Is Excision of Radial Scars Identified on CNB Necessary?

Introduction: Quantifying the risk of upgrade to malignancy with radial scars has been an ongoing challenge, as the published upgrade rate varies widely from 0-40%, making management strategy controversial. The lack of consensus on optimal management highlights the need for further analysis. We sought to identify our institutional upgrade rate of radial scar identified on core needle biopsy (CNB). Methods: A retrospective review of pathology and radiology databases was performed to identify radial scars found on CNB. We excluded patients with malignancy associated with radial scar and those who did not undergo surgical excision. The upgrade rates to malignancy or other atypia on surgical excision were then evaluated. Results: We identified 127 patients with radial scar on CNB, of which 75 patients were excluded, leaving 52 patients for analysis. Of these, 4 of 52 (7.7%) patients had an upgrade to malignancy upon excision. Eight patients had additional atypia with radial scar on CNB, two of which upgraded to malignancy on excision. The rate of malignancy upgrade for isolated radial scar was 2 of 44 (4.5%). Of the 44 patients with isolated radial scar, 15 (34%) were found to have additional atypia on excision. Discussion: Although the upgrade rate to malignancy was only 4.5%, there was a substantial upgrade rate of isolated radial scar to additional atypia which can alter subsequent management. Additionally, 25% of radial scars with atypia upgraded to malignancy. Thus, careful consideration should be given to surgical excision of CNB showing radial scar with and without atypia

Success of Preoperative Radiotherapy in Inflammatory Breast Cancer with Inadequate Response to Taxane-Based Chemotherapies

Inflammatory breast cancer is a locally-aggressive and highly malignant cancer which often carries a poor prognosis for afflicted patients. Multi-modality treatment is often required, and taxane-based chemotherapy has shown improved outcomes and allowed for the pursuit of mastectomies, which are critical to disease control. Inadequate response to taxane-based chemotherapy indicates aggressive disease, and the role of preoperative radiotherapy for treatment in this patient group and its effects on patient outcomes and toxicity has not been studied. This study evaluates the effectiveness of preoperative radiotherapy on this patient group. Inflammatory breast cancer patients between 2012-2018 who were not deemed appropriate for resection following taxane-based chemotherapy leading to their referral for preoperative radiotherapy were identified. Patient, disease, and pre-surgical treatment characteristics were collected. A statistical analysis of surgical outcomes with regards to conversion to resectability, surgical margins, treatment response, complication rates, and locoregional recurrence was performed. 9 patients received neoadjuvant radiation following their inadequate response to taxane-based chemotherapy. 8 of 9 patients converted to resectable disease, 100% of which achieved R0 mastectomy. Median residual primary disease was 1cm, with a grade 1 toxicity being noted in 1 patient which resolved with conservative management. A single low cervical recurrence was observed 4 years after mastectomy. Based on the results of this study, preoperative radiation should be considered in inflammatory breast cancer patients who do not demonstrate adequate response to taxane-based chemotherapy. Use of preoperative radiotherapy in this patient group may lead to the improvement of patient outcomes and a decrease in treatment toxicity

