[Conventional intubation and laryngeal tube in cervical spine instability : Changes in the width of the dural sac in unfixed human body donors]. / Konventionelle Intubation und Larynxtubus bei Halswirbelsäuleninstabilität : Änderungen der Duralsackweite am unfixierten humanen Körperspender.

BACKGROUND: Airway management in patients with an unstable cervical spine requires a cautious approach if secondary damage is to be prevented but the question regarding the optimum method remains unresolved. The primary aim of the study was to investigate whether there were differences between intubation by conventional Macintosh laryngoscopy and placement of a laryngeal tube (LTS-D) with respect to dural sac compression on an unfixed human cadaver model with unstable injuries of the upper cervical spine. Secondary parameters that could be relevant in patients with unstable spinal injuries were also investigated. MATERIAL AND METHODS: Orotracheal intubation by conventional direct laryngoscopy using a Macintosh blade and placement of a laryngeal tube (LTS-D) were performed in six fresh human cadavers. The dural sac was filled with contrast dye to allow continuous myelography by lateral fluoroscopy. Changes in the width of the dural sac at the cervical segments (C) C0/C1 and the C1/C2 levels as well as secondary parameters (angulation, distraction, intervention time) were assessed in the intact spine as well as in the presence of combined atlanto-occipital dislocation and atlanto-axial instability. The intubation methods were considered independent and examined using the Mann-Whitney U­test. RESULTS: At the C0/C1 level in the intact spine, conventional laryngoscopy caused less reduction of the width of the dural sac than placement of the LTS-D (0.33 mm vs. 0.46 mm, p = 0.035); however, in the presence of combined atlanto-occipital dislocation and atlanto-axial instability, placement of the LTS-D caused less reduction in the width of the dural sac than conventional intubation (1.18 mm vs. 0.68 mm, p = 0.005). At the C1/C2 level no differences were found with respect to changes in the width of the dural sac, neither in the intact spine nor in combined atlanto-occipital dislocation and atlanto-axial instability. Conventional intubation caused more angulation than placement of the LTS-D at both levels measured. Both methods did not cause distraction. The intervention times for placement of the laryngeal tube were shorter. CONCLUSION: In an unfixed human cadaver model with combined atlanto-occipital dislocation and atlanto-axial instability, placement of the LTS-D caused less reduction in the width of the dural sac than conventional intubation at the level of the craniocervical junction. The LTS-D also caused less angulation and could be placed faster. It could therefore also be advantageous over conventional intubation in living patients with an unstable cervical spine.

Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier.

A tumor cell line, HCC1937, was established from a primary breast carcinoma from a 24-year-old patient with a germ-line BRCA1 mutation. A corresponding B-lymphoblastoid cell line was established from the patient's peripheral blood lymphocytes. BRCA1 analysis revealed that the tumor cell line is homozygous for the BRCA1 5382insC mutation, whereas the patient's lymphocyte DNA is heterozygous for the same mutation, as are at least two other family members' lymphocyte DNA. The tumor cell line is marked by multiple additional genetic changes including a high degree of aneuploidy, an acquired mutation of TP53 with wild-type allele loss, an acquired homozygous deletion of the PTEN gene, and loss of heterozygosity at multiple loci known to be involved in the pathogenesis of breast cancer. Comparison of the primary tumor with the cell line revealed the same BRCA1 mutation and an identical pattern of allele loss at multiple loci, indicating that the cell line had maintained many of the properties of the original tumor. This breast tumor-derived cell line may provide a useful model system for the study of familial breast cancer pathogenesis and for elucidating BRCA1 function and localization.

Genetic epidemiology of familial aggregation of cancer.

