Systematic review and meta-analysis investigating the efficacy and safety of probiotics in people with cancer.

BACKGROUND/OBJECTIVES: Probiotics are living microorganisms that confer a health benefit on the host when administered. This systematic review and meta-analysis investigates the efficacy and safety of probiotics in adult and paediatric patients diagnosed with cancer. METHODS: A systematic review and meta-analysis was undertaken (PROSPERO registration: CRD42016050252). Randomised controlled trials (RCT), identified through screening multiple databases were included for analysis of efficacy. Non-randomised controlled trials and case reports were included for safety analysis. Outcomes included the reduction in the incidence and severity of diarrhoea, and adverse events. Where possible, data were combined for meta-analysis using a random-effects model. Planned subgroup analyses were not possible through marked heterogeneity of study characteristics. RESULTS: Twenty one studies (N = 2982 participants) were included for assessment of efficacy. Probiotics may reduce the incidence of diarrhoea in patients with cancer [odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.34-0.78, 95% prediction interval (PI) 0.3-0.92, I-sq 36.9%, 5 studies] and the duration of pyrexia [standardised mean difference 0.39 days, 95% CI 0.35-0.43, I-sq 0.01%, 5 studies]. Twenty five studies (N = 2242) were included in the safety analysis. Five case reports showed probiotic-related bacteraemia/fungaemia/positive blood cultures. Definitions and reporting of adverse events were variable and inconsistent. CONCLUSIONS: There remain insufficient studies to assess the true effect of probiotics in people with cancer. Meta-analysis suggests probiotics may be beneficial but further studies are still required. Improved reporting of outcomes and adverse events in clinical trials are required to improve accuracy and confidence of conclusions drawn in future updates.

A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1.

Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.

Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia.

Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence that common genetic variation influences the risk of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), identifying risk single-nucleotide polymorphisms (SNPs) localizing to 7p12.2, 9p21.3, 10q21.2 and 14q11.2. The testing of SNPs individually for an association in GWA studies necessitates the imposition of a very stringent P-value to address the issue of multiple testing. While this reduces false positives, real associations may be missed and therefore any estimate of the total heritability will be negatively biased. Using GWAS data on 823 BCP-ALL cases by considering all typed SNPs simultaneously, we have calculated that 24% of the total variation in BCP-ALL risk is accounted for common genetic variation (95% confidence interval 6-42%). Our findings provide support for a polygenic basis for susceptibility to BCP-ALL and have wider implications for future searches for novel disease-causing risk variants.

Survival trends of cancer amongst the south Asian and non-south Asian population under 30 years of age in Yorkshire, UK.

INTRODUCTION: Several studies have shown differences in survival trends between ethnic groups across adults with cancer in the UK. It is unclear whether these differences exist exclusively in the older adult population or whether they begin to emerge in children and young adults. METHODS: Subjects (n=3534) diagnosed with cancer under 30 years of age in Yorkshire between 1990 and 2005 were analysed. Differences in survival rates for diagnostic subgroups were estimated by ethnic group (south Asian or not) using Kaplan-Meier estimation and Cox regression. RESULTS: When compared to non-south Asians (all other ethnic groups excluding south Asians) a significant increased risk of death was seen for south Asians with leukaemia (hazard ratio (HR)=1.75; 95% confidence interval (CI)=1.11-2.76) and lymphoma (HR=2.05; 95% CI=1.09-3.87), whereas south Asians with solid tumours other than central nervous system tumours had a significantly reduced risk of death(HR=0.50; 95% CI=0.28-0.89). This was independent of socioeconomic deprivation. CONCLUSION: We found evidence of poorer survival outcomes for south Asians compared to non-south Asian children and young adults with leukaemia and lymphoma, but better outcomes for south Asian children and young adults with other solid tumours. This needs to be explained, and carefully addressed in the on-going development of cancer services.

Survival from childhood acute lymphoblastic leukaemia: the impact of social inequality in the United Kingdom.

