Pre-B cell acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy and remains one of the highest causes of childhood mortality. Despite this, the mechanisms leading to disease remain poorly understood. We asked if recurrent aberrant DNA methylation plays a role in childhood ALL and have defined a genome-scale DNA methylation profile associated with the ETV6-RUNX1 subtype of pediatric ALL. Archival bone marrow smears from 19 children collected at diagnosis and remission were used to derive a disease specific DNA methylation profile. The gene signature was confirmed in an independent cohort of 86 patients. A further 163 patients were analyzed for DNA methylation of a three gene signature. We found that the DNA methylation signature at diagnosis was unique from remission. Fifteen loci were sufficient to discriminate leukemia from disease-free samples and purified CD34+ cells. DNA methylation of these loci was recurrent irrespective of cytogenetic subtype of pre-B cell ALL. We show that recurrent aberrant genomic methylation is a common feature of pre-B ALL, suggesting a shared pathway for disease development. By revealing new DNA methylation markers associated with disease, this study has identified putative targets for development of novel epigenetic-based therapies.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children in the modern world. Recent efforts in characterizing the genetic contribution to this disease through uncovering gene mutations, deletions and structural variation by genome-scale methods have only accounted for a modest proportion of children with ALL. This suggests that either further genetic contributions to ALL have yet to be characterized or other factors, such as epigenetic aberrations are involved. A number of DNA methylation and miRNA profiling studies have investigated the role of both in childhood ALL. Here, we review these profiling efforts, summarize their major findings and speculate as to what the future may hold.

Both acute and chronic neurotoxicities are well-described with the use of oxaliplatin. We describe the case of a 50-year-old man with Dukes C colon carcinoma being treated with an adjuvant FOLFOX4 (5-fluorouracil, leucovorin and oxaliplatin (85 mg/m(2) per cycle)) who developed a widespread acute pain 5 min after commencing his twelfth cycle of chemotherapy. The pain was disabling and distressing, and remained for 16 h despite multimodality analgesia. The patient was not rechallenged with oxaliplatin. We believe this presentation represents an acute neurological phenomenon relating to oxaliplatin. Of note, this acute reaction occurred after 11 cycles of treatment, significantly later in the treatment course than other reports of atypical acute reactions.

BACKGROUND The Glasgow Blatchford Score (GBS) is increasingly being used to predict intervention and outcome following upper gastrointestinal haemorrhage (UGIH). AIM To compare the GBS with both the admission and full Rockall scores in predicting specific clinical end-points following UGIH. PATIENTS AND METHODS Data on consecutive patients presenting to four UK hospitals were collected. Admission history, clinical and laboratory data, endoscopic findings, treatment and clinical follow-up were recorded. Using ROC curves, we compared the three scores in the prediction of death, endoscopic or surgical intervention and transfusion. Results  A total of 1555 patients (mean age 56.7years) presented with UGIH during the study period. Seventy-four (4.8%) died, 223 (14.3%) had endoscopic or surgical intervention and 363 (23.3%) required transfusion. The GBS was similar at predicting death compared with both the admission Rockall (area under ROC curve 0.804 vs. 0.801) and full Rockall score (AUROC 0.741 vs. 0.790). In predicting endo-surgical intervention, the GBS was superior to the admission Rockall (AUROC 0.858 vs. 0.705; P<0.00005) and similar to the full Rockall score (AUROC 0.822 vs. 0.797). The GBS was superior to both admission Rockall (AUROC 0.944 vs. 0.756; P<0.00005) and full Rockall scores (AUROC 0.935 vs. 0.792; P<0.00005) in predicting need for transfusion. CONCLUSIONS Despite not incorporating age, the GBS is as effective as the admission and full Rockall scores in predicting death after UGIH. It is superior to both the admission and full Rockall scores in predicting need for transfusion, and superior to the admission Rockall score in predicting endoscopic or surgical intervention.