Nipple Sparing Mastectomy: A Review of Outcomes at a 1 Single Institution

Introduction Nipple sparing mastectomy (NSM) offers patients who are not candidates for breast conserving treatment an aesthetically pleasing alternative to traditional mastectomy. Some studies have demonstrated its oncologic safety while others have demonstrated residual occult tumor cells at the nipple areolar complex (NAC). These data prompt further review of oncologic outcomes after NSM. Methods A single institution retrospective chart review of all NSMs performed by 4 breast surgeons at Thomas Jefferson University Hospital over a span of 2012-2019. In this cohort we review the reconstruction performed, axillary lymph node status, surgical margins, final pathology, loss of the NAC, recurrence rates, and follow-up. Results In our cohort we reviewed 170 NSMs performed on 105 patients. All patients were female and the average age was 46.9 years. Prophylactic procedures were performed on 43% of patients with 17.1% of patients being BRCA positive. Of those undergoing NSM for cancer (n=94) the associated pathology was 28.8% DCIS, 32.9% IDC, and 3.5% ILC (This accounts for some patients with multiple diagnoses on final pathology). Sentinel lymph node biopsy (SLNB) was performed in 52.9% of cases with 10.6% of cases being positive for axillary disease. Margins were positive in 10.6% (n=10) of cases performed for cancer with 8.5% (n=8) of cases having positive margin at the NAC and the remainder being at the deep margin. Based on margin positivity 2.4% (n=4) of patients underwent redo surgery with 1 patient requiring re-resection at the NAC margin and 3 patients having total NAC resection. Total loss of NAC occurred in 5.9% (n=10) of cases due to positive margins (n=3) and necrosis (n=7). Recurrence occurred in 7.2% (n=7) of cases who underwent NSM for cancer. Locoregional recurrence in breast tissue, skin, or axilla occurred in 4.1% (n=4) of cases with 0 recurrences at the NAC. Distant recurrence occurred in 4.1% (n=4) of cases at both liver and bone. Average time to recurrence was 27.3 months. Of the 170 NSM performed 98% had immediate tissue expander placement with 60% converting to permanent sub-pectoral implant reconstruction, 14% latissimus dorsi flap reconstruction, 0.6% delayed deep inferior epigastric artery perforator free flap reconstruction, and 5.2% undergoing delayed free transversus abdominus muscle flap reconstruction. Of all the cases reviewed there was only 1 death. Our average follow-up was 26.7 months. Conclusion We demonstrate similar numbers in our analysis as other studies that have looked at oncologic outcomes after NSM. Although we demonstrate evidence of occult disease at the NAC margin when performing NSM there was no evidence of recurrence at the NAC demonstrating its efficacy and safety. With proper patient selection this procedure can be safely offered as an aesthetically appealing alternative to traditional mastectom

VirMAP for Cancer: Characterization of the Intratumoral Virome in Virally-Associated Cancers and a Resource for Investigators

View full abstracthttps://openworks.mdanderson.org/leading-edge/1040/thumbnail.jp

Vimentin is a novel AKT1 target mediating motility and invasion.

The PI3K/AKT signaling pathway is aberrant in a wide variety of cancers. Downstream effectors of AKT are involved in survival, growth and metabolic-related pathways. In contrast, contradictory data relating to AKT effects on cell motility and invasion, crucial prometastatic processes, have been reported pointing to a potential cell type and isoform type-specific AKT-driven function. By implication, study of AKT signaling should optimally be conducted in an appropriate intracellular environment. Prognosis in soft-tissue sarcoma (STS), the aggressive malignancies of mesenchymal origin, is poor, reflecting our modest ability to control metastasis, an effort hampered by lack of insight into molecular mechanisms driving STS progression and dissemination. We examined the impact of the cancer progression-relevant AKT pathway on the mesenchymal tumor cell internal milieu. We demonstrate that AKT1 activation induces STS cell motility and invasiveness at least partially through a novel interaction with the intermediate filament vimentin (Vim). The binding of AKT (tail region) to Vim (head region) results in Vim Ser39 phosphorylation enhancing the ability of Vim to induce motility and invasion while protecting Vim from caspase-induced proteolysis. Moreover, vimentin phosphorylation was shown to enhance tumor and metastasis growth in vivo. Insights into this mesenchymal-related molecular mechanism may facilitate the development of critically lacking therapeutic options for these devastating malignancies

Paleogenomic Evidence for Multi-generational Mixing between Neolithic Farmers and Mesolithic Hunter-Gatherers in the Lower Danube Basin

