Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study.

OBJECTIVES: To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. METHODS: SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)-erythrocyte sedimentation rate (ESR) over 6 months. RESULTS: 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3-ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3-ESR at 6 months was significantly greater in rituximab than TNFi patients: -1.5 (0.2) vs -1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (-1.7 vs -1.3; p=0.017) but not intolerance (-0.7 vs -0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3-ESR with rituximab than with TNFi (-1.6 (0.3) vs -1.2 (0.3); p=0.011), particularly those switching because of inefficacy (-1.9 (0.3) vs -1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. CONCLUSIONS: These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience.

BACKGROUND: Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1-4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors. PATIENTS AND METHODS: A national retrospective study of children ⩽18years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review. RESULTS: There were 50 patients (31 males; median age at diagnosis of 16.7months). Twelve patients were >36months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation. Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5months (0-32). The median survival time of the entire cohort was 13.5months (1-117.5months). Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2years overall survival (OS): 60%±12.6 versus 21.7%±8.5, p=0.03). HDC conferred better outcome (2years OS 47.9%±12.1 versus 27.3%±9.5, p=0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation. CONCLUSION: The outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear.

Epidemiological survey of central nervous system germ cell tumors in Canadian children.

OBJECTIVES: To determine the incidence and characteristics of pediatric patients with central nervous system (CNS) germ cell tumors (GCT) in Canada. METHOD: A national retrospective review of hospital charts was done on all patients with CNS GCT diagnosed between 1990 and 2004. Patients had to be under age 18 years at the time of diagnosis of a CNS germ cell tumor and be a resident of Canada. Information extracted included age and year of diagnosis, pathological diagnosis, location of tumor, evidence of disseminated disease at time of diagnosis and biological markers. RESULTS: One hundred and twenty-one cases were identified (83 germinoma; 38 non-germinoma germ cell tumor). The mean annual incidence of CNS GCT was 1.06 per million children (0.7 per million for germinoma; 0.3 per million for NGGCT). Though yearly incidences varied, there was no clear trend to increased incidence. Male predominance was noted (2.4:1 for germinoma; 11:1 for NGGCT). The primary locations were the pineal and suprasellar regions. At the time of diagnosis, disseminated disease was not uncommon (22% germinoma; 32% NGGCT). Beta human gonadotrophin was elevated in the serum, cerebrospinal fluid (CSF) or both in 7% of patients with germinoma and 36% of patients with NGGCT. Elevation of alpha-fetoprotein in serum, CSF or both was seen in 34% of patients with NGGCT. CONCLUSION: The incidence of CNS germ cell tumors in Canadian children is similar to that observed in other Western countries.

Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease.

