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Biomedical subjects

Richard Stone

Publications and source records attributed to Richard Stone.

At least 55 records · Page 3Linked to original sources
PubMed2006

Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome.

We reviewed 136 patients with advanced acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic transplantation to assess the impact of conditioning regimen intensity on outcome. Thirty-nine patients receiving nonmyeloablative stem cell transplantation (NST) were compared with 97 patients receiving myeloablative transplantation. Patients receiving NST were at high risk for treatment-related complications given that they were older, 57 vs 43 years (P < .001), and more likely had received previous or myeloablative transplantation (54% vs 2%; P < .0001). The cumulative risk of relapse was higher for patients after NST (61% vs 38%; P = .02). The 100-day mortality was less after NST (15% vs 32%) Overall survival (OS) at 2 years was 28% for NST and 34% for myeloablative transplantation (P = .89). Progression-free survival (PFS) at 2 years was 20% for NST and 31% for myeloablative transplantation (P = .31). Cox regression analysis showed that the intensity of the conditioning regimen had no effect on either OS or PFS. Despite the high-risk features of patients with advanced AML or MDS undergoing NST, OS and PFS in these patients was similar to those in patients receiving myeloablative transplantation. These results demonstrate that dose intensity plays a significant role in control of disease after transplantation, but that this benefit is negated by increasing treatment-related mortality. These results suggest that NST is a reasonable alternative for patients with advanced AML and MDS at high risk for complications after myeloablative transplantation.

Acute Disease↗
PubMed2005

The FLT3 internal tandem duplication mutation prevents apoptosis in interleukin-3-deprived BaF3 cells due to protein kinase A and ribosomal S6 kinase 1-mediated BAD phosphorylation at serine 112.

Internal tandem duplication (ITD) mutations in the FLT3 tyrosine kinase have been detected in approximately 20% of acute myeloid leukemia (AML) patients. Patients harboring FLT3/ITD mutations have a relatively poor prognosis. FLT3/ITD results in constitutive autophosphorylation of the receptor and factor-independent survival. Previous studies have shown that FLT3/ITD activates the signal transducers and activators of transcription 5 (STAT5), p42/p44 mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase (ERK) 1/2], and phosphatidylinositol 3-kinase/Akt pathways. We herein provide biochemical and biological evidence that ribosomal S6 kinase 1 (RSK1) and protein kinase A (PKA) are the two principal kinases that mediate the antiapoptotic function of FLT3/ITD via phosphorylation of BAD at Ser112. Inhibiting both MAPK kinase (MEK)/ERK and PKA pathways by a combination of U0126 (10 micromol/L) and H-89 (5 micromol/L) reduced most of BAD phosphorylation at Ser112 and induced apoptosis to a level comparable with that induced by FLT3 inhibitor AG1296 (5 micromol/L) in BaF3/FLT3/ITD cells. RNA interference of RSK1 or PKA catalytic subunit reduced BAD phosphorylation and induced apoptosis. The MEK inhibitor U0126 and/or the PKA inhibitor H-89 greatly enhanced the efficacy of the FLT3 inhibitor AG1296, suggesting that combining FLT3/ITD downstream pathway inhibition with FLT3 inhibitors may be a viable therapeutic strategy for AML caused by a FLT3/ITD mutation.

Amino Acid Sequence↗
PubMed2005

Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia.

PURPOSE: Lintuzumab (HuM195) is an unconjugated humanized murine monoclonal antibody directed against the cell surface myelomonocytic differentiation antigen CD33. In this study, the efficacy of lintuzumab in combination with induction chemotherapy was compared with chemotherapy alone in adults with first relapsed or primary refractory acute myeloid leukemia (AML). PATIENTS AND METHODS: Patients with relapsed or primary resistant AML (duration of first response, zero to 12 months) were randomly assigned to receive either mitoxantrone 8 mg/m(2), etoposide 80 mg/m(2), and cytarabine 1 g/m(2) daily for 6 days (MEC) in combination with lintuzumab 12 mg/m(2), or MEC alone. Overall response, defined as the rate of complete remission (CR) and CR with incomplete platelet recovery (CRp), was the primary end point of the study, with additional analyses of survival time and toxicity. RESULTS: A total of 191 patients were randomly assigned from November 1999 to April 2001. The percent CR plus CRp with MEC plus lintuzumab was 36% v 28% in patients treated with MEC alone (P = .28). The overall median survival was 156 days and was not different in the two arms of the study. Apart from mild antibody infusion-related toxicities (fever, chills, and hypotension), no differences in chemotherapy-related adverse effects, including hepatic and cardiac dysfunction, were observed with the addition of lintuzumab to induction chemotherapy. CONCLUSION: The addition of lintuzumab to salvage induction chemotherapy was safe, but did not result in a statistically significant improvement in response rate or survival in patients with refractory/relapsed AML.

Adult↗