Helical tomotherapy or intensity-modulated radiation therapy in the treatment of anal cancer: experience of Geneva and Lausanne

Background: To assess the early clinical outcomes and toxicities in patients treated with high precision radiation therapy (RT) consisting of helical tomotherapy (HT) or intensity-modulated radiation therapy (IMRT) for anal cancer. Materials and Methods: Since March 2006, 30 patients with stage I-IIIB anal squamous-cell carcinoma were treated curatively by IMRT or HT alone (n = 2) or by concomitant chemotherapy and IMRT or HT (n = 28). Median age was 59 years (range, 36−83 years) and the female/male ratio was 2.3 (21/9). Primary tumor site was anal canal, anal margin, or both in 26, 1, and 3 patients, respectively. Anal tumor, pelvic and inguinal nodes were irradiated with a median dose of 36 Gy using HT, or 5- or 7-field IMRT in 18 and 12 patients, respectively; After a planned gap of 1−2 weeks (median 1 week), a median boost dose of 23.4 Gwas delivered to the tumor and/or involved nodes using 3DRT (n = 24) or HT/IMRT (n = 6). The total delivered dose ranged between 59.4 and 64.8 Gy (median, 59.4 Gy). Concomitant chemotherapy consisted of mitomycin C alone (n = 1), mitomycin C and 5-fluorouracil (n = 17) or capecitabin (n = 10) in 28 patients. Common Terminology Criteria for Adverse Events v3.0 scale was used to score acute and late toxicities. Results: All but one patient, who developed progressive local and distant disease at the end of RT, achieved a complete response. Twelve months following RT, one patient had a recurrence at the primary tumor site, salvaged with brachytherapy. After a median follow-up of 7.5 months (range, 1−35 months), no deaths were observed. The 2-year actuarial locoregional control and probability of disease control without colostomy rates were 82% and 79%, respectively. RT was well tolerated without any unplanned treatment interruptions. Grade 1 or 2 acute adverse events consisted of skin toxicity in 8 and 22 patients, diarrhea in 18 and 3 patients, and cystitis in 9 and 2 patients; respectively. Only one patient developed grade 3 mucosal necrosis at the end of the treatment, requiring diverting colostomy. No difference in terms of acute toxicity was observed between patients treated with HT or IMRT. None of the 22 patients with a follow-up of more than 3 months developed grade 3 or more late toxicity. Conclusions: Our preliminary results suggest that HT or IMRT combined with concomitant chemotherapy for anal cancer is effective, and associated with favorable rates of toxicity compared with historical series. Further follow-up is warranted to assess late toxicity.

Mepraia spinolai in the Southeastern Pacific Ocean Coast (Chile) - First insular record and feeding pattern on the Pan de Azúcar Island

In a field collection performed at Pan de Azúcar Island in Northern Chile, 95 specimens representing all instars of Mepraia spinolai were collected. The intestinal contents of 55 specimens were examined for Trypanosoma cruzi infection and were found to be negative. This is the first record of an insular habitat for M. spinolai, where the insects had fed mainly on seabirds (78%), some on marine mammals (5%), and some on reptiles (7%).

HIV-associated neurocognitive disorders (HAND): a changing pattern

Combination antiretroviral therapy has dramatically decreased the incidence of HIV-related mortality and serious opportunistic diseases, among which is HIV- associated dementia. However, minor forms of cognitive dysfunction have not disappeared and may even have increased in frequency. Aging of HIV+ patients, insufficient penetration of antiretroviral drugs into the brain with continuous low- grade viral production and inflammation may play a role. A putative neurotoxicity of combination antiretroviral therapy is controversial. In this article, we will discuss these aspects, as well as clinical and pathophysiological features shared by HIV-associated neurocognitive disorders and other neurodegenerative diseases, especially Alzheimer's disease. This article will briefly summarize the current clinical trials on neuroprotective agents, and the management of patients with neurocognitive disorders will be discussed

Hybridisation and diversification in the adaptive radiation of clownfishes.

BackgroundThe importance of hybridisation during species diversification has long been debated among evolutionary biologists. It is increasingly recognised that hybridisation events occurred during the evolutionary history of numerous species, especially during the early stages of adaptive radiation. We study the effect of hybridisation on diversification in the clownfishes, a clade of coral reef fish that diversified through an adaptive radiation process. While two species of clownfish are likely to have been described from hybrid specimens, the occurrence and effect of hybridisation on the clade diversification is yet unknown.ResultsWe generate sequences of three mitochondrial genes to complete an existing dataset of nuclear sequences and document cytonuclear discordance at a node, which shows a drastic increase of diversification rate. Then, using a tree-based jack-knife method, we identify clownfish species likely stemming from hybridisation events. Finally, we use molecular cloning and identify the putative parental species of four clownfish specimens that display the morphological characteristics of hybrids.ConclusionsOur results show that consistently with the syngameon hypothesis, hybridisation events are linked with a burst of diversification in the clownfishes. Moreover, several recently diverged clownfish lineages likely originated through hybridisation, which indicates that diversification, catalysed by hybridisation events, may still be happening.

EORTC Radiation Oncology Group quality assurance platform: establishment of a digital central review facility.

OBJECTIVE: Quality assurance (QA) in clinical trials is essential to ensure treatment is safely and effectively delivered. As QA requirements have increased in complexity in parallel with evolution of radiation therapy (RT) delivery, a need to facilitate digital data exchange emerged. Our objective is to present the platform developed for the integration and standardization of QART activities across all EORTC trials involving RT. METHODS: The following essential requirements were identified: secure and easy access without on-site software installation; integration within the existing EORTC clinical remote data capture system; and the ability to both customize the platform to specific studies and adapt to future needs. After retrospective testing within several clinical trials, the platform was introduced in phases to participating sites and QART study reviewers. RESULTS: The resulting QA platform, integrating RT analysis software installed at EORTC Headquarters, permits timely, secure, and fully digital central DICOM-RT based data review. Participating sites submit data through a standard secure upload webpage. Supplemental information is submitted in parallel through web-based forms. An internal quality check by the QART office verifies data consistency, formatting, and anonymization. QART reviewers have remote access through a terminal server. Reviewers evaluate submissions for protocol compliance through an online evaluation matrix. Comments are collected by the coordinating centre and institutions are informed of the results. CONCLUSIONS: This web-based central review platform facilitates rapid, extensive, and prospective QART review. This reduces the risk that trial outcomes are compromised through inadequate radiotherapy and facilitates correlation of results with clinical outcomes.

Stereotactic body radiation therapy in stage I inoperable lung cancer: from palliative to curative options.

Surgery has historically been the standard of care for operable stage I non-small cell lung cancer (NSCLC). However, nearly one-quarter of patients with stage I NSCLC will not undergo surgery because of medical comorbidity or other factors. Stereotactic ablative radiotherapy (SABR) is the new standard of care for these patients. SABR offers high local tumour control rates rivalling the historical results of surgery and is generally well tolerated by patients with both peripheral and centrally located tumours. This article reviews the history of SABR for stage I NSCLC, summarises the currently available data on efficacy and toxicity, and describes some of the currently controversial aspects of this treatment.

The Development of Radiation Oncology Services in Ireland

The Development of Radiation Oncology Services in Ireland The provision of a high quality radiation oncology service is one of the cornerstones of a modern treatment programme for cancer patients. Timely and equitable access to a radiation oncology service of the highest international standard should be available to all cancer patients in Ireland and it was the achievement of this goal that guided and motivated the group in producing this report and its accompanying recommendations. Click here to download PDF 46kb

The Development of Radiation Oncology Services in Ireland

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Relationship between antennal sensilla pattern and habitat in six species of Triatominae

In order to determine if habitat similarity is correlated with a similarity of sensilla pattern, we analyzed six species of Triatominae present in two biogeographic regions of Brazil: the "caatinga" and the "cerrado". In broad terms Triatoma infestans (cerrado) and T. brasiliensis (caatinga) are found in human domiciles, T. sordida (cerrado) and T. pseudomaculata (caatinga) colonize peridomestic habitats, and Rhodnius neglectus (cerrado) and R. nasutus (caatinga) inhabit palm tree crowns. The number and distribution of four sensilla types (bristles, thin and thick walled trichoidea, and basiconica) were compared in these species. Sexual dimorphism of sensilla patterns was noted in T. sordida, T. brasiliensis and T. pseudomaculata. A principal component analysis showed three main groups: (i) species that live in the palms, (ii) domiciliated species and (iii) those living in the peridomestic habitat. T. infestans almost exclusively domestic, was placed at the centre of the canonical map and some individuals of other species overlapped there. These results support the idea that the patterns of antennal sensilla are sensitive indicators of adaptive process in Triatominae. We propose that those species that inhabit less stable habitats possess more types of sensilla on the pedicel, and higher number of antennal sensilla.

New insights into the long-term evolutionary history of the avian MHC

SummaryGene duplication and neofunctidnalization are important processes in the evolution of phenotypic complexity. They account for important evolutionary novelties that confer ecological adaptation, such as the major histocompatibility complex (MHC), a multigene family with a central role in vertebrates' adaptive immune system. Multigene families, which evolved in large part through duplication, represent promising systems to study the still strongly depbated relative roles of neutral and adaptive processes in the evolution of phenotypic complexity. Detailed knowledge on ecological function and a well-characterized evolutionary history place the mammals' MHC amongst ideal study systems. However mammalian MHCs usually encompass several million base pairs and hold a large number of functional and non-functional duplicate genes, which makes their study complex. Avian MHCs on the other hand are usually way more compact, but the reconstruction of. their evolutionary history has proven notoriously difficult. However, no focused attempt has been undertaken so far to study the avian MHC evolutionary history in a broad phylogenetic context and using adequate gene regions.In the present PhD, we were able to make important contributions to the understanding of the long-term evolution of the avian MHC class II Β (MHCI1B). First, we isolated and characterized MHCIIB genes in barn owl (Tyto alba?, Strigiformes, Tytonidae), a species from an avian lineage in which MHC has not been studied so far. Our results revealed that with only two functional MHCIIB genes the MHC organization of barn owl may be similar to the 'minimal essential' MHC of chicken (Gallus gallus), indicating that simple MHC organization may be ancestral to birds. Taking advantage of the sequence information from barn owl, we studied the evolution of MHCIIB genes in 13 additional species of 'typical' owls (Strigiformes, Strigidae). Phylogenetic analyses revealed that according to their function, in owls the peptide-binding region (PBR) encoding exon 2 and the non-PBR encoding exon 3 evolve by different patterns. Exon 2 exhibited an evolutionary history of positive selection and recombination, while exon 3 traced duplication history and revealed two paralogs evolving divergently from each other in owls, and in a shorebird, the great snipe {Gallinago media). The results from exon 3 were the first ever from birds to demonstrate gene orthology in species that diverged tens of millions of years ago, and strongly questioned whether the taxa studied before provided an adequate picture of avian MHC evolution. In a follow-up study, we aimed at explaining a striking pattern revealed by phylogenetic trees analyzing the owl sequences along with MHCIIB sequences from other birds: One owl paralog (termed DAB1) grouped with sequences of passerines and falcons, while the other (DAB2) grouped with wildfowl, penguins and birds of prey. This could be explained by either a duplication event preceding the evolution of these bird orders, or by convergent evolution of similar sequences in a number of orders. With extensive phylogenetic analyses we were able to show, that indeed a duplication event preceeded the major avian radiation -100 my ago, and that following this duplication, the paralogs evolved under positive selection. Furthermore, we showed that the divergently evolving amino acid residues in the MHCIIB-encoded β-chain potentially interact with the MHCI I α-chain, and that molecular coevolution of the interacting residues may have been involved in the divergent evolution of the MHCIIB paralogs.The findings of this PhD are of particular interest to the understanding of the evolutionary history of the avian MHC and, by providing essential information on long-term gene history in the avian MHC, open promising perspectives for advances in the understanding of the evolution of multigene families in general, and for avian MHC organization in particular. Amongst others I discuss the importance of including protein structure in the phylogenetic study of multigene families, and the roles of ecological versus molecular selection pressures. I conclude by providing a population genomic perspective on avian MHC, which may serve as a basis for future research to investigate the relative roles of neutral processes involving effective population size effects and of adaptation in the evolution of avian MHC diversity and organization.RésuméLa duplication de gènes et leur néo-fonctionnalisation sont des processus importants dans l'évolution de la complexité phénotypique. Ils sont impliqués dans l'apparition d'importantes nouveautés évolutives favorisant l'adaptation écologique, comme c'est le cas pour le complexe majeur d'histocompatibilité pattern surprenant révélé par les arbres phylogénétiques lorsque les séquences CMHIIB des chouettes sont analysées avec les séquences d'autres oiseaux: un paralogue de chouette (appelé DABI) forme un groupe avec les séquences de passereaux et faucons, tandis que l'autre (DAB2) se regroupe avec les gallo-ansériformes, les manchots et les rapaces diurnes. Ceci pourrait être expliqué soit par une duplication qui a précédé l'évolution de ces ordres aviaires soit par évolution convergente dans un certain nombre d'ordres. Grâce à des analyses phylogénétiques approfondies, nous avons pu montrer qu'un événement de duplication a effectivement précédé la radiation aviaire principale d'il y a environ 100 millions d'années, et qu'après cette duplication les paralogues ont évolué sous sélection positive. De plus, les résidus d'acides aminés évoluant de façon divergente dans la chaîne β codée par le CMHIIB interagissent potentiellement avec la chaîne α codée par le CMHII, et que la coévolution moléculaire de ces résidus pourrait être à la base de l'évolution divergente des paralogues CMHIIB.Dans cette thèse sont discutés entre autres l'importance d'inclure la structure des protéines dans l'étude phylogénétique des familles multigéniques, ainsi que les rôles respectifs des pressions sélectives écologique et moléculaire. La conclusion comporte une perspective sur la génomique des populations du CMH aviaire, qui pourrait servir de base pour de futures recherches sur les rôles relatifs joués par Îes processus neutres comprenant les effets de la taille efficace des populations et l'adaptation dans l'évolution de la diversité et l'organisation du MHC aviaire.

Effect of gamma radiation on the activity of hemocytes and on the course of Schistosoma mansoni infection in resistant Biomphalaria tenagophila snails

High doses of gamma radiation (10 Krad) in Biomphalaria tenagophila snails (Taim strain), which have been found to be resistant to Schistosoma mansoni, were not sufficient to impair their resistance to the parasite. The number of hemocytes, as well as their phagocytic activity, were not affected by irradiation, thus showing resemblance with mammal macrophages, which are resistant to gamma irradiation also.

Phenotypic divergence but not genetic distance predicts assortative mating among species of a cichlid fish radiation.

The hypothesis of ecological divergence giving rise to premating isolation in the face of gene flow is controversial. However, this may be an important mechanism to explain the rapid multiplication of species during adaptive radiation following the colonization of a new environment when geographical barriers to gene flow are largely absent but underutilized niche space is abundant. Using cichlid fish, we tested the prediction of ecological speciation that the strength of premating isolation among species is predicted by phenotypic rather than genetic distance. We conducted mate choice experiments between three closely related, sympatric species of a recent radiation in Lake Mweru (Zambia/DRC) that differ in habitat use and phenotype, and a distantly related population from Lake Bangweulu that resembles one of the species in Lake Mweru. We found significant assortative mating among all closely related, sympatric species that differed phenotypically, but none between the distantly related allopatric populations of more similar phenotype. Phenotypic distance between species was a good predictor of the strength of premating isolation, suggesting that assortative mating can evolve rapidly in association with ecological divergence during adaptive radiation. Our data also reveals that distantly related allopatric populations that have not diverged phenotypically, may hybridize when coming into secondary contact, e.g. upon river capture because of diversion of drainage systems.

Oviposition activity and seasonal pattern of a population of Aedes (Stegomyia) aegypti (L.) (Diptera: Culicidae) in subtropical Argentina

Monthly oviposition activity and the seasonal density pattern of Aedes aegypti were studied using larvitraps and ovitraps during a research carried out by the Public Health Ministry of Salta Province, in Tartagal, Aguaray and Salvador Mazza cities, in subtropical Argentina. The A. aegypti population was active in both dry and wet seasons with a peak in March, accordant with the heaviest rainfall. From May to November, the immature population level remained low, but increased in December. Ae. aegypti oviposition activity increased during the fall and summer, when the relative humidity was 60% or higher. Eggs were found in large numbers of ovitraps during all seasons but few eggs were observed in each one during winter. The occurrence and the number of eggs laid were variable when both seasons and cities were compared. The reduction of the population during the winter months was related to the low in the relative humidity of the atmosphere. Significant differences were detected between oviposition occurrences in Tartagal and Aguaray and Salvador Mazza cities, but no differences in the number of eggs were observed. Two factors characterize the seasonal distribution pattern of Ae. aegypti in subtropical Argentina, the absence of a break during winter and an oviposition activity concomitant of the high relative humidity of the atmosphere.

Intracellular pattern-recognition receptors

The last ten years of research in the field of innate immunity have been incredibly fertile: the transmembrane Toll-like receptors (TLRs) were discovered as guardians protecting the host against microbial attacks and the emerging pathways characterized in detail. More recently, cytoplasmic sensors were identified, which are capable of detecting not only microbial, but also self molecules. Importantly, while such receptors trigger crucial host responses to microbial insult, over-activity of some of them has been linked to autoinflammatory disorders, hence demonstrating the importance of tightly regulating their actions over time and space. Here, we provide an overview of recent findings covering this area of innate and inflammatory responses that originate from the cytoplasm

Decreased local control following radiation therapy alone in early-stage glottic carcinoma with anterior commissure extension.

PURPOSE: To assess the patterns of failure in the treatment of early-stage squamous cell carcinoma of the glottic larynx. PATIENTS AND METHODS: Between 1983-2000, 122 consecutive patients treated for early laryngeal cancer (UICC T1N0 and T2N0) by radical radiation therapy (RT) were retrospectively studied. Male-to-female ratio was 106 : 16, and median age 62 years (35-92 years). There were 68 patients with T1a, 18 with T1b, and 36 with T2 tumors. Diagnosis was made by biopsy in 104 patients, and by laser vaporization or stripping in 18. Treatment planning consisted of three-dimensional (3-D) conformal RT in 49 (40%) patients including nine patients irradiated using arytenoid protection. A median dose of 70 Gy (60-74 Gy) was given (2 Gy/fraction) over a median period of 46 days (21-79 days). Median follow-up period was 85 months. RESULTS: The 5-year overall, cancer-specific, and disease-free survival amounted to 80%, 94%, and 70%, respectively. 5-year local control was 83%. Median time to local recurrence in 19 patients was 13 months (5-58 months). Salvage treatment consisted of surgery in 17 patients (one patient refused salvage and one was inoperable; total laryngectomy in eleven, and partial laryngectomy or cordectomy in six patients). Six patients died because of laryngeal cancer. Univariate analyses revealed that prognostic factors negatively influencing local control were anterior commissure extension, arytenoid protection, and total RT dose < 66 Gy. Among the factors analyzed, multivariate analysis (Cox model) demonstrated that anterior commissure extension, arytenoid protection, and male gender were the worst independent prognostic factors in terms of local control. CONCLUSION: For early-stage laryngeal cancer, outcome after RT is excellent. In case of anterior commissure extension, surgery or higher RT doses are warranted. Because of a high relapse risk, arytenoid protection should not be attempted.