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Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10-15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single-nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin-Frankfurt-Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% confidence interval (CI): 1.6-6.3%) for the best group (72% of patients) to 76% (95% CI: 41-90%) for the worst group (5% of patients, P<0.001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation. [ABSTRACT FROM AUTHOR]

Recent applications of recombinant DNA techniques in cancer research led to the detection of cellular genes with potential transforming activity, called oncogenes (c-onc). Regularly they seem to be involved in normal cell differentiation and proliferation: a number of oncogene-encoded proteins specifically phosphorylates tyrosine, a key reaction in growth control. Certain human tumors exhibit activated forms of these genes and DNA fragments isolated from these neoplasms transform nonneoplastic cells (transfection assay). Oncogenes were first discovered and defined in a number of retroviruses; these viral oncogenes (v-onc) are thought to have been derived from the cellular oncogenes (c-onc). By integration of the v-onc genes into the host genome acute neoplastic transformation of the cell may occur. Several modes of oncogene activation are discussed that lead either to an increased dosage of gene product or to the formation of an altered gene product. The localization of oncogenes in the human genome near the breakpoints of specific chromosome aberrations involved in various neoplasms like Burkitt lymphoma and several leukemias emphasizes the importance of these genes in carcinogenesis. [ABSTRACT FROM AUTHOR]

Damaged DNA can be repaired by three different mechanisms: photoreactivation, excision repair and postreplication repair. Each mechanism is regulated by a highly specific set of enzymes. Defects within these systems result in diseases which have one common feature: affected individuals are cancer prone. Recently, newly developed methods not only make it possible to diagnose affected patients but also to detect individuals at risk. Furthermore, the results obtained elucidate some mechanisms of carcinogenesis. Clinical applications are discussed. [ABSTRACT FROM AUTHOR]

Background: To demonstrate the pelvic peritoneal recesses during voiding, evacuation proctography was combined with positive contrast peritoneography.Methods: In 30 constipated patients, peritoneography was performed, followed by proctography.Results: During evacuation rectogenital herniation developed in 20 patients (66%), without visceral filling in 12 (40%).Conclusions: Posterior pelvic floor hernia is common during defecation. Less than half fill with bowel and many may not be apparent on standard proctography. [ABSTRACT FROM AUTHOR]

To increase our knowledge of the clonal relationship of leukaemia relapse, the genotypes and phenotypes of ten children with acute lymphoblastic leukaemia (ALL) were examined at initial diagnosis and relapse. Seven patients were phenotyped as common ALL, two as mixed, and one as T-cell ALL (T-ALL). Comparative analyses of immunoglobulin (Ig) heavy and light chain as well as T-cell receptor beta-chain (T beta) sequences revealed clonal variations, i.e. appearance of a novel or an evoluted leukaemic cell clone in five patients coinciding with the loss of common acute lymphoblastic leukaemic antigen (CALLA) in four cases, irrespective of early or late relapse. Conversion of early B- to T-ALL or lymphoblastic to non-lymphoblastic leukaemia was not noted in any of the patients examined. Our results suggest that clonal variation is a frequent event in childhood ALL. [ABSTRACT FROM AUTHOR]

In the present study methods are described for the analysis of the genomic structure of DNA isolated from tissues that have been stored up to several years as air-dried or stained bone marrow smears, bone marrow biopsies in "Histicon", chromosomal preparations in fixative or as formalin fixed tissues embedded in paraffin. By application of the new techniques clonal B- and T-cell disorders, Philadelphia chromosome translocations and ras oncogene mutations in pancreatic carcinomas could be detected. Thus, these DNA extraction procedures may open new avenues to pathological archives and enable the analysis of samples when fresh material is not available. [ABSTRACT FROM AUTHOR]

The article presents a study which analyzes the presence of ERGdel gene coding in a large cohort of children with acute lymphoblastic leukemia (ALL) treated according to the Austrian-German-Swiss ALL-BFM-2000 protocol. It mentions the clonal stability of ERGdel from diagnosis to relapse in paired samples that occurred at a frequency of 4.5% in childhood ALL. The authors note that their observations support a positive impact of ERGdel on treatment susceptibility in ALL-BFM 2000.

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Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification. Patients (n=45) showed a median time to relapse of 1.5 years. In 89% of patients at least one T-cell-receptor/immunoglobulin gene rearrangement chosen for initial MRD quantification remained stable; however, at least one of the preferred markers for MRD stratification at relapse was different to diagnosis in 50% of patients. A similar proportion of very early, early and late relapses appeared to gain a marker at relapse although backtracking-analysis revealed that in 77% of cases, the gained markers were present as small sub-clones at initial diagnosis. Comparing initial and relapse MRD response to induction, 38% of patients showed a similar, 38% a better and 25% a poorer response after relapse. These data demonstrate an unexpectedly high clonal heterogeneity among very early/early relapses and challenge some current assumptions about relapsed ALL. [ABSTRACT FROM AUTHOR]

Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (10−4), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD 10−3 at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.Leukemia (2008) 22, 771–782; doi:10.1038/leu.2008.5; published online 31 January 2008 [ABSTRACT FROM AUTHOR]

Minimal residual disease (MRD) diagnostics is used for treatment stratification in childhood acute lymphoblastic leukemia. We aimed to identify and solve potential problems in multicenter MRD studies to achieve and maintain consistent results between the AIEOP/BFM ALL-2000 MRD laboratories. As the dot-blot hybridization method was replaced by the real-time quantitative polymerase chain reaction (RQ-PCR) method during the treatment protocol, special attention was given to the comparison of MRD data obtained by both methods and to the reproducibility of RQ-PCR data. Evaluation of all key steps in molecular MRD diagnostics identified several pitfalls that resulted in discordant MRD results. In particular, guidelines for RQ-PCR data interpretation appeared to be crucial for obtaining concordant MRD results. The experimental variation of the RQ-PCR was generally less than three-fold, but logically became larger at low MRD levels below the reproducible sensitivity of the assay (<10−4). Finally, MRD data obtained by dot-blot hybridization were comparable to those obtained by RQ-PCR analysis (r2=0.74). In conclusion, MRD diagnostics using RQ-PCR analysis of immunoglobulin/T-cell receptor gene rearrangements is feasible in multicenter studies but requires standardization; particularly strict guidelines for interpretation of RQ-PCR data are required. We further recommend regular quality control for laboratories performing MRD diagnostics in international treatment protocols.Leukemia (2007) 21, 706–713. doi:10.1038/sj.leu.2404535; published online 8 February 2007 [ABSTRACT FROM AUTHOR]

We genotyped six folate metabolic pathway genes for 11 polymorphisms in 460 cases of childhood acute lymphoblastic leukemia (ALL) and 552 ethnically matched controls. None of the polymorphisms except the 66A>G (I22M) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene showed any effect on disease risk. The carriers of the G-allele were associated with a marginal decreased risk of ALL (gender-adjusted global P=0.03; multiple-testing corrected P=0.25). Analysis of four polymorphisms in the MTRR gene showed statistically significant differences in haplotype distribution between cases and controls (global P<0.0001). The haplotypes GCAC (odds ratio (OR) 0.5, 95% confidence interval (CI) 0.4–0.6) and ATAC (OR 0.5, 95% CI 0.3–0.6) were associated with a reduced risk and the haplotypes ACAC (OR 2.3, 95% CI 1.8–2.9) and GTAC (OR 1.8, 95% CI 1.4–2.3) with an increased risk. The genotype-combination analyses indicated that the best model stratifies cases and controls based on the 66A>G and the 524C>T polymorphisms in the MTRR gene (global P=0.03). Our results suggest that, besides a weak association of childhood ALL with the 66A>G polymorphism, haplotypes within the MTRR gene may, in part, account for population-based differences in risk.Leukemia (2007) 21, 320–325. doi:10.1038/sj.leu.2404474; published online 30 November 2006 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Methylation analysis of asparagine synthetase gene in acute lymphoblastic leukemia cells" that appeared online in the April 6, 2006 issue of "Leukemia."

Focuses on the issue of imaging for functional anorectal conditions. Characteristics and types of functional disorders of the anorectum; Endosonography, fluoroscopy and magnetic resonance (MR) imaging as the imaging processes that may be used on anorectal disorders; Features of anal endosonography; Superiority of endocoil MR imaging in the diagnosis of external sphincter atrophy.

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies in childhood, with a widely variable outcome. Differences in the behavior and prognosis of the leukemia suggest that ALL can be divided into several biologic subgroups. We analyzed the loss of heterozygosity (LOH) of 6q, 9p, 11q and 12p using 31 microsatellite sites to determine their overall frequency and clinical value. We have studied 244 primary ALL samples obtained from the Multicenter Trial ALL-BFM 90 of Childhood ALL group. These patients have now been followed clinically for over 8 years. LOH occurred in 169 (69%) individuals in the following frequencies: 6q, 49 patients (20%); 9p, 97 patients (40%); 11q, 29 patients (12%); 12p, 60 patients (25%). Clinical data showed that those with 6q LOH were younger (P = 0.01) and had lower WBC counts (P = 0.02); patients with 9p LOH more frequently had CNS involvement (P = 0.01) and T cell phenotype (P = 0.0001); individuals with 11q LOH had a good response to induction chemotherapy (P = 0.02); those with 12p LOH were younger (P = 0.005), frequently had precursor B ALL (P = 0.001), and had a longer event-free survival (P = 0.05). Taken together, these data con-firm that LOH is a very frequent alteration in childhood ALL. [ABSTRACT FROM AUTHOR]

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DNA amplifications at 11q13 are frequently observed in esophageal squamous cell carcinoma (ESC) and correlate with a malignant phenotype. Although this amplicon spans a region of several megabases and harbors numerous genes, CCND1 and EMS1 are thought to be the relevant candidates in ESC. We investigated whether the putative transforming gene MYEOV, mapping 360kb centromeric to CCND1 and activated concomitantly with CCND1 in a subset of t(11;14)(q13;q32) positive multiple myeloma cell lines, represents a target of 11q13 amplification in ESC. To evaluate the role of MYEOV in ESC, we tested 31 ESC cell lines and 48 primary tumors for copy number levels of MYEOV and demonstrated that MYEOV was always coamplified with CCND1. However, MYEOV expression levels correlated only inconsistently with DNA amplification data. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored MYEOV expression in a subset of cell lines exhibiting DNA amplification without high MYEOV expression, suggesting that MYEOV is transcriptionally silenced by a DNA methylation mechanism in most of the latter cell lines. Our results indicate that MYEOV is a coamplified gene with CCND1 at 11q13, but its activation is sometimes inhibited by an epigenetic mechanism. [ABSTRACT FROM AUTHOR]

The reliability of routine BCR-ABL RT-nested-PCR was evaluated in 1453 B-lineage ALL or hybrid leukemia at initial diagnosis by RT-nested-PCR. All BCR-ABL-positive (n = 642) and 176 BCR-ABL-negative samples underwent a second RT-PCR. In 518 patients, karyotyping and/or FISH was compared to the BCR-ABL status. The second RT-PCR revealed in 155/642 initially positive samples a divergent result (153 BCR-ABL-negative, two other transcripts) that in most cases turned out to be caused by contaminations in the first RT-nested-PCR. Confirmatory RT-PCR detected 2/176 false negative first RT-nested-PCR results. Thirty-nine specimens remained ambiguous despite different RT-PCR approaches. As far as cytogenetic evaluation and FISH is available (n = 23), the majority but not all patients with an ambiguous RT-PCR result were Ph-negative (n = 18). RT-nested-PCR and cytogenetics yielded in 346 of 383 evaluable samples a concordant result. Differing results are given and account in part to the lower sensitivity of karyotyping. Taken together, confirmed RT-PCR detected BCR-ABL fusion transcripts consistently in 487 out of 1453 ALL samples (c-ALL: 43%, pre-B ALL: 34%, pro-B ALL: 5%, B-ALL: 0%, hybrid leukemia: 5/11). Since false positive initial RT-nested-PCR data were frequent, either confirmatory second RT-PCR or FISH analysis is warranted to guarantee sensitive and reliable results of utmost clinical relevance. [ABSTRACT FROM AUTHOR]

The reliability of routine BCR-ABL RT-nested-PCR was evaluated in 1453 B-lineage ALL or hybrid leukemia at initial diagnosis by RT-nested-PCR. All BCR-ABL-positive (n = 642) and 176 BCR-ABL-negative samples underwent a second RT-PCR. In 518 patients, karyotyping and/or FISH was compared to the BCR-ABL status. The second RT-PCR revealed in 155/642 initially positive samples a divergent result (153 BCR-ABL-negative, two other transcripts) that in most cases turned out to be caused by contaminations in the first RT-nested-PCR. Confirmatory RT-PCR detected 2/176 false negative first RT-nested-PCR results. Thirty-nine specimens remained ambiguous despite different RT-PCR approaches. As far as cytogenetic evaluation and FISH is available (n = 23), the majority but not all patients with an ambiguous RT-PCR result were Ph-negative (n = 18). RT-nested-PCR and cytogenetics yielded in 346 of 383 evaluable samples a concordant result. Differing results are given and account in part to the lower sensitivity of karyotyping. Taken together, confirmed RT-PCR detected BCR-ABL fusion transcripts consistently in 487 out of 1453 ALL samples (c-ALL: 43%, pre-B ALL: 34%, pro-B ALL: 5%, B-ALL: 0%, hybrid leukemia: 5/11). Since false positive initial RT-nested-PCR data were frequent, either confirmatory second RT-PCR or FISH analysis is warranted to guarantee sensitive and reliable results of utmost clinical relevance. [ABSTRACT FROM AUTHOR]

The medium-risk B cell precursor acute lymphoblastic leukemia (ALL) accounts for 50-60% of total childhood ALL and comprises the largest number of relapses still unpredictable with diagnostic criteria. To evaluate the prognostic impact of minimal residual disease (MRD) in this specific group, a case control study was performed in patients classified and treated as medium (or intermediate)-risk according to the criteria of national studies (ALL-BFM 90, DCLSG protocol ALL-8, AIEOP-ALL 91), which includes a good day 7 treatment response. Standardized polymerase chain reaction (PCR) analysis of patient-specific immunoglobulin and T cell receptor gene (TCR) rearrangements were used as targets for semi-quantitative estimation of MRD levels: > or =10(-2), 10(-3), < or =10(-4). Twenty-nine relapsing ALL patients were matched with the same number of controls by using white blood cell count (WBC), age, sex, and time in first complete remission, as matching factors. MRD was evaluated at time-point 1 (end of protocol Ia of induction treatment, ie 6 weeks from diagnosis) and time-point 2 (before consolidation treatment, ie 3 months from diagnosis). MRD-based high risk patients (> or =10(-3) at both time-points) were more frequently present in the relapsed cases than in controls (14 vs 2), while MRD-based low risk patients (MRD negative at both time-points) (1 vs 18) showed the opposite distribution. MRD-based high risk cases experienced a significantly higher relapse rate than all other patients, according to the estimated seven-fold increase in the odds of failure, and a much higher rate than MRD-based low risk patients (OR = 35.7; P= 0.003). Using the Cox model, the prediction of the relapse-free interval at 4 years was 44.7%, 76.4% and 97.7% according to the different MRD categories. MRD-based risk group classification demonstrate their clinical relevance within the medium-risk B cell precursor ALL which account for the largest number of unpredictable relapses, despite the current knowledge about clinical and biological characteristics at diagnosis. Therefore, MRD detection during the first 3 months of follow-up can provide the tools to target more intensive therapy to those patients at true risk of relapse. [ABSTRACT FROM AUTHOR]

The kappa deleting element (kappaDE) located 24 kb downstream of the Ckappa gene segment mediates the deletion of Ckappa and the Jkappa-Ckappa Intron enhancer, which results in allelic exclusion of the immunoglobulin kappa light chain locus. We here report that the kappaDE can recombine to each recombination signal sequence (RSS) flankappaing Jkappa1 to Jkappa5 in normal hematopoiesis. Moreover, usage of the JkappaRSS-kappaDE junctional sequence allows the detection of minimal residual disease in acute lymphoblastic leukemia. [ABSTRACT FROM AUTHOR]

The κ deleting element (κDE) located 24 kb downstream of the Cκ gene segment mediates the deletion of Cκ and the Jκ-Cκ Intron enhancer, which results in allelic exclusion of the immunoglobulin κ light chain locus. We here report that the κDE can recombine to each recombination signal sequence (RSS) flanking Jκ1 to Jκ5 in normal hematopoiesis. Moreover, usage of the JκRSS-κDE junctional sequence allows the detection of minimal residual disease in acute lymphoblastic leukemia. [ABSTRACT FROM AUTHOR]

We applied a new strategy for the detection of N-ras gene mutations based on LightCycler technology. We designed two sets of amplimers and internal hybridization probes representing N-ras codons 12/13 and codon 61, respectively. Genomic DNAs from 134 childhood acute lymphoblastic leukemia (ALL) patients (83 common ALL, nine pre-pre-B ALL, 19 pre-B ALL, 23 T-ALL) were amplified, followed by the analysis of the melting temperatures of the PCR products on the LightCycler. PCR products exhibiting an abnormal melting characteristic were directly sequenced. Sequence analyses unravelled nucleotide substitutions at codon 12 in 10 patients, at codon 13 in three, and at codon 61 in one case. The incidence of N-rasmutations (10%) is compatible with previous reports. The LightCycler technology facilitates the rapid analysis of other genes exhibiting hot spot mutations in human malignancies. [ABSTRACT FROM AUTHOR]

In certain situations it is preferable to perform small bowel examination using water-soluble contrast agents. Generally, ionic agents are used, but non-ionic agents may be an alternative in certain circumstances. We retrospectively reviewed a consecutive series of small bowel examinations using non-ionic media in order to determine their efficacy. A total of 52 water-soluble non-ionic small bowel follow-through examinations were performed in 42 patients using 100 ml iohexol. Indications for the study and the reasons why barium sulphate suspensions were contraindicated were established. Studies were assessed for radiographic quality and clinical findings were noted, and comparison was made with operative findings and clinical outcome. Obstruction was diagnosed in 12 examinations and the radiological findings were confirmed in all 7 patients surgically treated. Fistulae were identified in 11 examinations and the radiological findings were confirmed in all 8 patients who were treated by laparotomy. Additionally, at laparotomy no obstruction or fistula was found in the 5 patients in whom prior contrast examination had been negative. Non-ionic water-soluble follow-through examination is easily performed and well tolerated, allowing accurate diagnosis of obstruction and fistula when barium suspensions are contraindicated. [ABSTRACT FROM AUTHOR]

