Standard fractionation external beam radiotherapy with and without intraoperative radiotherapy for locally recurrent rectal cancer: the role of local therapy in patients with a high competing risk of death from distant disease

ObjectiveWe sought to evaluate the effectiveness and safety of utilizing radiotherapy (RT) with standard fractionation, with or without intraoperative RT (IORT), to treat locally recurrent rectal cancer (LRRC).MethodsRetrospective review of 25 patients with LRRC treated with standard fractionation RT from 2005 to 2011. 15 patients (60%) had prior pelvic RT and 10 (40%) had synchronous metastases. The median equivalent dose in 2-Gy fractions was 30 and 49.6 Gy in patients with and without prior RT, respectively. 23 patients (92%) received concurrent chemotherapy and 16 (64%) underwent surgical resection. Eight patients (33.3%, four with and four without prior RT) received IORT. A competing risks model was developed to estimate the cumulative incidence of local failure with death treated as a competing event.ResultsMedian follow-up was 36.9 months after the date of local recurrence. 3-year rates of overall survival (OS), local control (LC) and death with LC were 51.6%, 73.3% and 69.2%, respectively. On multivariable analysis, surgical resection was significantly predictive of improved OS (p < 0.05). If surgical resection were removed from the multivariable model, given the collinearity between IORT delivery and surgical resection, then IORT also became a significant predictor of OS (p < 0.05). Systemic disease at the time of local recurrence was not associated with either LC or OS. No patient had grade ≥3 acute or late toxicity.ConclusionRT with standard fractionation is safe and effective in the treatment of patients with LRRC, even in patients with significant risk of systemic disease and/or history of prior RT. Advances in knowledge: The utility of RT with standard fractionation, generally with chemotherapy, in the treatment of LRRC is demonstrated. In this high-risk cohort of patients with a 40% incidence of synchronous metastatic disease, surgical resection of the recurrence was the major predictor of OS, though a benefit to IORT was also suggested. No patients had grade ≥3 acute or late toxicity, though 40% had undergone prior RT, underscoring the tolerability of standard fractionation RT in this setting

Adherens junctions and cadherins in Drosophila development

Drosophila represents a paradigm for the analysis of the cellular, molecular and genetic mechanisms of development and is an ideal model system to study the contribution of Adherens Junctions (AJs) and their major components, cadherins, to morphogenesis. The combination of different techniques and approaches has allowed researchers to identify the requirements of these epithelial junctions in vivo in the context of a whole organism. The functional analysis of mutants for AJ core components, particularly for Drosophila DE-cadherin, has shown that AJs play critical roles in virtually all stages of development. For instance, AJs maintain tissue integrity while allowing the remodelling and homeostasis of many tissues. They control cell shape, contribute to cell polarity, facilitate cell-cell recognition during cell sorting, orient cell divisions, or regulate cell rearrangements, among other activities. Remarkably, these activities require a very fine control of the organisation and turnover of AJs during development. In addition, AJs engage in diverse and complex interactions with the cytoskeleton, signalling networks, intracellular trafficking machinery or polarity cues to perform these functions. Here, by summarising the requirements of AJs and cadherins during Drosophila morphogenesis, we illustrate the capital contribution of this model system to our knowledge of the mechanisms and biology of AJs.Work in our lab is supported by funds from the Ministerio de Ciencia e Innovación (BFU2009-09041/BMC) and AGAUR-Generalitat de Catalunya (2009-SGR1333) to ML, and from Programme Consolider 2007 (CSD2007-00008) project. A.L. acknowledges a contract from the “Juan de la Cierva” programme.Peer Reviewe