Neoadjuvant chemotherapy with MRI monitoring for breast cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is increasingly being offered to patients with breast cancer. No survival benefit has been demonstrated for NACT, but it may serve to reduce tumour size and improve prognosis through the attainment of a pathological complete response (pCR). The role and mode of MRI monitoring during NACT remain unclear. METHODS: Patients managed with NACT at a UK centre over 7 years were studied using a prospectively maintained database, which also included details of MRI. Clinicopathological and radiological predictors of NACT response were analysed in a univariable setting and survival analysis was undertaken using the Kaplan-Meier method. RESULTS: A total of 278 patients underwent surgery following NACT, of whom 200 (71·9 per cent) had residual invasive disease and 78 (28·1 per cent) achieved a pCR. Attaining a pCR improved survival significantly compared with that of patients with residual invasive disease (mean 77·1 versus 66·0 months; P = 0·004) and resulted in significantly fewer recurrences (6·0 versus 24·3 per cent; P = 0·001). The pCR rate varied significantly among molecular subgroups of breast cancer (P < 0·001): luminal A, 6 per cent; luminal B/human epidermal growth factor 2 receptor (Her2)-negative, 21 per cent; luminal B/Her2-positive, 35 per cent, Her2-positive/non-luminal, 72 per cent; and triple-negative breast cancer (TNBC), 32 per cent. High-grade disease (G3) correlated with an increased rate of pCR. A radiological response seen on the mid-treatment MRI was predictive of pCR (sensitivity 77·6 per cent, but specificity only 53·3 per cent), as was complete radiological response at final MRI (specificity 97·6 per cent, but sensitivity only 32·2 per cent). CONCLUSION: NACT allows identification of patient subgroups within TNBC and Her2-positive cohorts with a good prognosis. MRI can be used to identify patients who are responding to treatment.

An initial experience using transanal vacuum therapy in pelvic anastomotic leakage.

BACKGROUND: Treatment of the presacral cavity that forms after contained anastomotic leakage of a low pelvic anastomosis is challenging and often results in a permanent stoma. Endosponge™ therapy is a minimally invasive method of treating the presacral cavity which potentially avoids a permanent stoma. We report our initial experience of using Endosponge™ therapy. METHODS: All patients who underwent Endosponge™ treatment for low pelvic anastomotic leakage in our hospital over a 45-month period were identified and data collected from clinical, operative and endoscopic notes. RESULTS: Eight patients (seven males, one female) underwent Endosponge™ therapy for extraperitoneal pelvic anastomotic leak during the study period; all had had defunctioning ileostomies placed at their original surgery. Six out of eight patients had complete closure or a reduction in the size of the abscess cavity. Five patients have had their ileostomies reversed with good or reasonable bowel function after a median follow-up of 41 months and four of these patients had Endosponge™ therapy instituted within 6 weeks of initial surgery. One patient had Endosponge™ therapy abandoned and conversion to a permanent end colostomy after accidental intraperitoneal placement of the sponge. CONCLUSIONS: Early use of Endosponge™ therapy appears to offer a minimally invasive and effective way of closing the presacral cavity after a pelvic anastomotic leak, reducing the risk of permanent stoma and resulting in acceptable bowel function. Endosponge™-specific complications can occur.

Allelic loss of chromosome 1p36 in neuroblastoma is of preferential maternal origin and correlates with N-myc amplification.

Neuroblastomas frequently have deletions of chromosome 1p and amplification of the N-myc oncogene. We analysed 53 neuroblastomas for the N-myc copy number, loss of heterozygosity (LOH) of chromosome 1p36 and the parental origin of the lost alleles. Allelic loss of 1p36 was found in 15 tumours. All N-myc amplified tumours belonged to this subset. In 13/15 tumours with LOH of 1p36 the lost allele was of maternal origin. This non-random distribution implies that the two alleles of the putative neuroblastoma suppressor gene on chromosome 1p36 are functionally different, depending on their parental origin. This is the first evidence as far as we know for genomic imprinting on chromosome 1p.

Left renal vein ligation: a technique to mitigate low portal flow from splenic vein siphon during liver transplantation.

Low portal vein flows in liver transplant have been associated with poor allograft survival. Identifying and ameliorating causes of inadequate portal flow is paramount. We describe successful reversal of significant splenic vein siphon from a spontaneous splenorenal shunt during liver transplant. The patient is a 43-year-old male with cirrhosis from hepatitis C and Budd-Chiari syndrome, who had a variceal hemorrhage necessitating an emergent splenorenal shunt with 8 mm PTFE graft. Imaging in 2006 revealed thrombosis of the splenorenal shunt and evidence of a new spontaneous splenorenal shunt. The patient developed hepatocellular carcinoma and underwent transplant in 2009. After reperfusion, portal flows were low (150-200 mL/min). A mesenteric varix was ligated without improvement. Due to adhesions, direct collateral ligation was not attempted. In order to redirect the splenic siphon, the left renal vein was stapled at its confluence with the inferior vena cava. Portal flows subsequently increased to 1.28 L/min. Postoperatively, the patient had stable renal and liver function. We conclude that spontaneous splenorenal shunts can cause low portal flows. A diligent search for shunts with understanding of flow patterns is critical; ligation or rerouting of splanchnic flow may be necessary to improve portal flows and allograft outcomes.

Imbalanced MHC class II molecule expression at surface of murine B cell lymphomas.

To study the role of class II MHC expression in mouse lymphomagenesis, we examined the cell surface expression of I-A/E antigens on 24 spontaneous or murine leukemia virus (MuLV)-induced mouse B10.A (I-Ak, I-Ek) B cell lymphomas. Two primary B10.A B cell lymphomas were observed with strong I-Ek expression but with only minimal cell surface I-Ak expression. Both tumors are readily transplantable in syngeneic mice, with maintenance of their I-A-, I-E+ phenotype. Strikingly, one I-A-, I-E+ B cell lymphoma contains a (11; 17) translocation with a breakpoint on chromosome 17 that is localized within or very close to the H-2 complex. DNA of both tumors contains normal restriction enzyme fragments of the A alpha and A beta genes. Northern blot analyses indicated that one I-A-, I-E+ tumor strongly expressed A alpha, E alpha, and E beta mRNAs but possessed only a weak expression of A beta mRNA. The other B cell lymphoma showed A beta, E alpha, and E beta mRNA expression but only minimal A alpha mRNA expression. In 11 primary B10.A B cell lymphomas with a normal I-A+, I-E+ phenotype, no imbalances in A alpha/A beta mRNA levels were observed. The implications of these findings for the role of class II MHC expression in mouse B cell lymphoma-genesis are discussed.

Role of vacuum assisted excision in minimising overtreatment of ductal atypias.

PURPOSE: B3 lesions are indeterminate lesions of uncertain malignant potential. They include lesions with and without epithelial atypia. Those with atypia include atypical intraductal epithelial proliferation (AIDEP)/atypical ductal hyperplasia (ADH) and flat epithelial atypia (FEA). They are traditionally managed with surgery. Vacuum assisted excision (VAE) allows larger samples to be obtained using a vacuum assisted biopsy (VAB) device, which equates to a surgical biopsy. We propose that VAE and mammographic surveillance is a safe alternative to surgery in managing the ductal atypias; (AIDEP/ADH and FEA). METHOD: Retrospective analysis of prospectively collected data on B3 lesions (April 2009 - March 2016) from consecutive breast screening patients diagnosed with AIDEP/ADH or FEA on initial diagnostic core biopsy. Mammographic abnormality, breast density, size, management pathway and upgrade to cancer and types of cancer were also collected during the treatment pathway and 5 year surveillance period (April 2009 - April 2019). RESULTS: 273 cases of ductal atypia were identified. 187/273 (68.5 %) cases were managed with VAE only as no upgrade to malignancy and then 5 year mammographic surveillance. 34/273 (12.5 %) cases had a VAE diagnosing malignancy. 24/273 (8.8 %) cases had a VAE and then a surgical biopsy due to radiological or pathological concern, 8/24 upgraded to malignancy. 22/273 (8%) cases had a surgical diagnostic biopsy, 9/22 (41 %) cases were upgraded to malignancy. In total 51/273 (19 %) cases were diagnosed with cancer on the new pathway (13 invasive (all ER positive and Her2 negative) and 38 non-invasive, (34 ductal carcinoma in situ (DCIS) and 4 cases of lobular carcinoma in situ (LCIS)). While 17/273 (6.2 %) cases developed malignancy (12 invasive (all HER2 negative) and 4 DCIS and 1 LCIS) during the 5 year surveillance period. CONCLUSIONS: VAE is a safe alternative to surgery in managing ductal atypias. 187/273 (68.5 %) women avoided surgery. While 34/51 cancers (66.7 %) were diagnosed preoperatively using VAE, allowing the women to have a single therapeutic procedure.

