The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ (DCIS)

Introduction Ductal carcinoma in situ (DCIS) is a noninvasive non-obligate precursor of invasive breast cancer. With guideline concordant care (GCC), DCIS outcomes are at least as favourable as some other early stage cancer types such as prostate cancer, for which active surveillance (AS) is a standard of care option. However, AS has not yet been tested in relation to DCIS. The goal of the COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial for low-risk DCIS is to gather evidence to help future patients consider the range of treatment choices for low-risk DCIS, from standard therapies to AS. The trial will determine whether there may be some women who do not substantially benefit from current GCC and who could thus be safely managed with AS. This protocol is version 5 (11 July 2018). Any future protocol amendments will be submitted to Quorum Centralised Institutional Review Board/local institutional review boards for approval via the sponsor of the study (Alliance Foundation Trials). Methods and analysis COMET is a phase III, randomised controlled clinical trial for patients with low-risk DCIS. The primary outcome is ipsilateral invasive breast cancer rate in women undergoing GCC compared with AS. Secondary objectives will be to compare surgical, oncological and patient-reported outcomes. Patients randomised to the GCC group will undergo surgery as well as radiotherapy when appropriate; those in the AS group will be monitored closely with surgery only on identification of invasive breast cancer. Patients in both the GCC and AS groups will have the option of endocrine therapy. The total planned accrual goal is 1200 patients. Ethics and dissemination The COMET trial will be subject to biannual formal review at the Alliance Foundation Data Safety Monitoring Board meetings. Interim analyses for futility/safety will be completed annually, with reporting following Consolidated Standards of Reporting Trials (CONSORT) guidelines for noninferiority trials

Ductal carcinoma in situ: to treat or not to treat, that is the question

Abstract: Ductal carcinoma in situ (DCIS) now represents 20–25% of all ‘breast cancers’ consequent upon detection by population-based breast cancer screening programmes. Currently, all DCIS lesions are treated, and treatment comprises either mastectomy or breast-conserving surgery supplemented with radiotherapy. However, most DCIS lesions remain indolent. Difficulty in discerning harmless lesions from potentially invasive ones can lead to overtreatment of this condition in many patients. To counter overtreatment and to transform clinical practice, a global, comprehensive and multidisciplinary collaboration is required. Here we review the incidence of DCIS, the perception of risk for developing invasive breast cancer, the current treatment options and the known molecular aspects of progression. Further research is needed to gain new insights for improved diagnosis and management of DCIS, and this is integrated in the PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) initiative. This international effort will seek to determine which DCISs require treatment and prevent the consequences of overtreatment on the lives of many women affected by DCIS

NeuriteQuant: An open source toolkit for high content screens of neuronal Morphogenesis

<p>Abstract</p> <p>Background</p> <p>To date, some of the most useful and physiologically relevant neuronal cell culture systems, such as high density co-cultures of astrocytes and primary hippocampal neurons, or differentiated stem cell-derived cultures, are characterized by high cell density and partially overlapping cellular structures. Efficient analytical strategies are required to enable rapid, reliable, quantitative analysis of neuronal morphology in these valuable model systems.</p> <p>Results</p> <p>Here we present the development and validation of a novel bioinformatics pipeline called NeuriteQuant. This tool enables fully automated morphological analysis of large-scale image data from neuronal cultures or brain sections that display a high degree of complexity and overlap of neuronal outgrowths. It also provides an efficient web-based tool to review and evaluate the analysis process. In addition to its built-in functionality, NeuriteQuant can be readily extended based on the rich toolset offered by ImageJ and its associated community of developers. As proof of concept we performed automated screens for modulators of neuronal development in cultures of primary neurons and neuronally differentiated P19 stem cells, which demonstrated specific dose-dependent effects on neuronal morphology.</p> <p>Conclusions</p> <p>NeuriteQuant is a freely available open-source tool for the automated analysis and effective review of large-scale high-content screens. It is especially well suited to quantify the effect of experimental manipulations on physiologically relevant neuronal cultures or brain sections that display a high degree of complexity and overlap among neurites or other cellular structures.</p

Outcomes after Total Skin-sparing Mastectomy and Immediate Reconstruction in 657 Breasts

ABSTRACT Background. Total skin-sparing mastectomy (TSSM), a technique comprising removal of all breast and nipple tissue while preserving the entire skin envelope, is increasingly offered to women for therapeutic and prophylactic indications. However, standard use of the procedure remains controversial as a result oft concerns regarding oncologic safety and risk of complications. Methods. Outcomes from a prospectively maintained database of patients undergoing TSSM and immediate breast reconstruction from 2001 to 2010 were reviewed. Outcome measures included postoperative complications, tumor involvement of the nipple-areolar complex (NAC) on pathologic analysis, and cancer recurrence. Results. TSSM was performed on 657 breasts in 428 patients. Indications included in situ cancer [111 breasts (16.9 %)], invasive cancer [301 breasts (45.8 %)], and prophylactic risk-reduction [245 breasts (37.3 %)]. A total of 210 patients (49 %) had neoadjuvant chemotherapy, 78 (18.2 %) had adjuvant chemotherapy, and 114 (26.7 %) had postmastectomy radiotherapy. Nipple tissue contained in situ cancer in 11 breasts (1.7 %) and invasive cancer in 9 breasts (1.4 %); management included repeat excision (7 cases), NAC removal (9 cases), or radiotherapy without further excision (4 cases). Ischemic complications included 13 cases (2 %) of partial nipple loss, 10 cases (1.5 %) of complete nipple loss, and 78 cases (11.9 %) of skin flap necrosis. Overall locoregional recurrence rate was 2 % (median follow-up 28 months), with a 2.4 % rate observed in the subset of patients with at least 3 years&apos; follow-up (median 45 months). No NAC skin recurrences were observed. Conclusions. In this large, high-risk cohort, TSSM was associated with low rates of NAC complications, nipple involvement, and locoregional recurrence. Mastectomy with complete preservation of the skin envelope has been developed as an extension of skin-sparing mastectomy to improve aesthetic and psychological outcomes for patients. Nipple-sparing, or total skin-sparing, mastectomy techniques entail complete removal of all breast tissue with excision of the nipple tissue while preserving the entire skin envelope. The technique of total skin-sparing mastectomy (TSSM) is differentiated from subcutaneous mastectomy in that minimal, if any, nipple tissue is left behind. However, as with the initial reaction to skin-sparing mastectomy, there is still significant concern that preservation of the nipple-areolar complex (NAC) skin may increase locoregional recurrence rates. Although this concern has limited the widespread adoption of the technique, the recent publication of several studies with longer follow-up describing recurrence rates similar to those after skin-sparing mastectomy demonstrate that the technique does not appear to jeopardize oncologic safety

Surgical Patterns of Care in Patients with Invasive Breast Cancer Treated with Neoadjuvant Systemic Therapy and Breast Magnetic Resonance Imaging: Results of a Secondary Analysis of TBCRC 017

Neoadjuvant chemotherapy (NCT) down-stages advanced primary tumors, with magnetic resonance imaging (MRI) being the most sensitive imaging predictor of response. However, the impact of MRI evaluation on surgical treatment decisions in the neoadjuvant setting has not been well described. We report surgical patterns of care across 8 National Cancer Institute comprehensive cancer centers in women receiving both NCT and MRI to evaluate the impact of MRI findings on surgical planning

Arthropod Phylogenetics in Light of Three Novel Millipede (Myriapoda: Diplopoda) Mitochondrial Genomes with Comments on the Appropriateness of Mitochondrial Genome Sequence Data for Inferring Deep Level Relationships

Background Arthropods are the most diverse group of eukaryotic organisms, but their phylogenetic relationships are poorly understood. Herein, we describe three mitochondrial genomes representing orders of millipedes for which complete genomes had not been characterized. Newly sequenced genomes are combined with existing data to characterize the protein coding regions of myriapods and to attempt to reconstruct the evolutionary relationships within the Myriapoda and Arthropoda. Results The newly sequenced genomes are similar to previously characterized millipede sequences in terms of synteny and length. Unique translocations occurred within the newly sequenced taxa, including one half of the Appalachioria falcifera genome, which is inverted with respect to other millipede genomes. Across myriapods, amino acid conservation levels are highly dependent on the gene region. Additionally, individual loci varied in the level of amino acid conservation. Overall, most gene regions showed low levels of conservation at many sites. Attempts to reconstruct the evolutionary relationships suffered from questionable relationships and low support values. Analyses of phylogenetic informativeness show the lack of signal deep in the trees (i.e., genes evolve too quickly). As a result, the myriapod tree resembles previously published results but lacks convincing support, and, within the arthropod tree, well established groups were recovered as polyphyletic. Conclusions The novel genome sequences described herein provide useful genomic information concerning millipede groups that had not been investigated. Taken together with existing sequences, the variety of compositions and evolution of myriapod mitochondrial genomes are shown to be more complex than previously thought. Unfortunately, the use of mitochondrial protein-coding regions in deep arthropod phylogenetics appears problematic, a result consistent with previously published studies. Lack of phylogenetic signal renders the resulting tree topologies as suspect. As such, these data are likely inappropriate for investigating such ancient relationships