It is now widely accepted that the detection of minimal residual disease (MRD) has prognostic value in acute leukemia. However clinical MRD studies need standardized techniques. Therefore, several European laboratories have aligned their goals and performed comparative studies to achieve optimization and standardization of MRD techniques. This was achieved via the BIOMED-1 Concerted Action "Investigation of minimal residual disease in acute leukemia: International standardization and clinical evaluation." This report describes the development of PCR primers and protocols for the detection of MRD in acute lymphoblastic leukemia (ALL) using clone-specific junctional regions of immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets. A total of 54 primers was developed (1) to amplify rearrangements of the TCRD, TCRG, and IGK (Kde) genes as well as TAL1 deletions; (2) to sequence the junctional regions and breakpoint fusion regions; and (3) to perform MRD detection in bone marrow or peripheral blood samples during follow-up of ALL patients. Protocols were established to identify PCR targets at diagnosis by performing 25 PCR reactions per patient using appropriate positive and negative controls. Standardized protocols were developed for MRD monitoring via single amplification of the PCR target followed by dot blot hybridization with the corresponding patient-specific junctional region probe. In addition, alternative approaches were designed for cases where the target sensitivity of at least 10(-4) was not obtained. The standardization described here of MRD-PCR techniques is essential for the process of translating MRD research into clinical practice. [ABSTRACT FROM AUTHOR]

This paper describes the very rare occurrence of subacute sclerosing panencephalitis (SSPE) in two siblings: a Turkish boy and his younger sister. The clinical picture was characteristic, and the diagnosis was confirmed in both cases by appropriate laboratory examination. The interval between the occurrence of the first neurological symptoms in the boy, and subsequently in the girl was four years. Study of HLA- and 27 other polymorphic marker-systems did not reveal linkage to one of the systems tested. Therapeutic trials in the girl included intravenous and intraventricular application of a total of 87 X 10(6) U human fibroblast interferon (Hu INF-beta) over 21 days. However, up to 3 months after the end of interferon administration there were no significant changes in the girl's condition. [ABSTRACT FROM AUTHOR]

The plain abdominal radiograph is an important investigation in acute colitis, but may fail to demonstrate the state of the colon owing to a lack of intracolonic gas. The extent of the colitis can be demonstrated by introducing air directly into the large bowel; the air also provides sufficient contrast to distinguish a granular from an ulcerated mucosa. The 'air enema' may be used as an alternative to an unprepared barium enema. Its accuracy has been established by comparison with an unprepared barium enema in 10 patients with acute colitis. [ABSTRACT FROM AUTHOR]

Three cases of transient ischemic colitis are described in which the typical thumbprinting sign was obliterated by air insufflation during double-contrast barium enema examination. The causes of this sign, the possible mechanism of its loss during double-contrast enema, and implications of this are discussed. [ABSTRACT FROM AUTHOR]

Significant changes on a standard barium follow-through examination in celiac disease have been determined by comparison with functional changes (irritable bowel syndrome), malabsorption without a villous lesion (chronic pancreatitis), and a villous abnormality without malabsorption (dermatitis herpetiformis). Patients with iron deficiency anemia formed the control group. Slight jejunal dilatation (26-30 mm) was found in 15% of the celiacs and 17% of the irritable bowel patients. Dilatation in excess of 30 mm and/or effacement of jejunal fold pattern occurred only with an abnormal jejunal biopsy, in 54% of the celiacs and 33% of the dermatitis herpetiformis patients. Patients with malabsorption by itself and 46% of the celiacs could not be distinguished from those with irritable bowel syndrome. The concept of a malabsorption pattern is considered invalid, and the diagnosis of celiac disease can be reliably established only by peroral jejunal biopsy. [ABSTRACT FROM AUTHOR]

The value of dual-color fluorescence in situ hybridization (FISH) with BCR and ABL probes for the detection of the Philadelphia (Ph) translocation and of other alterations involving ABL and/or BCR was evaluated in adult acute lymphoblastic leukemia (ALL). One hundred and four patients were studied prospectively using interphase nuclei FISH, chromosome analysis (CA), and PCR assays for the chimeric BRC/ABL transcript. FISH detected a Ph translocation in 24 cases (23.1%), as was confirmed by CA and/or PCR. FISH revealed a false positive diagnosis of a Ph translocation in four cases (5% false positive rate). Among 54 cases with combined FISH, CA and PCR assays, FISH failed to establish a correct diagnosis in 3.7%, PCR in 5.6%, and CA in 7.4%. The combination of two screening methods led to discrepant results in 9.3% (FISH + PCR), 11.1% (FISH + CA), or 13% (CA + PCR) of the cases. In seven of 80 (8.8%) Ph-negative patients, gain of BCR and/or ABL was identified. Overall, FISH detected alterations of the BCR and/or ABL genes with an incidence of 29.8% of the current study. Due to the possibility of false positive diagnosis of a Ph translocation using dual-color FISH the combination with chromosome and/or RT-PCR analyses is recommended in adult ALL patients. [ABSTRACT FROM AUTHOR]

To gain a fuller understanding of the role of deletions of chromosome 9 in the development of childhood acute lymphoblastic leukemia (ALL), we performed detailed deletional mapping of chromosome 9 in 54 primary ALL samples with matched normal DNA using 22 highly polymorphic markers; and this information was combined with our previous data concerning the presence of deletions of CDKN2/INK4A/p16 and CDKN2B/INK4B/p15 in these samples. We have found a very high frequency of loss of heterozygosity (LOH) (31 of 54 cases (57%)) on chromosome arm 9p. As expected, the smallest region of LOH was between D9S1747 and D9S1748 at 9p21, including CDKN2/INK4A/p16, but excluding CDKN2B/INK4B/p15. Homozygous deletions at 9p21 occurred in 23 of 54 (43%) samples (seven of 11 (64%) T-ALL, 16 of 45 (36%) precursor-B ALL). We detected seven cases of homozygous deletions at 9p21 which had not been detected by Southern blot hybridization, showing the power of microsatellite analysis in detecting homozygous deletions. In most cases, homozygous deletions were limited to the region between D9S1747 and CDKN2B/INK4B/p15. We have attempted to determine the mechanism and timing of 9p deletions. Of the 23 samples with homozygous deletions at 9p21, 21 samples had surrounding large LOH. Of the 29 samples with LOH of 9p, homozygous deletion at 9p21 was identified in 22 cases. In addition, six patients have been studied at diagnosis and relapse, all six showed the same 9p21 structure at relapse (normal, three patients; hemizygous deletions, two patients; homozygous deletion, one patient) as their initial presentation. Finally, three patients (homozygous deletion, one patient; hemizygous deletion, two patients) had the IFN-alpha rather than CDKN2/INK4A/p16 deleted. In summary, these data further emphasize the importance of 9p21 loss in the development of childhood ALL. [ABSTRACT FROM AUTHOR]

Abnormalities of the short arm of chromosome 12 including loss of heterozygosity (LOH) and TEL/AML-1 fusion resulting from a t(12;21)(p13;q22) translocation are frequently observed in childhood acute lymphoblastic leukemia (ALL). We investigated 21 DNA samples of childhood ALL which had LOH at 12p13. Rearrangement of TEL was observed in eight cases and another case showed a homozygous deletion of TEL. Two informative samples with TEL rearrangement had a deletion localized to the 5' region of this gene. The deletion in these two cases includes the helix-loop-helix (HLH) domain. This is consistent with the hypothesis that the normal tel can heterodimerize with the TEL/AML-1 gene product and inhibit the transforming capacity of the chimeric protein. Presumably, loss of the HLH of the normal remaining TEL allele abrogates this tumor suppressor-like function. The case with homozygous deletion of TEL is also consistent with this gene having qualities of a tumor suppressor. One unusual case had T-ALL rather than B-lineage ALL and the leukemic cells had rearrangement of TEL, but they did not have an alteration of the remaining TEL allele suggesting that the etiology of this disease may be different. This analysis further emphasizes the importance of loss of the normal TEL allele in childhood precursor B-lineage ALL. [ABSTRACT FROM AUTHOR]

Background: This study aimed to document the radiological features and distribution of small bowel Crohn disease (CD) in adults by using a barium follow-through (BaFT) technique and to determine whether disease would be missed or its distribution underestimated if only colonoscopy with ileoscopy were performed.Methods: The BaFT examinations of 121 adults with proven CD were reviewed retrospectively with respect to the stage and distribution of disease. Colonoscopy with attempted ileoscopy was performed in 37 of these subjects, and the results were compared with radiological findings.Results: A normal villous pattern was visualized in 89 studies (74%). BaFT showed small bowel CD in 71 (59%) of 121 patients studied. The terminal ileum (TI) was the most common site of disease, affecting 62 (87%) of patients with small bowel CD. Forty-six patients (65%) had more proximal small bowel disease, including nine (13%) with a normal TI. BaFT showed early mucosal changes of CD in 52 subjects (73%), which was the sole manifestation in 15 (21%). Ileoscopy was possible in the majority of patients colonoscoped but was not achieved in 14 (38%), nine of whom had CD on BaFT. Of the 23 patients in whom ileoscopy was performed, findings agreed with BaFT assessment of the TI in 22.Conclusion: BaFT adequately demonstrates the stage and extent of small bowel CD. The majority of patients with small bowel CD have disease proximal to the TI, which cannot be diagnosed by ileoscopy. [ABSTRACT FROM AUTHOR]

