Integrin signaling potentiates transforming growth factor-beta 1 (TGF-ß1) dependent down-regulation of E-Cadherin expression - Important implications for epithelial to mesenchymal transition (EMT) in renal cell carcinoma.

Signal transduction through the transforming growth factor-beta 1 (TGF-ß1) pathway affects epithelial to mesenchymal transition (EMT), partly by modulation of E-Cadherin expression. The concurrent impact of extracellular matrix driven regulation of integrin signaling on EMT has not been well characterized. We assessed the cumulative effect and molecular mechanisms of TGF-ß1 and integrin signal transduction on E-Cadherin in a renal cell cancer (RCC) model. Stimulation of RCC cells with TGF-ß1 demonstrated a three-fold increased expression of integrin αv. A ligand of integrin αv-ß3, (cyclopentapeptide containing Arginyl-Glycyl-Aspartic acid motif, RGD), was used to mimic integrin signaling. Treatment of cells with RGD and TGF-ß1 demonstrated significantly greater E-cadherin depletion than either ligand alone. This cooperative action on E-Cadherin expression is regulated by transcription factor Snai1 and is followed on a cellular level by increased cellular mobility as evidenced in a wound healing assay. Subsequent silencing of potential downstream mediators of the cumulative action of RGD and TGF-ß1 was carried out by small interfering RNA transfection and confirmed by Western blotting and/or RT-PCR. SiRNA mediated silencing of FAK and PINCH1 independently abrogated the cumulative effect of RGD and TGF-ß1 on E-Cadherin expression. We have identified a novel mechanism through which extracellular matrix event transduction by integrins further augments TGF-ß1 related effects on EMT. Molecular machinery involved in the integrin αv-TGF-ß1 interplay may represent a therapeutic target in RCC.

5 year retrospective follow-up of new cases of Charcot neuroarthropathy-A single centre experience.

BACKGROUND: Few data describe the natural history of Charcot neuroarthropathy treated with a total contact plaster cast (TCC). METHODS: A 5 year retrospective analysis of 50 patients presenting with an acute CN, Assessing time to clinical resolution into appropriate footwear and assessing if initial immobilisation device influenced resolution time. RESULTS: During the study period 42 patients (84%) of patients went into remission, 2 died during their treatment, 4 had major amputations, in 2 patients treatment was ongoing. 36 patients were treated with combination offloading devices, 6 were treated with one modality only. Median time to resolution for patients initially treated with a TCC was not significantly shorter than for those treated with a removable below knee boot. 34.9% required re-casting due to clinical deterioration in the removable device. CONCLUSIONS: More precise measures of resolution of CN are needed to assess the impact of initial treatment modality on time to resolution.

An antibiotic formulary for a tertiary care foot clinic: admission avoidance using intramuscular antibiotics for borderline foot infections in people with diabetes.

AIMS: To develop an antibiotic foot formulary for the empirical treatment of diabetes-related foot infections presenting to our service. Subsequently, to asses costs associated with the introduction of our protocol, in particular to assess the effect on admissions avoidance and any cost savings achieved. METHODS: We reviewed several existing antibiotic protocols. We analysed data on costs related to treatment and admission rates prior to and after the introduction of the protocol. RESULTS: We rationalized our antibiotic protocol and adapted the Infectious Disease Society of America guideline by introducing a category of 'moderate infection-borderline admission' to our classification. This enabled the administration of outpatient intramuscular antibiotics. After introducing the rationalized protocol, our average antibiotic prescribing costs for a 3-week course of treatment fell from £17.12 to £16.42. Over 22 months of follow-up, 26 episodes were eligible for treatment with intramuscular antibiotics. Over the same time period, 121 people were admitted directly from the foot clinic. The costs saved as a result of avoided or delayed admission for those 26 episodes was over £76 000. For 12 people who required subsequent admission, their length of hospital stay was significantly shorter than those admitted directly [9.25 days (range 2-25) vs. 16.11 (2-64), P = 0.045]. CONCLUSIONS: By modifying the Infectious Disease Society of America classification and adopting a protocol to administer outpatient oral and intramuscular antibiotics, we have led to substantial cost savings, shorter hospital admissions and also have developed a successful admissions avoidance strategy.

DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene.

Lipoprotein lipase plays a central role in lipid metabolism and the gene that encodes this enzyme (LPL) is a candidate susceptibility gene for cardiovascular disease. Here we report the complete sequence of a fraction of the LPL gene for 71 individuals (142 chromosomes) from three populations that may have different histories affecting the organization of the sequence variation. Eighty-eight sites in this 9.7 kb vary among individuals from these three populations. Of these, 79 were single nucleotide substitutions and 9 sites involved insertion-deletion variations. The average nucleotide diversity across the region was 0.2% (or on average 1 variable site every 500 bp). At 34 of these sites, the variation was found in only one of the populations, reflecting the differing population and mutational histories. If LPL is a typical human gene, the pattern of sequence variation that exists in introns as well as exons, even for the small number of samples considered here, will present challenges for the identification of sites, or combinations of sites, that influence variation in risk of disease in the population at large.

Community scientists produce open data for understanding insects and climate change.

Insect species are responding to human-caused global changes, sparking an urgent need for more conservation and management. Recent publications indicate the speed and scale of these changes to be both fast and large, impacting ecosystem function and human health. Community scientists are contributing vast amounts of data on insect occurrence and abundance to publicly available biodiversity platforms. These data are then used by ecologists to estimate insect diversity and distributions and forecast species' responses to the stressors of the Anthropocene. Yet, challenges remain with taxonomy, species identification, and sampling, some of which can be improved by new tools and approaches. Here we review the open, global community science programs providing the majority of publicly available insect data. We explore the advantages, challenges, and next steps with these large-scale community science ventures, emphasizing the importance of collaboration between professionals and community scientists to jointly address the conservation of insects.

Intravenous antibiotics in preterm infants have a negative effect upon microbiome development throughout preterm life.

BACKGROUND: Intestinal dysbiosis is implicated in the origins of necrotising enterocolitis and late-onset sepsis in preterm babies. However, the effect of modulators of bacterial growth (e.g. antibiotics) upon the developing microbiome is not well-characterised. In this prospectively-recruited, retrospectively-classified, case-control study, high-throughput 16S rRNA gene sequencing was combined with contemporaneous clinical data collection, to assess the within-subject relationship between antibiotic administration and microbiome development, in comparison to preterm infants with minimal antibiotic exposure. RESULTS: During courses of antibiotics, diversity progression fell in comparison to that seen outside periods of antibiotic use (-0.71units/week vs. + 0.63units/week, p < 0.01); Enterobacteriaceae relative abundance progression conversely rose (+ 10.6%/week vs. -8.9%/week, p < 0.01). After antibiotic cessation, diversity progression remained suppressed (+ 0.2units/week, p = 0.02). CONCLUSIONS: Antibiotic use has an acute and longer-lasting impact on the developing preterm intestinal microbiome. This has clinical implications with regard to the contribution of antibiotic use to evolving dysbiosis, and affects the interpretation of existing microbiome studies where this effect modulator is rarely accounted for.

Modification of anodised aluminium surfaces using a picosecond fibre laser for printing applications.

The use of an ultrafast fibre laser at a wavelength of 1064 nm has allowed the surface modification of anodised aluminium plates coated with a 2 micron thick anodised layer for potential industrial applications. The micro- and nano-scale structuring of the anodised aluminium using picosecond pulses of approximately 25 ps duration at 200 kHz repetition rate was investigated. The interaction of the laser with the substrate created a hydrophilic surface, giving a contact angle of less than 10 degrees. On examination under a Scanning Electron Microscope (SEM), a morphology created due to laser induced spallation was observed. It has been found that these laser processed hydrophilic surfaces revert to a hydrophobic state with time. This has potential for application in the printing industry and offers reusability and sustainability of the process materials. This has been confirmed in initial trials.

Vibrio illness in Florida, 1998-2007.

