferative disorder characterized by systemic inflammatory symptoms secondary to the unregulated overproduction of IL-6. It can be characterized as either unicentric or HVV or multicentric or PCV (1–4). The unicentric type is defined as being confined to a single lymph node, whereas the multicentric type involves multiple lymph nodes with resulting systemic effects. Resection of the single involved node in the hyaline–vascular type is
Abbreviations: CD, Castleman’s disease; COP, cyclophosphamide; CRP, C-reactive protein; FDG, fluorodeoxyglucose; HVV, hyaline–vascular variant; IL-6, interleukin-6; LVAD, left ventricular assist device; MCS, mechanical circulatory support; MRI, magnetic resonance imaging; PCV, plasma cell variant.
The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA, 2Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Key words: pediatric heart transplant – cardiomyopathy – cardiac function – lymphoproliferative disorder – Castleman’s disease – mechanical circulatory – support Tamara O. Thomas, MD, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, ML 2003, Cincinnati, OH 45229, USA Tel.: +1 817 937 2055 Fax: +1 513 636 3952 E-mail: [email protected] Accepted for publication 27 October 2014
usually curative; however, the multicentric form is characterized by profound systemic effects secondary to the unregulated overproduction of IL6 and usually requires steroids and chemotherapy agents for treatment. Outcomes in adults are generally poor and characterized by recurrent flares of disease, but in children, disease course is poorly described (3, 5, 6). We present a child with PCV multicentric CD and concomitant restrictive cardiomyopathy who was treated with multi-agent chemotherapy while mechanically supported with a Berlin Heart EXCOR LVAD as a bridge to cardiac transplantation. Case report
A four-yr-old previously healthy male, with a recent diagnosis of restrictive cardiomyopathy, E15
Thomas et al.
suffered a post-anesthesia bradycardic arrest after cardiac MRI, requiring veno-arterial extracorporeal membrane oxygenation. He was decannulated after three days, and his initial echocardiogram demonstrated mildly depressed left ventricular systolic function, an asymmetrically and echobright ventricular septum, and bi-atrial enlargement (Fig. 1a,b). However, he had progressive ventricular dysfunction with hemodynamic instability meeting criteria for MCS; however, his cardiac MRI demonstrated mediastinal adenopathy (Fig. 1c,d). Mediastinal mass biopsy was performed, and he was simultaneously placed on temporary Rotaflow (Maquet) LVAD. Final pathology revealed small atrophic germinal centers with rare lollipop-like lesions and sheets of plasma cells consistent with PCV CD (Fig. 2a–d). HHV-8 immunohistochemistry staining was negative. Serum HHV-8 and HIV testing were negative. Serum cytokines showed massive IL-6 elevation (561 pg/mL, normal ≤7 pg/mL). Therapy was initiated with methylprednisolone 4 mg/kg/day IV and tocilizumab (IL-6 receptor blockade) at 12 mg/kg IV every two wk. His CRP normalized within six days of starting therapy and fevers resolved; however, serial echocardiograms did not demonstrate improvement in myocardial function. After two wk of LVAD support, an attempt to wean flow failed and due to lack of improvement in cardiac function, the decision was made to initiate chemotherapy with 21-day cycles of COP (750 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and methylprednisolone 80 mg/m2/day on day 1–5)
a
b
c
d
E16
with filgrastim support to minimize neutropenia. Tocilizumab was continued every two wk. CT and PET obtained one wk after initiating COP therapy showed decreased adenopathy with no Fluorodeoxyglucose (FDG) uptake and decreased FDG uptake in the myocardium. Given evidence of early response, a Berlin EXCOR LVAD was implanted via left atrial cannulation to allow improved left ventricular decompression given his restrictive physiology and the hypertrophic appearance of his myocardium. Genetic testing for sarcomeric mutations revealed a heterozygous mutation in c.575G>A (p.Arg192His) in exon 8 of the TNNI3 gene (disease-causing mutation), and thus, the chance of cardiac recovery was unlikely. He received three cycles of COP chemotherapy, with tocilizumab every two wk throughout and rituximab 375 mg/ m2 IV weekly during third cycle. Following his third cycle, his response was felt to be sufficient to list for cardiac transplantation and chemotherapy was discontinued. He experienced no wound infections or bacteremia throughout therapy. His course on both the Rotaflow and the Berlin was complicated by extreme difficulty in maintaining hemostasis. Early in his course, his unfractionated heparin requirements paralleled his inflammatory state in that he needed higher levels whenever his inflammatory markers were elevated; however, this was not evident when he was transitioned to Lovenox therapy. While on Lovenox therapy, with appropriate levels, he did suffer a hemorrhagic stroke during his fourth month on MCS (goal range anti-Xa was 0.5–0.7). Following his hemorrhagic stroke, he
Fig. 1. Echocardiogram images showing an apical 4-chamber view (a) and a parasternal short axis view (b) with mild septal hypertrophy and echobright myocardium appreciated, especially involving the ventricular septum. Cardiac MRI images in a coronal view (c) and an axial view (d) showing multifocal mediastinal masses with right paraspinal, subcarinal, right and left hilar, and left paraspinal components. The largest component is the right paraspinal component, which measures 2.6 9 3.2 cm in transverse dimension and appears to be contiguous with a subcarinal component that splays the bronchi.
Chemotherapy on a Berlin LVAD
Fig. 2. Variably atrophic lymphoid follicles (a, H&E 409) in background vascular dilatation, edema, and hemorrhage are intervened by irregular sheets of mature plasma cells (b, H&E 4009). There is a normal ratio of IgG (c, immunoperoxidase 1009)positive plasma cells to IgG4 (d, immunoperoxidase 1009)positive plasma cells. Immunohistochemistry for human herpesvirus-8 was negative.
a
b
c
d
was converted back to an unfractionated heparin infusion for quick titration of anticoagulation. When he was restarted on a heparin infusion after his stroke, he again had episodes of waxing and waning of his inflammatory state and heparin requirements. It may have been that his inflammatory milieu varied, leading to changes in his anti-Xa levels when he was on Lovenox that were difficult to appreciate without frequent monitoring. IL-6 levels and CT scans were monitored and continued to show a favorable response to therapy, leading to the discontinuation of his tocilizumab therapy. He achieved sufficient neurologic recovery to be reactivated for cardiac transplant and underwent successful transplantation eight months after his original presentation and four months after discontinuing chemotherapy. Pathology of the explanted heart demonstrated biventricular transmural fibrosis and hypertrophy with patchy myofiber disarray consistent with a restrictive cardiomyopathy diagnosis and no evidence of CD. Discussion
There are no reported cases of restrictive cardiomyopathy associated with CD, so this patient presented a unique challenge. There are few cases in the literature describing cardiomyopathy associated with CD, and all cases described are of dilated cardiomyopathies with ventricular systolic dysfunction, presumably due to severe systemic inflammation (3, 7–9). Slow improvement in dilated cardiomyopathy was reported in two
cases with the use of the IL-6 receptor-blocking antibody tocilizumab (3, 7). Without cardiac biopsy and with the dramatic FDG uptake on PET scan, we speculated the myocardium may be infiltrated by plasma cells with subsequent restrictive physiology. Ultimately, genetic testing and pathology of the explanted heart demonstrated a sarcomeric mutation in troponin I (TNNI3), the inhibitory subunit that blocks actin–myosin interactions and therefore mediates cardiac muscle relaxation. Mutations in this gene are commonly associated with familial hypertrophic cardiomyopathy and familial restrictive cardiomyopathy (10). As we previously alluded to, administering chemotherapy to a patient while supported on a Berlin has not been described in the literature and this posed several complex clinical management dilemmas. Hemostasis was difficult to manage, initially secondary to inflammation from his CD and then from his chemotherapyinduced thrombocytopenia, so judicious monitoring was essential for accurate levels. The risk of infection on the device was high due to his immune suppression from chemotherapy, and drivelines were meticulously cared for and monitored for infection. Finally, because of the rarity of occurrence of CD in children, there is little known about the risk of reactivation with transplantation, but available studies regarding CD implies a low risk of recurrence. Current literature would support waiting at least one yr from last chemotherapy prior to cardiac transplantation; however, given the fact that CD is not a true malignancy and prolonged device therapy E17
Thomas et al.
increases the risk of a devastating hemorrhagic or thrombotic event, this timeline was not feasible for our patient. This case supports the use of MCS as a feasible support option for patients requiring chemotherapy but due to concomitant adverse effects of chemotherapy, special care needs to be taken in regard to anticoagulation and driveline care. Disclosures
No conflicts to disclose. Authors’ contributions Dr. Thomas, Dr. Lorts, Dr. Chandrakasan, and Dr. O’Brien: Performed conception, design, drafting, and revision of the manuscript; Dr. Chin, Dr. Jefferies, Dr. Ryan, Dr. Wilmot, and Dr. Morales: Performed critical revision and design of the article; Dr. Madueme: Provided noninvasive images and critical revision; Dr. Baker: Provided pathology imaging and critical revision; all authors approved the final manuscript submitted.
References 1. CASTLEMAN B, IVERSON L, MENENDEZ VP. Localized mediastinal lymphnode hyperplasia resembling thymoma. Cancer 1956: 9: 822–830.
E18
2. POWELL RW, LIGHTSEY AL, THOMAS WJ, MARSH WL. Castleman’s disease in children. J Pediatr Surg 1986: 21: 678–682. 3. KAWABATA H, KADOWAKI N, NISHIKORI M. Clinical features and treatment of multicentric Castleman’s disease: A retrospective study of 21 Japanese patients at a single institute. J Clin Exp Hematop 2013: 53: 69–77. 4. GALEOTTI C, BOUCHERON A, GUILLAUME S, ,KONE-PAUT I. Sustained remission of multicentric Castleman disease in children treated with tocilizumab, an anti-interleukin-6 receptor antibody. Mol Cancer Ther 2012: 11: 1623–1626. 5. FRIZZERA G, PETERSON BA, BAYRD ED, GOLDMAN A. A systemic lymphoproliferative disorder with morphologic features of Castleman’s disease: Clinical findings and clinicopathologic correlations in 15 patients. J Clin Oncol 1985: 3: 1202–1216. 6. ZHU SH, YU YH, ZHANG Y, SUN JJ, HAN DL, LI J. Clinical features and outcome of patients with HIV-negative multicentric Castleman’s disease treated with combination chemotherapy: A report on 10 patients. Med Oncol 2013: 30: 492. 7. MAN L, GOUDAR RK. Reversal of cardiomyopathy with tocilizumab in a case of HIV-negative Castleman’s disease. Eur J Haematol 2013: 91: 273–276. 8. CASAROTTO D, BOTTIO T, GAMBINO A, TESTOLIN L, GEROSA G. The last to die is hope: Prolonged mechanical circulatory support with a Novacor left ventricular assist device as a bridge to transplantation. J Thorac Cardiovasc Surg 2003: 125: 417–418. 9. KINGSMORE SF, SILVA OE, HALL BD, SHELDON EA, CRIPE LD, ST CLAIR EW. Presentation of multicentric Castleman’s disease with sicca syndrome, cardiomyopathy, palmar and plantar rash. J Rheumatol 1993: 20: 1588–1591. 10. TOWBIN JA. Inherited cardiomyopathies. Circ J 2014: 78: 2347– 2356.
Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12398
The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman’s disease Thomas TO, Chandrakasan S, O’Brien M, Jefferies JL, Ryan TD, Wilmot I, Baker ML, Madueme PC, Morales D, Lorts A. (2015) The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman’s disease. Pediatr Transplant, 19: E15–E18. DOI: 10.1111/petr.12398.
Tamara O. Thomas1, Shanmuganathan Chandrakasan2, Maureen O’Brien2, John L. Jefferies1, Thomas D. Ryan1, Ivan Wilmot1, Michael L. Baker1, Peace C. Madueme1, David Morales1 and Angela Lorts1
Abstract: We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four-yr-old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non-malignant lymphoproliferative disorder fueled by excessive IL-6 production. Treatment with IL-6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti-coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anticoagulation regimen to coincide with changes in the inflammatory state.
1
CD is a rare non-malignant lymphoproliferative disorder characterized by systemic inflammatory symptoms secondary to the unregulated overproduction of IL-6. It can be characterized as either unicentric or HVV or multicentric or PCV (1–4). The unicentric type is defined as being confined to a single lymph node, whereas the multicentric type involves multiple lymph nodes with resulting systemic effects. Resection of the single involved node in the hyaline–vascular type is
Abbreviations: CD, Castleman’s disease; COP, cyclophosphamide; CRP, C-reactive protein; FDG, fluorodeoxyglucose; HVV, hyaline–vascular variant; IL-6, interleukin-6; LVAD, left ventricular assist device; MCS, mechanical circulatory support; MRI, magnetic resonance imaging; PCV, plasma cell variant.
The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA, 2Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Key words: pediatric heart transplant – cardiomyopathy – cardiac function – lymphoproliferative disorder – Castleman’s disease – mechanical circulatory – support Tamara O. Thomas, MD, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, ML 2003, Cincinnati, OH 45229, USA Tel.: +1 817 937 2055 Fax: +1 513 636 3952 E-mail: [email protected] Accepted for publication 27 October 2014
usually curative; however, the multicentric form is characterized by profound systemic effects secondary to the unregulated overproduction of IL6 and usually requires steroids and chemotherapy agents for treatment. Outcomes in adults are generally poor and characterized by recurrent flares of disease, but in children, disease course is poorly described (3, 5, 6). We present a child with PCV multicentric CD and concomitant restrictive cardiomyopathy who was treated with multi-agent chemotherapy while mechanically supported with a Berlin Heart EXCOR LVAD as a bridge to cardiac transplantation. Case report
A four-yr-old previously healthy male, with a recent diagnosis of restrictive cardiomyopathy, E15
Thomas et al.
suffered a post-anesthesia bradycardic arrest after cardiac MRI, requiring veno-arterial extracorporeal membrane oxygenation. He was decannulated after three days, and his initial echocardiogram demonstrated mildly depressed left ventricular systolic function, an asymmetrically and echobright ventricular septum, and bi-atrial enlargement (Fig. 1a,b). However, he had progressive ventricular dysfunction with hemodynamic instability meeting criteria for MCS; however, his cardiac MRI demonstrated mediastinal adenopathy (Fig. 1c,d). Mediastinal mass biopsy was performed, and he was simultaneously placed on temporary Rotaflow (Maquet) LVAD. Final pathology revealed small atrophic germinal centers with rare lollipop-like lesions and sheets of plasma cells consistent with PCV CD (Fig. 2a–d). HHV-8 immunohistochemistry staining was negative. Serum HHV-8 and HIV testing were negative. Serum cytokines showed massive IL-6 elevation (561 pg/mL, normal ≤7 pg/mL). Therapy was initiated with methylprednisolone 4 mg/kg/day IV and tocilizumab (IL-6 receptor blockade) at 12 mg/kg IV every two wk. His CRP normalized within six days of starting therapy and fevers resolved; however, serial echocardiograms did not demonstrate improvement in myocardial function. After two wk of LVAD support, an attempt to wean flow failed and due to lack of improvement in cardiac function, the decision was made to initiate chemotherapy with 21-day cycles of COP (750 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and methylprednisolone 80 mg/m2/day on day 1–5)
a
b
c
d
E16
with filgrastim support to minimize neutropenia. Tocilizumab was continued every two wk. CT and PET obtained one wk after initiating COP therapy showed decreased adenopathy with no Fluorodeoxyglucose (FDG) uptake and decreased FDG uptake in the myocardium. Given evidence of early response, a Berlin EXCOR LVAD was implanted via left atrial cannulation to allow improved left ventricular decompression given his restrictive physiology and the hypertrophic appearance of his myocardium. Genetic testing for sarcomeric mutations revealed a heterozygous mutation in c.575G>A (p.Arg192His) in exon 8 of the TNNI3 gene (disease-causing mutation), and thus, the chance of cardiac recovery was unlikely. He received three cycles of COP chemotherapy, with tocilizumab