BACKGROUND: Patients with longstanding ulcerative colitis and colonic Crohn's disease have an increased risk of colorectal cancer compared with the general population. This review assesses the evidence that endoscopic surveillance may prolong life by allowing earlier detection of colon cancer or its pre-cursor lesion, dysplasia, in patients with inflammatory bowel disease. OBJECTIVES: To assess the effectiveness of cancer surveillance programs in reducing the death rate from colorectal cancer in patients with ulcerative colitis and colonic Crohn's disease. SEARCH STRATEGY: The following strategies were used to identify relevant studies:1. MEDLINE and the Cochrane Central Register of Controlled Trials were searched from 1966 to August 2005. The medical subject headings "Ulcerative Colitis", "Crohn Disease" or "Inflammatory Bowel Disease" and "Surveillance" or "Cancer" were used to perform key-word searches of the databases.2. Hand searching of reference lists from papers. SELECTION CRITERIA: Potentially relevant articles were reviewed independently and unblinded by three authors to determine if they fulfilled the selection criteria. Each article was rated as being eligible, ineligible, or without sufficient information to determine eligibility. Any disagreement between reviewers was resolved by consensus. Any trials published in abstract form were only considered if it was possible to obtain full details of the protocol and results from the authors. DATA COLLECTION AND ANALYSIS: Eligible articles were reviewed in duplicate and the results of the primary research trials were abstracted onto specially designed data extraction forms. The proportion of patients dying from bowel cancer or other causes in the control and surveillance groups of each study was derived from life tables, survival curves or where possible, by calculating life tables from the data provided. Data from the original research articles were converted into 2x2 tables (survival versus death x surveillance versus control) for each of the individual studies for comparable follow-up intervals. The presence of significant heterogeneity among studies was tested by the chi-square test. Because this is a relatively insensitive test, a P value of less than 0.1 was considered statistically significant. Provided statistical heterogeneity was not present, the fixed effects model was used for the pooling of data. The 2x2 tables were combined into a summary test statistic using the pooled relative risk (RR) and 95% confidence intervals as described by Cochrane and Mantel and Haenszel. MAIN RESULTS: Karlen 1998a in a nested case-control study comprising 142 patients from a study population of 4664 UC patients, found that 2/40 patients dying of colorectal cancer had undergone surveillance colonoscopy on at least one occasion compared with 18/102 controls (RR 0.28, 95% CI 0.07 to 1.17). One of 40 patients who died from colorectal cancer had undergone surveillance colonoscopies on two or more occasions compared with 12/102 controls (RR 0.22, 95% CI 0.03 to 1.74) in contrast to a more modest effect observed for patients who had only one colonoscopy (RR 0.43, 95% CI 0.05 to 3.76). Choi 1993 found that carcinoma was detected at a significantly earlier stage in the surveilled patients; 15/19 had Duke's A or B carcinoma in the surveilled group compared to 9/22 in the non-surveilled group (P = 0.039). The 5-year survival rate was 77.2% for cancers occurring in the surveillance group and 36.3% for the no-surveillance group (P = 0.026). Four of 19 patients in the surveillance group died from colorectal cancer compared to 11 of 22 patients in the non-surveillance group (RR 0.42, 95% CI 0.16 to 1.11). Lashner 1990 found that four of 91 patients in a surveillance group died from colorectal cancer compared to 2 of 95 patients in a non-surveilled group (RR 2.09, 95% CI 0.39 to 11.12). Colectomy was less common in the surveillance group, 33 compared to 51 (P < 0.05) and was performed four years later (after 10 years of disease) in the surveillance group. For the pooled data analysis 8/110 patients in the surveillance group died from colorectal cancer compared to 13/117 patients in the non-surveillance group (RR 0.81, 95% CI 0.17 to 3.83). AUTHORS' CONCLUSIONS: There is no clear evidence that surveillance colonoscopy prolongs survival in patients with extensive colitis. There is evidence that cancers tend to be detected at an earlier stage in patients who are undergoing surveillance, and these patients have a correspondingly better prognosis, but lead-time bias could contribute substantially to this apparent benefit. There is indirect evidence that surveillance is likely to be effective at reducing the risk of death from IBD-associated colorectal cancer and indirect evidence that it may be acceptably cost-effective.

Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions.

BACKGROUND: Corticosteroids and non-steroidal anti-inflammatory drugs are widely used for the treatment of rheumatic conditions, but their gastrointestinal damage significantly limits their use. Sigmoid diverticular abscess perforation (SDAP) is a very serious complication of diverticular disease. OBJECTIVE: To determine the aetiology of large bowel SDAP in rheumatic conditions. METHODS: 64 patients with SPAD and 320 controls from a similar geographical area and of similar socioeconomic status were studied. RESULTS: The results showed that independently of rheumatic diagnosis corticosteroid treatment is strongly associated with SDAP (OR 31.9 (95% CI 6.4 to 159.2; p<0.001), and non-steroidal anti-inflammatory drugs only weakly associated (OR 1.8 (95% CI 0.96 to 3.4); p = 0.069). A rheumatic diagnosis is also strongly associated with the development of SDAP (OR 3.5 (95% CI 1.9 to 6.7); p<0.001). CONCLUSIONS: SDAP has serious implications for patients and consumes many healthcare resources. Patients and physicians should be warned of this potential complication.

Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease.

