Patients with impaired acid secretion require an increased dose of thyroxine, suggesting that normal gastric acid secretion is necessary for effective absorption of oral thyroxine.

The inability to undergo apoptosis is a crucial mechanism of multidrug resistance in acute myeloid leukemia (AML), and the analysis of mitochondrial apoptotic proteins may represent a significant prognostic tool to predict outcome. Bcl-2 and Bax oncoproteins were evaluated in 255 de novo AML patients (pts) by flow cytometry using an anti-bcl-2 monoclonal antibody (MoAb) and an anti-bax MoAb. The results were expressed as an index (bax/bcl-2) obtained by dividing bax mean fluorescence intensity (MFI) and bcl-2 MFI. Lower bax/bcl-2 ratio was associated with French-American-British (FAB) M0-M1 classes (P ‫؍‬ .000 01) and CD34 more than 20% (P < .000 01). There were striking inverse correlations between CD34 or CD117 MFI and bax/bcl-2 values (r ‫؍‬ ؊.40, P < .000 001 and r ‫؍‬ ؊.29, P ‫؍‬ .000 002), confirming that immaturity is consistent with this index. Moreover, lower bax/bcl-2 levels were correlated with poor-risk cytogenetics (P ‫؍‬ .0002). A significant higher complete remission (CR) rate was found in pts with higher bax/bcl-2 levels (79% versus 45%; P ‫؍‬ .000 01). Also, both a longer overall survival (OS) and disease-free survival (DFS) were observed in pts with higher bax/bcl-2 levels (P ‫؍‬ .000 01 and ‫؍‬ .019). Noteworthy, bax/bcl-2 levels accurately predicted the clinical response and outcome of pts with normal or unknown cytogenetics. Indeed, within this subset of 147 pts, higher bax/bcl-2 ratio was significantly associated both with a higher CR rate (86% versus 42%; P < .000 01) and a longer OS (P ‫؍‬ .0016). The independent prognostic value of bax/bcl-2 ratio was confirmed in multivariate analysis. Therefore, mitochondrial oncoproteins, such as bcl-2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel proapoptotic molecules in order to circumvent chemoresistance. (Blood. 2003;

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A total of 31 adult patients with AML entered in the EORTC/ GIMEMA AML-10 trial, who received autologous stem cell transplantation (ASCT) after induction and consolidation chemotherapy, were prospectively evaluated for minimal residual disease (MRD) by multidimensional flow cytometry (MFC). Using a cutoff level of 3.5 Â 10 À4 leukemic cells pre-ASCT, 12 patients (39%) were stratified to MRD high-risk group and 19 (61%) into MRD low-risk group. During follow-up, all patients who were in the high-risk group relapsed at a median time of 7 months; in the low-risk group, five patients relapsed at a median time of 11 months and 14 remained in remission for 56 (range 7-80) months (P ¼ 0.00004). Longitudinal MFC determinations post-ASCT showed increased MRD levels in three of the five patients who underwent subsequent relapse, while disease recurrence was unpredicted in the remaining two cases. The pre-ASCT MRD status was the factor most strongly associated with relapse risk in the multivariate analysis (P ¼ 0.0014). We conclude that: (1) pre-ASCT MRD status predicts successful outcome in patients receiving ASCT; (2) high-dose chemotherapy conditioning regimen followed by ASCT has no impact on the unfavorable prognostic value of high pre-ASCT MRD level; and (3) sequential MRD monitoring post-ASCT may allow the prediction of impending relapse.

SummaryFLT3 internal tandem duplication (ITD) mutations are frequently detected at diagnosis in cytogenetically normal acute myeloid leukaemia (CN-AML) and predict unfavourable outcome. FLT3 ITD is an unstable aberration and may be lost or acquired at relapse. Recent whole genome sequencing studies have suggested that FLT3 ITD + ve AML relapse may evolve from small subclones undetectable at diagnosis by routine polymerase chain reaction (PCR). We developed a patient-specific real-time quantitative-PCR (RQ-PCR) to implement FLT3 ITD detection in six AML patients whose blasts carried wild-type FLT3 at diagnosis and who relapsed with FLT3 ITD by routine PCR. Patient-specific forward primers were designed after cloning and sequencing the FLT3 ITD in each case. The assay allowed retrospective detection of FLT3 ITD in diagnostic samples of 4/6 cases and to establish the kinetics of clonal evolution preceding relapse. After conventional chemotherapy, all patients had early relapse despite having been classified as NPM1 + ve/FLT3 ITD À ve at presentation, with shorter remissions being observed in four patients re-classified as FLT3 ITD + ve by the new assay.Notably, FLT3 ITD clone became detectable by conventional PCR in three patients tested during remission after initial treatment. Our data underscore the need of identifying low FLT3 ITD levels, which are probably associated with relapse in otherwise good prognosis CN-AML.