Comparative study and clinical implementation of two breathing-adapted radiotherapy techniques: dosimetric benefits for lung cancer treatment]

Breathing can lead to organ motions up to several centimeters. For radiotherapy of lung, these motions are generally taken into account by adding a specific margin around the target. Thus, treated volumes are often too large to allow for the high-dose values requested for local control. To manage respiratory motion, deep-inspiration breath-hold technique (DIBH) and gated radiotherapy are starting being used clinically. DIBH consists in asking the patient to perform breath-hold during the treatment and the image acquisition, DIBH level being measured by a spirometer. Gated radiotherapy consists in treating the patient at a certain phase of the free breathing. Linac is synchronized with the motion of a marker located on the patient chest. Planning images are obtained by a four-dimensional CT (4D-CT) using the same marker. We have assessed the value of these two methods. For lung treatment, compared to a standard treatment, toxicity reduction was mainly due to the lung total volume increase. It is therefore more significant for breath-hold approach. It is also due to the reduction of safety margins, which is similar for both methods. These two techniques, which have specific advantages and drawbacks, are used routinely at Curie Institute for a large proportion of lung patients, but also for some breast, liver or even Hodgkin disease treatments.     

Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity

Anaplastic large cell lymphomas are associated with chromosomal aberrations involving the anaplastic lymphoma kinase (ALK) gene at 2p23 that result in the expression of novel chimeric ALK proteins with transforming properties. In most of these tumors, the t(2;5)(p23;q35) generates the NPM-ALK fusion gene. However, several studies have now demonstrated that genes other than NPM may be fused to the ALK gene. We have recently described two different ALK rearrangements involving the TRK-fused gene (TFG) in which the same portion of ALK was fused to different length fragments of the 5' TFG region. These two rearrangements encoded chimeric proteins of 85 kd (TFG-ALK(S)) and 97 kd (TFG-ALK(L)), respectively. In this study, we have identified a new ALK rearrangement in which the catalytic domain of ALK was fused to a larger fragment of the TFG gene (TFG-ALK(XL)), encoding for a fusion protein of 113 kd. Genomic analysis of these three TFG-ALK rearrangements revealed that the TFG breakpoints occur at introns 3, 4, and 5, respectively, whereas the ALK breakpoints always occur in the same intron. No homologous regions or known recombination sequences were found in these regions. Transfection experiments using NIH-3T3 fibroblasts showed a similar transforming efficiency of TFG-ALK variants compared with NPM-ALK. In addition, in common with NPM-ALK, the TFG-ALK proteins formed stable complexes with the signaling proteins Grb2, Shc, and PLC-gamma. In conclusion, these findings indicate that the TFG may use a variety of intronic breakpoints in ALK rearrangements generating fusion proteins of different molecular weights, but with similar transforming potential than NPM-ALK.     

Recurrent genetic aberrations in thymoma and thymic carcinoma

Apart from single reported aberrant karyotypes, genetic alterations in thymic epithelial neoplasms have not been investigated so far. In this study, 12 World Health Organization classification type A thymomas (medullary thymomas), 16 type B3 thymomas (well-differentiated thymic carcinomas), and nine type C thymomas, all of them primary thymic squamous cell carcinomas, were analyzed by comparative genomic hybridization and fluorescence in situ hybridization. With the exception of one single case, type A thymomas did not reveal chromosomal gains or losses in comparative genomic hybridization. In contrast, all type B3 thymomas showed chromosomal imbalances, with gain of 1q, loss of chromosome 6, and loss of 13q occurring in 11 (69%), six (38%), and five (31%) of 16 cases, respectively. In primary thymic squamous cell carcinoma, the most frequent chromosomal losses were observed for 16q (six of nine cases, 67%), 6 (4 of 9, 44%), and 3p and 17p (three of nine each, 33%), whereas recurrent gains of chromosomal material were gains of 1q (5 of 9, 56%), 17q, and 18 (three of nine each, 33%). This study shows that the distinct histological thymoma types A and B3 exhibit distinct genetic phenotypes, whereas type B3 thymoma and primary thymic squamous cell carcinoma partially share genetic aberrations. In addition to the possible tumorigenic role, the deletion in type B3 thymoma of chromosome 6, harboring the HLA locus, might play a role in the pathogenesis of paraneoplastic autoimmunity characteristic of thymoma.     

