Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions.

Ductal carcinoma in situ (DCIS) of the breast is a lesion characterized by significant heterogeneity, in terms of morphology, immunohistochemical staining, molecular signatures, and clinical expression. For some patients, surgical excision provides adequate treatment, but a subset of patients will experience recurrence of DCIS or progression to invasive ductal carcinoma (IDC). Recent years have seen extensive research aimed at identifying the molecular events that characterize the transition from normal epithelium to DCIS and IDC. Tumor epithelial cells, myoepithelial cells, and stromal cells undergo alterations in gene expression, which are most important in the early stages of breast carcinogenesis. Epigenetic modifications, such as DNA methylation, together with microRNA alterations, play a major role in these genetic events. In addition, tumor proliferation and invasion is facilitated by the lesional microenvironment, which includes stromal fibroblasts and macrophages that secrete growth factors and angiogenesis-promoting substances. Characterization of DCIS on a molecular level may better account for the heterogeneity of these lesions and how this manifests as differences in patient outcome and response to therapy. Molecular assays originally developed for assessing likelihood of recurrence in IDC are recently being applied to DCIS, with promising results. In the future, the classification of DCIS will likely incorporate molecular findings along with histologic and immunohistochemical features, allowing for personalized prognostic information and therapeutic options for patients with DCIS. This review summarizes current data regarding the molecular characterization of DCIS and discusses the potential clinical relevance

APFEL Web: a web-based application for the graphical visualization of parton distribution functions

We present APFEL Web, a web-based application designed to provide a flexible user-friendly tool for the graphical visualization of parton distribution functions (PDFs). In this note we describe the technical design of the APFEL Web application, motivating the choices and the framework used for the development of this project. We document the basic usage of APFEL Web and show how it can be used to provide useful input for a variety of collider phenomenological studies. Finally we provide some examples showing the output generated by the application.Comment: Final version, matches published version in JPhysG. Web-application available from http://apfel.mi.infn.it

Molecular Profiling of the Metaplastic Spindle Cell Carcinoma of the Breast Reveals Potentially Targetable Biomarkers

Introduction: Spindle cell carcinoma is a rare subtype of metaplastic breast cancer, with triple-negative (TNBC: estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-negative) phenotype. It is associated with a marked resistance to conventional chemotherapy and has an overall poor outcome. Materials and methods: Twenty-three pure spindle cell carcinomas of the breast (18 primary and 5 recurrent/metastatic) were comprehensively explored for biomarkers of immuno-oncology and targeted therapies using immunohistochemistry and DNA/RNA sequencing. Results: The majority (21/23) of spindle cell carcinomas were TNBC. Estrogen and androgen receptor expression above the therapeutic thresholds were detected in 2 cases each. Pathogenic gene mutations were identified in 21 of 23 cases, including PIK3CA, TP53, HRAS, NF1, and PTEN. One case with matched pre- and post-chemotherapy samples exhibited a consistent mutational profile (PIK3CA and HRAS mutations) in both samples. Gene amplifications were present in 5 cases, including 1 case without detectable mutations. The spindle cell carcinomas cohort had consistently low total mutational burden (all below the 80th percentile for the entire TNBC cohort). All tumors were microsatellite stable. Programmed death-ligand 1 expression was observed on both tumor cells (in 7/21 cases), and in tumor-infiltrating immune cells (2/21 cases). Conclusions: Spindle cell carcinomas are characterized by targetable molecular alterations in the majority of cases, but owing to the lack of uniform findings, individual patient profiling is necessary. Detection of individual combinations of biomarkers should improve treatment options for this rare but aggressive disease

Novel targetable biomarkers in clear cell carcinoma of the breast uncovered by molecular profiling: A study of nine cases

We profiled nine pure clear cell carcinomas of the breast using massively parallel DNA and RNA sequencing (NGS), in situ hybridization (ISH), and immunohistochemistry (IHC). All cases were primary mammary clear cell carcinomas that were diagnosed in female patients (mean age: 53.4 years; range: 31-69 years). Based on our findings, we conclude that the majority of clear cell carcinomas are ER/PR positive and consequently amenable to anti-ER treatment modalities. A subset of clear cell carcinomas also harbored alterations in PIK3CA/PTEN/AKT pathway, particularly PTEN, indicating a potential benefit of PI3K/Akt/mTOR inhibitors. The status of I-O biomarkers in clear cell carcinomas indicates a limited therapeutic benefit of immune checkpoint inhibitors (against PD-1/PD-L1). Keywords: breast cancer; clear cell carcinoma; immunotherapy; molecular profiling; targeted therap

A Distinct Pattern of Beclin-1 Staining Helps Distinguish Sessile Serrated Adenomas

Autophagy, a lysosomal degradation system, has both cell survival and cell death-promoting capabilities, and its versatility is exploited in many pathologic entities. In neoplastic processes, autophagy has been demonstrated to contribute to both tumor suppression and tumorigenesis in a relatively tumor-specific fashion. Beclin-1 is a protein involved in the formation of the autophagosome, the core unit of autophagy, and serves as one of the general markers for this process. Previous studies have shown Beclin-1 overexpression in both pre-neoplastic and invasive colon carcinoma but weak to absent expression in normal colonic mucosa. Serrated polyps (SPs) of the colon represent morphologically and molecularly unique precursor lesions in the serrated adenoma-carcinoma pathway. The pathophysiology of the serrated pathway and its natural progression is of great interest. The specific role of autophagy in SPs is not fully described. We evaluated SPs and autophagy using Beclin-1 protein, a general autophagy marker, to aid in the assessment of autophagy along the serrated pathway. Difference in Beclin-1 staining may represent variation in autophagy among polyp subtypes, exposing biological and possible clinically useful properties