Experiencia de cuerpos extraños en vía aérea en el Hospital Clínico UC / The experience of foreign bodies in the airway in the Hospital Clínico UC

Introducción: El cuerpo extraño en vía aérea es una patología infrecuente en el área Otorrinolaringológica, siendo la primera causa de muerte accidental de la especialidad. La alta sospecha clínica es fundamental para lograr un diagnóstico precoz. El Hospital Clínico de la Universidad Católica es un centro de referencia a nivel nacional para el manejo de esta patología. Objetivo: Realizar una descripción epidemiológica de los pacientes con diagnóstico de cuerpo extraño en vía aérea sometidos a revisión de vía aérea de los pacientes atendidos en el Hospital Clínico de la Universidad Católica entre los años 2018-2021. Material y Método: Estudio retrospectivo y descriptivo. Se revisaron las fichas clínicas de pacientes con revisión de vía aérea realizada entre junio 2018 y julio 2021. Estudio cuenta con la aprobación del comité de ética de nuestro hospital. Resultados: Se incluyó un total de 13 pacientes con diagnóstico de cuerpo extraño en vía aérea. 62% de los pacientes fueron de sexo masculino. Rango de edad entre 0 y 11 años, mediana de edad de 1 año. El 100% de los pacientes presentó algún síntoma respiratorio y un 90% presentó síndrome de penetración. El cuerpo extraño se evidenció en el 30% de las radiografías. El 100% de las revisiones de vía aérea se hizo con ventilación espontánea. El 70% se localizó en los bronquios. No hubo mortalidad asociada al procedimiento. Conclusión: Las cifras encontradas en nuestro estudio fueron similares a las reportadas en las diferentes series a nivel internacional.

Introduction: Foreign body in the airway is a rare condition in the Otorhinolaryngology field, being the leading cause of accidental death in the specialty. High clinical suspicion is crucial for achieving an early diagnosis. The Hospital Clínico de la Universidad Católica is a national reference center for the management of this condition. Aim: To provide an epidemiological description of patients diagnosed with foreign bodies in the airway who underwent airway review at the Hospital Clínico de la Universidad Católica between the years 2018-2021. Materials and Method: A retrospective and descriptive study. Clinical records of patients who underwent airway review between June 2018 and July 2021 were reviewed. The study has received approval from our hospital's ethics committee. Results: A total of 13 patients with a diagnosis of foreign bodies in the airway were included. 62% of the patients were male. The age ranged from 0 to 11 years, with a median age of 1 year. 100% of the patients presented respiratory symptoms, and 90% presented with a penetration syndrome. The foreign body was evident in 30% of the X-rays. All airway reviews were conducted with spontaneous ventilation. 70% of the foreign bodies were located in the bronchi. There was no mortality associated with the procedure. Conclusion: The findings in our study were similar to those reported in various international series.

Reduction of digital plantar pressure by debridement and silicone orthosis.

