Intracoronary Brachytherapy for Restenosis: 20 Years of Follow-Up.

Intracoronary brachytherapy (ICB) has mainly been used to treat in-stent restenosis following percutaneous coronary intervention and was virtually abandoned about 20 years ago. However, patients treated with this strategy are still alive and some teams continue to perform this therapy. We aimed to investigate the very long-term clinical outcome of patients treated with ICB. A total of 173 consecutive patients who had been treated with ICB at a large tertiary referral centre between 1998 and 2003 were included. The primary endpoint of the study was all-cause mortality. The secondary endpoints were as follows: occurrence of major adverse cardiac events (MACE, defined as all-cause death, non-fatal myocardial infarction, or target vessel revascularization), cardiac death, and presence of angina at the end of follow-up. Patients' mean age at the time of ICB was 64 ± 10 years and 77 % were male. Restenosis (bare metal stent vs. balloon angioplasty) was the only indication for ICB. Unstable angina was present in 34 % of the patients. Follow-up was available for 166 patients. After a mean follow-up of 20 ± 1.3 years, 66 % of the patients had died (including 74 patients (67 %) with cardiac death). Cumulative MACE rate at 20 years was 96 %. Very long-term follow-up of patients with in-stent restenosis treated with ICB confirmed a high all-cause mortality rate mainly due to cardiac causes and MACEs

A treatment planning intercomparison of proton and intensity modulated photon radiotherapy.

peer reviewedAbstract Purpose: A comparative treatment planning study has been undertaken between standard photon delivery techniques,b intensity modulated photon methods and spot scanned protons in order to investigate the merits and limitations of each of these treatment approaches. Methods: Plans for each modality were performed using CT scans and planning information for nine patients with varying indications and lesion sites and the results have been analysed using a variety of dose and volume based parameters. Results: Over all cases, it is predicted that the use of protons could lead to a reduction of the total integral dose by a factor three compared to standard photon techniques and a factor two compared to IM photon plans. In addition, in all but one Organ at Risk (OAR) for one case, protons are predicted to reduce both mean OAR dose and the irradiated volume at the 50% mean target dose level compared to both photon methods. However, when considering the volume of an OAR irradiated to 70% or more of the target dose, little difference could be shown between proton and intensity modulated photon plans. On comparing the magnitude of dose hot spots in OARs resulting from the proton and IM photon plans, more variation was observed, and the ranking of the plans was then found to be case and OAR dependent. Conclusions: The use of protons has been found to reduce the medium to low dose load (below about 70% of the target dose) to OARs and all non-target tissues compared to both standard and inversely planned photons, but that the use of intensity modulated photons can result in similar levels of high dose conformation to that afforded by protons. However, the introduction of inverse planning methods for protons is necessary before general conclusions on the relative efficacy of photons and protons can be drawn

Initial experience using the Palmaz Corinthian stent for right ventricular outflow obstruction in infants and small children

The original Palmaz balloon expandable stent has been used extensively for the treatment of vascular stenoses in older children and young adults. Placement of the Palmaz stent in infants and small children, however, is limited by stent inflexibility, large delivery sheath size, and concerns about creating fixed obstructions after the placement of small diameter stents in growing patients. New Palmaz Corinthian stents were placed through 6 French sheaths in four high-risk patients with postoperative right ventricular outflow obstruction. Patients were not considered candidates for surgical repair. Median patient age and weight were 17 months (range 5–32 months) and 7.7 kg (range 4.6–11.1 kg), respectively. Median fluoroscopy time was 58.2 min (range 55.2–172 min). No complications were encountered. In each case, successful stent placement was achieved, and surgery with cardiopulmonary bypass was avoided. Palmaz Corinthian stents are more flexible, require a smaller delivery sheath, have equal or increased radial strength, and can be maximally expanded to a greater cross sectional area when compared to the original Palmaz stent. These characteristics make the Palmaz Corinthian stent a reasonable alternative for use in a select group of infants and small children who are not candidates for surgical repair of postoperative right ventricular outflow obstruction. Cathet. Cardiovasc. Intervent. 51:444–449, 2000. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35251/1/14_ftp.pd

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%)

Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.

Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms