Rationale for carbon ion therapy in high-grade glioma based on a review and a meta-analysis of neutron beam trials.

PURPOSE: The standard treatment of high-grade glioma is still unsatisfactory: the 2-year survival after radiotherapy being only 10-25%. A high linear energy transfer (LET) ionising radiotherapy has been used to overcome tumour radioresistance. An overview of the field is needed to justify future prospective controlled studies on carbon ion therapy. MATERIALS AND METHODS: A meta-analysis of clinical trials on neutron beam therapy and a literature review of clinical investigations on light ion use in high-grade glioma were carried out. RESULTS: Four randomised controlled trials on neutron beam therapy were retained. The meta-analysis showed a non-significant 6% increase of two-year mortality (Relative risk [RR]=1.06 [0.97-1.15]) in comparison with photon therapy. Two phase I/II trials on carbon and neon ion therapy reported for glioblastoma 10% and 31% two-year overall survivals and 13.9 and 19.0 months median survivals, respectively. CONCLUSION: This meta-analysis suggests that neutron beam therapy does not improve the survival of high-grade glioma patients while there is no definitive conclusion yet regarding carbon therapy. The ballistic accuracy and the improved biological efficacy of carbon ions renew the interest in prospective clinical trials on particle beam radiotherapy of glioma and let us expect favourable effects of dose escalation on patients' survival.

A computational analysis of sonic booms penetrating a realistic ocean surface.

The last decade has seen a revival of sonic boom research, a direct result of the projected market for a new breed of supersonic passenger aircraft, its design, and its operation. One area of the research involves sonic boom penetration into the ocean, one concern being the possible disturbance of marine mammals from the noise generated by proposed high-speed civil transport (HSCT) flyovers. Although theory is available to predict underwater sound levels due to a sonic boom hitting a homogeneous ocean with a flat surface, theory for a realistic ocean, one with a wavy surface and bubbles near the surface, is missing and will be presented in this paper. First, reviews are given of a computational method to calculate the underwater pressure field and the effects of a simple wavy ocean surface on the impinging sonic boom. Second, effects are described for the implementation of three additional conditions: a sonic boom/ocean "wavelength" comparison, complex ocean surfaces, and bubbles near the ocean surface. Overall, results from the model suggest that the realistic ocean features affect the penetrating proposed HSCT sonic booms by modifying the underwater sound-pressure levels only about 1 decibel or less.

Identification of genetic markers for prostatic cancer progression.

Despite the high incidence of prostate cancer, only limited data are available on genes or chromosomes specifically involved in its initiation and progression. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded, tissues at different times in prostatic tumor progression to screen the tumor genome for gains and losses. Our panel included specimens derived from 56 different patients: 23 patients with primary, prostate-confined carcinomas; 18 patients with regional lymph node metastases; and 15 patients with distant metastases. Chromosome arms that most frequently showed losses, included 13q (55%), 8p (48%), 6q (43%), 5q (32%), 16q (25%), 18q (20%), 2q (18%), 4q (18%), 10q (18%), and Y (16%). Gains were often seen of chromosome arms 8q (36%), 17q (23%), Xq (23%), 7q (21%), 3q (18%), 9q (18%), 1q (16%), Xp (16%). Furthermore, specific high-level amplifications, eg, of 1q21, 1q25, and Xq12 to q13, were found in metastatic cancers. A significant accumulation of genetic changes in distant metastases was observed, eg, loss of 10q (p = 0.03) and gain of 7q (p = 0.03) sequences. In addition, investigation of a potential biomarker identified in previous studies by our group, ie, extra copies of #7 and/or #8, revealed a high prevalence of 7pq and/or 8q gain in the distant metastases (p = 0.02). Importantly, gains were observed more frequently in tumors derived from progressors after radical prostatectomy, than in nonprogressors (mean time of follow-up, 74 months). Specifically, gain of chromosome 7pq and/or 8q sequences appeared an accurate discriminator between the progressors and nonprogressors. Multivariate analysis showed a significant correlation between progressive disease and the number of chromosomes with gains. This correlation also held true when stage (p = 0.007) or grade (p = 0.002) were taken into account. Likewise, this applied for gain of chromosome 7pq and/or 8q sequences (p = 0.03 and p = 0.005 for stage or grade, respectively). Additionally, an increase in the number of chromosomes with gains per case was related to a decrease in biochemical progression-free survival (Ptrend <0.001). More specifically, the gain of 7pq and/or 8q sequences markedly reduced the biochemical progression-free survival (p < 0.001). In conclusion, this study has, firstly, documented the spectrum of chromosomal alterations in subsequent stages of prostate cancer, a number of which had not been described previously. It allowed us to identify chromosomal regions related to advanced tumor stage, ie, loss of 10q24 and gain of 7q11.2 and/or 7q31 sequences. Secondly, gain of 7pq and/or 8q was identified as a potential genetic discriminator between progressors and nonprogressors after radical surgery.

Universal linkage system: an improved method for labeling archival DNA for comparative genomic hybridization.

Comparative genomic hybridization (CGH) has become a powerful technique for studying gains and losses of DNA sequences in solid tumors. Importantly, DNA derived from archival tumor tissue is also applicable in CGH analysis. However, DNA isolated from routinely processed, formalin-fixed, paraffin-embedded tissue is often degraded, with the bulk of DNA showing fragment sizes of only 400-750 bp. Enzymatic labeling of archival DNA by standard nick translation (NT) decreases DNA size even further, until it becomes too small for CGH (<300 bp). This study presents application in CGH of a commercially available, non-enzymatic labeling method, called Universal Linkage System (ULS), that leaves the DNA fragment size intact. To compare the effect of chemical labeling of archival DNA by ULS vs. enzymatic by NT on the quality of CGH, DNA derived from 16 tumors was labeled by both ULS and NT. In those cases (n = 8), in which the bulk of DNA had a fragment size of 400-1,000 bp, CGH was successful with ULS-labeled probes, but not with NT-labeled probes. In the DNA samples (n = 6) with a fragment size > 1 kb, the intensity of CGH signals was comparable for both ULS- and NT-labeled probes, but CGH with ULS-labeled samples showed a high, speckled, background, which seriously hampered image analysis. In the remaining two cases, which had evenly distributed DNA fragment sizes (range 250-5,000 bp), CGH was successful with both labeling methods. Using DNA fragment size < 1 kb as a selection criterion for ULS labeling, we were able to obtain good quality CGH of a large panel (n = 77) of a variety of archival solid tumors. We conclude that ULS is an excellent labeling method for performing CGH on small-fragment-sized DNA.

Cytolytic T cell hybridomas. III. The antigen specificity and the restriction specificity of cytolytic T cells do not phenotypically mix.

We have obtained cytolytic T-T hybrids by fusing an H-2Kk restricted clone specific for the hapten 3-(p-sulfophenyldiazo)-4-hydroxyphenyl acetic acid (SP) with an H-2Dd-restricted clone specific for the hapten fluorescein (FL). Several hybrid clones express both parental specificities but fail to lyse SP-coupled H-2Dd and FL-coupled H-2Kk target cells. We also fused the H-2Kk-restricted, SP-specific clone with a clone which recognizes FL in the context of any class I major histocompatibility complex antigen. Again several hybrids show both parental specificities but fail to recognize SP coupled to target cells which are not recognized by the parental SP-specific clone. These findings indicate that the observed cytotoxic T lymphocyte specificities for haptens on the one hand and polymorphic as well as nonpolymorphic class I major histocompatibility complex antigenic determinants on the other hand are not carried by independent proteins.

Cytotoxic T cell responses to haptenated cells. IV. Requirements for in vivo priming.

Hapten-specific cytotoxic T cells (CTL) can be generated in cultures containing mouse spleen cells and hapten-coupled syngeneic stimulator cells. A response to sparsely hapten-coupled stimulator cells is only obtained with responder cells from immunized H-2k mice. Immunization was effective with hapten coupled to syngeneic, allogeneic or xenogeneic nucleated cells or membranes thereof. Hapten-coupled erythrocytes, bacteriophages or soluble proteins did not induce CTL precursors (CTL-P) nor responses of other lymphocytes which would interfere with the response of CTL-P. The results show that antigen presentation to CTL-P is very efficient in vivo. Haptens could be presented to and recognized by CTL-P only if coupled to surface membranes of nucleated cells.

Toxicity and QSAR of chlorophenols on Lebistes reticulatus.

The 24-h toxicity of 20 substituted chlorophenols upon Lebistes reticulatus has been determined. The biological results have been tentatively connected with several of the following six parameters: logarithm of the octanol-water partition coefficient (log P); index of molecular connectivity (1 chi v); molecular refraction (RM); perimeter of the efficient section of the molecule (sigma D); constants of HAMMET (sigma); and melting point (F). A correlation is achieved using sigma D and sigma D2 with a correlation coefficient of 0.943.

[Tamoxifen fluorescence as a marker of hormone-dependence: physicochemical aspects]. / La fluorescence du tamoxifène comme marqueur de l'hormonodépendance: aspect physico-chimique.

In acid solutions, Tamoxifen is protonized and forms with eosin a fluorescent ionic association (lambda exc 480 nm, lambda em 565 nm). This reaction is quantitatively linked to the concentration of Tamoxifen. Thus the Tamoxifen induced fluorescence observed in hormone-dependent malignant breast tumor cells after Papanicolaou staining procedure, appears as a consequence of the binding of Tamoxifen to eosin.

Cytotoxic T cell responses to haptenated cells. III. Isolation and specificity analysis of continuously growing clones.

Various procedures were used to derive continuously growing cytotoxic T lymphocyte (CTL) clones from a primary culture containing responder cells from immunized mice and 3-(p-sulfophenyldiazo)-4-hydroxylphenyl acetic acid (SP)- or fluorescein isothiocyanate (FL)-coupled stimulator cells. It seems likely that CTL have to undergo some change, possibly genetic, to be able to grow continuously in T cell growth factor conditioned medium in the absence of any stimulator or filler cells. The most convenient and reliable procedure to generate CTL clones with different specificities was to establish from several aliquots of a primary culture cell populations continuously growing in medium conditioned with T cell growth factor(s). Clones with different specificities segregated in the different populations. SP- and FL-specific CTL clones restricted to H-2Kk and H-2Dd and two FL-specific CTL clones with no apparent H-2 restriction are described.

[Toxicologic study of a fluorescent tracer: rhodamine B]. / Contribution à l'étude toxicologique d'un traceur fluorescent: la Rhodamine B.

The use of the rhodamine B as fluorescent tracer in hydrology ask the question of its possible toxic effects in the environment. This study aspire to specify and to complete the results of the former works by the successive examinations of the activity of the rhodamine B in regard to the "daphnies test", its DL50 on the rat and on the mouse, and its cutaneous tolerance. The obtained results confirm the former remarks and express that the solutions of the rhodamine B show any more immediate risks as soon as they appear no more coloured (higher dilutions 1.10(-7)). However it remains to evaluate its long-term carcenogenic activity.