Literature pertaining to genetic epidemiological studies of familial cancer has been reviewed from a historical perspective. Although interest in the question of heritability of cancer was extant at least as early as the beginning of the nineteenth century, early investigators were unable to produce consistent and meaningful evidence pertaining to the issue because of unsystematic methods of data collection and inadequate methods of data analysis. During the early twentieth century, developments in the fields of genetics, statistics, and epidemiology provided concepts and methods that permitted investigators to recognize important deficiencies in past studies, and to design others in which the critical comparisons could be made between patient groups and control groups. Registries of cancer incidence in large populations became available in several countries in the middle twentieth century, providing a standard "control group" for comparison. Large surveys of site-specific cancer experience in families, rigorously designed and analyzed, found for most kinds of cancers a two- to threefold increased risk for close relatives of propositi. These studies also reemphasized the great difficulty in obtaining even minimally complete family health history information, and the importance of verifying all reported cases with medical or vital records. Although clinical and laboratory investigation will be necessary to understand the mechanisms by which human genes may predispose to cancer, epidemiological approaches can estimate the extent to which genetic etiological factors may be present in a population, whether a general population or one defined by other factors under investigation. Population-based studies are already of practical significance to the clinical geneticist in the estimation of risk of eventual cancer development in unaffected family members, and can be expected to continue to identify specific groups and characteristics associated with genetic cancer predisposition. Finally, segregation and linkage analysis and their present applications to family studies of cancer were reviewed. As a result of the increasing number of DNA polymorphisms that are becoming available due to developments in molecular biology, the human gene map can be expected to be well defined in the near future, and investigation of families using segregation and linkage analysis will then be instrumental in defining the role of heredity in the development of cancer in human populations.

Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide.

PURPOSE: To describe the occurrence of secondary acute myeloid leukemia (AML) in children with acute lymphoblastic leukemia (ALL) treated with etoposide (VP-16). PATIENTS AND METHODS: Two hundred five consecutive children with early B-lineage ALL were treated according to the Dallas/Fort Worth (DFW) protocol between January 1986 and July 1, 1991. Therapy included a four-drug induction followed by consolidation and continuation phases of nightly oral mercaptopurine (6-MP) and repetitive courses of divided-dose oral methotrexate (dMTX) and asparaginase (L-asp). Three doses of VP-16 and cytarabine (Ara-C) were given during consolidation and later, during continuation, two doses were given 3 to 4 days apart, every 9 weeks. Intrathecal (IT) chemotherapy was given throughout the treatment period. RESULTS: Two hundred three of the 205 patients entered remission. Only eight of these 203 children have had a bone marrow relapse (ALL). However, 10 other children have developed secondary AML 23 to 68 months following the diagnosis of ALL. Overall event-free survival (EFS) at 4 years is 79.3% +/- 5.1%, with a risk of secondary AML at 4 years of 5.9% +/- 3.2%. CONCLUSION: This experience provides strong evidence for a link between epipodophyllotoxin therapy and secondary AML since none of these children received alkylating agent therapy or irradiation. This serious complication raises concern as to the appropriate use of epipodophyllotoxins in the treatment of childhood ALL.

Childhood acute lymphoblastic leukemia with both t(1;19) and t(9;22).

The chromosomal rearrangements t(1;19)(q23;p13.3) and t(9;22) (q34;q11.2) are independent abnormalities commonly observed in the blast cells of children with acute lymphoblastic leukemia (ALL). We report three children whose leukemic cells contained both translocations at diagnosis. The patients, two males aged 3 and 8 years and a female aged 14 years, all presented with central nervous system involvement. One patient exhibited a pre-B leukemic phenotype (cytoplasmic immunoglobulin, cIg, positive), while two had an early pre-B phenotype (cIg negative). All three patients received radiotherapy and multiagent chemotherapy which included an epipodophyllotoxin in two patients. Two patients suffered relapses of ALL, in both cases with disappearance of t(1;19)-containing clones but persistence of t(9;22). The two patients who received an epipodophyllotoxin as part of their chemotherapeutic regimen both developed secondary myeloid leukemia with entirely new cytogenetic findings, including abnormalities of chromosome band 11q23. These patients are the first to be described with this unusual combination of cytogenetic abnormalities.

Suprasellar germinoma. Unresolved problems in diagnosis, pathogenesis, and management.

A suprasellar germinoma, initially thought to be granulomatous diencephalitis of uncertain cause, responded following chloramphenicol and methicillin treatment both by clinical and radiographic criteria and was not diagnosed until a third biopsy was performed. Analysis of this case and review of the literature lead to the conclusion that adequate diagnostic workup of such lesions requires that biopsy be extensive enough to include the central core as well as the granulomatous reaction that surrounds such tumors. Furthermore, since the degree of inflammation may fluctuate, regression does not mean that the lesion is not neoplastic in origin. In the present instance, the correct diagnosis could have been made earlier if the beta-chain of human chorionic gonadotropin had been measured in spinal fluid.

In situ hybridization shows direct evidence of skewed X inactivation in one of monozygotic twin females manifesting Duchenne muscular dystrophy.

A novel combination of conventional and molecular cytogenetic techniques was used to investigate the expression of an X-linked recessive disorder in one of monozygotic (MZ) twin females. These twins carry a deletion, approximately 300 kb in length, in one of their X chromosomes within the dystrophin gene, which is responsible for Duchenne muscular dystrophy (DMD) in one twin [Richards et al.: Am J Hum Genet 46:672-681, 1990]. A unique DNA fragment generated from an exon within this gene deletion was hybridized in situ to both twins' metaphase chromosomes, a probe which would presumably hybridize only to the normal X chromosome and not to the X chromosome carrying the gene deletion. Chromosomes were identified by reverse-banding (R-banding) and by the addition of 5-bromodeoxyuridine (BrdU) in culture to distinguish early and late replicating X chromosomes, corresponding to active and inactive X chromosomes, respectively. Hybridization experiments showed predominant inactivation of the normal X chromosome in the twin with DMD. This is the first report showing direct evidence at the chromosome level of unequal inactivation of cytogenetically normal X chromosomes resulting in the manifestation of an X-linked recessive disorder in one of monozygotic twin females. This study may now facilitate other research of unequal X inactivation and of females manifesting X-linked recessive disorders.

Three cases of dup(10p)/del(10q) syndrome resulting from maternal pericentric inversion.

Two families and 3 patients with dup(10p)/del(10q) syndrome segregating from a maternal pericentric inversion are described, including a stillborn female with Potter sequence and multicystic renal dysplasia. Comparison of 32 dup(10p) patients to 11 del(10)(q25) patients emphasized dolichocephaly, wide sutures, frontal bossing, micrognathia, and renal defects as distinguishing characteristics of the dup(10p) syndrome. The 3 new and 6 previously reported dup(10p)/del(10q) patients had several manifestations in common with the dup(10p) and del(10q) syndromes, but were more typical of dup(10p) syndrome with respect to all 5 distinguishing characters.

Balanced translocation 12/13 and situs abnormalities: homology of early pattern formation in man and lower organisms?

Studies in "lower" organisms have identified a set of homologous sequences expressed in oocytes and early embryos that is critical for pattern formation. Mutations in such genes may exhibit maternal effect--they cause abnormalities in the fetus only when present in the mother. We report on a mother and child with identical, apparently balanced translocations having the breakpoints 12q13.1 and 13p13. The fetus had multiple anomalies including bilateral trilobar lungs, complex heart defect, malrotation of the gut, and asplenia, while the mother was entirely normal. Several hypotheses are advanced to explain this variable expression including transection of a gene with maternal effect--lateral asymmetry in the fetus is influenced by the maternal genotype. This explanation would account for the higher transmission of congenital heart disease to offspring by affected females noted in several studies. The human counterparts of 2 loci (int-1 and HOX 3) involved in Drosophila early pattern formation are located near the translocation breakpoint 12q13.1. If one of these genes is responsible for situs abnormality, then university of positional code (but not of embryologic mechanism) is suggested for higher metazoans.

Identification and molecular confirmation of a small chromosome 10q duplication [dir dup(10)(q24.2-->q24.3)] inherited from a mother mosaic for the abnormality.

We describe a family in which two siblings exhibited developmental delay, reduced muscle tone and mild muscle weakness. Cytogenetic evaluation demonstrated that both children had a tandem duplication of a small portion of the long arm of chromosome 10 [46,XX or XY,dir dup(10)(q24.2-->q24.3)], inherited from their clinically normal mother, who was found to be mosaic for the duplicated chromosome 10. Fluorescence in situ hybridization approaches, including total chromosome painting and the use of regional specific cosmid probes, were used to confirm the chromosome 10q origin of the duplicated material. This is the smallest confirmed duplication of this portion of chromosome 10 reported to date.