Objective: Our objective is to assess the safety of a surgical technique applied to the difficult left upper lobectomy. The inflow-outflow occlusion technique features: dividing the superior pulmonary vein first, then proximal control by clamping the main pulmonary artery (PA), and then distal control by clamping the inferior pulmonary vein. Methods: A retrospective cohort study of a prospective database was carried out. Patients who underwent left upper lobectomy and required clamping of the vessels were compared to those that did not. Results: Between January 1999 and March 2010, 1796 lobectomies were performed and 360 (23%) of these were left upper lobectomies. Of these, 84 (23%) required the inflow-outflow occlusion technique. There were 70 (83%) men (median age 65 years). Fifty-one patients (61%) required resection of the PA and 33 did not. Heparin was not used in the last 17 patients. These 84 patients were compared to the remaining 276 patients who underwent standard left upper lobectomy. Although the median operative time was longer (150 vs 105min, p<0.001) and the median blood loss was greater (120 vs 87ml, p=0.03) for the inflow-outflow technique, there were no significant differences in hospital length of stay, morbidity, or mortality between the two groups. Conclusion: In our experience, clamping of the inferior pulmonary vein instead of the distal PA achieves safe distal vascular control. It affords greater PA mobility and assessment of the tumor and easier PA repair. This technique can be used even when PA resection is not required.

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome.

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BACKGROUND While the International Diabetes Federation (IDF) has ethnic specific waist circumference (WC) cut-points for the metabolic syndrome for Asian populations it is not known whether the cut-points for black populations should differ from those for European populations. We examined the validity of IDF WC cut points for identifying insulin resistance (IR), the underlying cause of the metabolic syndrome, in predominantly black, young Jamaican adults. METHODS Participants from a 1986 birth cohort were evaluated between 2005 and 2007 when they were 18-20 years old. Trained observers took anthropometric measurements and collected a fasting blood sample. IR was assessed using the homeostasis model assessment computer programme (HOMA-IR). Sex specific quartiles for IR were generated using HOMA-IR values and participants in the highest quartile were classified as "insulin resistant". Receiver operator characteristic (ROC) curves were used to estimate the best WC to identify insulin resistance. The sensitivity and specificity of these values were compared with the IDF recommended WC cut-points. RESULTS Data from 707 participants (315 males; 392females) were analysed. In both sexes those with IR were more obese, had higher mean systolic blood pressure, glucose and triglycerides and lower mean HDL cholesterol. The WC was a good predictor of IR with an ROC area under the curve (95% CI) of 0.71(0.64,0.79) for men and 0.72(0.65,0.79) for women. Using the Youden Index (J) the best WC cut point for identifying IR in male participants was 82 cm (sensitivity 45%, specificity 93%, J 0.38) while the standard cut point of 94 cm had a sensitivity of 14% and specificity of 98%(J 0.12). In the female participants 82 cm was also a good cut point for identifying IR (sensitivity 52%, specificity 87%, J 0.39) and was similar to the standard IDF 80 cm cut point (sensitivity 53%, specificity 82%, J 0.35). CONCLUSIONS The WC that identified IR in young black men is lower than the IDF recommended WC cut point. Sex differences in WC cut points for identifying IR were less marked in this population than in other ethnic groups.

The purpose of this survey is to determine health-seeking behaviour, nutritional status and lifestyles of adolescents aged 10-15 years. A random sample of 3003 (1422 males and 1581 females) schoolchildren, aged 10-15 years, was studied in a cross-sectional, interviewer-administered school-based survey conducted in all school types islandwide in a nationally representative sample of Jamaican children currently attending school. Some 3003 youths, 1422 males and 1581 females were interviewed. Males and females had similar healthcare-seeking behaviour but fewer students attending schools in rural areas reported having their eyes or hearing checked, or had seen a dentist than those attending urban schools. Some twelve per cent of adolescents were overweight/obese. More females than males and more urban than rural students were overweight or obese. More boys (86.3%) were physically active in the last week than girls (75%). Physical activity peaked at age 13 years and was lowest at ages 11 and 14-15 years. Some 13% of adolescents 10-15 years old reported having had sexual intercourse, with boys being four times as likely as girls to report sexual activity (OR - 4.97; C.I.- 3.82, 6.47). The median age of sexual debut was 15.43 years for boys and over 15 years for girls. One-third of adolescents drank alcohol and 3% smoked marijuana in the past year. More boys than girls used drugs (p < 0.01). Some 14% of adolescents felt lonely, sad or wanted to cry most of the time/always. One-tenth seriously considered suicide. This study concluded that most adolescents attending primary and secondary schools in Jamaica were not involved in risky behaviour. However, it reveals some critical areas of concern with regard to nutritional status and physical activity, emotional well-being, drug use and sexual activity.

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