The lesser digits are frequent sites of elevated plantar pressure and ulceration in the diabetic foot. We sought to determine whether debridement of callus and the wearing of a custom molded digital orthosis could significantly reduce digital plantar pressure. Fourteen patients with distal digital callus were studied. For each patient, the toe with the highest plantar pressure was selected. A computerized pressure mat was used to record the plantar pressure before and after debridement with and without a moldable silicone digital orthosis. Mean peak plantar digital pressures before treatment were 2.80+/-0.7 kg/cm2 for the entire group. The digital orthosis alone reduced plantar pressure to a mean of 1.95+/-0.65 kg/cm2 p < 0.05. Treatment by debridement similarly reduced pressure to 1.99+/-0.76 kg/cm2 p < 0.05. The most effective reduction of pressure for all patients, as well as the most statistically significant, occurred when both treatments were given, with mean peak plantar pressure falling to 1.28+/-0.61 kg/cm2 p < 0.01. Debridement and custom molded digital orthoses alleviate distal digital plantar pressure. Since elevated plantar pressure increases the risk of neuropathic ulceration, these treatments should be considered in the prophylactic care of appropriate patients.

Loss of heterozygosity in Wilms' tumors, studied for six putative tumor suppressor regions, is limited to chromosome 11.

Studies on the loss of heterozygosity (LOH) in human malignancies have shown that a number of different chromosomal regions associated with putative tumor suppressor genes may be involved in any one given tumor. We have carried out a similar study on Wilms' tumor using a range of DNA markers for a number of tumor suppressor regions. We tested a total of 44 Wilms' tumors including material from bilateral cases and from patients with Beckwith-Wiedemann syndrome, Drash syndrome, Perlman syndrome, and hemihypertrophy. In 11 of 36 informative tumors we found LOH for markers for the short arm of chromosome 11; only one of these tumors had additional LOH for regions 5q and 17p. No LOH was found for regions 3p, 13q, and 22q. Thus our findings support a major role for chromosome 11p in Wilms' tumor development and apparent noninvolvement of other tumor suppressor genes. No correlation was found between allelic losses and the International Society of Paediatric Oncology tumor stage or histology.

Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13).

Recently, we and others reported a recurrent t(7;12)(q36;p13) found in myeloid malignancies in children < or =18 months of age and associated with a poor prognosis. Fluorescence in situ hybridization studies mapped the 12p13 breakpoint to the first intron of ETV6 and narrowed down the region of 7q36 involved. By using the sequences made public recently by the Human Genome Project, two candidate genes in 7q36 were identified: the homeobox gene HLXB9 and c7orf3, a gene with unknown function. Reverse transcription-PCR of two cases with t(7;12), using primers for c7orf3 and ETV6, was negative. However, reverse transcription-PCR for HLXB9-ETV6 demonstrated alternative splicing; the two major bands corresponded to fusion of exon 1 of HLXB9 to exons 2 and 3, respectively, of ETV6. The reciprocal ETV6-HLXB9 transcript was not detected. It remains to be elucidated if the leukemic phenotype is attributable to the formation of the HLXB9-ETV6 fusion protein, which includes the helix-loop-helix and E26 transformation-specific DNA binding domains of ETV6 or to the disruption of the normal ETV6 protein.

Isochromosome 12p-positive pineal germ cell tumor.

We report the chromosomal characteristics of a recurrent pineal non-seminomatous germ cell tumor in a 16-year-old male patient. This non-seminomatous tumor had the following components: embryonal carcinoma, teratoma, yolk sac tumor, and trophoblastic giant cells. Chromosome analysis showed a near-triploid karyotype (64 chromosomes), including two copies of an isochromosome 12p. This latter finding could be confirmed using 12p-specific competitive in situ hybridization techniques applied to cultured cells (T2219-P6 cell line) derived from the tumor. The present findings are in keeping with the hypothesis that isochromosome 12p formation is associated with the development of malignant extragonadal germ cell tumors.

Human chromosome 21 determines growth factor dependence in human/mouse B-cell hybridomas.

Interleukin 6 (IL-6) serves as a growth factor for mouse plasmacytomas. As a model for IL-6-mediated growth of plasmacytomas, we study IL-6-dependent B-cell hybridomas, which can be generated through fusion of B lymphocytes with a plasmacytoma cell line, e.g., SP2/0. In the present report, we have investigated the peculiar behavior of B-cell hybridomas with respect to IL-6 dependence. We demonstrate that although newly generated hybridomas are IL-6 dependent, many hybridomas lose this dependency at frequencies as high as 50%, shortly after fusion. We speculated that the loss of IL-6-dependent growth is due to the well-known chromosomal instability of B-cell hybridomas. Consequently, loss of IL-6 dependence is the result of loss of a specific chromosome(s). This model implies the existence of an "IL-6 dependency" gene, the loss of which makes hybridomas capable of proliferating in the absence of IL-6. Because SP2/0 is IL-6 independent, the IL-6-dependent phenotype of B-cell hybridomas, and hence the IL-6 dependency gene, must be derived from the B lymphocyte. We have tested this model by generating human/mouse B-cell hybridomas through fusion of human B lymphocytes with SP2/0. We then analyzed the human chromosome content of 10 IL-6-dependent and 14 IL-6-independent subclones. From that analysis we concluded that the presence of human chromosome 21 correlated with IL-6 dependence. This correlation was confirmed by microcell fusion experiments in which a single copy of chromosome 21 was introduced into IL-6-independent hybridomas, resulting in reconstitution of the IL-6-dependent phenotype. We therefore conclude that chromosome 21 carries an IL-6 dependency gene.

Outcome of a new patient pathway for managing B3 breast lesions by vacuum-assisted biopsy: time to change current UK practice?

AIMS: B3 lesions of the breast represent a difficult management dilemma. The umbrella term 'B3' incorporates lesions with little associated malignancy risk as well as lesions with significant risk of concurrent neoplasia. Diagnosis of B3 lesions in screening populations is largely made on needle core biopsy, which provides little tissue to adequately diagnose pathologically diverse lesions. The advent of vacuum-assisted biopsy (VAB) provides the multidisciplinary team with a more representative pathology sample to direct management. METHODS: In this unit, in 2009, a pathway to guide management of B3 lesions detected on needle core biopsy in screening patients was implemented to assess whether VAB was a safe and viable alternative to surgery in selected cases.Here we present the 5-year follow-up results of this pathway. RESULTS: 398 patients with B3 lesions were suitable for this pathway, of which 321 went on to have second-line VAB. 24% of these patients subsequently required surgery for malignancy or ongoing concerns, and thus 245 avoided surgery being subsequently referred for 5-year mammographic surveillance or back to screening. Median follow-up was 3 years (IQR 2), and no cancers were detected at the original B3 site during follow-up. CONCLUSIONS: We have demonstrated here that with large volume tissue sampling for indeterminate lesions of the breast surgery can be safely avoided in selected B3 lesions with and without atypia.

Promoter transgenics reveal multiple gonadotropin-releasing hormone-I-expressing cell populations of different embryological origin in mouse brain.

Gonadotropin-releasing hormone-I (GnRH-I) is thought to be expressed by a single, highly spatially restricted group of neurons, which originate in the olfactory placode and migrate through the nose into the medial septum and hypothalamus from where they control fertility. Transgenic mice bearing a 13.5 kb GnRH-I-lacZ reporter construct were derived and found to express high levels of beta-galactosidase mRNA and protein within the septohypothalamic GnRH neurons in a correct temporal and spatial manner. Unexpectedly, low levels of beta-galactosidase were also present in three further populations of cells within the lateral septum, bed nucleus of the stria terminalis, and tectum. Analysis of wild-type mice with three different GnRH-I antibodies revealed distinct and transient patterns of GnRH-I peptide expression during development in all three of these populations revealed by transgenics. The synthesis of GnRH by cells of the lateral septum was the most persistent and remained until the third postnatal week. Embryonic "small eye" Pax-6 null mice, which fail to develop an olfactory placode, were also examined and shown to have equivalent populations of GnRH-I-immunoreactive cells in the lateral septum, tectum, and bed nucleus of the stria terminalis but none of the migrating cells that form the septohypothalamic GnRH population. These results prove that so-called "ectopic" expression in promoter transgenic lines can reflect authentic developmental patterns of gene expression. They further provide the first demonstration in mammalian brain that multiple neuronal populations of different embryological origin express GnRH-I peptide during embryonic and postnatal development.

Human acute myeloid leukemia cells with internal tandem duplications in the Flt3 gene show reduced proliferative ability in stroma supported long-term cultures.

Recently, in-frame internal tandem duplications have been reported within the regions coding for the juxtamembrane through the first tyrosine kinase domain of the Flt3 gene. These duplications have been reported to lead to autophosphorylation of the receptor. In this study we investigated the effect of such mutations in the Flt3 gene on the in vitro proliferation of human acute myeloid leukemia cells. The mutations were detected in 10 out of 59 AML bone marrow samples analyzed and were not restricted to a specific FAB class or cytogenetic aberration. PCR analysis of those samples showed all mutations to be present in exon 11 of the gene. Whilst samples without a mutation of the Flt3 gene showed an increased cell production in response to either IL-3 and G-CSF or IL-6, SCF, TPO and Flt3L in long-term stroma supported cultures, mutant samples failed to do so. As we could not find a relationship between the absence of a response and either FAB class or cytogenetic aberrations, we interpret these results as an indication that the internal tandem duplications in the Flt3 gene are the prime cause of this unresponsiveness. Although our study does not explain the mechanism by which these mutations cause this unresponsiveness it does suggest that AML cells need a wild-type Flt3 for optimal in vitro proliferation.

Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants.

This paper reports clinical and cytogenetic data from 125 cases with t(9;11)(p21-22;q32) which were accepted for a European Union Concerted Action Workshop on 11q23. This chromosome abnormality is known to occur predominantly in acute myeloid leukemia (AML) FAB type M5a and less often in AML M4; in this series it was also found to occur, uncommonly, in other AML FAB types, in childhood acute lymphoblastic leukemia (ALL) (nine cases), in relatively young patients with myelodysplastic syndrome (MDS) (five cases), acute biphenotypic leukemia (two cases), and acute undifferentiated leukemia (one case). All age groups were represented but 50% of the patients were aged less than 15 years. The t(9;11) was the sole abnormality in 57 cases with AML; trisomy 8 was the most common additional abnormality (23 cases, including seven with further abnormalities), and 28 cases had other additional abnormalities. Among the t(9;11)+ve patients with AML, the white cell count (WBC) and age group were significant predictors of event-free survival; central nervous system (CNS) involvement or karyotype class (sole, with trisomy 8, or with other), also contributed to prognosis although our data could not show these to be independent factors. The best outcome was for patients aged 1-9 years, with low WBC, and with absence of CNS disease or presence of trisomy 8. For patients aged less than 15 years, the event-free survival for ALL patients was not significantly worse than that of AML patients.

A non-random chromosome abnormality found in precursor-B lineage acute lymphoblastic leukaemia: dic(9;20)(p1?3;q11).

A comparison of cytogenetical data on acute lymphoblastic leukaemia studied at four large European centres has revealed a non-random dicentric chromosome abnormality: dic(9;20) (p1?3;q11) in 10 patients, nine of whom were children. All had early precursor-B lineage ALL, and eight children had a non-standard risk clinical presentation. The origin of the dicentric chromosome was demonstrated using a range of chromosome banding techniques. This was confirmed by FISH using paints and centromeric probes for chromosomes 9 and 20, together with a number of cosmid probes. The follow-up time of these patients is presently too short and the number of patients too few to determine the prognostic significant of this chromosome abnormality.

Long-term follow-up of Dutch Childhood Leukemia Study Group (DCLSG) protocols for children with acute lymphoblastic leukemia, 1984-1991.