BACKGROUND: Survival from childhood acute lymphoblastic leukaemia (ALL) has continued to improve in economically-developed regions of the world, but 20% of patients still die within 5-years of diagnosis. Treatment is prolonged and complex; and as survival rates plateau, factors relating to socio-economic status and/or treatment adherence are increasingly scrutinised as potentially important determinants of outcome. METHODS: Predicated on the frame-work of the United Kingdom (UK) NHS, the relationship between socio-demographic factors and ALL survival is examined here using data from a large follow-up study conducted in the 1990s. One thousand five hundred and fifty nine children (0-14 years) diagnosed in England, Scotland &Wales during the era of the national UKALL XI randomized-controlled trial (RCT) were followed-up for an average of 15.9 years (20,826.3 person-years). Area-based deprivation scores and father's occupational social class at the time of the child's birth were used as markers of socio-economic status. Information on deaths was obtained from the NHS Information Centre for Health and Social Care. All children were included in the analyses, irrespective of RCT enrolment or participation in the founding epidemiological study (www.UKCCS.org).Survival effects were assessed using proportional hazards regressions models. RESULTS: Survival varied with both area-based deprivation at diagnosis (hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.05-1.57) and fathers occupational social class at birth (HR 1.12; 95% CI 0.97-1.29); the divergence beginning 6-9 months after diagnosis, and widening thereafter during home-administered therapy. The findings became more marked when analyses were restricted to those enrolled in UKALL XI (n = 1341). As expected, survival differences were also observed with sex, and age at diagnosis. CONCLUSION: The existence of significant social disparities in ALL survival, which are not due to treatment accessibility, is of major clinical importance. Trends should be monitored and further research into potentially modifiable risk factors conducted.

Cancer incidence among the south Asian and non-south Asian population under 30 years of age in Yorkshire, UK.

BACKGROUND: Few studies have examined epidemiological differences between ethnic groups for children and young adults with cancer. METHODS: Subjects aged 0-29 years, diagnosed between 1990 and 2005 in the former Yorkshire Regional Health Authority, were included in the analysis. Ethnicity (south Asian or not) was assigned using name analysis program and Hospital Episode Statistics data. Differences in incidence (per 1,000,000 person-years) rates and trends were analysed using joinpoint and Poisson regression analysis. RESULTS: Overall cancer incidence was similar for south Asians (12.1, 95% CI: 10.7-13.5; n=275) and non-south Asians (12.6, 95% CI: 12.2-13.1; n=3259). Annual incidence rates increased significantly by 1.9% per year on average (95% CI: 1.2-2.6%), especially for south Asians (7.0%; 95% CI: 4.2-9.9%). CONCLUSION: If present trends continue, the higher rate of increase seen among south Asians aged 0-29 years in Yorkshire will result in three times higher cancer incidence than non-south Asians by 2020.

Temporal changes in the incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council trials, 1985-2001.

Despite the success of contemporary treatment protocols in childhood acute lymphoblastic leukaemia (ALL), relapse within the central nervous system (CNS) remains a challenge. To better understand this phenomenon, we have analysed the changes in incidence and pattern of CNS relapses in 5564 children enrolled in four successive Medical Research Council-ALL trials between 1985 and 2001. Changes in the incidence and pattern of CNS relapses were examined and the relationship with patient characteristics was assessed. The factors affecting outcome after relapse were determined. Overall, relapses declined by 49%. Decreases occurred primarily in non-CNS and combined relapses with a progressive shift towards later (> or =30 months from diagnosis) relapses (P<0.0001). Although isolated CNS relapses declined, the proportional incidence and timing of relapse remained unchanged. Age and presenting white blood cell (WBC) count were risk factors for CNS relapse. On multivariate analysis, the time to relapse and the trial period influenced outcomes after relapse. Relapse trends differed within biological subtypes. In ETV6-RUNX1 ALL, relapse patterns mirrored overall trends whereas in high hyperdiploidy (HH) ALL, these seem to have plateaued over the latter two trial periods. Intensive systemic and intrathecal chemotherapy have decreased the overall CNS relapse rates and changed the patterns of recurrence. The heterogeneity of therapeutic response in the biological subtypes suggests room for further optimization using currently available chemotherapy.

Survival following relapse in childhood haematological malignancies diagnosed in 1974-2003 in Yorkshire, UK.

We examined population-based information on relapsed childhood haematological cancers, investigating factors that might influence both overall survival and survival following relapse among the 1177 children (0-14 years) diagnosed with a haematological malignancy in Yorkshire from 1974 to 2003, of whom 342 (29%) relapsed at least once. Leukaemia patients from more deprived areas were significantly less likely to relapse (odds ratio=0.54, 95% confidence interval 0.32-0.93 for most deprived quintile vs least deprived quintile; P(trend)=0.06), especially those with acute myeloid leukaemia (P=0.04). Neither ethnic group nor distance to the main treatment centre was associated with risk of relapse. Overall, patients who relapsed at least once had 5-year survival rates of 46% (41-51%) compared with 79% (76-81%) of those who did not. Five-year survival rates from the time of first relapse increased from 20% in 1974-1983 to 45% in 1984-2003. Length of first remission was a strong predictor of survival for leukaemia with a 46% reduced risk of death for every additional year of event-free survival. Of children who experienced a relapse, 46% survived at least 5 years, whereas just under half of patients survived 5 years beyond disease recurrence. This provides a baseline for future comparisons and demonstrates that relapsed childhood cancer need not imply a poor outcome.

The investigation and management of chronic neutropenia in children.

Unravelling the cause of a neutropenia poses a complex diagnostic challenge. The differential diagnosis ranges from life threatening disease to transient benign causes of little clinical significance. This review offers a practical guide to investigating the neutropenic child, and highlights features that merit specialist referral. Therapeutic options, the role of long term follow up, and the complications of severe chronic neutropenia are considered.

Successful recovery of aplastic anemia following orthotopic liver transplantation for non-A-E acute liver failure.

This report describes a teenager who developed aplastic anemia (AA) because of non-A-E acute liver failure (ALF) requiring orthotopic liver transplantation (OLT). His AA did not recover spontaneously and he required treatment with ATG 9 months post-OLT. Bone marrow recovery occurred 4 months after immunotherapy and coincided with further intensification of immunusuppression required to treat early chronic rejection of the liver graft. Three years post-OLT he remains well with good bone marrow and liver function. Intensification of immunosuppression can lead to successful resolution of AA associated with non-A-E ALF.

Leukemic infiltration of the orbit: report of three cases and literature review.

Orbital infiltration by acute lymphoblastic leukemia is rare. The authors present 3 patients, 2 with optic nerve involvement and 1 with anterior chamber infiltration, treated by chemotherapy and radiotherapy. Two are in continuous remission at 64 and 59 months and 1 relapsed in the central nervous system 35 months after ocular relapse. Visual deterioration was prevented in two. Early diagnosis and treatment are important for preservation of vision.

Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial.

Corticosteroids are an essential component of treatment for acute lymphoblastic leukaemia (ALL). Prednisolone is the most commonly used steroid, particularly in the maintenance phase of therapy. There is increasing evidence that, even in equipotent dosage for glucocorticoid effect, dexamethasone has enhanced lymphoblast cytotoxicity and penetration of the central nervous system (CNS) compared with prednisolone. Substitution of dexamethasone for prednisolone in the treatment of ALL might, therefore, result in improved event-free and overall survival. Children with newly diagnosed ALL were randomly assigned to receive either dexamethasone or prednisolone in the induction, consolidation (all received dexamethasone in intensification) and continuation phases of treatment. Among 1603 eligible randomized patients, those receiving dexamethasone had half the risk of isolated CNS relapse (P = 0.0007). Event-free survival was significantly improved with dexamethasone (84.2% vs. 75.6% at 5 years; P = 0.01), with no evidence of differing effects in any subgroup of patients. The use of 6.5 mg/m(2) dexamethasone throughout treatment for ALL led to a significant decrease in the risk of relapse for all risk-groups of patients and, despite the increased toxicity, should now be regarded as part of standard therapy for childhood ALL.

Diagnosing childhood cancer in primary care--a realistic expectation?

The burden of childhood cancer for Primary Care Trusts (PCTs) is unknown. PCTs in Yorkshire are representative of England and Wales and show little heterogeneity in the incidence rates of childhood cancer. Each PCT will expect three to five newly diagnosed children per year. A single GP is likely to see an incident case once every 20 years.

Geographic mobility following cancer treatment in Yorkshire, UK.

Long term cure and maximising reintegration into society are major goals of childhood cancer treatment. Whether reintegration had occurred was assessed using geographic mobility as an objective proxy. Age, sex, and socioeconomic status were identified as being independently associated with mobility whereas diagnosis and relapse were not.

Non-Hodgkin lymphoma presenting with obstructive jaundice.

BACKGROUND: Obstructive jaundice is a rare presenting feature of non-Hodgkin lymphoma (NHL). Lymphomatous masses in the peripancreatic and hepatic hilar regions are potentially difficult to diagnose. METHODS: A retrospective analysis was undertaken of patients presenting with obstructive jaundice secondary to NHL at a tertiary care hepatobiliary unit. RESULTS: Over a 7-year period, six adults and three children with NHL were managed. The site of the lymphomatous mass was at the hepatic hilum in six patients and the peripancreatic area in three. Diagnostic procedures included a laparotomy and biopsy in four patients, hepatic trisectionectomy in two, percutaneous biopsy in two and lymph node biopsy in one patient. Percutaneous biopsy confirmed the diagnosis in both the patients in whom it was attempted. One patient died following liver resection. Chemotherapy was the mainstay of treatment and achieved complete remission in four patients, partial remission in three and no response in one patient. Two patients subsequently required operation for a benign biliary stricture after achieving complete remission. CONCLUSION: NHL must be considered in the differential diagnosis of obstructive jaundice in adults and children. Attempts must be made to diagnose the condition using non-operative techniques. Chemotherapy is the mainstay of treatment. Late benign strictures of the bile duct requiring operation may develop.

Patterns of childhood cancer by ethnic group in Bradford, UK 1974-1997.

The highly urbanised northern English city of Bradford contains a diverse population from different ethnic backgrounds, including a high proportion of south Asians. We aimed to identify the effect of ethnic group on the incidence and temporal trends of childhood cancer in Bradford. Children (0-14 years) from the district of Bradford, who were diagnosed with a malignancy between 1974 and 1997, were selected from a population-based register. Each child was classified as south Asian (Indian, Pakistani and Bangladeshi), or not, based on their full name using 2 computer algorithms and individual inspection. Mid-year population estimates were used to calculate incidence rates and differences were assessed using Poisson regression. The study included 318 children, of whom 81 (25%) were south Asian. The incidence of all cancers in south Asian children (14.9 per 100,000 person years, 95% CI 11.6-18.2) was higher than non-south Asian children (12.0, 10.5-13.5) although not significantly so (P=0.14). Comparisons by diagnostic subgroup showed no major differences apart from significantly higher rates of acute myeloid leukaemia (AML) in south Asian children (1.9 versus 0.7, P=0.02). The age-specific incidence peaks of all childhood cancers and leukaemias were present in south Asian children aged 5-9 years compared with 0-4 years olds in the non-south Asian population. Non-significant increases of 1.4 and 1.5% in the average annual incidence of all cancers were seen for south Asians and non-south Asians respectively, with a significant rise for non-south Asians with leukaemia of 3.0% (P=0.04). Our timely study shows patterns of occurrence of childhood cancer that differ with respect to ethnic group. Differences are particularly apparent in the excess of AML and incidence peak in 5-9 year olds in south Asian children.

Population mixing, childhood leukaemia, CNS tumours and other childhood cancers in Yorkshire.

We tested the hypothesis that variation in population mixing attributable to the diversity of migrants moving to an area is associated with the incidence of childhood leukaemia and other childhood cancers. An ecological analysis was performed on 954 children (<15 years) diagnosed with a malignancy between 1986 and 1996 in 532 electoral wards in Yorkshire, UK. Incidence rate ratios (IRR) were calculated for all childhood leukaemias (n=325), acute lymphoblastic leukaemia (ALL) (n=248), central nervous system (CNS) tumours (n=236) and other solid tumours (n=393) Incidence of all childhood leukaemias was significantly lower in areas of high (top decile) population mixing (IRR 0.72, 95% Confidence Interval (CI) 0.54-0.97) and higher in areas of low (bottom decile) population mixing (IRR 1.56, 95% CI 0.73-3.34), but similar patterns of incidence were not observed for central nervous system or other solid tumours. Population mixing may be a proxy for the range of infections circulating in a community and these results are consistent with the hypothesis that greater exposure to infections reduces the risk of developing childhood leukaemia by conferring efficient modulation of the immune system.

Incidence of childhood acute lymphoblastic leukaemia in Yorkshire, UK.

Between 1980 and 1998, in the north-west of England, a significant rise in childhood acute lymphoblastic leukaemia was caused by an increase in the precursor B-cell form of this disease. We analysed data on children who were diagnosed with leukaemia in Yorkshire, UK, between 1974 and 1997. The incidence of acute lymphoblastic leukaemia remained stable, although a non-significant yearly increase of 2.4% was noted for the precursor B-cell form of this disease from 1980 onwards. The precursor B-cell form accounted for 80% of all acute lymphoblastic leukaemia. Our data are not consistent with increasing incidence for precursor B-cell acute lymphoblastic leukaemia, although numbers of children with acute myeloid leukaemia are rising.