This study characterized the current epidemiology of vibrio infections in Florida and examined cases reported from 1998 to 2007. Logistic regression was used to determine risk of death. There were 834 vibrio infections in 825 individuals (average annual incidence rate 4·8/1,000,000). Common Vibrio species reported were Vibrio vulnificus (33%), V. parahaemolyticus (29%), and V. alginolyticus (16%). Most exposures were attributed to wounds (42%), and the most common clinical syndromes were wound infections (45%) and gastroenteritis (42%). Almost half of individuals reported an underlying health condition. Risk of death was associated with any underlying condition and increased with the number of conditions (P<0·0001). In Florida, incidence of vibriosis associated with raw oyster consumption has decreased while incidence associated with wound infections has increased. Most prevention efforts to date have focused on oyster consumption. New educational messages focusing on the risk of vibriosis from wound infections should target high-risk populations.

Surface modification of anodised aluminium using a femtosecond laser.

Femtosecond laser pulses at 775 nm, combined with a scanning galvonometer system, have allowed the micro scale structuring of an aluminium plate coated with a 2 micron thick anodised aluminium layer for potential industrial applications. The micro-scale structuring of aluminium was investigated using ultrafast pulses of 180 fs duration at a repetition rate of 1 kHz. Under suitably optimised conditions, the interaction of the laser pulses with the substrate created a hydrophilic surface with a contact angle of less than 10 degrees. These surfaces revealed a 'lotus-leaf' like morphology when examined under a Scanning Electron Microscope (SEM). It has been found that these laser processed hydrophilic surfaces revert with time and they undergo this cycle of alternate hydrophilic/hydrophobic behaviour several times upon exposure to the laser pulses. Their potential application in the printing industries is strong due to their reusability and sustainability; initial trials on printing confirm this. This technology would offer extra advantages as a non-chemical process without the need for developer, thereby reducing the overall cost and time of printing.

Toxin producing Vibrio cholerae O75 outbreak, United States, March to April 2011.

The Florida Department of Health, Florida, United States, is investigating a Vibrio cholerae O75 outbreak. Ten cases with disease onsets from 23 March to 13 April 2011, presented with gastrointestinal symptoms of diarrhoea, nausea, vomiting, cramps, chills, and/or fever, after consuming raw or lightly cooked oysters harvested from Apalachicola Bay, Florida. Symptoms were milder than those during outbreaks of epidemic (serogroup O1 and O139) Vibrio cholerae; no case required rehydration treatment or hospitalisation.

Perinatal inflammation influences but does not arrest rapid immune development in preterm babies.

Infection and infection-related complications are important causes of death and morbidity following preterm birth. Despite this risk, there is limited understanding of the development of the immune system in those born prematurely, and of how this development is influenced by perinatal factors. Here we prospectively and longitudinally follow a cohort of babies born before 32 weeks of gestation. We demonstrate that preterm babies, including those born extremely prematurely (<28 weeks), are capable of rapidly acquiring some adult levels of immune functionality, in which immune maturation occurs independently of the developing heterogeneous microbiome. By contrast, we observe a reduced percentage of CXCL8-producing T cells, but comparable levels of TNF-producing T cells, from babies exposed to in utero or postnatal infection, which precedes an unstable post-natal clinical course. These data show that rapid immune development is possible in preterm babies, but distinct identifiable differences in functionality may predict subsequent infection mediated outcomes.

Preoperative staging of rectal cancer: pelvic MRI plus abdomen and pelvic CT. Does extrahepatic abdomen imaging matter? A case for routine thoracic CT.

