Clinical presentation of childhood leukaemia: a systematic review and meta-analysis.

OBJECTIVE: Leukaemia is the most common cancer of childhood, accounting for a third of cases. In order to assist clinicians in its early detection, we systematically reviewed all existing data on its clinical presentation and estimated the frequency of signs and symptoms presenting at or prior to diagnosis. DESIGN: We searched MEDLINE and EMBASE for all studies describing presenting features of leukaemia in children (0-18 years) without date or language restriction, and, when appropriate, meta-analysed data from the included studies. RESULTS: We screened 12 303 abstracts for eligibility and included 33 studies (n=3084) in the analysis. All were cohort studies without control groups. 95 presenting signs and symptoms were identified and ranked according to frequency. Five features were present in >50% of children: hepatomegaly (64%), splenomegaly (61%), pallor (54%), fever (53%) and bruising (52%). An additional eight features were present in a third to a half of children: recurrent infections (49%), fatigue (46%), limb pain (43%), hepatosplenomegaly (42%), bruising/petechiae (42%), lymphadenopathy (41%), bleeding tendency (38%) and rash (35%). 6% of children were asymptomatic on diagnosis. CONCLUSIONS: Over 50% of children with leukaemia have palpable livers, palpable spleens, pallor, fever or bruising on diagnosis. Abdominal symptoms such as anorexia, weight loss, abdominal pain and abdominal distension are common. Musculoskeletal symptoms such as limp and joint pain also feature prominently. Children with unexplained illness require a thorough history and focused clinical examination, which should include abdominal palpation, palpation for lymphadenopathy and careful scrutiny of the skin. Occurrence of multiple symptoms and signs should alert clinicians to possible leukaemia.

A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia.

Recent genomic studies have provided a refined genetic map of acute lymphoblastic leukemia (ALL) and increased the number of potential prognostic markers. Therefore, we integrated copy-number alteration data from the 8 most commonly deleted genes, subordinately, with established chromosomal abnormalities to derive a 2-tier genetic classification. The classification was developed using 809 ALL97/99 patients and validated using 742 United Kingdom (UK)ALL2003 patients. Good-risk (GR) genetic features included ETV6-RUNX1, high hyperdiploidy, normal copy-number status for all 8 genes, isolated deletions affecting ETV6/PAX5/BTG1, and ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. All other genetic features were classified as poor risk (PR). Three-quarters of UKALL2003 patients had a GR genetic profile and a significantly improved event-free survival (EFS) (94%) compared with patients with a PR genetic profile (79%). This difference was driven by a lower relapse rate (4% vs 17%), was seen across all patient subgroups, and was independent of other risk factors. Even genetic GR patients with minimal residual disease (>0.01%) at day 29 had an EFS in excess of 90%. In conclusion, the integration of genomic and cytogenetic data defines 2 subgroups with distinct responses to treatment and identifies a large subset of children suitable for treatment deintensification.

IGH@ translocations are prevalent in teenagers and young adults with acute lymphoblastic leukemia and are associated with a poor outcome.

PURPOSE: To determine the prevalence and prognostic association of immunoglobulin heavy chain (IGH@) translocations in acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: The cohort comprised 3,269 patients treated on either the UKALL2003 trial for children and adolescents (1 to 24 years old) or the UKALLXII trial for adolescents and adults (15 to 59 years old). High-throughput fluorescent in situ hybridization was used to detect IGH@ translocations. RESULTS: We identified IGH@ translocations in 5% of patients with ALL (159 of 3,269 patients), in patients with both B-cell (148 of 2,863 patients) and T-cell (11 of 408 patients) disease. Multiple partner genes were identified including CRLF2 (n = 35), five members of the CEPB gene family (n = 17), and ID4 (n = 11). The level of the IGH@-positive clone varied and indicated that some IGH@ translocations were primary events, whereas others were secondary aberrations often associated with other established aberrations. The age profile of patients with IGH@ translocations was distinctive, with a median age of 16 years and peak incidence of 11% among 20- to 24-year-old patients. Among patients with B-cell precursor ALL who were Philadelphia chromosome negative, those with an IGH@ translocation had an inferior overall survival compared with other patients (UKALL2003: hazard ratio, 2.37; 95% CI, 1.34 to 4.18; P = .003; UKALLXII: hazard ratio, 1.73; 95% CI, 1.22 to 2.47; P = .002). However, this adverse effect was not independent of age or minimal residual disease status and did not seem to be driven by an increased risk of relapse. CONCLUSION: IGH@ translocations define a genetic feature that is frequent among adolescents and young adults with ALL. Although associated with an adverse outcome in adults, it is not an independent prognostic factor in children and adolescents.

