Hyperhaploidy is a novel high-risk cytogenetic subgroup in multiple myeloma.

Hyperhaploid clones (24-34 chromosomes) were identified in 33 patients with multiple myeloma (MM), demonstrating a novel numerical cytogenetic subgroup. Strikingly, all hyperhaploid karyotypes were found to harbor monosomy 17p, the single most important risk stratification lesion in MM. A catastrophic loss of nearly a haploid set of chromosomes results in disomies of chromosomes 3, 5, 7, 9, 11, 15, 18, 19 and 21, the same basic set of odd-numbered chromosomes found in trisomy in hyperdiploid myeloma. All other autosomes are found in monosomy, resulting in additional clinically relevant monosomies of 1p, 6q, 13q and 16q. Hypotriploid subclones (58-68 chromosomes) were also identified in 11 of the 33 patients and represent a duplication of the hyperhaploid clone. Analysis of clones utilizing interphase fluorescence in situ hybridization (iFISH), metaphase FISH and spectral karyotyping identified either monosomy 17 or del17p in all patients. Amplification of 1q21 was identified in eight patients, demonstrating an additional high-risk marker. Importantly, our findings indicate that current iFISH strategies may be uninformative or ambiguous in the detection of these clones, suggesting this patient subgroup maybe underreported. Overall survival for patients with hyperhaploid clones was poor, with a 5-year survival rate of 23.1%. These findings identify a distinct numerical subgroup with cytogenetically defined high-risk disease.

Telomeric fusion and chromosome instability in multiple tissues of a patient with mosaic Ullrich-Turner syndrome.

We describe the cytogenetic evolution of multiple cell lines in the gonadal tissue of a 10-year-old girl with mosaic Ullrich-Turner syndrome (UTS) involving clonal telomeric associations (tas) of the Y chromosome. G-band analysis of all tissues showed at least 2 cell lines; 45, X and 46,X,tas(Y;21)(q12;p13). However, analysis of left gonadal tissue of this patient showed the evolution of 2 additional cell lines, one designated 45,X,tas(Y;21)(q12;p13),-22 and the other 46,X,tas(Y;21)(q12;p13),+tas(Y;14)(q12;p13), -22. Fluorescence in situ hybridization (FISH) analysis of interphase nuclei from uncultured gonadal tissue confirmed the findings of aneuploidy in the left gonadal tissue and extended the findings of aneuploidy to the tissue of the right gonad. The chromosome findings in the gonadal tissue of this patient suggest a preneoplastic karyotype relating to several distinct tumor associations. The clonal evolution of telomeric fusions indicates chromosomes instability and suggests the extra copy of the Y chromosome may have resulted from a fusion-related malsegregation. In addition, the extra Y suggests low-level amplification of a putative gonadoblastoma gene, while the loss of chromosome 22 suggests the loss of heterozygosity for genes on chromosome 22. This case demonstrates the utility of the study of gonadal tissue in 45,X/46XY UTS patients, and provides evidence that clonal telomeric fusions may, in rare cases, be associated with chromosome malsegregation and with the subsequent evolution of unstable karyotypes.

Sub-band deletion of 7q36.3 in a patient with ring chromosome 7: association with holoprosencephaly.

We report on a patient with ring chromosome 7 analyzed by both high-resolution mid-prophase G-banding and fluorescence in situ hybridization (FISH) resolving a subband deletion of 7q36.3 associated with the clinical manifestation of holoprosencephaly (HPE).

Factors in nurse practitioner role adjustment.

In a survey to determine the existence, extent and nature of an adjustment for nurse practitioners as they assumed responsibilities associated with the NP role, 135 nurse practitioners were surveyed. Results showed that 86.7 percent of respondents experiences a distinct adjustment period which averaged 5.9 months. Also, respondents rates "greater autonomy in work" as most important in the decision to seek training, and "increased skill and knowledge" as the most realistic expectation for others considering NP training. Respondents rated "uncertainty about diagnosis and treatment" and "fear of missing something" as the most descriptive of feelings in the first six months of practice. Data from this study support preparation of NP students for role transition while enrolled in a training program; suggestions for designing "role adjustment" seminars and preparing preceptors are presented.

Strategic planning in hospitals. Applications for nurse executives.

Strategic planning has been used in business to strengthen competitive position and improve overall performance. This method of analysis also offers nurse executives a way to increase management effectiveness by matching departmental strengths with environmental opportunities. A strategic planning method developed for application by nurse executives at the departmental level is presented.

Concentrations of follicle-stimulating hormone correlate with alkaline phosphatase and a marker for vitamin K status in the perimenopause.

Serum alkaline phosphatase (ALP), a gross marker of bone turnover, has been reported to be elevated after menopause, a period characterized by hallmark increases in follicle-stimulating hormone (FSH). Whether the ALP rise coincides with the perimenopausal transition when changes in FSH, estrogen levels, and menstrual cycles are first apparent is not known. The purpose of this cross-sectional study was twofold: (1) to characterize the influence of the perimenopausal transition on ALP activity and (2) to correlate ALP activity with more precise markers for bone, osteocalcin (OC), and vitamin K status assessed with undercarboxylated osteocalcin (ucOC). Thirty-eight studies of hourly FSH were conducted on cycle day 6 of the follicular phase in perimenopausal women volunteers, aged 40-54 years (mean body mass index [BMI] = 24.2 +/- 0.5). Mean FSH was used to define the perimenopausal stage (early perimenopausal, mean FSH 15 IU/L, n = 11). As expected, late perimenopausal women had irregular and longer menstrual cycles, lower estradiol (E(2)) and estrone (E(1)) levels, and a lower frequency of ovulations vs. the early group. ALP was higher (76.5 +/- 8.3 vs. 58.3 +/- 2.7 IU/L, p = 0.045) compared with the early perimenopausal group. In a subsample (n = 10), OC was associated with ALP (r = 0.69, p < 0.03), FSH was positively related to ucOC concentrations (r = 0.7, p < 0.03), and women with E(1) concentrations <40 pg/ml had double the percentage of ucOC compared with those where E(1) was >40 pg/ml (46.3% +/- 6.6% vs. 22.0% +/- 3. 1%, p < 0.006). Clinical markers of the perimenopause are associated with a nonspecific but inexpensive marker of enhanced bone turnover (i.e., higher ALP) and correlate well with more precise markers of bone activity. These findings suggest that health-promotion strategies for preserving bone should be instituted well before the last menstrual period.