Intra-anal intussusception was diagnosed in eight of 39 patients on evacuation proctography. Posteroanterior views revealed prolapse of the infolded rectum into the anal canal on staining in seven of eight patients, associated with splaying open of the anal canal and sudden distal movement of the fold during prolapse. Similar changes were seen in four of 31 patients in whom intussusception had not been diagnosed on lateral evacuation proctography. The pattern of the collapsed rectum was assessed for fold length, thickness, and angulation in relation to the midline of the rectum. Infoldings that prolapsed were closer to the anorectal junction on stress (mean 14.6: 42.4 mm, p < 0.0001) showed greater change in height between rest and strain (28.8: 14.6 mm, p < 0.05) and became more acutely angled during straining (41.9: 5.3 degrees, p < 0.01). Intra-anal intussusception may be missed in 33% (four of 12 patients) on routine evacuation proctography. Posteroanterior stress proctography is a simple supplementary examination to validate intussusception. [ABSTRACT FROM AUTHOR]

Copyright of International Journal of Colorectal Disease is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of International Journal of Colorectal Disease is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of International Journal of Colorectal Disease is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of International Journal of Colorectal Disease is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cocultivation of fibroblast cells from a male patient with Bloom syndrome (BS) and a female control reduced the rate of sister chromatid exchanges in the BS cells from a mean of 54 SCE per metaphase (range 42-65) to 41 (range 24-59). Medium used to culture control cells for 48 h also reduced the rate of SCE (from 40-65 to 33-54), whereas medium used for only 24h altered the SCE rate only slightly (to 39-61). Dialyzed medium concentrate with molecular cutoff at 15,000 did not alter the SCE rate. These initial studies suggest that normal cells produce an agent, presumably lacking in BS cells, that is capable of mitigating the chromosomal manifestation of the BS mutation ( bl) in bl/bl cells. [ABSTRACT FROM AUTHOR]

The effect of benzpyrene on sister chromatid exchange was determined in PHA-stimulated lymphocytes of 18 patients with lung cancer and 11 controls without cancer or bronchopulmonary diseases. Patients and controls did not differ either with respect to the spontaneous rate of sister chromatid exchanges or in their response to the carcinogen. We conclude that individual susceptibility to lung cancer cannot be detected by an individual response to benzpyrene, at least in lymphocytes and at the chromosomal level. [ABSTRACT FROM AUTHOR]

Copyright of Klinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Nine previously untreated patients with Philadelphia chromosome-positive chronic myelocytic leukemia (CML) were treated with recombinant interferon alpha 2a (rIFN-alpha 2a) and hydroxyurea. Patients received 6×10 U rIFN-alpha 2a daily for the first week and 3×10 U rIFN-alpha 2a daily for the second week. As maintenance treatment starting on day 15, patients received 3×10 U rIFN-alpha 2 a 3 times a week. Simultaneously, hydroxyurea was given, starting at a dose of 40 mg/kg on day one. The maintenance dosage was adjusted to the white blood cell count. Two patients responded with complete hematological remissions but without cytogenetic and molecular-genetic improvements. Seven patients responded with partial hematological remissions. Response to therapy was rapid; normal white blood cell counts were reached after a median of 12 days. The doses of rIFN-alpha 2a and hydroxyurea needed to keep the leucocyte count in the normal range were low (3×10 U rIFN-alpha 2a 3 times per week, 0.5-1.5 g hydroxyurea/day). Acute toxicity of the combination therapy consisted of fever (9 of 9 patients), flulike symptoms (7 of 9 patients), pruritus and/or rash (3 of 9 patients) and evidence of a tumor cell lysis syndrome (1 of 9 patients). The side effects were not dose-limiting. Combination therapy with rIFN-alpha 2a and hydroxyurea for CML is well tolerated and allows quick and effective hematological control of the disease. [ABSTRACT FROM AUTHOR]

Clinical and laboratory features of seven patients with acute leukemia associated with the (4; 11) chromosome translocation are presented. Leukemic blasts of these patients showed lymphoid morphology in 6 (although 1 was treated for monoblastic leukemia 3 years earlier) and monocytoid morphology in 1, were positive for TdT and HD 37 (CD 19) in 6 patients, whereas weak expression of CALLA was seen in only 1 patient and T-lineage-associated antigens in none. Leukemic blasts from four patients showed the simultaneous expression of B-lymphoid and myeloid antigens, suggesting leukemogenesis in a very early multipotent progenitor cell. In 2 patients an isochromosome of the long arm of No. 7 chromosome was found in the leukemic karyotypes in addition to t (4; 11) (q21; q23); in one instance present at diagnosis, in the other one occurring at relapse. In one other patient leukemia karyotype also demonstrated trisomy 8. Leukemic cells of three patients were investigated by molecular genetics and demonstrated immunoglobulin gene rearrangements for the Ig heavy chain sequences but not for the light chain constant regions and T cell receptor sequences. All patients were treated by intensive chemotherapy. Four of the 7 patients are in continuous complete remission. The longest event-free survival time (over 2 1/2 years) was seen in one patient who had also DOWN-syndrome. Including these 7 patients a clinical analysis of 71 patients with t (4; 11) acute leukemia was made, emphasizing the following characteristics at diagnosis: female sex (62%), age under 2 years (49%), leukocyte count over 100×10/1 (61%), splenomegaly (80%), CNS-disease (11%). Survival of over 2 years was reported in less than 15% of the patients. It remains to be seen if risk-adapted treatment can alter the course of this early B-precursor acute leukemia with hitherto very bad prognosis. [ABSTRACT FROM AUTHOR]