Trisomy 3 Is Not a Common Feature in Malignant Lymphomas of Mucosa-Associated Lymphoid Tissue Type

The genetic background of extranodal marginal zone B-cell non-Hodgkin’s lymphoma (NHL) of mucosa-associated lymphoid tissue (MALT) type is poorly understood. In contrast to most entities of primary nodal lymphomas, few cytogenetic data are available, and gene rearrangements frequently encountered in and highly characteristic of certain entities of systemic NHL are absent in this type of lymphoma. Recently, it was suggested that MALT-type NHLs are associated with certain numerical chromosome aberrations and especially with trisomy 3. We performed an extensive study using a sensitive double (bicolor) fluorescence in situ hybridization technique for the analysis of trisomies for chromosomes 3, 7, 12, and 18 in 60 samples of low-grade and 45 high-grade MALT-type tumors. In the low-grade cases, trisomy 3 was found in a frequency of only 20%. High-grade lymphomas of MALT type were associated with trisomies 3, 7, 12, and 18 in 36, 20, 18, and 13% of the cases, respectively. Whereas no difference was encountered for trisomy 3 in primary and secondary/simultaneous high-grade lymphomas, +7 and +12 were associated with primary lymphomas, and a +18 was predominantly found in secondary/simultaneous high-grade NHL. These results challenge earlier reports describing a high frequency of +3 in low-grade MALT-type NHL and indicate a possibly different genetic evolution pattern of primary and secondary/simultaneous high-grade lymphomas of primary mucosal origin.     

A method to check the accuracy of dose computation using quality index: application to scatter contribution in high energy photon beams

Computerized dose calculation verification is a relevant component of radiotherapy treatment planning quality assurance. The usual procedure is to compare measurements to computations for several standard situations. As cases become more complex, special test phantoms and beam arrangements must be used, and an experimental procedure must be carefully established. In this paper we follow a new methodology to prepare a set of reference data that may be used to verify the accuracy of dose calculations involving changes in the scatter component of photon beams. The advantage of this methodology is that local measurements are not required. A quantitative evaluation of dose modifications was performed by means of correction factors (CF). For this purpose, three geometrical configurations were designed (asymmetric, symmetric, and reference) where the primary component was kept constant and the scatter component was varied by changing the height (h) of lateral columns. Measurements were performed in polystyrene phantoms for seven photon beam energies. CF were derived as the ratio of the absolute dose measured at the point of interest to the absolute dose for the reference configuration, for the asymmetric and symmetric configurations, respectively. They were expressed as a function of beam quality (QI). We have verified that, for all configurations studied, CF decrease with QI. For h = 15 cm, CF remain practically constant, whatever machine technology is used [the mean values of CF for the asymmetric and symmetric cases are CFa= 1.028 (0.2% 1 s.d.) and CFs= 1.058 (0.4% 1 s.d.)]. We have developed a test protocol and we have chosen those configurations corresponding to h = 15 cm because they both present greater values of the CF and lower standard deviations. The direct application of the method is straightforward. The user can reproduce on his local TPS the three experimental configurations described in the test protocol, and then compute CF which can be compared to our reference data set for any beam quality.     

A 3-D beam subtraction method for inhomogeneity correction in high energy X-ray radiotherapy

Most methods of inhomogeneity correction in high energy X-ray beams, assume an infinite lateral extent of the heterogeneous volumes ("slab models") or require sophisticated time-consuming computer algorithms. We present here a method, developed for parallelepiped inhomogeneities based on a beam subtraction concept combined with a conventional "slab model". Provided that the conventional model is appropriately chosen, this method gives agreement with experimental results better than 1% in most cases. It accounts properly for the scatter modification according to the size and position of the inhomogeneous volume. One example of a computer application is also presented.     

Lymphome des Mediastinums

Lymphomas infiltrating the mediastinum are a challenge for the treating physician as well as for the pathological diagnostics. The clinical scenario is often an emergency situation, while the pathologist is usually confronted only with small biopsy samples. Classical Hodgkin’s lymphoma is by far the most frequently occurring lymphoma in the mediastinum and predominantly the nodular sclerosis subtype. In small and very sclerotic specimens it can be difficult to morphologically detect Hodgkin and Reed-Sternberg cells and to identify the characteristic phenotype by immunohistochemistry. Primary mediastinal large B?cell lymphomas should be distinguished from classical Hodgkin’s lymphomas as the treatment is different. This is characterized by the detection of sheets of blast cells, which immunohistochemically show a strong B?cell phenotype (positivity for CD20 and CD79a), while CD30 can also often be expressed. The intimate biological relationship between classical Hodgkin’s lymphomas and mediastinal large B?cell lymphomas is illustrated by the existence of B?cell lymphomas with intermediate features (so-called mediastinal grey zone lymphomas). It is important to recognize and diagnose these lymphomas as they are associated with a slightly inferior prognosis. Extranodal thymic marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type are a rare form of lymphoma encountered in the mediastinum, which can be associated with autoimmune diseases. T?lymphoblastic lymphomas and leukemia, which occur predominantly in children and young adults, represent a rapidly growing precursor cell neoplasia and must be distinguished from thymomas in the differential diagnostics as well as from normal and hyperplastic thymus glands.