T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 ...(RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We report direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion, and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBFβ. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.
Summary Background The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and ...female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy. Methods We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group. Findings We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4–12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6–15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio HR 0·63, 95% CI 0·58–0·68; p<0·0001; female survivors: 0·87, 0·81–0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58–0·69; p<0·0001; female survivors: 0·82, 0·76–0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51–0·71; p<0·0001), ifosfamide (0·42, 0·23–0·79; p=0·0069), procarbazine (0·30, 0·20–0·46; p<0·0001) and cisplatin (0·56, 0·39–0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m2 increments: HR 0·82, 95% CI 0·79–0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m2 HR 0·22, 95% CI 0·06–0·79; p=0·020; ≥450 mg/m2 0·14, 0·03–0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m2 (0·41, 0·17–0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74–0·98; p=0·023). Results for livebirth were similar to those for pregnancy. Interpretation Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer. Funding National Cancer Institute, National Institutes of Health, and the American Lebanese–Syrian Associated Charities.
Hockberger RS, Binder LS, Graber MA, Hoffman GL, Perina DG, Schneider SM, Sklar DP, Strauss RW, Viravec DR, Koenig WJ, Augustine JJ, Burdick WP, Henderson WV, Lawrence LL, Levy DB, McCall J, Parnell ...MA, Shoji KT. The model of the clinical practice of emergency medicine. Ann Emerg Med. June 2001;37:745-770.
To assess the efficacy of occupant protection systems, the authors measured the mortality reduction associated with air bag deployment and seat belt use for drivers involved in head-on passenger car ...collisions in the United States. They used a matched case-control design of all head-on collisions involving two passenger cars reported to the Fatality Analysis Reporting System in 1992-1997, and driver mortality differences between the paired crash vehicles for air bag deployment and seat belt use were measured with matched-pair odds ratios. Conditional logistic regression was used to adjust for multiple effects. There were 9,859 head-on collisions involving 19,718 passenger cars and drivers. Air bag deployment reduced mortality 63% (crude odds ratio (OR) = 0.37, 95% confidence interval (CI): 0.32, 0.42), while lap-shoulder belt use reduced mortality 72% (OR = 0.28, 95% CI: 0.25, 0.31). In a conditional logistic model that adjusted for vehicle (rollover, weight, age) and driver (age, sex) factors, air bags (OR = 0.71, 95% CI: 0.58, 0.87) and any combination of seat belts (OR = 0.25, 95% CI: 0.22, 0.29) were both associated with reduced mortality. Combined air bag and seat belt use reduced mortality by more than 80% (OR = 0.18, 95% CI: 0.13, 0.25). Thus, this study confirms the independent effect of air bags and seat belts in reducing mortality.
Survivors of malignant disease in childhood who have had radiotherapy to the head, neck, or upper thorax have an increased risk of subsequent primary thyroid cancer, but the magnitude of risk over ...the therapeutic dose range has not been well established. We aimed to quantify the long-term risk of thyroid cancer after radiotherapy and chemotherapy.
In a nested case-control study, 69 cases with pathologically confirmed thyroid cancer and 265 matched controls without thyroid cancer were identified from 14 054 5-year survivors of cancer during childhood from the Childhood Cancer Survivor Study cohort. Childhood cancers were diagnosed between 1970 and 1986 with cohort follow-up to 2000.
Risk of thyroid cancer increased with radiation doses up to 20–29 Gy (odds ratio 9·8 95% CI 3·2–34·8). At doses greater than 30 Gy, a fall in the dose-response relation was seen. Both the increased and decreased risks were more pronounced in those diagnosed with a first primary malignant disease before age 10 years than in those older than 10 years. Furthermore, the fall in risk remained when those diagnosed with Hodgkin's lymphoma were excluded. Chemotherapy for the first cancer was not associated with thyroid-cancer risk, and it did not modify the effect of radiotherapy. 29 (42%) cases had a first diagnosis of Hodgkin's lymphoma compared with 49 (19%) controls. 11 (42%) of those who had Hodgkin's lymphoma had subsequent thyroid cancers smaller than 1 cm compared with six (17%) of those who had other types of childhood cancer (p=0·07).
The reduction in radiation dose-response for risk of thyroid cancer after childhood exposure to thyroid doses higher than 30 Gy is consistent with a cell-killing effect. Standard long-term follow-up of patients who have had Hodgkin's lymphoma for detection of thyroid cancer should also be undertaken for survivors of any cancer during childhood who received radiotherapy to the thorax or head and neck region.
Crowding is an increasingly common occurrence in hospital-based emergency departments (EDs) across the globe. This 2-article series offers an ethical and policy analysis of ED crowding. Part 1 begins ...with a discussion of terms used to describe this situation and proposes that the term “crowding” be preferred to “overcrowding.” The article discusses definitions, measures, and causes of ED crowding and concludes that the inability to transfer emergency patients to inpatient beds and resultant boarding of admitted patients in the ED are among the root causes of ED crowding. Finally, the article identifies and describes a variety of adverse moral consequences of ED crowding, including increased risks of harm to patients, delays in providing needed care, compromised privacy and confidentiality, impaired communication, and diminished access to care. Part 2 of the series examines barriers to resolving the problem of ED crowding and strategies proposed to overcome those barriers.
To determine whether adult survivors (>or= 18 years of age) of childhood acute lymphoblastic leukemia (ALL) are at increased risk for obesity and to assess patient and treatment variables that ...influence risk.
A retrospective cohort of participants of the Childhood Cancer Survivor Study was used to compare 1,765 adult survivors of childhood ALL to 2,565 adult siblings of childhood cancer survivors. Body-mass index (BMI; kilograms per square meter), calculated from self-reported heights and weights, was used to determine the prevalence of being overweight (BMI, 25-29.9) or obese (BMI >or= 30.0). Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for being overweight or obese among ALL survivors relative to the sibling control group.
The age- and race-adjusted OR for being obese in survivors treated with cranial radiation doses >or= 20 Gy in comparison with siblings was 2.59 for females (95% CI, 1.88 to 3.55; P <.001) and 1.86 for males (95% CI, 1.33 to 2.57; P <.001). The OR for obesity was greatest among females diagnosed at 0 to 4 years of age and treated with radiation doses >or= 20 Gy (OR, 3.81; 95% CI, 2.34 to 5.99; P <.001). Obesity was not associated with treatment consisting of chemotherapy only or with cranial radiation doses of 10 to 19 Gy.
Cranial radiotherapy >or= 20 Gy is associated with an increased prevalence of obesity, especially in females treated at a young age. It is imperative that healthcare professionals recognize this risk and develop strategies to enhance weight control and encourage longitudinal follow-up.
To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated ...with the development of these deficits.
Detailed questionnaires were completed on 1,607 patients diagnosed between 1970 and 1986 with a primary CNS tumor. Neurosensory and neurologic dysfunctions were assessed and results compared with those of a sibling control group. Medical records on all patients were abstracted, including radiotherapy dose and volume.
Seventeen percent of patients developed neurosensory impairment. Relative to the sibling comparison group, patients surviving BTs were at elevated risk for hearing impairments (relative risk RR, 17.3; P = <.0001), legal blindness in one or both eyes (RR, 14.8; P = <.0001), cataracts (RR, 11.9; P = <.0001), and double vision (RR, 8.8; P = <.0001). Radiation exposure greater than 50 Gy to the posterior fossa was associated with a higher likelihood of developing any hearing impairment. Coordination and motor control problems were reported in 49% and 26%, respectively, of survivors. Children receiving at least 50 Gy to the frontal brain regions had a moderately elevated risk for motor problems (RR, 2.0; P <.05). Seizure disorders were reported in 25% of patients, including 6.5% who had a late first occurrence. Radiation dose of 30 Gy or more to any cortical segment of the brain was associated with a two-fold elevated risk for a late seizure disorder.
Children surviving BTs are at significant risk for both early and late neurologic or neurosensory sequelae. These sequelae need to be prospectively monitored.
Part 1 of this 2-article series reviews serious moral problems created by emergency department (ED) crowding. In this second part of the series, we identify and describe operational and financial ...barriers to resolving the crisis of ED crowding, along with a variety of institutional and public policy strategies proposed or implemented to overcome those barriers. Finally, the article evaluates 2 additional actions designed to address the problem of ED crowding, namely, distribution of a warning statement to ED patients and implementation of a “reverse triage” system for safe early discharge of hospital inpatients.
See related editorial, p 506
Study objective: Little is known about the accuracy and reliability of current triage methods. We examined agreement among observers with regard to the need for ED care ...and the ability to predict at triage the need for admission to the hospital and compared these findings with admission rates after medical evaluation and management.
Methods: We used a crossover design in which each subject was subjected to nurse or computer-guided triage first, the other type of triage second, and physician triage last. Our null hypothesis: Triage methods will yield the same results. Our patients were a consecutive sample of patients at the ED of a university-affiliated county referral center. Critically ill patients were excluded. Triage categorization was examined for interobserver agreement (κ-statistic) and prediction of admission (sensitivity, specificity, and predictive values).
Results: Of the 5,106 patients enrolled in the study, 289 (6.2%) were admitted. With regard to the agreement of triage categorizations, we found κ-values of .452 and .185, respectively, for physician triage compared with nurse (SE±.012) and computer triage (SE±.012) (
P=.001 for the difference between the κ-values). Sensitivity and specificity in predicting admission were 41.3 and 93.8, respectively, for nurses; 61.6 and 87.1, respectively, for physicians; and 68.2 and 73.6, respectively, for computer-aided triage.
Conclusion: We found great variability among physicians, nurses, and a computer program with regard to triage decisions. Comparison of the three groups' triage decisions with actual data after medical evaluation and management showed that none of the three performed well in predicting which patients required admission. Until triage methods are standardized and validated, triage decisions should not be used to determine the timeliness of access to emergency care. Brillman JC, Doezema D, Tandberg D, Sklar DP, Davis KD, Simms S, Skipper BJ: Triage: Limitations in predicting need for emergent care and hospital admission.
Ann Emerg Med April 1996;27:493-500.
See related editorial, Triage and Emergency Department Services
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