In many medical treatments oscillating (non-equilibrium) bubbles appear. They can be the result of high-intensity-focused ultrasound, laser treatments or shock wave lithotripsy for example. The physics of such oscillating bubbles is often not very well understood. This is especially so if the bubbles are oscillating near (soft) bio-materials. It is well known that bubbles oscillating near (hard) materials have a tendency to form a high speed jet directed towards the material during the collapse phase of the bubble. It is equally well studied that bubbles near a free interface (air) tend to collapse with a jet directed away from this interface. If the interface is neither 'free' nor 'hard', such as often occurs in bio-materials, the resulting flow physics can be very complex. Yet, in many bio-applications, it is crucial to know in which direction the jet will go (if there is a jet at all). Some applications require a jet towards the tissue, for example to destroy it. For other applications, damage due to impacting jets is to be prevented at all cost. This paper tries to address some of the physics involved in these treatments by using a numerical method, the boundary element method (BEM), to study the dynamics of such bubbles near several bio-materials. In the present work, the behaviour of a bubble placed in a water-like medium near various bio-materials (modelled as elastic fluids) is investigated. It is found that its behaviour depends on the material properties (Young's modulus, Poisson ratio and density) of the bio-material. For soft bio-materials (fat, skin, brain and muscle), the bubble tends to split into smaller bubbles. In certain cases, the resulting bubbles develop opposing jets. For hard bio-materials (cornea, cartilage and bone), the bubble collapses towards the interface with high speed jets (between 100 and about 250 m s(-1)). A summary graph is provided identifying the combined effects of the dimensionless elasticity (kappa) and density ratio (alpha) of the elastic materials which will result in a nearby oscillating bubble jetting towards, splitting or jetting away from the elastic material interface. Since the phenomenon of a bubble jetting away from an elastic material as it collapses has not been reported before in the literature, experiments were performed to validate the numerical observation. A bubble is created in a heavy fluid (hydrofluoroether (HFE)) using a laser pulse. The bubble collapses near the elastic material polydimethylsiloxane (PDMS). The experimental results obtained are compared with the corresponding simulation. The simulation provides spatial and temporal details about the bubble dynamics beyond experimental limits and can therefore be considered as a very useful tool to get a better understanding of the physics involved.

Genomic material from chromosome band 13q14.3 distal to the retinoblastoma locus is recurrently lost in a variety of human neoplasms, indicating an as-yet-unidentified tumor-suppressor mechanism. No pathogenic mutations have been found in the minimally deleted region until now. However, in B cell chronic lymphocytic leukemia tumors with loss of one copy of the critical region, respective candidate tumor-suppressor genes are down-regulated by a factor >2, which would be expected by a normal gene-dosage effect. This finding points to an epigenetic pathomechanism. We find that the two copies of the critical region replicate asynchronously, suggesting differential chromatin packaging of the two copies of 13q14.3. Although we also detect monoallelic silencing of genes localized in the critical region, monoallelic expression originates from either the maternal or paternal copy, excluding an imprinting mechanism. DNA methylation analyses revealed one CpG island of the region to be methylated. DNA demethylation of this CpG island and global histone hyperacetylation induced biallelic expression, whereas replication timing was not affected. We propose that differential replication timing represents an early epigenetic mark that distinguishes the two copies of 13q14.3, resulting in differential chromatin packaging and monoallelic expression. Accordingly, deletion of the single active copy of 13q14.3 results in significant down-regulation of the candidate genes and loss of function, providing a model for the interaction of genetic lesions and epigenetic silencing at 13q14.3 in B cell chronic lymphocytic leukemia.

Peritoneal carcinomatosis is a frequent mode of metastasis in patients with gastric, duodenal, or pancreatic cancer. Survival in this setting is short and therapeutic options are limited. This analysis examines the outcomes of 18 patients treated with operative cytoreduction and continuous hyperthermic peritoneal perfusion. Eighteen patients (6 males and 12 females) with gastric (n = 9), pancreatic (n = 7), or duodenal (n = 2) cancer were treated on protocol. Patients underwent optimal cytoreduction (complete gross resection, 11; minimal residual disease, 7) and a 90-minute perfusion with cisplatin. Clinical parameters and tumor and treatment characteristics were analyzed. Survival curves were estimated using the Kaplan-Meier method. Procedures included gastrectomy (n = 8), pancreaticoduodenectomy (n = 3), and hemicolectomy (n = 2). After cytoreduction, patients had no evidence of residual disease (n = 11), fewer than 100 implants less than 5 mm (n = 1), more than 100 implants between 5-10 mm (n = 3), or multiple implants with greater than 1 cm (n = 3). Five patients received a postoperative intraperitoneal dwell with 5-fluorouracil and paclitaxel. There was one perioperative mortality, and complications occurred in 10 patients. The median progression-free survival was 8 months (mean, 10 months; range, 1-47 months) with a median overall survival of 8 months (mean, 18 months; range, 1-74 months). In this cohort, peritoneal perfusion with cisplatin used to treat foregut malignancies has a high incidence of complications and does not significantly alter the natural history of the disease. Investigation of novel therapeutic approaches should be considered.

