Diagnosis and treatment of post-transplantation lymphoproliferative disorder in pediatric heart transplant patients.

PTLD is a severe complication in transplant recipients. Detection of increased EBV load in the peripheral blood acts as a surrogate marker for increased risk of PTLD development. We analyzed the time course of the disease, its severity, the organs involved, and mortality rates in our institutional experience of pediatric heart transplantation. This paper identifies risk factors for PTLD and describes the different ways of diagnosing and treating the disease. PTLD was screened for in 146 pediatric heart transplant patients using a retrospective analysis in patients who received transplantation before 1998. Prospective determination was performed in 72/146 patients transplanted after 1998 within the post-transplant follow-up. The occurrence of PTLD with all interventions, including tapering of immunosuppression, surgery, viral monitoring, and antiviral interventions, was recorded. PTLD was diagnosed in 12/147 (8.2%) children at a mean age of 7.2 +/- 3.3 yr after a mean post-transplant period of 3.2 +/- 2.2 yr. PTLD manifested in: lymph nodes (n = 4), intestine (n = 3), tonsils and adenoids (n = 2), eye (n = 2), and lung (n = 1). It was diagnosed in 7/12 as a monomorphic B-cell lymphoma and in four patients as a monomorphic Burkitt lymphoma, a polymorphic B-cell lymphoma, a T-cell rich or angiocentric lymphoma (Liebow) and as reactive plasmacytic hyperplasia (early lesion), respectively. Histology was not possible in one patient with ocular manifestation. EBV association was 83%. Risk factors in the comparison with patients without PTLD were age at time of Tx, primary EBV infection after Tx, use of Azathioprine and >or=3 doses of ATG. CMV mismatch and CMV infection, rejection episodes and steroids were not risk factors. Despite reduction of immunosuppression, treatment consisted of surgical procedures to remove tumor masses (n = 6), Rituximab (n = 5), polychemotherapy (n = 3), antiviral (n = 1) and autologous T-cell therapy (n = 1). All patients demonstrated full remission without death related to PTLD or treatment at 3.9 (1.3-6.2) yr median follow-up time. The manifestation of PTLD in pediatric heart transplant recipients is associated with EBV infection and is predominantly in the form of a B-cell lymphoma. A tight and specific follow-up including early assessment of immunity status and specific therapeutic intervention to improve cellular immunity is warranted and may contribute to a significant reduction of PTLD-related morbidity and mortality.

Absence of mutations in the CDKN2 binding site of CDK4 in childhood acute lymphoblastic leukemia.

The cell cycle regulatory circuit resulting in phosphorylation of the retinoblastoma protein (pRB) is frequently altered in human cancers. Several mechanisms of disruption are known in that pathway. In childhood acute lymphoblastic leukemia (ALL), the main disrupting mechanism is the homozygous deletion of the CDKN2 (cyclin dependent kinase inhibitor 2) genes: p16CDKN2a, p15CDKN2b, and p19ARF. Another pRB pathway disturbance is a previously described point mutation in the exon 2 of CDK4, a pRB phosphorylating enzyme, which abrogates binding of the latter to its inhibitors, p16CDKN2a and p15CDKN2b. Here we report the absence of point mutations in the CDKN2-binding site of CDK4 in 100 cases of childhood ALL, 2 cases of childhood chronic myeloid leukemia and 9 hematologic cell lines screened by PCR-SSCP (polymerase chain reaction single stranded conformational polymorphism gel electrophoresis), thereby minimizing the possibility of the existence of these specific CDK4 mutations in childhood ALL.