BACKGROUND: Patients with longstanding ulcerative colitis and colonic Crohn's disease have an increased risk of colorectal cancer compared with the general population. This review assesses the evidence that endoscopic surveillance may prolong life by allowing earlier detection of colon cancer or its pre-cursor lesion, dysplasia in patients with inflammatory bowel disease. OBJECTIVES: To assess the effectiveness of cancer surveillance programs in reducing the death rate from colorectal cancer in patients with ulcerative colitis and colonic Crohn's disease. SEARCH STRATEGY: The following strategies were used to identify relevant studies: 1. MEDLINE and the Cochrane Central Register of Controlled Trials were searched from 1966 to December 2002. The medical subject headings "Ulcerative Colitis", "Crohn Disease" or "Inflammatory Bowel Disease" and "Surveillance" or "Cancer" were used to perform key-word searches of the databases. 2. Hand searching of reference lists from papers. SELECTION CRITERIA: Potentially relevant articles were reviewed independently and unblinded by three authors to determine if they fulfilled the selection criteria. Each article was rated as being eligible, ineligible, or without sufficient information to determine eligibility. Any disagreement between reviewers was resolved by consensus. Any trials published in abstract form were only considered if it was possible to obtain full details of the protocol and results from the authors. DATA COLLECTION AND ANALYSIS: Eligible articles were reviewed in duplicate and the results of the primary research trials were abstracted onto specially designed data extraction forms. The proportion of patients dying from bowel cancer or other causes in the control and surveillance groups of each study was derived from life tables, survival curves or where possible, by calculating life tables from the data provided. Data from the original research articles were converted into 2x2 tables (survival versus death x surveillance versus control) for each of the individual studies for comparable follow-up intervals. The presence of significant heterogeneity among studies was tested by the chi-square test. Because this is a relatively insensitive test, a p value of less than 0.1 was considered statistically significant. Provided statistical heterogeneity was not present (p>0.10), the fixed effects model was used for the pooling of data. The 2x2 tables were combined into a summary test statistic using the pooled relative risk (RR) and 95% confidence intervals as described by Cochrane and Mantel and Haenszel. MAIN RESULTS: Karlen 1998a found that 2/40 of the patients dying of colorectal cancer had undergone surveillance colonoscopy on at least one occasion compared with 18/102 of the controls (RR 0.28, 95% confidence interval 0.07 to 1.17). One of 40 patients who died from colorectal cancer had undergone surveillance colonoscopies on two or more occasions compared with 12/102 controls (RR 0.22, 95% confidence interval 0.03 to 1.74) in contrast to a more modest effect observed for patients who had only one colonoscopy (RR 0.43, 95% confidence intervals 0.05 to 3.76). Choi 1993 found that carcinoma was detected at a significantly earlier stage in the surveillance group; 15/19 had Duke's A or B carcinoma in the surveilled group compared to 9/22 in the non-surveilled group (P= 0.039). The 5-year survival rate was 77.2% for cancers occurring in the surveillance group and 36.3% for the no-surveillance group (P= 0.026). Four of 19 patients in the surveillance group died from colorectal cancer compared to 11 of 22 patients in the non-surveillance group (RR 0.42, 95% CI 0.16 to 1.11). Lashner 1990 found that four of 91 patients in the surveillance group died from colorectal cancer compared to 2 of 95 patients in the non-surveilled group (RR 2.09, 95% CI 0.39 to 11.12). Colectomy was less common in the surveillance group, 33 compared to 51 (p < 0.05) and was performed four years later (after 10 years of disease) in the surveillance group. For the pooled data analysis 8/110 patients in the surveillance group died from colorectal cancer compared to 13/117 patients in the non-surveillance group (RR 0.81, 95% CI 0.17 to 3.83). REVIEWERS' CONCLUSIONS: There is no clear evidence that surveillance colonoscopy prolongs survival in patients with extensive colitis. There is evidence that cancers tend to be detected at an earlier stage in patients who are undergoing surveillance and these patients have a correspondingly better prognosis but lead-time bias could contribute substantially to this apparent benefit. There is indirect evidence that surveillance is likely to be effective at reducing the risk of death from IBD-associated colorectal cancer and indirect evidence that it is acceptably cost-effective.

An unusual cause of acute renal failure in systemic sclerosis.

BACKGROUND: Scleroderma renal crisis is one of the most life threatening complications of scleroderma. Enteric hyperoxaluria complicates extensive disease or resection of the small intestine in the presence of an intact colon, and is associated with calcium oxalate nephrolithiasis. This cause of renal failure may be underestimated and should be considered in all patients with malabsorption and renal failure. CASE REPORT: A 78 year old woman with systemic sclerosis affecting the bowel developed acute renal failure caused by oxalate nephropathy. RESULTS: The patient's renal failure improved on an oxalate free diet.