Evidence of an association between 6q13-21 chromosome aberrations and locally aggressive behavior in patients with cartilage tumors.

BACKGROUND: The finding of a cytogenetic-pathologic correlation between complex karyotypes and high grade cartilaginous tumors has been reported. However, few cytogenetic reports exist regarding benign or low grade lesions. A subset of low grade malignant cartilaginous tumors is characterized by locally aggressive behavior but no metastatic potential. Because the histopathologic distinction between benign, borderline, or low grade malignant cartilaginous lesions can be difficult, the finding of additional tumor markers associated with the clinical behavior of borderline cartilaginous lesions could be clinically significant. METHODS: Four cartilaginous tumors, including an osteochondroma (OC), a chondromyxoid fibroma (CF), an enchondroma (EC), and a dedifferentiated chondrosarcoma (DCS), were cultured and harvested using short term, in situ culture techniques. Chromosome analysis was performed by conventional G-banding and fluorescence in situ hybridization was used to confirm G-banding. RESULTS: The stemlines of all four tumors showed multiple chromosome anomalies that included aberrations of 6q13-21. The OC showed a t(6;16)(q21;p13.3). The CF showed a complex rearrangement between the chromosome 6 homologues, resulting in an inv(6)(p25q23)t(6;6)(q23;q13). This tumor also showed the clonal evolution of telomeric associations resulting in duplications, deletions, and the formation of a ring 15. The EC showed a der(6)t(6;15)(q13;q11)t(15;22)(q22;q13) stemline and subclones with an unstable iso 17q that subsequently fused to both ends of chromosome 16. The DCS showed a del(6)(q13), r(9), +12 stemline. CONCLUSIONS: The cytogenetic findings of this study suggest the cytogenetic-pathologic correlation of complex karyotypes found in high grade cartilage tumors may extend to lower grade tumors with complex karyotypes. These findings further suggest that chromosome aberrations in the region of 6q13-21 may be associated with locally aggressive behavior in patients with cartilage tumors.

Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping.

Multicolor spectral karyotyping (SKY) was performed on bone marrow samples from 50 patients with multiple myeloma (MM) in anticipation of discovering new previously unidentified translocations. All samples showed complex karyotypes with chromosome aberrations which, in most cases, were not fully characterized by G-banding. Patients of special interest were those who showed add(14)(q32), add(8)(q24) and those whose G-banding karyotypes showed poor chromosome morphology. Three new recurring chromosome translocations not previously reported in MM were identified. Two of the translocations involve recurring aberrations at band 14q32.3, the site of the IgH locus, with different exchange partners. The most frequently recurring rearrangement was a subtle translocation at 14q32.3 designated as a t(14;16)(q32;q22 approximately 23), which was identified in six patients. A second and larger translocation at 14q32, identified in two patients, was designated as a t(9;14)(p13;q32), previously associated with Waldenstrom's macroglobulinemia and lymphoplasmacytoid lymphoma. A third translocation, identified in two patients, involved a whole-arm t(6;8)(p10;q10) translocation. The SKY technique was able to refine the designations of over 156 aberrations not fully characterized by G-banding in this study and resolved additional chromosome aberrations in every patient studied except two. The t(14;16)(q32;q22 approximately 23) identified by SKY in this study suggests this may be a frequent translocation in MM associated with complex karyotypes and disease progression. Therefore, the SKY technique provides a useful adjunct to routine G-banding and fluorescence in situ hybridization studies in the cytogenetic analysis of MM.

Multicolour spectral karyotyping identifies new translocations and a recurring pathway for chromosome loss in multiple myeloma.

Multicolour spectral karyotyping (SKY) was performed on primary tumour specimens from 100 patients with multiple myeloma (MM) that showed complex clonal chromosome aberrations not fully characterized by G-banding. In this study, SKY was able to identify or revise translocations with breakpoints involving 14q32, 11q13 or 8q24 in 32 patients (32%). Five new recurring translocations were identified, two of which involved chromosome 22. A subtle reciprocal translocation t(14;22) (q32;q11 approximately 12) was identified using SKY in two patients and a second, much larger, translocation t(11;22)(q13;q13) was identified using G-banding in three patients. A third new translocation was identified in two patients using SKY and G-banding as der(7)t(7;7)(p15 approximately 22;q22 approximately 32). Twenty-three patients (23%) showed the loss of 8p by whole-arm translocations with different whole-arm donor chromosomes. Among this group, two new recurring whole-arm translocations involving the centromeric breakpoint 8q10 were identified as der(8;20)(q10;q10) and der(8;18) (q10;q10) in three patients each. In addition, a novel pattern of three-way translocations involving the clonal evolution of the t(8;22)(q24;q11) by the subsequent loss of 8p by whole-arm translocations was found in three patients. The chromosome instability identified here demonstrates that the loss of 8p can occur by multiple whole-arm translocations, indicating a new pathway for the loss of a specific chromosome region in MM.