The transition from hunting and gathering to farming involved profound cultural and technological changes. In Western and Central Europe, these changes occurred rapidly and synchronously after the arrival of early farmers of Anatolian origin [1-3], who largely replaced the local Mesolithic hunter-gatherers [1, 4-6]. Further east, in the Baltic region, the transition was gradual, with little or no genetic input from incoming farmers [7]. Here we use ancient DNA to investigate the relationship between hunter-gatherers and farmers in the Lower Danube basin, a geographically intermediate area that is characterized by a rapid Neolithic transition but also by the presence of archaeological evidence that points to cultural exchange, and thus possible admixture, between hunter-gatherers and farmers. We recovered four human paleogenomes (1.1× to 4.1× coverage) from Romania spanning a time transect between 8.8 thousand years ago (kya) and 5.4 kya and supplemented them with two Mesolithic genomes (1.7× and 5.3×) from Spain to provide further context on the genetic background of Mesolithic Europe. Our results show major Western hunter-gatherer (WHG) ancestry in a Romanian Eneolithic sample with a minor, but sizeable, contribution from Anatolian farmers, suggesting multiple admixture events between hunter-gatherers and farmers. Dietary stable-isotope analysis of this sample suggests a mixed terrestrial/aquatic diet. Our results provide support for complex interactions among hunter-gatherers and farmers in the Danube basin, demonstrating that in some regions, demic and cultural diffusion were not mutually exclusive, but merely the ends of a continuum for the process of Neolithization.This research was supported by a European Research Council (ERC) Starting Grant (ERC-2010-StG 263441) to R.P. G.G.-F. was also supported by MSC Individual Fellowship (NeoGenHeritage, grant no. 655478). E.R.J. was supported by a Herchel Smith Research Fellowship. M.H. and A.M. were supported by ERC consolidator grants 310763 GeneFlow and 647797 LocalAdaptation, respectively. V.S. was supported by the Gates Cambridge Trust. The work of C.L. was undertaken through the Partnerships in Priority Areas Program PN II, developed with the support of MEN-UEFISCDI (project no. PN-II-PTPCCA-2013-4-2302). A.G.-D. is supported by the research project BIOGEOS (CGL2014-57209-P) of the Spanish MINECO. The research of P.A., M.D.G., and L.D. on Los Canes is currently supported by the project CoChange (HAR2014-51830-P) of the Spanish State Plan for R+D+i (MINECO)

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Batch effect confounding leads to strong bias in performance estimates obtained by cross-validation.

BACKGROUND: With the large amount of biological data that is currently publicly available, many investigators combine multiple data sets to increase the sample size and potentially also the power of their analyses. However, technical differences ("batch effects") as well as differences in sample composition between the data sets may significantly affect the ability to draw generalizable conclusions from such studies. FOCUS: The current study focuses on the construction of classifiers, and the use of cross-validation to estimate their performance. In particular, we investigate the impact of batch effects and differences in sample composition between batches on the accuracy of the classification performance estimate obtained via cross-validation. The focus on estimation bias is a main difference compared to previous studies, which have mostly focused on the predictive performance and how it relates to the presence of batch effects. DATA: We work on simulated data sets. To have realistic intensity distributions, we use real gene expression data as the basis for our simulation. Random samples from this expression matrix are selected and assigned to group 1 (e.g., 'control') or group 2 (e.g., 'treated'). We introduce batch effects and select some features to be differentially expressed between the two groups. We consider several scenarios for our study, most importantly different levels of confounding between groups and batch effects. METHODS: We focus on well-known classifiers: logistic regression, Support Vector Machines (SVM), k-nearest neighbors (kNN) and Random Forests (RF). Feature selection is performed with the Wilcoxon test or the lasso. Parameter tuning and feature selection, as well as the estimation of the prediction performance of each classifier, is performed within a nested cross-validation scheme. The estimated classification performance is then compared to what is obtained when applying the classifier to independent data

Impact of aprotinin and renal function on mortality: a retrospective single center analysis

<p>Abstract</p> <p>Background</p> <p>An estimated up to 7% of high-risk cardiac surgery patients return to the operating room for bleeding. Aprotinin was used extensively as an antifibrinolytic agent in cardiac surgery patients for over 15 years and it showed efficacy in reducing bleeding. Aprotinin was removed from the market by the U.S. Food and Drug Administration after a large prospective, randomized clinical trial documented an increased mortality risk associated with the drug. Further debate arose when a meta-analysis of 211 randomized controlled trials showed no risk of renal failure or death associated with aprotinin. However, only patients with normal kidney function have been studied.</p> <p>Methods</p> <p>In this study, we look at a single center clinical trial using patients with varying degrees of baseline kidney function to answer the question: Does aprotinin increase odds of death given varying levels of preoperative kidney dysfunction?</p> <p>Results</p> <p>Based on our model, aprotinin use was associated with a 3.8-fold increase in odds of death one year later compared to no aprotinin use with p-value = 0.0018, regardless of level of preoperative kidney dysfunction after adjusting for other perioperative variables.</p> <p>Conclusions</p> <p>Lessons learned from our experience using aprotinin in the perioperative setting as an antifibrinolytic during open cardiac surgery should guide us in testing future antifibrinolytic drugs for not only efficacy of preventing bleeding, but for overall safety to the whole organism using long-term clinical outcome studies, including those with varying degree of baseline kidney function.</p