OBJECTIVE: To assess the quality of preoperative magnetic resonance imaging (MRI) staging of rectal cancer, and the clinical significance of abdomen and pelvic computed tomogram (CT) scans in preoperative staging of rectal cancer in a district general hospital. We postulated that the 'metastatic yield' of extrahepatic abdominal imaging is poor, and rarely altered management of rectal cancer. METHODS: This is a retrospective study of preoperative MRI, CT scans and postoperative histology results of patients who had definitive surgery for rectal cancer at the Mid-Staffordshire General Hospitals NHS Trust over a 36-month period. Preoperative multiplanar pelvic MRI locoregional staging was compared with eventual histology. The incidence of and significance of abdomen and pelvic CT detected pathology (including metastasis) in the management of rectal cancers was also assessed. RESULTS: Preoperative pelvic MRI correctly predicted 'clear' Circumferential resection margins, in 28 of 29 patients who had primary surgery. This is comparable with many published studies. Significant CT detected pathology (including metastasis) on preoperative abdomen and pelvic CT scans was uncommon, and did not influence management of any rectal cancer patient in our study. DISCUSSION: Given that exclusive CT detected significant pathology caudal to the liver (extrahepatic abdomen) is rare, can full abdomen and pelvic CT scans be justified for preoperative staging of rectal cancers? - especially where chest X rays are employed for lung staging. Preoperative thoracic and upper abdomen CT scan may be a more productive use of resources. Full abdominal scans may be more appropriate for selection of rectal cancer patients with isolated liver metastasis for metastasectomy.

Synergistic regulation of human megakaryocyte development.

Little information exists concerning differing levels of regulation occurring during human megakaryocyte development. We hypothesize that megakaryocytic proliferation and maturation is controlled by two, synergistic regulatory factors. One, megakaryocyte colony-stimulating activity, is an obligate requirement for colony formation and drives the development of relatively immature cells. Megakaryocyte colony-stimulating activity is a functional component of the human recombinant proteins, interleukin 3 or GM-CSF. Human recombinant growth factors, interleukin 1, interleukin 6, or crythropoietin, do not effect megakaryocyte development either alone or in combination with interleukin 3. Full maturation requires a second synergistic activity which increases megakaryocyte number, size, and cytoplasmic and antigenic content. In culture, this synergistic regulator augments maturation by increasing the number of colonies, colony cellularity, and size. In suspension cultures, this cofactor increases megakaryocyte cytoplasmic and antigenic content, and shifts the morphological distribution from immature to mature megakaryocytes. Finally, this activity also increases the number of antigen positive megakaryocytes, either by stimulating proliferation or conversion of antigen-negative to antigen-positive cells. Comparative studies of megakaryocytic regulation suggests that this in vitro regulator mimicks some of the known effects of thrombopoietin in vivo.

The impact of age on major orthopaedic trauma: an analysis of the United Kingdom Trauma Audit Research Network database.

AIMS: To compare the early management and mortality of older patients sustaining major orthopaedic trauma with that of a younger population with similar injuries. PATIENTS AND METHODS: The Trauma Audit Research Network database was reviewed to identify eligible patients admitted between April 2012 and June 2015. Distribution and severity of injury, interventions, comorbidity, critical care episodes and mortality were recorded. The population was divided into young (64 years or younger) and older (65 years and older) patients. RESULTS: Of 142 765 adults sustaining major trauma, 72 942 (51.09 %) had long bone or pelvic fractures and 45.81% of these were > 65 years old. Road traffic collision was the most common mechanism in the young (40.4%) and, in older people, fall from standing height (80.4%) predominated. The 30 day mortality in older patients with fractures is greater (6.8% versus 2.5%), although critical care episodes are more common in the young (18.2% versus 9.7%). Older people are less likely to be admitted to critical care beds and are often managed in isolation by surgeons. Orthopaedic surgery is the most common admitting and operating specialty and, in older people, fracture surgery accounted for 82.1% of procedures. CONCLUSION: Orthopaedic trauma in older people is associated with mortality that is significantly greater than for similar fractures in the young. As with the hip fracture population, major trauma in the elderly is a growing concern which highlights the need for a review of admission pathways and shared orthogeriatric care models. Cite this article: Bone Joint J 2017;99-B:1677-80.

Self-appraisal hierarchical task analysis of laparoscopic surgery performed by expert surgeons.