Extending MadFlow: device-specific optimization

In this proceedings we demonstrate some advantages of a top-bottom approach in the development of hardware-accelerated code. We start with an autogenerated hardware-agnostic Monte Carlo generator, which is parallelized in the event axis. This allow us to take advantage of the parallelizable nature of Monte Carlo integrals even if we don't have control of the hardware in which the computation will run (i.e., an external cluster). The generic nature of such an implementation can introduce spurious bottlenecks or overheads. Fortunately, said bottlenecks are usually restricted to a subset of operations and not to the whole vectorized program. By identifying the more critical parts of the calculation one can get very efficient code and at the same time minimize the amount of hardware-specific code that needs to be written. We show benchmarks demonstrating how simply reducing the memory footprint of the calculation can increase the performance of a $2 \to 4$ process.Comment: Proceedings ICHEP 2022, 6 page

A New Frontier in Breast Cancer Management: Oncotype DX

Diagnosing and prognosticating breast cancer has traditionally relied upon histomorphologic analysis and immunohistochemistry. With the recent advent of multigene molecular assays, traditional methods are being augmented with molecular biomarkers. Implementation of the Oncotype DX assay has led to a change in treatment of patients with early stage, estrogen positive cancer. Oncotype DX uses the expression of 21 genes at the mRNA level to determine a 10 year recurrence risk in node negative and 5 year recurrence risk in node positive cancer. 16 malignancy markers related to estrogen, HER2, cell proliferation, and invasion potential are compared with 5 reference genes and run through a proprietary algorithm to provide a recurrence score of either low, intermediate, or high risk. Using the results of this assay provides an opportunity for personalized treatment based on unique malignancy markers. Oncotype DX allows patients with low recurrence risk to be spared the adverse effects of chemotherapy, while ensuring that high risk patients are treated systemically. For the first time, the most recent treatment guidelines specify the use of Oncotype DX for the management of breast cancer

The Value of Intraoperative Examination of Axillary Sentinel Nodes in Carcinoma of the Breast.

Abstract Axillary sentinel lymph node biopsy (SLNB) has become the standard of care for T1-2, N-0, M-0 carcinoma of the breast. However, the accuracy of frozen section in the intra-operative examination of sentinel nodes (SN) remains controversial. The senior author has championed the use of the intraoperative examination of SN by frozen section ex-amination from the inception of its use, and we present our experience with frozen section examination of SN, confirming that this technique is both practical and highly accurate. Materials & Methods: Between 2000 and 2007, 236 SLNB procedures were performed that were read as “fro-zen section negative.” SN were identified by 1% lymphazurin blue dye only. The identification of SN in these 236 women was 100%. Each SN specimen was prosected by the senior author; a dedicated surgical pathology technician prepared the frozen sections. Nodes were dissected from the specimen individually and cut at 2.5 to 3.0 mm. intervals. Each of these sections was then cut at three levels. The frozen sections were read by the attending pathologist assigned to frozen sections for that day, not by a dedicated breast pathologist. During the period of the study, 14 different attending pathologists read the slides, with 6 pathologists each reading more than 20 cases. Others read from 1 to14 cases. Results: In this group of 236 cases, 11 patients had positive nodes on subsequent examination of the H&E slides; thus, the false negative rate of intraoperative frozen section was 4.7%, i.e., the frozen section was read as negative but the paraffin sections were posi-tive for metastasis. Therefore, the sensitivity of the negative frozen section was \u3e95%. Nine of the 11 false positives were micrometastases, less than 2 mm diameter, one was considered a macrometastasis, with two areas in one node measuring 2.0 and 2.1 mm each, and one was a sub-micrometastasis. The following variables were compared for significance: Pathologist, nuclear grade, histologic grade, margins, lymphovascular invasion, tumor type (ductal vs lobular), ER & PR values. The only significant variables were lymphovascular invasion (p=.019) and presence of in situ ductal carcinoma (p=.001). Only one of the false negatives was a purely lobular carcinoma (1/11). Discussion: Our data confirm the high accuracy of intraoperative examination of SN, \u3e95%, even without a dedicated breast pathologist reviewing the sections. The missed metastases are likely to be micrometastases, and the likelihood of missing a macrometastasis is \u3c1%. In patients with large primary tumors, presence of in situ ductal carcinoma or if lymphovascular invasion is associated with the tumor, special care should be taken to review these cases more thoroughly since these characteristics of tumors seem to make them more likely than others to have micrometastases to the axillary nodes over-looked

Complete resolution of gastric amyloidosis after autologous stem cell transplantation.

A 48-year-old female with multiple myeloma (MM) and amyloidosis presented with massive upper gastrointestinal (GI) bleeding one week after autologous stem cell transplantation (autologous-SCT). Esophagogastroduodenoscopy (EGD) demonstrated necrotic, purple, pigmented, friable lesions throughout the stomach (Figure 1a), along with a bleeding ulcer in the cardia (Figure 1b, Video 1) which was successfully treated with epinephrine (1:10,000) injections. Biopsies demonstrated nodular amyloid deposition (Figures 2) which was Congo red positive. The patient had no further hematemesis and was discharged home 4 days later. Ten months after autologous-SCT, EGD revealed a normal stomach (Figure 3, Video 2) with no histologic evidence of amyloid

Solitary fibrous tumor of the breast.

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