Adenoid cystic carcinoma (ACC) of the salivary gland is a neoplasm characterized by slow but inevitable local progression and terminal hematogenous metastasis. To detect novel imbalanced chromosomal regions associated with tumorigenesis, we used chromosomal comparative genomic hybridization to screen 27 ACC. The most common aberration was copy number gain of 22q13 (nine cases) followed by gains of 16p (seven cases) and 17q (four cases) and copy number losses on 6q (six cases). To further delineate the prevalence of 22q13 copy number gains in ACC, fluorescence in situ hybridization was performed for five bacterial/phage artificial chromosome (BAC/PAC) probes from the 22q13 consensus region with 57 ACC on a tissue microarray. The overall prevalence of copy number gains on 22q13 was 30% of the tumors in the fluorescence in situ hybridization analysis, irrespective of histologic differentiation (cribriform/tubular vs. solid) or tumor event (primary vs. recurrent). We therefore assume that copy number gain of 22q13 is a novel frequent finding in ACC that may be involved in the initial pathogenesis of this neoplasm by proto-oncogene activation.

Using comparative genomic hybridization, DNA copy number changes were studied in 14 pleomorphic liposarcomas and compared to those detected in high-grade areas of 9 dedifferentiated liposarcomas. A total of 251 gains and 84 losses were detected. The most frequent gains involved subregions of chromosomal arms 12q and 20q (70% each), 5p (57%), 6q and 9q (52% each), 1q, 7p and 17p (48% each), 1p (43%), 6p and 17q (39% each), 20p and 22q (35% each) as well as 7q and 12p (30% each). The same subregions were also affected by 30 high level amplifications. The most frequent losses were found in subregions of chromosomal arms 13q (35%) as well as 11q and 12p (30% each). Overall, gains of chromosomal material were more frequent than losses (p < 0.001). There were significant differences in the frequency and distribution of recurrent chromosomal imbalances between pleomorphic liposarcomas and the dedifferentiated areas of dedifferentiated liposarcomas. Gains of chromosomal material detected predominantly in pleomorphic liposarcomas involved subbands 5p13-p15 (p < 0.010), 1p21 (p < 0.019), 1q21-q22 (p < 0.040) and 7q22 (p < 0.049). Conversely, high level amplifications within chromosomal subregion 12q13-q21 were only found in the dedifferentiated components of dedifferentiated liposarcomas (p < 0.001). Overall, both gains and the less pronounced losses of chromosomal material were more frequent in pleomorphic than in dedifferentiated liposarcomas (p < 0.001 and p < 0.025, respectively). These results show that pleomorphic liposarcomas display a considerable number of recurrent chromosomal imbalances that are essentially different from those present in high-grade areas of dedifferentiated liposarcomas. Therefore, genetic data are considered as a helpful diagnostic adjunct for the discrimination between these 2 types of liposarcoma. The overall higher frequency of chromosomal imbalances in pleomorphic as compared to dedifferentiated liposarcomas could account for the more aggressive biological behavior of pleomorphic relative to dedifferentiated liposarcoma types.

Hodgkin- and Reed-Sternberg (HRS) cells microdissected from 41 classical Hodgkin lymphomas (cHL) of 40 patients comprising 8 lymphocyte-rich (cHL-LR), 16 nodular sclerosis (cHL-NS), 15 mixed-cellularity (cHL-MC), and 2 lymphocyte-depletion (cHL-LD) subtypes were analyzed by comparative genomic hybridization for recurrently imbalanced chromosomal subregions. Chromosomal gains most frequently involved chromosome 2p (54%), 12q (37%), 17p (27%), 9p and 16p (24% each), and 17q and 20q (20% each), whereas losses primarily affected chromosome 13q (22%). Using fluorescence in situ hybridization, amplification of the REL oncogene was demonstrated within a distinct 2p15-p16 amplicon. The high frequency of 2p overrepresentations including REL, particularly in cHL-NS (88%), suggests that an alternative mechanism of constitutive activation of nuclear factor NF-kappaB is a hallmark of HRS cells. Hierarchical cluster analysis of chromosomal imbalances revealed a closer relationship among cHL-NS than other subtypes. Furthermore, there is a tendency for different subtypes of cHL-MC tumors characterized by different ages at the time of tumor onset and gain of chromosome 17p. The imbalance pattern of cHL subtypes suggests that different molecular pathways are activated, with REL or other genes on chromosomal band 2p15-p16 playing a fundamental role in the pathogenesis of classical Hodgkin lymphoma.