BACKGROUND: Evaluation of technical skill is notoriously difficult because of the subjectivity and time-consuming expert analysis. No ongoing evaluation scheme exists to assess the continuing competency of surgeons. This study examined whether surgeons' self-assessment accurately reflects their actual surgical technique. METHODS: Hierarchical task analysis (HTA) of laparoscopic cholecystectomy was constructed. Ten expert surgeons were asked to modify the HTA for their own technique. The HTAs of these surgeons then were compared with their actual operations, which had been recorded and assessed by two observers. RESULTS: A total of 40 operations were assessed. All the gallbladders subjected to surgery were classified as grades 1 to 3. The mean interrater reliability for the two observers had a k value of 0.84 (p < 0.05), and the mean intrarater reliability between surgeons and observers had a k value of 0.79 (p < 0.05). CONCLUSIONS: Surgeons' self-evaluation is accurate for technical skills aspects of their operations. This study demonstrates that self-appraisal using HTA is feasible, accurate, and practical. The authors aim to increase the numbers in their study and also to recruit residents.

Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression.

Dendritic cells (DCs) have been shown to be a promising adjuvant for inducing immunity to cancer. We evaluated tumor lysate-pulsed DC in a Phase I trial of pediatric patients with solid tumors. Children with relapsed solid malignancies who had failed standard therapies were eligible. The vaccine used immature DC (CD14-, CD80+, CD86+, CD83-, and HLA-DR+) generated from peripheral blood monocytes in the presence of granulocyte/monocyte colony-stimulating factor and interleukin-4. These DC were then pulsed separately with tumor cell lysates and the immunogenic protein keyhole limpet hemocyanin (KLH) for 24 h and then combined. A total of 1 x 10(6) to 1 x 10(7) DC are administered intradermally every 2 weeks for a total of three vaccinations. Fifteen patients (ages 3-17 years) were enrolled with 10 patients completing all vaccinations. Leukapheresis yields averaged 2.8 x 10(8) peripheral blood mononuclear cells (PBMC)/kg, and DC yields averaged 10.9% of starting PBMC. Patients with neuroblastoma, sarcoma, and renal malignancies were treated without obvious toxicity. Delayed-type hypersensitivity (DTH) response was detected in 7 of 10 patients for KLH and 3 of 6 patients for tumor lysates. Priming of T cells to KLH was seen in 6 of 10 patients and to tumor in 3 of 7 patients as demonstrated by specific IFN-gamma-secreting T cells in unstimulated PBMCs. Significant regression of multiple metastatic sites was seen in 1 patient. Five patients showed stable disease, including 3 who had minimal disease at time of vaccine therapy and remain free of tumor with 16-30 months follow-up. Our results demonstrate that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden. The DC can be administered in an outpatient setting without any observable toxicity. Most importantly, we have demonstrated the ability of the tumor lysate/KLH-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease.

Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study.

PURPOSE: Leukemic cells from T-lineage acute lymphoblastic leukemia (ALL) patients are thought to originate from T-lymphocyte precursors corresponding to discrete stages of T-cell ontogeny. Here we sought to determine the influence of leukemic cell apparent maturational stage on treatment outcomes in pediatric T-lineage ALL. PATIENTS AND METHODS: From 1983 through 1993, 407 pediatric T-lineage ALL patients were enrolled onto two sequential series of risk-adjusted treatment protocols of the Children's Cancer Group. In the current analysis, T-lineage ALL patients were immunophenotypically classified as follows: CD7+ CD2- CD5- pro-thymocyte leukemia (pro-TL), CD7+ (CD2 or CD5)+ CD3- immature TL, and CD7+ CD2+ CD5+ CD3+ mature TL. RESULTS: Similar induction outcomes of 91.4%, 97.1%, and 98.3% were obtained by the pro-, immature, and mature TL groups, respectively. Four-year event-free survival (EFS) was lower for pro-TL patients (57.1%; SD = 8.4%,) compared with immature and mature TL patients (68.5%; SD = 3.5%; and 77.1%; SD = 4.0%, respectively) with an overall significance of .05 (log-rank test) or .04 (log-rank trend test). Relative hazards rates (RHR) were 2.11 and 1.22 for pro-TL and immature TL versus mature TL, respectively. Highly significant differences were found for overall survival (P = .005, log-rank test; P = .009, log-rank trend test). Multivariate analysis confirmed that the prognostic influence of ontogeny grouping was independent of that of other prognostic factors. CONCLUSION: Leukemic cells of the pro-TL maturation stage identify a small subgroup of T-lineage ALL patients who have a significantly worse EFS outcome than patients whose cells are of a more mature stage of development.

Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes).

PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children's Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P<.0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P =.01), or neither trisomy (P<.0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P =.02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.

Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group.

PURPOSE: The nonrandom translocation t(1;19) has been associated with poor outcome in pediatric B-lineage acute lymphoblastic leukemia (ALL). Because most patients treated by contemporary therapies now achieve improved outcomes, we have reassessed the prognostic significance of t(1;19). PATIENTS AND METHODS: Cytogenetic data were accepted for 1,322 children (<21 years old) with newly diagnosed ALL enrolled between 1988 and 1994 on risk-adjusted studies of the Children's Cancer Group (CCG). Forty-seven patients (3.6%) were t(1;19) positive (+); 1,275 (96.4%) were t(1;19) negative (-). Clinical characteristics and treatment outcome were compared using standard methods. RESULTS: Translocation (1;19)+ patients were more likely than t(1;19)- patients to be 10 years of age or greater (P < .001) or CD10+ CD19+ CD34- (P < .0001), or nonwhite (P = .02). Patients with a balanced t(1;19) were less likely to be hyperdiploid than patients with an unbalanced der(19)t(1;19). Event-free survival (EFS) was similar for the overall group of t(1;19)+ and t(1;19)- patients, with 4-year estimates of 69.5% (SD, 6.8%) and 74.8% (SD, 1.3%; P = .48), respectively. However, patients with unbalanced der(19)t(1;19) had significantly better outcomes than patients with balanced t(1;19): 4-year EFS were 80.6% (SD, 7.1%) and 41.7% (SD, 13.5%), respectively (P = .003). These differences were maintained within the individual studies analyses and after exclusion of t(1;19)+ patients whose cells were hyperdiploid with more than 50 chromosomes. CONCLUSION: The overall group of t(1;19)+ patients, as well as the subgroup with an unbalanced der(19)+ (1;19) had outcomes similar to that of t(1;19)- patients, whereas patients with balanced t(1;19) had poorer outcomes. Thus, although the overall prognostic significance of t(1;19) has been obviated by contemporary risk-adjusted protocols, the balanced t(1;19) translocation remains an adverse prognostic factor.

MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin's disease in children: results of the Children's Cancer Group Phase III Trial.

PURPOSE: A randomized trial designed to compare mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and daccarbazine (ABVD) (regimen A) with ABVD plus low-dose regional (extended-field) radiation therapy (EF RT) (regimen B) for the treatment of children and adolescents with stages III and IV Hodgkin's disease was conducted by the Children's Cancer Group (CCG-521) from 1986 until 1990. PATIENTS AND METHODS: One hundred eleven eligible patients were randomized, 57 to regimen A and 54 to regimen B. All patients had pathologically verified stage III or stage IV Hodgkin's disease. RESULTS: Overall survival (S) is 87% at 4 years and event-free survival (EFS) is 82%. Patients randomized to ABVD plus EF RT have a 4-year EFS of 87% compared with 77% for patients randomized to MOPP/ABVD (P = .09, two-sided). Patients randomized to ABVD plus EF RT have a 4-year S of 90% compared with 84% for patients randomized to MOPP/ABVD (P = .45, two-sided). Significant prognostic factors in multivariate analysis for EFS are stage of disease, erythrocyte sedimentation rate (ESR) at diagnosis, liver size at diagnosis, and, among stage III patients, the size of the mediastinal mass at diagnosis. The acute toxicities of treatment are largely hematopoietic in nature, whereas acute pulmonary and cardiac toxicities are modest and not limiting. CONCLUSION: The results of this study show that, in advanced-stage Hodgkin's disease in children, equivalent results can be obtained by the addition of either MOPP or low-dose EF RT to the ABVD regimen; whether the addition of either contributes to outcome was not addressed in this study and will require additional testing. It is clear, however, that MOPP chemotherapy can safely be eliminated from front-line combination chemotherapy regimens for advanced Hodgkin's disease in pediatric patients.