Summary Pegylated recombinant human megakaryocyte growth and development factor (PEG‐rHuMGDF) and granulocyte colony‐stimulating factor (G‐CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG‐rHuMGDF or G‐CSF administration. Information was reviewed for three of 538 volunteers who received PEG‐rHuMGDF in clinical trials and two of 200 donors who underwent G‐CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B‐cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1–5 years after PEG‐rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG‐rHuMGDF developed shortly after PEG‐rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G‐CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long‐term follow‐up among healthy individuals who receive haematopoietic growth factors is needed.

The p38 mitogen-activated protein kinase (MAPK) pathway is activated by IFNs and other cytokines to mediate signals for important cellular functions, including transcriptional regulation and apoptosis. We examined the role of the p38 pathway in the generation of the effects of myelosuppressive cytokines on human hematopoiesis. Pharmacologic inhibition of p38 using BIX-01208 resulted in reversal of IFN-, tumor necrosis factor-A (TNF-A)-, and transforming growth factor-B (TGF-B)-mediated suppression of human erythroid (blast-forming unit-erythroid) and myeloid (granulocyte-macrophage colony-forming unit) colony formation, consistent with a key role for p38 in the generation of myelosuppressive signals by different cytokines. Similarly, the myelosuppressive effects of TNF-A and TGF-B were reversed by small interfering RNAs targeting p38A expression, further establishing the requirement of this kinase in the induction of myelosuppressive responses. As TNF overproduction has been implicated in the pathophysiology of bone marrow failure states, we determined whether pharmacologic inhibition of p38 reverses the hematopoietic defects seen in bone marrows from patients with myelodysplastic syndromes (MDS) and the anemia of chronic disease. Addition of pharmacologic inhibitors of p38 on such bone marrows resulted in increased numbers of erythroid and myeloid progenitors. Similarly, inhibition of the activity of the downstream effectors of p38, MAPK activated protein kinase-2, and mitogen and stress activated kinase 1 partially restored the hematopoietic defect seen in these bone marrows. Taken altogether, our data implicate the p38 MAPK in the pathophysiology of myelodysplasias and suggest that p38 pharmacologic inhibitors may have therapeutic applications in the treatment of MDS. (Cancer Res 2005; 65(19): 9029-37)

These data support the hypothesis that CTGF plays an important role in scarring and wound contracture after GFS. Inhibition of CTGF synthesis or its action may help prevent bleb failure and improve long-term GFS outcomes.

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Preclinical mechanistic study and clinical trials are continuing in order to evaluate the therapeutic role and ultimately validate the efficacy of the varied anti-angiogenesis agents in soft tissue and bone sarcoma.