Here we report the long-term results of the DCLSG protocols ALL-6 and -7 with special emphasis on the incidence of CNS relapse after treatment without cranial irradiation. In DCLSG protocol ALL-6 (1984-1988), designed for patients with ALL non-high risk (ALL-NHR) (WBC <50 x 10(9)/l, no mediastinal mass, no B cell phenotype and no CNS involvement at diagnosis, comprising 71% of all ALL patients), CNS prophylaxis consisted of a combination of three methods of chemotherapeutic CNS prophylaxis (the use of dexamethasone during induction and maintenance therapy, i.v. medium dose methotrexate and prolonged administration of intrathecal triple therapy). Total duration of treatment: 116 weeks. 190 patients were enrolled in the study. At 10 years, the EFS rate for all patients is 81.5 +/- 2.8%, the survival rate 84.8 +/- 2.7%, and the cumulative incidence of isolated CNS relapse 1.1 +/- 0.8%. The 10-year survival rate for the 139/190 (73.1%) patients with standard risk non-T lineage ALL according to the NCI risk criteria is 80.5 +/- 3.4%. DCLSG protocol-7 was identical to the intensive ALL-BFM-86 protocol, but cranial irradiation was restricted to patients with initial CNS involvement. Patients were stratified into three risk groups (SRG, RG and EG). Treatment duration was 18 months. 218 patients were enrolled in the study. At 10 years, the EFS rate for all patients is 63.4 +/- 3.3%, the survival rate 76.4 +/- 3.0%, the 5-year cumulative incidence of isolated CNS relapse 5.7 +/- 1.8%. The EFS rate at 10 years of the 127/218 (58.3%) patients with standard risk non-T-lineage ALL according to the NCI risk criteria was 67.9 +/- 4.3%, which is not significantly different from the results achieved in this category of patients with the moderately intensive treatment according to protocol ALL-6 (logrank P = 0.17). These DCLSG studies indicate that omission of cranial irradiation does not jeopardize the overall good results.

Characterization of the blast cells in acute leukemia with translocation (4;11): report of eight additional cases and of one case with a variant translocation.

Eight new cases (five adults and three children) of acute leukemia characterized by the presence in bone marrow cells of a t(4;11)(q21;q23)and one similar case, a child, with a t(1;11)(p32;q23) are reported. All patients were diagnosed as having acute lymphoblastic leukemia (ALL) with high-risk features. Immunologically the blast cells of the nine cases showed a strikingly consistent immature lymphoid phenotype, i.e., TdT+, HLA-DR+, B4(CD19)+, CALLA(CD10)-, Smlg-, cmu-, BA-2(CD9)+ corresponding to a "null ALL." In addition, six of nine cases expressed the myeloid marker VIM-D5(CD15). By double immunofluorescence staining it was determined that the VIM-D5(CD15) antigen was expressed by terminal deoxynucleotidyl transferase-positive blast cells, excluding the possibility of double leukemia. In five cases investigation of the Ig heavy chain genes by Southern blot analysis showed clonal rearrangement of both Ig heavy chain gene alleles. These data suggest that the blast cells involved in t(4;11) leukemia represent early B-cell progenitors with "aberrant" expression of myelomonocytic features, possibly related to the 11q23 breakpoint.

Rapid and sensitive detection of all types of MLL gene translocations with a single FISH probe set.

The MLL gene on chromosome 11 band q23 is frequently involved in chromosome translocations in acute lymphoblastic leukemia and acute myeloid leukemia. The translocation results in the formation of a fusion gene on the derivative 11 chromosome consisting of the 5' part of the MLL gene and the 3' part of another gene; already more than 30 different partner chromosome regions have been described. MLL gene rearrangements are generally correlated with a poor prognosis. Therefore the presence of an 11q23 aberration has direct implications for treatment stratification, making early and rapid detection of utmost importance. In this study, we developed a FISH probe set for detection of MLL gene rearrangements according to strict design criteria. The cosmid probes are derived from the flanking regions of the MLL breakpoint region on chromosome 11 and when used in dual colored FISH experiments give rise to a split of the normally colocalizing (fused) signals in case of a translocation. This split signal was observed in seven out of 10 cases with an 11q23 translocation with various partner chromosomes. In the three other cases, a deletion of the 3' part of the MLL gene, downstream of the breakpoint region was also found. A low false positive value of only 1.7% was obtained for interphase cells in contrast to conventional dual colored FISH where the creation of a fusion signal has cut off values of at least 5-10%. A major advantage of our type of probe set is the application of a single FISH experiment to detect all types of MLL translocations. Moreover, since this cosmid probe set can be used for either interphase or metaphase studies, metaphases are no longer a prerequisite for detecting the presence of an 11q23 translocation. Nevertheless, metaphase FISH with the new probe set is helpful in determining the partner chromosome and therefore may lead to the identification of new partner genes.