Citations

High-dose melphalan with autologous blood stem cell transplantation (SCT) can reverse the disease process in selected patients with primary systemic amyloidosis (AL); however, SCT for AL remains controversial because of the treatment-related mortality in patients with cardiac and multisystem organ involvement. In this review, we briefly discuss recent advances in AL, such as the free light-chain assay and the role of immunoglobulin light-chain variable region germline genes in the disease, and then we discuss the current status of SCT for AL with emphases on patient selection, approaches to stem cell mobilization, and peri-SCT management. It is clear that patients with AL who have advanced amyloid cardiomyopathy or more than 2 major viscera involved with disease are poor candidates for SCT. Therefore, the importance of patient selection cannot be overemphasized, and patients with 1 or 2 involved organs or with early cardiac involvement are usually appropriate candidates for SCT. Because the toxicity of melphalan is dose-related and survival with AL may be age-related, patient age and the extent of organ involvement can provide a basis for patient stratification. We discuss such a risk-adapted approach to melphalan dosing in detail and conclude with a brief overview of current research using SCT to treat patients with AL.

PURPOSE: Current standard therapy for children and adolescents with Hodgkin’s disease includes combination chemotherapy and low-dose involved-field radiation (LD-IFRT). Because radiation may be associated with adverse late effects, the Children’s Cancer Group (CCG) investigated whether radiation could be omitted in patients achieving a complete response to initial chemotherapy without jeopardizing the excellent outcome obtained with combined-modality therapy. PATIENTS AND METHODS: Between January 1995 and December 1998, 829 eligible patients were enrolled onto CCG 5942. A total of 501 patients who achieved an initial complete response after risk-adapted combination chemotherapy were randomized to receive LD-IFRT or no further treatment. Event-free survival (EFS) and overall survival were assessed from the date of study entry or the date of randomization, as appropriate. RESULTS: The projected 3-year EFS from study entry for the entire cohort was 87% ± 1.2%. Among patients who achieved a complete response to initial chemotherapy, 92% ± 1.9% of those randomized to receive LD-IFRT were alive and disease free 3 years after randomization, versus 87% ± 2.2% for patients randomized to receive no further therapy (stratified log-rank test; P = .057). With an “as-treated” analysis, 3-year EFS after randomization for the radiation cohort was 93% ± 1.7% versus 85% ± 2.3% for patients receiving no further therapy (stratified log-rank test; P = .0024). Three-year survival estimates for patients treated with and without LD-IFRT were 98% ± 1.1% for patients who received radiation and 99% ± 0.5% for patients who did not receive radiation. CONCLUSION: LD-IFRT after an initial complete response to risk-adapted chemotherapy improved EFS. At this time, there is no survival advantage for LD-IFRT, but follow-up remains short.

Background — The TIMI myocardial perfusion grade (TMPG) and ST-segment resolution both reflect perfusion and are associated with mortality after thrombolysis for acute myocardial infarction. We hypothesized that these measures would also be associated with infarct size by single photon emission computed tomography (SPECT). Methods and Results — In the LIMIT AMI trial (Limitation of Myocardial Injury following Thrombolysis in Acute Myocardial Infarction) of lytic monotherapy versus lytic plus rhuMAb CD18, early 90-minute TMPG (n=221) and ST segment resolution (n=242) were compared with subsequent SPECT Technetium-99 m Sestamibi, measuring the percentage of the left ventricle with no Sestamibi uptake. Infarct sizes were larger with TMPG 0 or 1 (a closed or stained myocardium) than with TMPG 2 or 3 (open myocardium, median 13% versus 7%, P =0.004). Infarcts were also larger in patients with no ST segment resolution (median 15%) or incomplete resolution (11%) than in those with complete resolution (6%, overall P =0.0001). The difference in infarct size by TMPG persisted when stratified by category of ST resolution. Conclusions — There may be a pathophysiological link between early restoration of tissue-level perfusion and reduced subsequent infarct size that may partially explain why these early angiographic and electrocardiographic measures are associated with long-term survival.

ABSTRACT Increased recognition of the prevalence of human babesiosis in the United States, together with rising concern about the potential for transmission of this infection by blood transfusion, has provided motivation to develop definitive serologic and molecular tests for the causative agent, Babesia microti . To develop more sensitive and specific assays for B. microti , we screened a genomic expression library with patient serum pools. This screening resulted in the identification of three classes of novel genes and an additional two novel, unrelated genes, which together encode a total of 17 unique B. microti antigens. The first class (BMN1-2 family) of genes encodes seven closely related antigens with a degenerate six-amino-acid repeat that shows limited homology to Plasmodium sp. merozoite and sporozoite surface antigens. A second class (BMN1-8 family) of genes encodes six related antigens, and the third class (BMN1-17 family) of genes encodes two related antigens. The two remaining genes code for novel and unrelated sequences. Among the three classes of antigens and remaining novel sequences, five were chosen to code for the most immunodominant antigens (BMN1-2, -9, -15, and -17 and MN-10). Western blot analysis with the resulting recombinant proteins indicated that these antigens were targets of humoral immune responses during B. microti infection in humans.

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non–dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity.