A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.

Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits

Endovascular repair of a life-threatening radiation-induced ruptured false aneurysm of the intrathoracic left subclavian artery: Case report

Massive hemorrhage in tracheostomy patients is generally described as a result of a tracheoinnominate artery fistula. Other etiologies for rupture of a false aneurysm are rare. The classical procedure for subclavian artery aneurysm is open surgery. Endovascular techniques have been accepted by several authors as a possible minimally invasive alternative. We report a life-threatening radiation-induced ruptured false aneurysm of the intrathoracic subclavian artery successfully treated by endovascular stent graft through left brachial access in a tracheostomy patient.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Neuronal localization in the rat brain of the messenger RNA encoding calcyphosine, a new calcium-binding protein

The cDNA encoding calcyphosine, a new calcium-binding protein of the calmodulin superfamily which is regulated by cAMP, has been cloned in the dog thyroid (EMBO J. 8 (1989) 111-116). By in situ hybridization with synthetic oligonucleotides, we here demonstrate for the first time its neuronal localization in the rat brain. Hybridization signal was detected in all the olfactory areas; in pyramidal and non pyramidal-shaped neurons in the different layers of the cerebral cortex, especially the superficial ones; in the pyramidal cells of the different sectors of the Ammon's horn and in the granule cells of the dentate gyrus of the hippocampus; in the subiculum; in the medium-sized and large neurons of the different quadrants of the caudate-putamen and accumbens and in the cerebellar Purkinje cells. Hybridization was also observed to a lesser extent in the majority of the neurons in the basal areas of the forebrain, including septum, nucleus of the diagonal band and amygala; in the globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata and compacta, ventral tegmental area; in the subthalamic nucleus; in the thalamus; in the hypothalamus; in the brainstem and in the upper cervical spinal cord. In addition to its neuronal localization, calcyphosine mRNA was also found in ependymal cells. The non-detection of positive cells in the white matter was not in favor of prominent glial localization, although it does not exclude it.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Preliminary results from a prospective study of laparoscopic aortobifemoral bypass using a clampless and sutureless aortic anastomotic technique

Objective This prospective study describes the feasibility and safety of a new clampless and sutureless aortic anastomotic technique used during retroperitoneal laparoscopic aortobifemoral bypass in extensive aortoiliac occlusive lesions. This is a case series of a previously published technique, demonstrating wider applicability of the technique. Materials and methods Twelve patients underwent a clampless and sutureless laparoscopic bypass for TASC D aortoiliac occlusive lesions using the EndoVascular REtroperitoneoScopic Technique (EVREST). Dissection of the retroperitoneal space and the infrarenal aorta was performed laparoscopically. A bifurcated graft was inserted into the retroperitoneal space. The main body of the graft was connected on the left side of the aorta by an intra- and extra-aortic covered stent-graft. An aortic clamp was used temporarily on four patients because of excessive bleeding when the connector was deployed. The femoral anastomoses were performed by classic open surgery. Initial technical success, complications, and bypass patency were assessed. Results Median follow-up was 9.3 months. Median operative time was 265 minutes. Median duration of aorto-prosthetic connection was 60 seconds. Thirty-day postoperative mortality was 0%. No major postoperative complications were observed. All grafts were patent at the end of follow-up and there was no early or late disruption of the proximal assembly. Conclusions EVREST greatly facilitates laparoscopic aortic surgery in occlusive disease with no need for suture or clamping of the aorta. This technique performed in a single center on 12 patients, seems to be feasible and safe. It offers the advantages of laparoscopy and those of endovascular surgery, especially in the challenging conditions encountered during aortic laparoscopic surgery. Early experience supports procedural and initial postprocedural safety and demonstrates proof-of-concept for EVREST.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Study of numerical aberrations of chromosome 1 by fluorescent in situ hybridization and DNA content by densitometric analysis on (pre)-malignant cervical lesions

In an attempt to determine whether the fluorescent in situ hybridization (FISH) can be used as a rapid approach for the identification of aneuploidy in premalignant cervical smears, a centromeric probe for chromosome 1 was used. The results from the FISH experiments were compared with measurements of the overall DNA content obtained by means of an image analysis system. With progression to neoplasia, a decrease of the frequency of cells with two spots was observed, due to an increasing polysomy of chromosome 1. As far as the DNA content was concerned, an increasing DNA index and 5C-exceeding ratio (fraction of cells with a DNA content higher than 5C) was observed. Classification of the FISH results by a linear discriminant analysis revealed that 67.6% of the cases were classified in agreement with the CIN classification. These data suggest that chromosome 1 may be considered as a marker chromosome for pre-malignant cervical lesions and that the DNA content measurements are complementary to the FISH results. © 1995 Chapman & Hall.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Virologic therapy response significantly correlates with the number of active drugs as evaluated using a LiPA HIV-1 resistance scoring system

Background: Resistance testing is increasingly accepted as a tool in guiding the selection of human immunodeficiency virus type 1 (HIV-1) antiretroviral therapy in HIV-1 infected individuals who fail their current regimen. Objectives: To descriptively compare the correlation between virologic treatment response and results using three genotypic HIV-1 drug resistance interpretation systems: the VERSANT(R) HIV-1 Resistance Assay (LiPA) system and two sequence-based interpretation systems. Study design: Specimens from 213 HIV-1-infected subjects, either starting (n = 104) or switching to (n = 109) a regimen of three or four antiretroviral drugs, were collected retrospectively at baseline and after 3 months of uninterrupted therapy. The correlation between viral load change and the number of predicted active drugs in the treatment regimen was assessed. An interpretation algorithm was recently developed to process VERSANT(R) HIV-1 Resistance Assay (LiPA) data. The number of active drugs predicted using this algorithm was rank correlated with the viral load change over a 3-month treatment period. For comparison, a similar calculation was made using two sequence-based algorithms (REGA version 5.5 and VGI GuideLines(TM) Rules 4.0), both applied on the same sequences. Results: Statistically significant (p < 0.05) correlation coefficients for each of the three HIV-1 drug resistance interpretation systems were observed in the treatment-experienced subjects on a 3-drug regimen (-0.39, -0.38, and -0.42, respectively) as well as on a 4-drug regimen (-0.33, -0.31, and -0.37, respectively). However, no significant correlation was observed in treatment-naive subjects, probably due to the very low frequency of drug resistance in these subjects. Conclusion: All three genotypic drug resistance interpretation systems (LiPA version 1, REGA version 5.5, and VGI GuideLines(TM) Rules 4.0) were statistically significantly correlated with virologic therapy response as measured by viral load testing. (C) 2004 Elsevier B.V. All rights reserved

Influence of short-term unweighing and reloading on running kinetics and muscle activity

International audienceIn running, body weight reduction is reported to result in decreased lower limb muscle activity with no change in the global activation pattern (Liebenberg et al. in J Sports Sci 29:207-214). Our study examined the acute effects on running mechanics and lower limb muscle activity of short-term unweighing and reloading conditions while running on a treadmill with a lower body positive pressure (LBPP) device. Eleven healthy males performed two randomized running series of 9 min at preferred speed. Each series included three successive running conditions of 3 min [at 100 % body weight (BW), 60 or 80 % BW, and 100 % BW]. Vertical ground reaction force and center of mass accelerations were analyzed together with surface EMG activity recorded from six major muscles of the left lower limb for the first and last 30 s of each running condition. Effort sensation and mean heart rate were also recorded. In both running series, the unloaded running pattern was characterized by a lower step frequency (due to increased flight time with no change in contact time), lower impact and active force peaks, and also by reduced loading rate and push-off impulse. Amplitude of muscle activity overall decreased, but pre-contact and braking phase extensor muscle activity did not change, whereas it was reduced during the subsequent push-off phase. The combined neuro-mechanical changes suggest that LBPP technology provides runners with an efficient support during the stride. The after-effects recorded after reloading highlight the fact that 3 min of unweighing may be sufficient for updating the running pattern