'Shouting from the roof tops': a qualitative study of how children with leukaemia are diagnosed in primary care.

OBJECTIVES: To investigate the prehospital presentation of paediatric leukaemia and identify the disease and non-disease related factors which facilitate or impede diagnosis. DESIGN: Thematic analysis of qualitative semistructured interviews. SETTING: One tertiary referral centre in Southern England. PARTICIPANTS: 21 parents and 9 general practitioners (GPs) of 18 children (<18-year-old) with a new diagnosis of acute leukaemia. RESULTS: The majority of children were first seen by GPs before the characteristic signs and symptoms of leukaemia had developed. In their absence, behavioural cues such as the child becoming apathetic or 'not themselves' often triggered parents to seek medical help. Most GPs were unclear about the nature and severity of the child's presentation: then, safety netting, thorough history-taking and examination, and reliance on contextual information about the parents or from prior hospital paediatrics experience were used to manage diagnostic uncertainty. The nature of the doctor-parent relationship helped and hindered the diagnostic pathway. GPs' prior perceptions of parents as being 'sensible' or 'worriers' influenced how gravely they treated parental concerns, with 'worriers' being taken less seriously. Some parents believed GPs failed to listen to their anxieties and discounted their expert knowledge of their child. Specific delay factors included lack of continuity of GP; some GPs' reluctance to take blood from children; and some parents feeling unable to voice effectively their concerns. CONCLUSIONS: The presentation of paediatric leukaemia in primary care differs from that described in many hospital studies, with greater diversity and intermittency of symptoms, and the frequent absence of 'red flags' of serious illness. A wide range of non-disease related factors potentially delay the diagnosis of paediatric leukaemia, including tensions in the doctor-patient relationship and the doctors' cognitive biases. The identification and attempted modification of these factors may minimise diagnostic delay more successfully than raising awareness of 'red flags' of disease.

Outcome of Down syndrome associated acute lymphoblastic leukaemia treated on a contemporary protocol.

We report the outcome for children and young people with Down syndrome-associated acute lymphoblastic leukaemia (DS-ALL) treated on a contemporary protocol. Compared with non-DS ALL, patients with DS-ALL had an inferior event-free survival (65·6% vs. 87·7% at 5 years; P < 0·00005) and overall survival (70·0% vs. 92·2%; P < 0·00005). Excess treatment-related mortality - was primarily responsible for the worse outcomes for DS-ALL (21·6% at 5 years, vs. 3·3%, P < 0·00005). Minimal residual disease (MRD) risk status was highly discriminant for relapse in DS patients with 0/28 relapses in the MRD low risk group.

Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials.

PURPOSE: To evaluate the effect on outcome of intensifying therapy for patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21). PATIENTS AND METHODS: We report two cohorts of patients treated on Medical Research Council ALL97 or United Kingdom (UK) ALL2003. iAMP21 was identified retrospectively in ALL97 and was not used to guide therapy. However, in UKALL2003, iAMP21 was determined prospectively, and patients were allocated to the most intensive treatment arm (regimen C), which included augmented Berlin-Frankfurt-Munster consolidation, escalating Capizzi maintenance, double delayed intensification, and an option for first remission transplantation. The presence of iAMP21 was determined by fluorescence in situ hybridization using probes specific for the RUNX1 gene. RESULTS: iAMP21 was identified in 2% of patients with B-cell precursor ALL treated on UKALL2003 and ALL97. The event-free survival, relapse, and overall survival rates at 5 years for iAMP21 patients treated on ALL97 and UKALL2003 were 29% and 78%, 70% and 16%, and 67% and 89%, respectively (all P < .01). Patients treated on ALL97 had an increased risk of relapse compared with patients treated on UKALL2003 (hazard ratio, 7.2; 95% CI, 2.91 to 17.87; P < .001). CONCLUSION: iAMP21 patients with ALL benefitted from receiving more intensive therapy in UKALL2003. In UKALL2011, they will continue to be treated as cytogenetic high risk, receive intensive chemotherapy (regimen C), and will only be recommended for transplantation if they do not achieve a complete remission by the end of induction therapy. This study illustrates how the discovery and characterization of disease-specific genetic aberrations can be used to tailor therapy more precisely.

Treatment outcome of CRLF2-rearranged childhood acute lymphoblastic leukaemia: a comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups.

The prognostic relevance of CRLF2 -rearrangements in childhood acute B-cell precursor lymphoblastic leukaemia (ALL), was assessed by a comparative analysis of 114 non-Down-syndrome patients (99 P2RY8-CRLF2+ , 15 IGH@-CRLF2+ ), 76 from the AIEOP-BFM ALL 2000 and 38 from the MRC ALL97 trials. The 6-year cumulative relapse incidence of P2RY8-CRLF2+ patients treated on the two trials was not statistically different: 0·37 ± 0·06 vs. 0·25 ± 0·08 (P = 0·194). In contrast, 0/9 IGH@-CRLF2+ AIEOP-BFM, but 5/6 ALL97 patients relapsed. Conclusively, P2RY8-CRLF2+ patients had an intermediate protocol-independent outcome while the different prognosis of IGH@-CRLF2+ patients could be related to the different structures of the applied treatment protocols.

Who will cover the cost of undocumented immigrant trauma care?

BACKGROUND: Health care reform under the "Patient Protection and Affordable Care Act" (PPACA) will lead to changes in reimbursement. Although this legislation provides a mechanism for uninsured Americans to obtain coverage, it excludes undocumented immigrants (UDI). Reimbursement for UDIs comes from the disproportionate share hospital (DSH) program and was previously supported by Section-1011 of the 2003 Medicare Modernization Act (S1011). The PPACA details a cut of DSH funds starting in 2014. This could impose a significant financial burden on trauma centers. METHODS: From May 2005 to May 2008, we retrospectively reviewed all trauma-related emergency room visits by UDIs. We quantified charges for three entities: emergency department physicians, trauma surgeons, and the hospital. We applied our average institutional collection rate to these charges and compared these projected collections with the actual collections. RESULTS: Over a three-year period, we identified 1,325 trauma UDIs. The financial records revealed a projected emergency department physicians collection of $452,686, a projected trauma surgeons collection of $1.2 million, and a projected hospital collection of $6.9 million (total $8.6 million). Actual funding from S1011 provided $1.7 million and DSH provided $1.9 million (total $3.6 million). Texas State Funding and UDI self-payment contributed $611,082. Overall, our institution had a reimbursement discrepancy of $4.3 million with DSH/S1011 assistance. This increased to $6.0 million after the termination of S1011 and may increase to $7.9 million under PPACA. CONCLUSION: These figures underestimate the total cost of UDI trauma care as it only includes three entities. Our data represent a fraction of national figures. Failure to address these issues could result in ongoing financial problems for trauma centers. LEVEL OF EVIDENCE: II, economic and decision analysis.

Geriatric trauma service: a one-year experience.

BACKGROUND: Trauma centers nationwide have been experiencing an increase in their elderly trauma patients because of an ever growing elderly population within the United States. Many studies have demonstrated the physiologic differences between an older trauma patient versus a younger trauma patient. Coupling these differences with their coexisting medical comorbidities, makes caring for this population extremely challenging. To meet these challenges, we organized a geriatric trauma unit specifically designed with a multidisciplinary approach to take a more aggressive stance to the care of the geriatric trauma patient. METHODS: We created a geriatric trauma unit at our Level II trauma facility, called the G-60 unit. This unit opened for admission in August 2009. Inclusion criteria included all trauma patients older than 60 years. Data were abstracted from our G-60 unit from the period of August 2009 to July 2010. We compared these data to a similar patient population (control group) from January 2008 to December 2008. RESULTS: Our Trauma Data Bank yielded 673 patients for the above queried time period. The G-60 group contained 393 patients, while the control group had 280 patients. A decrease was seen among the G-60 group in all categories: average emergency department length of stay (LOS), average emergency department to operating room time, average surgical intensive care unit LOS, and average hospital LOS. A 3.8% mortality rate was found in the G-60 group compared with a 5.7% mortality rate in the control group. Our analysis also showed rate of 0% pneumonia, 1.3% respiratory failure, and 1.5% urinary tract infection in the G-6O group, while the control group had a rate of 1.8% pneumonia, 6.8% respiratory failure, and 3.9% urinary tract infection. CONCLUSION: Our data from the 1-year experience of our G-60 unit show that addressing the specific needs of elderly trauma patients will lead to better outcomes.

The creation of a geriatric trauma unit "G-60".

Many elderly trauma patients have isolated orthopedic injuries compounded by chronic medical conditions. We organized a trauma unit, led by trauma surgeons, that is designed to expedite the care of geriatric patients through a multidisciplinary approach. The development of G-60, our Geriatric Trauma Unit, began with discussion between trauma surgeons and hospital administration. Dialogue between trauma surgeons and emergency department physicians yielded triaging, disposition, and admission criteria. Orthopedic surgeons helped implement a goal of operative management in 48 hours. Internal medicine assisted in optimizing chronic disease and providing preoperative clearance with involvement of cardiology and anesthesiology. Meetings were held among surgeons, physical therapists, occupational therapists, respiratory therapists, nutritionists, pharmacists, social workers, case managers, internists, a geriatrician, and physical medicine and rehabilitation. A unit in the hospital was chosen, and a paging system was implemented. Six months lapsed from inception to fulfillment. The multidisciplinary team has achieved several improvements in this population. Through a multidisciplinary approach, a geriatric trauma unit was created that expedites triage, optimizes chronic illness to facilitate definitive management, and provides safe discharge.

Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial.

Deregulated expression of CRLF2 (CRLF2-d) arises via its juxtaposition to the IGH@ enhancer or P2RY8 promoter. Among 865 BCP-ALL children treated on MRC ALL97, 52 (6%) had CRLF2-d, but it was more prevalent among Down syndrome patients (54%). P2RY8-CRLF2 (n = 43) was more frequent than IGH@-CRLF2 (n = 9). CRLF2-d was not associated with age, sex, or white cell count, but IGH@-CRLF2 patients were older than P2RY8-CRLF2 patients (median 8 vs 4 years, P = .0017). Patients with CRLF2-d were more likely to present with enlarged livers and spleens (38% vs 18%, P < .001). CRLF2-d was not seen in conjunction with established chromosomal translocations but 6 (12%) cases had high hyperdiploidy, and 5 (10%) had iAMP21. Univariate analysis suggested that CRLF2-d was associated with an inferior outcome: (event-free survival [EFS] hazard ratio 2.27 [95% confidence interval 1.48-3.47], P < .001; OS 3.69 [2.34-5.84], P < .001). However, multivariate analysis indicated that its effect was mediated by other risk factors such as cytogenetics and DS status (EFS 1.45 [0.88-2.39], P = .140; OS 1.90 [1.08-3.36], P = .027). Although the outcome of IGH@-CRLF2 patients appeared inferior compared with P2RY8-CRLF2 patients, the result was not significant (EFS 2.69 [1.15-6.31], P = .023; OS 2.86 [1.15-6.79], P = .021). Therefore, we concluded that patients with CRLF2-d should be classified into the intermediate cytogenetic risk group.

Resident fatigue: is there a patient safety issue?

BACKGROUND: In 2003, the 80-hour resident workweek was implemented in response to concerns that fatigued residents led to substandard patient care. Existing evidence links fatigue with impaired human performance; however, this has not consistently translated into similar impairment in the clinical arena. There is now discussion of additional work hour restrictions. Sentinel events are major medical mistakes tracked by the Joint Commission (JC). Root cause analysis of these events can determine if resident fatigue plays a role in medical errors. METHODS: A retrospective review of sentinel events in our health system from January 2004 to July 2008 was performed. A root cause analysis for each event was performed. The JC national databank of sentinel events from 1995 to 2007 was also reviewed. In addition, a literature search was performed. RESULTS: At our institution, 110 sentinel events were identified. Root cause analysis showed no evidence of resident fatigue involvement. The JC's national databank includes 4,817 sentinel events. No documented evidence of resident fatigue was found. CONCLUSIONS: Our data did not provide any evidence to support the contention that resident fatigue leads to increased medical errors. Clinical data supporting a direct relationship between resident fatigue and compromised patient safety must be demonstrated before further work hour restrictions are made. More research must be done. The JC should consider monitoring sentinel events for resident fatigue.

"Barking up the right tree": challenges for health care reform.

Current approaches to health care reform are largely based on the metaphor of imminent flood waves threatening to inundate the health care system. This metaphor reflects the system's preoccupation with disease and disease management in a hospital-centric environment. We suggest that the debate needs to be reframed around health, or more precisely the patient's health experience. Most patients are healthy most of the time, and even those with identifiable morbidities generally regard themselves as being in good health. The majority of people receive most of their care in the community from primary care professionals. An integrated, effective and efficient primary health care system supports continuity of care through a primary care provider and fosters clinical leadership that is supported by other primary health care professionals and medical specialists. Each primary care setting will have its own model that best provides flexible and responsive services to meet its patients' needs and expectations.

Allergy and risk of childhood leukaemia: results from the UKCCS.

We investigated the relationship between childhood leukaemia and preceding history of allergy. A nationwide case-control study of childhood cancers was conducted in the United Kingdom with population-based sampling of cases (n = 839) and controls (n = 1,337), matched on age, sex and region of residence. Information about clinically diagnosed allergies was obtained from primary care records. More than a third of subjects had at least one allergy diagnosed prior to leukaemia diagnosis (cases) or pseudo-diagnosis (controls). For both total acute lymphoblastic leukaemia (ALL) and common-ALL/precursor B-cell ALL (c-ALL), a history of eczema was associated with a 30% significant reduction in risk: the odds ratios (OR) and 95% confidence intervals (CI) were 0.70 (0.51-0.97) and 0.68 (0.48-0.98), respectively. Similar associations were observed for hayfever (OR = 0.47; 95% CI: 0.26-0.85 and OR = 0.62; 95% CI: 0.33-1.16 for ALL and c-ALL, respectively). No such patterns were seen either for asthma and ALL, or for any allergy and acute myeloid leukaemia. A comparative analysis of primary care records with parents recall of allergy revealed only moderate agreement with contemporaneous clinical diagnoses for both cases and controls--confirming the unreliability of parental report at interview. Our finding of a reciprocal relationship between allergy and ALL in children is compatible with the hypothesis that a dysregulated immune response is a critical determinant of childhood ALL.

Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21).

Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval [CI], 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.

Principles for supporting task substitution in Australian general practice.

The workforce crisis in Australian general practice provides an impetus to consider new roles for other health professionals. Any innovations need to be appraised in advance for their potential risks and benefits. We propose six principles for this appraisal. These are the need for the new roles to: support the relationship between patients and their general practitioners; be clearly defined, aligned with competency and with relevant professional registration; be supported by practice systems providing safeguards against medical error; be underpinned by a system ensuring informed patient consent to activities being undertaken by members of the general practice team; be supported by effective medical indemnity insurance and be supported with appropriate financing.

Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia.

This study of children and adults with acute lymphoblastic leukaemia (ALL) is the largest series of patients with hypodiploidy (<46 chromosomes) yet reported. The incidence of 5% was independent of age. Patients were subdivided by the number of chromosomes; near-haploidy (23-29 chromosomes), low hypodiploidy (33-39 chromosomes) and high hypodiploidy (42-45 chromosomes). The near-haploid and low hypodiploid groups were characterized by their chromosomal gains and a doubled hyperdiploid population. Structural abnormalities were more frequent in the low hypodiploid group. Near-haploidy was restricted to children of median age 7 years (range 2-15) whereas low hypodiploidy occurred in an older group of median age 15 years (range 9-54). Patients with 42-45 chromosomes were characterized by complex karyotypes involving chromosomes 7, 9 and 12. The features shared by the few patients with 42-44 chromosomes and the large number with 45 justified their inclusion in the same group. Survival analysis showed a poor outcome for the near-haploid and low hypodiploid groups compared to those with 42-45 chromosomes. Thus cytogenetics, or at least a clear definition of the modal chromosome number, is essential at diagnosis in order to stratify patients with hypodiploidy into the appropriate risk group for treatment.

Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HeH) (51 to 65 chromosomes) is found in one third of children with acute lymphoblastic leukemia and is associated with a good prognosis. Cytogenetic features may further refine this prognosis and identify patients with a poor outcome. We examined the effect of sex, age, individual trisomies, modal number, and structural abnormalities on survival among 700 children with HeH. Univariate analysis showed that age. sex, +4, +10, +18, and a high modal number were associated with survival. Multivariate analysis however, revealed that only age, sex, +4, and +18 were independent indicators. Hazard scores for predicting relapse and mortality were constructed. Three risk groups with 5-year event-free survival (EFS) rates of 86%, 75%, and 50% (P <.0001) were identified. The high-risk group comprised boys older than 9 years, boys aged 1 through 9 years without +18, and girls older than 9 years without +18, while girls aged 1 through 9 years with +18 had the best EFS. In terms of mortality, those younger than age 10 years with both +4 and +18 had an improved survival (96% vs 84% at 5 years, P <.0001). These findings confirm that the outcome of children with HeH is heterogeneous and that specific trisomies can identify patients with the greatest and least risk of treatment failure.

Use of sarcoma-based chemotherapy in a case of congenital mesoblastic nephroma with liver metastases.

Congenital mesoblastic nephroma was originally considered to be a benign neoplasm. A more aggressive cellular form, however, that has a close relationship to congenital fibrosarcoma, is widely described. Previous reported sites of metastases are the lungs, heart, brain, and bone. We describe a patient with isolated metastasis to liver and review the management, together with evidence that it may be more appropriate to use a vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) regimen rather than Wilm's tumor-based regimens in those cases for which chemotherapy is indicated.