The most frequent chromosomal imbalance in B-cell chronic lymphocytic leukemia (B-CLL) and mantle-cell lymphoma (MCL) is loss of material from 13q14.3. BCMSUN (previously Leu2, t4, cDNA 1B4) is one of 3 proposed candidate genes isolated from the minimally deleted region. We identified a homolog of BCMSUN, termed BCMSUNL (for BCMSUN-like). Radiation-hybrid mapping with a PCR-amplified fragment and fluorescence in situ hybridization with 2 PAC clones containing coding information for BCMSUNL revealed its localization at 1p22-p31. Interphase fluorescence in situ hybridization, however, revealed that the BCMSUNL gene locus is not part of the critical deletion region of 1p22 in MCLs. Analysis of DNA sequences derived from the respective PAC clones and available in public databases uncovered an intronless structure of BCMSUNL. Compared to BCMSUN, the new gene lacks exon 2 and shows 90.3% homology on the nucleic acid level. Both genes are expressed in peripheral blood lymphocytes from healthy donors as well as B-CLL and MCL tumors, with retention of genetic material at 13q14.3. Therefore, analysis of the candidate tumor-suppressor gene BCMSUN at 13q14.3 must be based on assays that distinguish between the 2 homologous genes.

Leiomyosarcomas comprise a group of malignant soft-tissue tumors with smooth-muscle differentiation. In this study, 14 cases of leiomyosarcoma were screened for changes in relative chromosome copy number by comparative genomic hybridization. A high number of imbalances (mean, 16.3; range, 6-26) was detected, with chromosomal gains occurring about twice as much as losses. The most frequent gains were found in 5p15, 8q24, 15q25-->q26, 17p, and Xp (43% to 50%), whereas the most frequent losses were found in 10q and 13q (50% and 78%, respectively). Twenty high-level amplifications affecting 15 different chromosomal subregions were detected in nine different tumors. In three leiomyosarcomas, sequences on chromosome arm 17p were found to be highly amplified, with a minimal overlapping region on subbands 17p12-->p11. We further discovered that the Smith-Magenis syndrome critical region on 17p11.2 is included in the 17p amplicons of two leiomyosarcoma cases. Using probes flanking this genetically unstable region, a mean of 14 and 22 signals per nucleus, respectively, was detected in both leiomyosarcomas by fluorescence in situ hybridization. In conclusion, this analysis identifies a number of characteristic chromosomal imbalances in leiomyosarcomas and provides evidence for the localization of potential oncogenes and tumor suppressor genes active in leiomyosarcoma genomes.

Comparative genomic hybridization was applied for a comprehensive screening of frequently occurring net gains and losses of chromosomal subregions in small populations of CD30+ Hodgkin cells and their morphological variants. In 12 Hodgkin's lymphomas, recurrent gains were detected on chromosomal arms 2p, 9p, and 12q (in six, four, and five tumors, respectively) and distinct high-level amplifications were identified on chromosomal bands 4p16, 4q23-q24, and 9p23-p24. In Hodgkin cells with 9p23-p24 amplification, fluorescence in situ hybridization revealed an increased copy number of chromosomal sequences spanning the tyrosine kinase gene JAK2. Several of the imbalances described, in particular a gain in chromosomal arm 9p that includes JAK2 amplification, are similar to the genomic changes detected in primary mediastinal B-cell lymphoma.

Peripheral nerve sheath tumors arise either sporadically or in association with neurofibromatosis type 1 (von Recklinghausen's neurofibromatosis, NF1) or type 2. In this study, comprehensive screening for relative chromosome copy number changes was performed on 10 benign and 19 malignant peripheral nerve sheath tumors (MPNSTs) by applying comparative genomic hybridization (CGH). In benign tumors, no chromosomal imbalances were found by CGH, whereas in MPNSTs chromosomal gains and losses were frequently detected. No differences regarding the frequency and distribution of chromosomal imbalances were observed between the 13 sporadic and 6 NF1-associated MPNSTs analyzed. In both, the number of gains was significantly higher than the number of losses, suggesting a predominant role of proto-oncogene activation during MPNST progression. Candidate regions with potentially relevant proto-oncogenes included chromosomal bands 17q24-q25, 7p11-p13, 5p15, 8q22-q24, and 12q21-q24; those with putative tumor suppressor genes were 9p21-p24, 13q14-q22, and 1p. High-level amplifications were restricted to sporadic tumors and affected eight different chromosomal subregions. In three of these MPNSTs, identical subregions on chromosomal arms 5p and 12q were coamplified. This study revealed a number of new characteristic chromosomal imbalances and provides a basis for molecular identification of oncogenes and tumor suppressor genes of pathogenetic relevance in both sporadic and NF1-associated MPNSTs. Genes Chromosomes Cancer 25:362-369, 1999.