Our previous studies showed that the depletion of the outer kinetochore protein hBub1 upon activation of spindle assembly checkpoint (SAC) primarily triggers early cell death mediated by p53 rather than aneuploidy. Here, we report that phosphorylation of p53 at Ser37 is critical for proapoptotic activity upon SAC activation. Furthermore, we show that p53 physically interacts with hBub1 at kinetochores in response to mitotic spindle damage suggesting a direct role for hBub1 in the suppression of p53 mediated cell death. This observation is further substantiated by the inhibition of p53 mediated transactivation of the proapoptotic target genes, PUMA and BAX, by hBub1 in SAC activated cells. In summary, our data from these and our previous studies strongly suggest that in response to SAC activation, hBub1 acts as a negative regulator of p53 mediated early cell death in a novel checkpoint pathway. On the translational medicine front, it is tempting to speculate that by disabling hBub1 in p53 proficient cancer cells, apoptosis may be induced as a therapeutic approach to eradicate the tumor cells.
BACKGROUND The incidence of nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is higher among African Americans than among other races, but to the authors' knowledge, the characteristics of NLPHL in this population have not been evaluated. The authors compared clinical features, treatments, and survival of black and white patients with NLPHL using the National Cancer Data Base. METHODS The authors extracted the records of 602 black and 1950 white patients with NLPHL who were diagnosed between 1998 and 2011. Overall survival (OS) was compared using the log‐rank test. RESULTS Black patients were on average younger than white patients (median age, 42 years vs 45 years; P =.0001), more often female (49% vs 29%; P<.0001), and more likely to have the axillary lymph nodes as the primary disease site (25% vs 17%; P =.0002). They also had unfavorable socioeconomic characteristics, a higher rate of no treatment in patients with early‐stage disease, and a longer time to therapy initiation (median, 53.5 days vs 47 days; P<.0001). Despite this, the authors found no significant difference between the races with regard to stage distribution or survival (P =.39). OS at 7 years was 90.1% in patients with early‐stage (American Joint Committee on Cancer stage IA/B, IIA) and 79.4% in patients with advanced stage (American Joint Committee on Cancer stage IIB, III/IV) NLPHL. Survival in the early stage of disease was not found to be significantly different after various treatment strategies (stratified log‐rank P = .18), except that the administration of chemotherapy was associated with a better outcome in black patients (log‐rank P =.011 vs P =.81 for white patients). CONCLUSIONS Differences in clinical presentation suggest the interaction of race‐specific and sex‐specific susceptibility factors for NLPHL. Further research is needed to elucidate these factors, and to investigate possible heterogeneous effects of treatments by race. Clinical trials comparing standard treatment strategies are unlikely to detect differences in OS among patients with early‐stage NLPHL. Cancer 2015;121:3435–43. © 2015 American Cancer Society.
Introduction: Many patients with Acute Myelogenous Leukemia (AML) will transiently develop blasts in the peripheral blood upon recovery of induction chemotherapy, despite going on to obtain a complete remission. These are presumably non-leukemic marrow blasts. Recovery blasts can sometimes reach over 20% in the peripheral blood in remission patients. The significance of recovery blasts cells after induction chemotherapy in patients with AML is not clear. We sought to define the incidence of recovery blastocytosis (RB) and determine if the presence of RB has prognostic relevance. Methods: We performed a retrospective analysis of 72 patients with newly diagnosed AML who underwent induction chemotherapy with 7+3 (cytarabine and daunorubicin) with or without etoposide between the years of 2006 and 2013 at our institution. Patients were included in the analysis as having RB only if their blasts resolved by day 14 of induction chemotherapy, blasts reappeared upon recovery after day 14, recovery blasts were > 5% in the peripheral blood of a duration of >5 days, and subsequently resolved by day 45 and remission was obtained. We recorded patient's absolute and percentage peripheral blast counts on presentation, upon nadir and throughout recovery of induction chemotherapy. The incidence and level of RB in patients who achieved a remission was tabulated. This group (group 1) was compared to the patients who achieved a remission whom did not develop RB (group 2). Results: 45/77 AML patients obtained a CR after induction chemotherapy. Recovery blasts were seen in 9/45 (20%) remission patients (group 1), with a median RB of 9% for a median duration of 8 days. Of these 9 patients, 4 developed RB > 10%, and 2 developed RB >20 % Group 1 did not differ in respect to age, gender, cytogenetic profile, etoposide use, or whether the patient received 1 or 2 induction therapies from the 36/45 remission AML patients who did not develop RB (group 2). Median survival for group 1 was = 1,376 days, and 1,036 days for group 2 (p= .035). Conclusion: Recovery Blasts in the peripheral blood after induction chemotherapy is seen commonly in AML patients who obtain a complete remission. RB can be seen even as high as > 20% in remission patients. AML patients who develop RB on their way to remission after induction chemotherapy have a better overall survival then patients who do not develop RB. Figure 1 Figure 1. Graph 1. Kaplan-Meier survival curves for AML patients with RB (group 1) and without RB (group 2). Disclosures No relevant conflicts of interest to declare.