every two wk throughout and rituximab 375 mg/ m2 IV weekly during third cycle. Following his third cycle, his response was felt to be sufficient to list for cardiac transplantation and chemotherapy was discontinued. He experienced no wound infections or bacteremia throughout therapy. His course on both the Rotaflow and the Berlin was complicated by extreme difficulty in maintaining hemostasis. Early in his course, his unfractionated heparin requirements paralleled his inflammatory state in that he needed higher levels whenever his inflammatory markers were elevated; however, this was not evident when he was transitioned to Lovenox therapy. While on Lovenox therapy, with appropriate levels, he did suffer a hemorrhagic stroke during his fourth month on MCS (goal range anti-Xa was 0.5–0.7). Following his hemorrhagic stroke, he
Fig. 1. Echocardiogram images showing an apical 4-chamber view (a) and a parasternal short axis view (b) with mild septal hypertrophy and echobright myocardium appreciated, especially involving the ventricular septum. Cardiac MRI images in a coronal view (c) and an axial view (d) showing multifocal mediastinal masses with right paraspinal, subcarinal, right and left hilar, and left paraspinal components. The largest component is the right paraspinal component, which measures 2.6 9 3.2 cm in transverse dimension and appears to be contiguous with a subcarinal component that splays the bronchi.
Chemotherapy on a Berlin LVAD
Fig. 2. Variably atrophic lymphoid follicles (a, H&E 409) in background vascular dilatation, edema, and hemorrhage are intervened by irregular sheets of mature plasma cells (b, H&E 4009). There is a normal ratio of IgG (c, immunoperoxidase 1009)positive plasma cells to IgG4 (d, immunoperoxidase 1009)positive plasma cells. Immunohistochemistry for human herpesvirus-8 was negative.
a
b
c
d
was converted back to an unfractionated heparin infusion for quick titration of anticoagulation. When he was restarted on a heparin infusion after his stroke, he again had episodes of waxing and waning of his inflammatory state and heparin requirements. It may have been that his inflammatory milieu varied, leading to changes in his anti-Xa levels when he was on Lovenox that were difficult to appreciate without frequent monitoring. IL-6 levels and CT scans were monitored and continued to show a favorable response to therapy, leading to the discontinuation of his tocilizumab therapy. He achieved sufficient neurologic recovery to be reactivated for cardiac transplant and underwent successful transplantation eight months after his original presentation and four months after discontinuing chemotherapy. Pathology of the explanted heart demonstrated biventricular transmural fibrosis and hypertrophy with patchy myofiber disarray consistent with a restrictive cardiomyopathy diagnosis and no evidence of CD. Discussion
There are no reported cases of restrictive cardiomyopathy associated with CD, so this patient presented a unique challenge. There are few cases in the literature describing cardiomyopathy associated with CD, and all cases described are of dilated cardiomyopathies with ventricular systolic dysfunction, presumably due to severe systemic inflammation (3, 7–9). Slow improvement in dilated cardiomyopathy was reported in two
cases with the use of the IL-6 receptor-blocking antibody tocilizumab (3, 7). Without cardiac biopsy and with the dramatic FDG uptake on PET scan, we speculated the myocardium may be infiltrated by plasma cells with subsequent restrictive physiology. Ultimately, genetic testing and pathology of the explanted heart demonstrated a sarcomeric mutation in troponin I (TNNI3), the inhibitory subunit that blocks actin–myosin interactions and therefore mediates cardiac muscle relaxation. Mutations in this gene are commonly associated with familial hypertrophic cardiomyopathy and familial restrictive cardiomyopathy (10). As we previously alluded to, administering chemotherapy to a patient while supported on a Berlin has not been described in the literature and this posed several complex clinical management dilemmas. Hemostasis was difficult to manage, initially secondary to inflammation from his CD and then from his chemotherapyinduced thrombocytopenia, so judicious monitoring was essential for accurate levels. The risk of infection on the device was high due to his immune suppression from chemotherapy, and drivelines were meticulously cared for and monitored for infection. Finally, because of the rarity of occurrence of CD in children, there is little known about the risk of reactivation with transplantation, but available studies regarding CD implies a low risk of recurrence. Current literature would support waiting at least one yr from last chemotherapy prior to cardiac transplantation; however, given the fact that CD is not a true malignancy and prolonged device therapy E17
Thomas et al.