Euchromatic 16p+ heteromorphism: first report in North America.

A heteromorphism of the short arm of 16 (16p+) was discovered in 2 unrelated infants. By G banding, the euchromatic variant appears as a light and a medium dark band just distal to the centromere. This results in an increase of the short arm by about 1/3. The same variant was present in the normal father and the normal paternal grandmother in one family and mildly retarded mother in the 2nd family. The anomalies of the 2 infants are not similar and are apparently unrelated to the 16p+ variant. Though the discovery of such euchromatic variants is highly significant for clinical diagnosis, their genetic significance and mode of origin remain to be elucidated.

Partial trisomy 18 with minimal anomalies: lack of correspondence between phenotypic manifestations and triplicated loci along chromosome 18.

A 2-year-old boy with microcephaly, developmental delay, and minimal anomalies was found to have an extra submetacentric chromosome equivalent to 18pter----q12. Review of the phenotypes produced by various triplicated 18 regions supports the hypothesis that no one chromosome 18 region is sufficient to produce the phenotype of trisomy 18. The mild phenotype of trisomy 18p, the variable phenotype of trisomy 18pter----q12, and the discontinuous phenotype of triplication for band 18q12 alone emphasizes that the contribution of triplicated loci to the phenotype is neither additive nor invariant.

Prune-belly syndrome and other anomalies in a stillborn fetus with a ring X chromosome lacking XIST.

Ring X chromosomes that lack the X inactivation center and fail to be inactivated have been implicated as a cause of mental retardation and multiple congenital anomalies. We report on a stillborn fetus with karyotype mos45,X/46,X,r(X) and early urethral obstruction or prune-belly sequence, single umbilical artery, limb deficiency, horseshoe kidney, cardiac hypertrophy, persistent left superior vena cava, and axial skeleton abnormalities. Fluorescent in situ hydridization (FISH) studies confirmed that the ring chromosome is X-derived and demonstrated that it lacks the XIST locus. The findings in this fetus are discussed with regard to the spectrum of phenotypes associated with monosomy X and small ring X chromosomes.

Interstitial deletions 4q21.1q25 and 4q25q27: phenotypic variability and relation to Rieger anomaly.

We describe clinical and chromosomal findings in two patients with del(4q). Patient 1, with interstitial deletion (4)(q21.1q25), had craniofacial and skeletal anomalies and died at 8 months of hydrocephalus. Patient 2, with interstitial deletion (4)(q25q27), had craniofacial and skeletal anomalies with congenital hypotonia and developmental delay. These patients shared certain manifestations with other del(4q) patients but did not have Rieger anomaly. Clinical variability among patients with interstitial deletions of 4q may be related to variable expression, variable deletion, or imprinting of genes within the 4q region.

Precursor B-cell lymphoblastic lymphoma. A study of nine cases lacking blood and bone marrow involvement and review of the literature.

We describe 9 cases of precursor B-cell lymphoblastic lymphoma (LYL) without evidence of marrow or blood involvement. Four patients had superficial nodal disease, 2 cutaneous involvement, and 1 each ovarian, retroperitoneal, or tonsillar primary tumor. Six patients had limited disease; 3 patients were stage III. Immunophenotyping revealed a terminal deoxynucleotidyl transferase (TdT)-positive, immature B-cell population with variable expression of CD10, CD20, and CD45. All patients are in complete clinical remission (median follow-up, 14 months). A literature review yielded 105 patients with a diagnosis of precursor B-cell LYL based on less than 25% marrow involvement. Of these, 64% were younger than 18 years. Skin, lymph nodes, and bone were the most common sites of disease. Mediastinal involvement was uncommon. TdT, CD19, CD79a, CD10, and HLA-DR were the most frequently expressed antigens, while CD45 and CD20 were expressed in only two thirds of the cases. Cytogenetic analysis showed additional 21q material as a recurring karyotypic abnormality. At a median follow-up of 26 months, 74% of patients were alive; the median survival was 19 months for patients dying of disease. Comparison with precursor B-cell acute lymphoblastic leukemia showed several overlapping features, although distinct differences were identified.

Primary body cavity-based AIDS-related lymphomas.

Five patients with advanced AIDS developed a unique type of high grade primary body cavity-based non-Hodgkin's lymphoma (NHL). The lymphomas were exclusively in serous effusions with no detectable mass disease in the body cavities and no lymphadenopathy or organomegaly. All of the lymphomas exhibited virtually identical morphology, which could not be precisely classified, but appeared to bridge features of large cell immunoblastic and anaplastic large cell lymphomas. Immunophenotypically the lymphoma cells lacked expression of any B- or T-lymphocyte antigens, but expressed CD45 and the activation antigens CD30, CD38, CD71, and HLA-DR. Clonally rearranged immunoglobulin heavy chain and kappa light chain genes were identified by Southern blot analysis. Molecular studies also revealed Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) genomes and germline configuration of the c-myc protooncogene. In two cases studied cytogenetically, the lymphoma cells manifested complex chromosome abnormalities. These lymphomas are clinically and biologically unique and found predominantly in patients with advanced AIDS, in many cases with pre-existing Kaposi's sarcoma.

Renal cell carcinoma with translocation (X;1). Further evidence for a cytogenetically defined subtype.

A renal cell carcinoma from a 15-year-old male had a 49,Y,t(X;1)(p11.2;q21), +der(X)t(X;1) (p11.2;q21), +5, -16, +17, +18 karyotype. This is the third report of a translocation involving a breakpoint at Xp11.2 in a renal cell carcinoma in a child. A total of nine cases of renal cell carcinoma involving Xp11, including this case, have been reported. Of the eight cases for which there are genetics reports, all are male. Patients with renal cell carcinoma with abnormalities at Xp11 appear to be younger than renal cell carcinoma patients overall.

Temporal variation in nucleolar organizer region expression in bone marrow cells of individuals with leukemia.

Silver staining was used to study nucleolar organizer region (NOR) expression in bone marrow cells obtained at two or, in one case, three time points from each of six leukemia patients. Using three measures of silver positivity, we observed that NOR expression was influenced by both metaphase stage and time. Silver positivity decreased significantly from one metaphase stage to the next, from prometaphase through late metaphase. When this variable was controlled for, significant changes in NOR activity were documented in comparisons between disease stages in the patients examined. However, patterns of NOR expression were not consistently associated with disease stage. These results indicate that in previous reports both the metaphase stage effect and the temporally changing nature of NOR activity have, as unrecognized variables, influenced observations of heterogeneity in NOR expression.

Report of a complex karyotype in recurrent metastatic fibrolamellar hepatocellular carcinoma and a review of hepatocellular carcinoma cytogenetics.

Metastatic fibrolamellar hepatocellular carcinoma (HCC) was detected in the abdominal lymph nodes of an adolescent male after resection of the primary tumor. No dividing cells were isolated from attempted cytogenetic studies of the primary tumor. However, cytogenetic analysis of lymph node metastases detected 9 and 12 months after partial hepatectomy revealed abnormal hypertriploid karyotypes, with a suggestion of clonal evolution: 62-92 < 3n >,XX, -Y, +3, +6, +6, +7, +7, +8, +10, +13, +15, +16, +20, -21, -22, +mar1 x 2, +mar[cp6]/46,XY[8] and 78 < 3n >,XX, -Y,der(1)t(1;1)(p36.1;q21), +4, +6, +6, +7, +7,i(8)(q10), +10, +15, +20, -21, -22, +mar1 x 2, +mar2[3]/46, XY[17], respectively. Karyotypes of this variant of HCC have not been reported previously. The cytogenetics of HCC are reviewed.

Cytogenetics of a renal cell carcinoma in a 17-month-old child. Evidence for Xp11.2 as a recurring breakpoint.

A renal cell carcinoma from a 17-month-old boy with a history of maternal hydrocarbon exposure was found to have a 46,Y,t(X;17)(p11.2;q25) karyotype. Although this translocation has not previously been reported, other translocations involving Xp11.2 have been described, suggesting that this may represent a non-random breakpoint involved in the pathogenesis of childhood renal cell carcinoma. Both chromosomes 3 in the tumor were normal by both karyotype and RFLP analysis.