Self-perception profile in children with cancer: self vs parent report.

Self-perception about competence, behaviour, and self-worth were examined in 30 children (8 to 14 years) recently diagnosed as having cancer and were compared with that of their parents' perception. The poor agreement between parents' and children's ratings on physical appearance and social acceptance is noteworthy in that these two domains are particularly vulnerable in children with cancer, given the effect of chemotherapy on physical appearance and children's tendency to view themselves as socially undesirable or a burden to others. This finding, if replicated, can have implications for therapeutic intervention since the discrepancy score could be used to challenge children's negative views in the context of cognitive therapy to improve their self-esteem.

Synchronous bilateral Wilms' tumor.

Synchronous bilateral Wilms' tumor (WT) accounts for 5% of all WTs. Of 34 cases of WT we treated, 7 (20.6%) were bilateral, 5 of them males. This high frequency of bilaterality as well as the male preponderance in our series is different from that reported in other parts of the world; this may reflect regional variations of WT. The details of diagnosis, therapy, including the role of preoperative chemotherapy, and outcome are presented.

Socioeconomic factors in the families of children with lymphoid malignancy in the UAE.

Children of subcontinental (Indian and Pakistani) origin living in the United Arab Emirates (UAE) have previously been shown to have a higher relative frequency of ALL when compared to other ethnic groups. To analyze the possible effect of social class in this difference, a study of socioeconomic factors was conducted through personal interviews with the families of 115 children with lymphoid malignancies. The patients belonged to three ethnic groups: (1) UAE; (2) other Arabs; and (3) Indian subcontinent. UAE parents had the highest income and number of rooms in their house, but the lowest level of education. Occupational categories were significantly different for the three ethnic groups. While 41% of the UAE fathers worked in the army or the police, the majority of Arab and subcontinental fathers worked as government administrators or professionals. UAE families had the highest number of children in the family, subcontinental families the lowest. The number of children per family was inversely related to the parents' education level. Multiple regression analysis showed parental education level and house size to be significantly associated with ethnicity, while parental consanguinity was significantly associated with the diagnosis of lymphoma. It is difficult to define social class in the UAE population. While income and property ownership would place the UAE nationals in the highest category and the subcontinental group in the lowest, education level and occupational category would place the Arab and subcontinental groups higher. The smaller family size and higher education level in subcontinental families corresponds to the previously found higher relative frequency of ALL in this ethnic group and could lend support to the possible infectious etiology of the disease.

Neuroblastoma-associated paraneoplastic syndrome with anti-Hu antineuronal antibodies presenting at the time of recurrence.

A 27-month-old girl presented with chest pain. Further evaluation confirmed posterior mediastinal neuroblastoma with bone marrow infiltration, which was treated with a combination of chemotherapy and surgery. Four months after completing treatment, she presented with myoclonus and weakness of her right arm. The myoclonus eventually subsided but her right arm weakness progressed to a right hemiplegia. High titers of antineuronal nuclear antibodies identified as anti-Hu were found in both serum and cerebrospinal fluid. One month later she presented with a relapse of her original tumor, from which she died. Identification of anti-Hu antineuronal nuclear antibodies in this neuroblastoma-associated paraneoplastic syndrome supports the hypothesis that the syndrome is due to autoimmune disease.

Febrile episodes in children with cancer in the United Arab Emirates.

The febrile episodes encountered in our pediatric oncology unit over a 2-year period were reviewed. A total of 138 febrile episodes were recorded in 59 patients (29 with leukemia and 30 with a solid tumor). There was no difference in the number of episodes between leukemia and solid tumor patients, nor between neutropenic and non-neutropenic patients. The degree of neutropenia was more severe in leukemia patients. A total of 18.8% of the episodes were accompanied by positive blood cultures. Gram-positive bacteria were more frequent than gram-negative bacteria, and there were four anaerobic isolates. Seventeen episodes were accompanied by clinical signs of central venous line (CVL) infection. A total of 70.2% of the episodes resolved with a first-line antibiotic combination of flucloxacillin, piperacillin, and netilmicin, 27.5% required modification of the antibiotic combination, and three patients (5%) died due to gram-negative septicemia. These findings indicate that the pattern of infectious complications in the United Arab Emirates is now similar to that observed in Europe and the United States.

History and current state of pediatric oncology and hematology in the United Arab Emirates.

There are three oncology centers in the United Arab Emirates, but only one with a dedicated pediatric unit (Tawam Hospital). The unit is 12 years old and is staffed by two pediatric oncologists working with pediatric but not oncology nurses. It handles approximately two thirds of the pediatric cancer cases in the country. Approximately 60% of all cases are either acute leukemia or lymphoma. A large variety of treatment regimens were used in the past for the same diseases, making audit of the unit's work very difficult. In the last 7 years a policy has evolved whereby uniform management protocols are used. A database is in existence, although not yet complete, and diagnostic facilities are continuing to improve. Imaging facilities are modern, and cell surface phenotyping for leukemia is available. There are plans to establish a bone marrow transplant unit.

The role of Epstein-Barr virus in Hodgkin's disease from different geographical areas.

Recent studies have suggested that Epstein-Barr virus (EBV) may play a role in the aetiology of Hodgkin's disease. To determine the role of EBV in childhood Hodgkin's disease in different geographical areas, immunohistochemical staining and in situ hybridisation were used to analyse latent membrane protein 1 (LMP 1) and small nuclear non-transcribed RNAs (EBER-1) respectively. Testing for EBV within the Reed-Sternberg and Hodgkin's cells was carried out in childhood Hodgkin's disease from 10 different countries. The proportion of LMP 1 positive cases varied significantly, being 50% of cases from the United Kingdom (38/75), South Africa (9/18), Egypt (7/14), and Jordan (8/16), 60% from the United Arab Emirates (6/10), 70% from Australia (11/16), 81% from Costa Rica (34/42), 88% from Iran (7/8), 90% from Greece (20/22), and 100% of the 56 cases from Kenya. A sensitive polymerase chain reaction based EBV strain typing technique was established using archival tissues. EBV strain type 1 was shown to be predominant in childhood Hodgkin's disease from the United Kingdom, South Africa, Australia, and Greece. Type 2 was predominant in Egypt. EBV strain types 1 and 2 were both detected in some cases of childhood Hodgkin's disease in the United Kingdom, Costa Rica, and Kenya. The high incidence of EBV and the presence especially in developing countries of dual infection with both strain types 1 and 2 may reflect socioeconomic conditions leading to malnutrition induced immunological impairment. The possibility of HIV infection also needs to be explored.

Leukaemia phenotype and ethnicity in children living in the United Arab Emirates.

Immunophenotyping was carried out in the presentation bone marrow samples of 32 children with acute lymphoblastic leukaemia (ALL), living in the UAE. Twenty two had B-cell precursor ALL, 10 had T-cell precursor leukaemia. Clinical features were in accordance with internationally reported series. Analysis of ethnic origin showed that children of subcontinental origin (Indian and Pakistani) had a significantly higher proportion of T-cell ALL than their Arabic counterparts. This may reflect an interim phase in the pattern of ALL, between those of the developing and industrialized countries.

Churg Strauss syndrome in childhood.

We describe a 7-year-old boy with Churg Strauss syndrome who presented with a 3-month history of cough, wheeze, fever, weight loss, abdominal pain, skin lesions, proteinuria and pulmonary infiltrates with eosinophilia. He showed a good response to corticosteroid treatment and is currently doing well. The case illustrates the difficulty and importance of reaching a diagnosis in a rare condition for which there is an effective treatment, and serves to remind paediatricians of its existence.

Severe lactic acidosis and renal involvement in a patient with relapsed Burkitt's lymphoma.

We describe an 8-year-old patient with relapsed Burkitt's lymphoma who developed complex metabolic problems, including renal diabetes insipidus and severe lactic acidosis. The lactic acidosis responded temporarily to chemo- and radiotherapy but not to bicarbonate or thiamine administration. These metabolic changes were most likely due to the lymphomatous infiltration of the kidneys. Severe lactic acidosis, without evidence of thiamine deficiency, seems to be a very rare event in children with cancer.