increases the risk of a devastating hemorrhagic or thrombotic event, this timeline was not feasible for our patient. This case supports the use of MCS as a feasible support option for patients requiring chemotherapy but due to concomitant adverse effects of chemotherapy, special care needs to be taken in regard to anticoagulation and driveline care. Disclosures
No conflicts to disclose. Authors’ contributions Dr. Thomas, Dr. Lorts, Dr. Chandrakasan, and Dr. O’Brien: Performed conception, design, drafting, and revision of the manuscript; Dr. Chin, Dr. Jefferies, Dr. Ryan, Dr. Wilmot, and Dr. Morales: Performed critical revision and design of the article; Dr. Madueme: Provided noninvasive images and critical revision; Dr. Baker: Provided pathology imaging and critical revision; all authors approved the final manuscript submitted.
References 1. CASTLEMAN B, IVERSON L, MENENDEZ VP. Localized mediastinal lymphnode hyperplasia resembling thymoma. Cancer 1956: 9: 822–830.
E18
2. POWELL RW, LIGHTSEY AL, THOMAS WJ, MARSH WL. Castleman’s disease in children. J Pediatr Surg 1986: 21: 678–682. 3. KAWABATA H, KADOWAKI N, NISHIKORI M. Clinical features and treatment of multicentric Castleman’s disease: A retrospective study of 21 Japanese patients at a single institute. J Clin Exp Hematop 2013: 53: 69–77. 4. GALEOTTI C, BOUCHERON A, GUILLAUME S, ,KONE-PAUT I. Sustained remission of multicentric Castleman disease in children treated with tocilizumab, an anti-interleukin-6 receptor antibody. Mol Cancer Ther 2012: 11: 1623–1626. 5. FRIZZERA G, PETERSON BA, BAYRD ED, GOLDMAN A. A systemic lymphoproliferative disorder with morphologic features of Castleman’s disease: Clinical findings and clinicopathologic correlations in 15 patients. J Clin Oncol 1985: 3: 1202–1216. 6. ZHU SH, YU YH, ZHANG Y, SUN JJ, HAN DL, LI J. Clinical features and outcome of patients with HIV-negative multicentric Castleman’s disease treated with combination chemotherapy: A report on 10 patients. Med Oncol 2013: 30: 492. 7. MAN L, GOUDAR RK. Reversal of cardiomyopathy with tocilizumab in a case of HIV-negative Castleman’s disease. Eur J Haematol 2013: 91: 273–276. 8. CASAROTTO D, BOTTIO T, GAMBINO A, TESTOLIN L, GEROSA G. The last to die is hope: Prolonged mechanical circulatory support with a Novacor left ventricular assist device as a bridge to transplantation. J Thorac Cardiovasc Surg 2003: 125: 417–418. 9. KINGSMORE SF, SILVA OE, HALL BD, SHELDON EA, CRIPE LD, ST CLAIR EW. Presentation of multicentric Castleman’s disease with sicca syndrome, cardiomyopathy, palmar and plantar rash. J Rheumatol 1993: 20: 1588–1591. 10. TOWBIN JA. Inherited cardiomyopathies. Circ J 2014: 78: 2347– 2356.
Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