Background: NLPHL is a rare, biologically distinct subtype of Hodgkin lymphoma (HL) characterized by late recurrences and risk of transformation to non-Hodgkin histology. The incidence of NLPHL is markedly increased among black patients (pts), but they were not distinguished in prior studies, and data are lacking about specific features in this group. Relative benefits of various treatment modalities in early-stage NLPHL are also controversial. Radiation therapy (RT) is endorsed by guidelines, but one large study suggested a survival advantage of combined modality therapy (CMT) over historical controls treated with RT alone (Savage et al., Blood 2011:118:4585). The objective of this study was to compare clinical features of NLPHL in black and other pts, and to describe treatment patterns and survival using the National Cancer Data Basea registry capturing over 70% of incident cancers in the United States (US). Methods: We identified NLPHL and classical HL cases diagnosed between 1998 and 2011, with survival data available for the 1998-2006 cohort. Receipt of chemotherapy (ChT), RT or CMT as initial course of treatment was recorded. Stage was categorized as limited (Ann Arbor I, IIA) or advanced (IIB, III, IV). Overall survival (OS) was the primary outcome and was compared using log-rank tests stratified by stage, sex and age group. Trends were assessed using log-linear regression. All confidence intervals (CI) were set at 95%. Results: Among the NLPHL pts (N=2,656), 23% were of black race (N=602), compared with 10% of classical HL cases (N=66,369). Most NLPHL pts presented with limited stage disease (66%), without any difference between races (P=0.79). Stage migration was evident between 1998 and 2003 with the proportion of stage III/IV cases increasing by 13.2% per year (CI, 3.3-24.0, P=0.008). The male-to-female ratio was 1.0 (CI, 0.9-1.2) in black pts, whereas pronounced male predominance was present in others (ratio 2.5, CI, 2.2-2.7). Black pts were also on average younger (median age 42 years, versus 45 for others, P=0.0001), and their NLPHL more often originated from the axillary nodes (25%, versus 17% for other races, P=0.0003). Median follow-up was 7.1 years. OS at 7 years was 90.1% (CI, 87.7-92.1) for limited- and 80.1% (CI, 75.6-83.8) for advanced-stage NLPHL, with no difference between the races (P=0.15, Fig. A). In limited disease, RT alone was used in 55%, 31% and 27% of pts with stage IA, IB and IIA, respectively, while CMT was used in 21%, 33% and 35%, and ChT alone in 12%, 24% and 31%, respectively. Black pts were more likely to have no treatment recorded (P<0.0001), but the proportions of various modalities was otherwise the same (P=0.76). The difference in OS between the treatments was not significant, with 7-year OS of 93.3% (CI, 88.8-96.1) after CMT, 90.0% (CI, 85.7-92.9) after RT, and 86.5% (CI, 79.5-91.2) after ChT alone (P=0.12, Fig. B). There was a significant trend towards decreased utilization of RT over time (on average by 1.6% per year, P=0.0002). In advanced NLPHL, 71% of patients were treated with ChT alone, 15% with CMT, 3% with RT alone and 11% had no recorded treatment. A significant trend towards less RT was again evident (8.9% per year, P<0.0001). Conclusions: The specific gender, age and primary site distribution in black pts with NLPHL suggests an inherited susceptibility, possibly mediated by immune or endocrine factors. Survival outcomes are not different from other races. In early-stage NLPHL, various treatment modalities are not associated with significant OS differences, although survival is numerically highest with CMT. Because of stage migration coinciding with the introduction of positron emission tomography, stage-based survival comparisons with cohorts from 1990's may be biased. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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