Acute nonlymphocytic leukemia (ANLL) was diagnosed in 18 patients based on morphological, cytochemical and immunological criteria. Leukemic cells of these cases were subjected to Southern blot analysis and subsequent hybridization to heavy chain immunoglobulin and T-cell-receptor gene probes. A rearrangement within the immunoglobulin joining region was detected in 2 cases, while the T-cell-receptor β-chain gene was in germline configuration in all samples investigated. These data confirm recent reports indicating that immunoglobulin heavy chain gene rearrangements are not restricted to B-lineage neoplasms. [ABSTRACT FROM AUTHOR]

We have studied four cases of fatal B-cell lymphoproliferative syndrome (LPS) developing among 333 patients (incidence 1.2%) treated with allogeneic bone marrow transplantion (BMT). All four patients had received a T-cell depleted graft. Onset of the first clinical symptoms (palpable lymph node enlargement in three and IgA-lambda paraproteinemia in two patients) occurred between 41 and 188 days post-BMT (median 76 days). The course of the LPS was rapidly progressive in all cases, leading to death in 2-5 weeks. The peripheral blood showed progressive pancytopenia with disproportionally high numbers of activated NK cells, apparently compensating for the T-cell deficiency. Post-mortem histological studies disclosed polymorphic B-cell proliferations, most pronounced in the lymph nodes, spleen, liver, lungs and kidneys. Lymphohemopoietic cells were of donor origin in three patients. In the fourth patient, graft failure suggested a host origin for the proliferating cells. Immunophenotyping and gene rearrangement analysis revealed polyclonal proliferation in one patient, monoclonal proliferation in another patient, and an oligoclonal pattern in the other two patients. The clinical behavior of the LPS was independent of clonality. Immunohistologically, the proliferating cells showed characteristics of relatively mature B-cells in three cases, and pre-B-cell features in one case. Epstein Barr virus (EBV) serology indicated seroconversion (primary infection) in one child, and chronic active EBV infection in both adults. EBV DNA as well as EBV nuclear antigen (EBNA) were detected in infiltrated tissues of all four patients. The labeling pattern on in situ hybridization suggested a replicative EBV infection comparable to that in lymphoblastoid cells lines. We conclude that EBV-associated LPS developing as a result of post-transplant immunodeficiency is a distinct clinicopathologic entity, differing from non-Hodgkin's lymphoma (including Burkitt's lymphoma) and infectious mononucleosis of the immunocompetent host. [ABSTRACT FROM AUTHOR]

Unlabelled: We report a 16-year-old girl who presented with anaemia, thrombocytopenia, leukocytosis and disseminated intravascular coagulation. Bone marrow analysis showed promyelocyte-like myeloblasts with rare Auer rods and very few granula. CD2 antigen was not expressed in bone marrow blasts. Karyotype analysis revealed a complex pattern of chromosomal aberrations without the promyelocytic leukaemia (PML) specific translocation t(15;17) (q22;q21). Southern blot analysis revealed a rearrangement of the retinoic acid receptor alpha (RAR alpha) locus. Reverse transcribed polymerase chain reaction assay confirmed the initial diagnosis of PML by amplification of the PML-specific PML/RAR alpha fusion transcript.Conclusion: This case report confirms that a characteristic translocation t(15;17) is not always detectable in PML blasts by karyotype analysis despite presence of specific PML/RAR alpha-transcripts. Together with careful morphological analysis of bone marrow blasts this assay apparently is the most specific and sensitive method to confirm the diagnosis. [ABSTRACT FROM AUTHOR]

We report a 16-year-old girl who presented with anaemia, thrombocytopenia, leukocytosis and disseminated intravascular coagulation. Bone marrow analysis showed promyelocyte-like myeloblasts with rare Auer rods and very few granula. CD2 antigen was not expressed in bone marrow blasts. Karyotype analysis revealed a complex pattern of chromosomal aberrations without the promyelocytic leukaemia (PML) specific translocation t(15;17) (q22;q21). Southern blot analysis revealed a rearrangement of the retinoic acid receptor alpha (RARα) locus. Reverse transcribed polymerase chain reaction assay confirmed the initial diagnosis of PML by amplification of the PML-specific PML/RARα fusion transcript. Conclusion: This case report confirms that a characteristic translocation t(15;17) is not always detectable in PML blasts by karyotype analysis despite presence of specific PML/RARα-transcripts. Together with careful morphological analysis of bone marrow blasts this assay apparently is the most specific and sensitive method to confirm the diagnosis. [ABSTRACT FROM AUTHOR]