Irradiation du petit bassin et fonction ano-rectale.

peer reviewedLe traitement adjuvant des cancers du rectum a pour buts de stériliser la maladie résiduelle infra-clinique et d’améliorer le contrôle local. Depuis plus de 20 ans, des milliers de malades ont été inclus dans des études randomisées, visant d’abord à mettre en évidence un gain de survie et une réduction des récidives loco-régionales, en relation avec la radiothérapie pré- ou postopératoire, combinée ou non à la chimiothérapie. Les conséquences en termes de qualité de vie de ces traitements ont pourtant été peu étudiées, et la tolérance fonctionnelle du néo-rectum et de l’appareil sphinctérien à la radiothérapie restent mal connues [1]. Les difficultés liées à l’étude des effets de l’irradiation sur les tissus normaux, ainsi que la variabilité inter-individuelle de la réponse à la radiothérapie, s’ajoutent et rendent le sujet plus complexe encore. Les radiothérapeutes adaptent leur technique afin de réduire autant que possible la dose administrée aux tissus normaux avoisinant la tumeur. Dans le cas de l’irradiation du petit bassin, c’est l’intestin grêle qui a longtemps été considéré comme la structure à risque de complications, alors que l’atteinte du sphincter anal était rarement mentionnée [2]. Malgré les répercussions importantes de la dysfonction ano-rectale sur la qualité de vie des malades, l’atteinte du sphincter anal par la radiothérapie est restée un aspect négligé du traitement adjuvant des cancers du petit bassin [3]. Cet article a pour but, à travers une revue de la littérature, de mettre en évidence les effets qualitatifs et quantitatifs de la radiothérapie sur la fonction du sphincter anal, ainsi que de proposer une modification de la technique actuelle d’irradiation des cancers du bas rectum

RENO, a European Postmarket Surveillance Registry, confirms effectiveness of coronary brachytheraypy in routine clinical practice.

Purpose: To assess, by a European registry trial, the clinical event rate in patients with discrete stenotic lesions of coronary arteries (de novo or restenotic) in single or multiple vessels (native or bypass grafts) treated with -radiation. Methods and Materials: Between April 1999 and September 2000, 1098 consecutive patients treated in 46 centers in Europe and the Middle East with the Novoste Beta-Cath System were included in Registry Novoste (RENO). Results: Six-month follow-up data were obtained for 1085 patients. Of 1174 target lesions, 94.1% were located in native vessels and 5.9% in a bypass graft; 17.7% were de novo lesions, 4.1% were restenotic, and 77.7% were in-stent restenotic lesions. Intravascular brachytherapy was technically successful in 95.9% of lesions. Multisegmental irradiation, using a manual pullback stepping maneuver to treat longer lesions, was used in 16.3% of the procedures. The in-hospital rate of major adverse cardiac events was 1.8%. At 6 months, the rate was 18.7%. Angiographic follow-up was available for 70.4% of the patients. Nonocclusive restenosis was seen in 18.8% and total occlusion in 5.7% of patients. A combined end point for late (30–180 days) definitive or suspected target vessel closure was reached in 5.4%, but with only 2% of clinical events. Multivariate analysis was performed for major adverse cardiac events and late thrombosis. Conclusion: Data obtained from the multicenter RENO registry study, derived from a large cohort of unselected consecutive patients, suggest that the good results of recent randomized controlled clinical trials can be replicated in routine clinical practice. © 2003 Elsevier Science Inc

CPT-11 and concomitant hyperfractionated accelerated radiotherapy induce efficient local control in rectal cancer patients: results from a phase II

Patients with rectal cancer are at high risk of disease recurrence despite neoadjuvant radiochemotherapy with 5-Fluorouracil (5FU), a regimen that is now widely applied. In order to develop a regimen with increased antitumour activity, we previously established the recommended dose of neoadjuvant CPT-11 (three times weekly 90 mg m−2) concomitant to hyperfractionated accelerated radiotherapy (HART) followed by surgery within 1 week. Thirty-three patients (20 men) with a locally advanced adenocarcinoma of the rectum were enrolled in this prospective phase II trial (1 cT2, 29 cT3, 3 cT4 and 21 cN+). Median age was 60 years (range 43–75 years). All patients received all three injections of CPT-11 and all but two patients completed radiotherapy as planned. Surgery with total mesorectal excision (TME) was performed within 1 week (range 2–15 days). The preoperative chemoradiotherapy was overall well tolerated, 24% of the patients experienced grade 3 diarrhoea that was easily manageable. At a median follow-up of 2 years no local recurrence occurred, however, nine patients developed distant metastases. The 2-year disease-free survival was 66% (95% confidence interval 0.48–0.83). Neoadjuvant CPT-11 and HART allow for excellent local control; however, distant relapse remains a concern in this patient population

Next Generation Sequencing to Determine the Cystic Fibrosis Mutation Spectrum in Palestinian Population

An extensive molecular analysis of the CF transmembrane regulator (CFTR) gene was performed to establish the CFTR mutation spectrum and frequencies in the Palestinian population, which can be considered as an understudied population. We used a targeted Next Generation Sequencing approach to sequence the entire coding region and the adjacent sequences of the CFTR gene combined with MLPA analysis of 60 unrelated CF patients. Eighteen different CF-causing mutations, including one previously undescribed mutation p.(Gly1265Arg), were identified. The overall detection rate is up to 67%, and when we consider only CF patients with sweat chloride concentrations >70 mEq/L, we even have a pickup rate of 92%. Whereas p.(Phe508del) is the most frequent allele (35% of the positive cases), 3 other mutations c.2988+1Kbdel8.6Kb, c.1393-1G>A, and p.(Gly85Glu) showed frequencies higher than 5% and a total of 9 mutations account for 84% of the mutations. This limited spectrum of CF mutations is in agreement with the homozygous ethnic origin of the Palestinian population. The relative large portion of patients without a mutation is most likely due to clinical misdiagnosis. Our results will be important in the development of an adequate molecular diagnostic test for CF in Palestine

Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model

Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor β (TGFβ)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGFβ receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGFβ signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378*nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno)histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS

Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP

Background: Nonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity. Methods: We identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression. Results: Affected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old. Conclusion: This study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype

Automatic Identification of Defects on Eggshell Through a Multispectral Vision System

The objective of this research was to develop an off-line artificial vision system to automatically detect defective eggshells, i.e., dirty or cracked eggshells, by employing multispectral images with the final purpose to adapt the system to an on-line grading machine. In particular, this work was focused to study the feasibility of identifying organic stains on brown eggshells (dirty eggshell), caused by blood, feathers, feces, etc., from natural stains, caused by deposits of pigments on the outer layer of clean eggshells. During the analysis a total of 384 eggs were evaluated (clean: 148, dirty: 236). Dirty samples were evaluated visually in order to classify them according to the kind of defect (blood, feathers, and white, clear or dark feces), and clean eggshells were classified on the basis of the colour of the natural stains (clear or dark). For each sample digital images were acquired by employing a Charged Coupled Device (CCD) camera endowed with 15 monochromatic filters (440-940 nm). A Matlab® function was developed in order to automate the process and analyze images, with the aim to classify samples as clean or dirty. The program was constituted by three major steps: first, the research of an opportune combination of monochromatic images in order to isolate the eggshell from the background; second, the detection of the dirt stains; third, the classification of the images samples into the dirty or clean group on the basis of geometric characteristics of the stains (area in pixel). The proposed classification algorithm was able to correctly classify near 98% of the samples with a very low processing time (0.05s). The robustness of the proposed classification was observed applying an external validation to a second set of samples (n = 178), obtaining similar percentage of correctly classified samples (97%)