Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations.

CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.

Nonlobular Invasive Breast Carcinomas with Biallelic Pathogenic CDH1 Somatic Alterations: A Histologic, Immunophenotypic, and Genomic Characterization.

CDH1 encodes for E-cadherin, and its loss of function is the hallmark of invasive lobular carcinoma (ILC). Albeit vanishingly rare, biallelic CDH1 alterations may be found in nonlobular breast carcinomas (NL-BCs). We sought to determine the clinicopathologic characteristics and repertoire of genetic alterations of NL-BCs harboring CDH1 biallelic genetic alterations. Analysis of 5842 breast cancers (BCs) subjected to clinical tumor-normal sequencing with an FDA-cleared multigene panel was conducted to identify BCs with biallelic CDH1 pathogenic/likely pathogenic somatic mutations lacking lobular features. The genomic profiles of NL-BCs with CDH1 biallelic genetic alterations were compared with those of ILCs and invasive ductal carcinomas (IDCs), matched by clinicopathologic characteristics. Of the 896 CDH1-altered BCs, 889 samples were excluded based on the diagnosis of invasive mixed ductal/lobular carcinoma or ILC or the detection of monoallelic CDH1 alterations. Only 7 of the 5842 (0.11%) BCs harbored biallelic CDH1 alterations and lacked lobular features. Of these, 4/7 (57%) cases were ER-positive/HER2-negative, 1/7 (14%) was ER-positive/HER2-positive, and 2/7 (29%) were ER-negative/HER2-negative. In total, 5/7 (71%) were of Nottingham grade 2, and 2/7 (29%) were of grade 3. The NL-BCs with CDH1 biallelic genetic alterations included a mucinous carcinoma (n = 1), IDCs with focal nested growth (n = 2), IDC with solid papillary (n = 1) or apocrine (n = 2) features, and an IDC of no special type (NST; n = 1). E-cadherin expression, as detected by immunohistochemistry, was absent (3/5) or aberrant (discontinuous membranous/cytoplasmic/granular; 2/5). However, NL-BCs with CDH1 biallelic genetic alterations displayed recurrent genetic alterations, including TP53, PIK3CA (57%, 4/7; each), FGFR1, and NCOR1 (28%, 2/7, each) alterations. Compared with CDH1 wild-type IDC-NSTs, NL-BCs less frequently harbored GATA3 mutations (0% vs 47%, P = .03), but no significant differences were detected when compared with matched ILCs. Therefore, NL-BCs with CDH1 biallelic genetic alterations are vanishingly rare, predominantly comprise IDCs with special histologic features, and have genomic features akin to luminal B ER-positive BCs.

Second-Opinion Subspecialty Consultations in Musculoskeletal Radiology.

OBJECTIVE: The purpose of this article is to evaluate the significance of subspecialty second-opinion consultations for CT and MRI examinations in musculoskeletal (MSK) radiology. MATERIALS AND METHODS: All 3165 MSK CT and MRI examinations referred to one academic institution for second-opinion consultation during a 24-month period were reviewed by three MSK-trained radiologists. Outside and inside reports were compared by two independent MSK radiology fellows using a previously published 5-point scale. Clinically important differences (categories 4 and 5) were defined as those likely to change patient management. Statistical comparisons of rates were performed using a chi-square test with Bonferroni corrections. Interobserver reliability was reported using linear weighted kappa statistics and the percentage of agreement. RESULTS: Of all second-opinion examinations, 73.5% (2326/3165) had an outside report available for comparison and inclusion in this study. There were 610 of 2326 (26.2%) examinations with clinically important differences. The rate of clinically important discrepant readings was even higher in oncologic cases (36.3%; 331/911). When the final diagnosis was determined from pathology reports performed after internal interpretation, the second-opinion consultation was noted to be correct in 82.0% (334/407) of examinations with category 4 or 5 discrepancies. There was very good agreement (κ = 0.93) in scoring the discrepancies between second-opinion consultants. CONCLUSION: The subspecialty second-opinion consultation was more accurate than outside reports in 82.0% of examinations when pathologic confirmation was made. A moderate rate (26.2%) of discrepant interpretations was noted between outside and inside MSK imaging examinations, especially in tumor cases (36.3%). Most discrepancies were in interpreting rather than detecting abnormalities.

Effects of Reciproc, Mtwo and ProTaper Instruments on Formation of Root Fracture.

INTRODUCTION: The aim of this study was to compare the formation of dentinal crack and craze lines in the root dentin during root canal preparation with three different NiTi endodontic systems, naming Reciproc (RCP), ProTaper Universal (PTU) and Mtwo. METHODS AND MATERIALS: One hundred extracted mandibular premolars with single canals were selected and decoronated. The teeth were randomly divided into four groups of 25 each (n=25). In groups 1, 2 and 3 the teeth were prepared using Mtwo, PTU and RCP, respectively. While in group 4 (control group) the samples were left unprepared. After preparation, all specimens were sectioned perpendicular to the long axis of root at 3, 5 and 9-mm distances from the apex. The sections were then individually observed under 12× magnification using stereomicroscope. The data was analyzed using the chi-square and Fisher's exact tests. The level of significance was set at 0.05. RESULTS: No cracks were observed in the control group. All engine-driven systems caused dentinal cracks. Mtwo and PTU caused cracks significantly more than RCP (P<0.05). There was no significant difference between RCP and control group (P>0.05). CONCLUSION: All three engine-driven systems created dentinal defects. Reciproc caused less cracks than Mtwo and ProTaper Universal.

Analgesic effect of odontopaste and a compound intracanal medicament between root canal therapy appointments.

BACKGROUND: Pain experience makes a serious anxiety for both patient and clinician before and after root canal treatment. Pain is a complex psychophysiologic phenomenon. OBJECTIVES: The aim of this randomized control trial study was to evaluate the analgesic effect of Odontopaste® and a corticosteroid containing compound medicament between root canal therapy appointments. MATERIALS AND METHODS: One hundred and twenty lower first and second mandibular molars with spontaneous pain and sensitivity to percussion were selected and divided into three groups (40 patients per each group). After root canal preparation, patients were entered one of these groups randomly. Root canals in group 1 were dressed with Odontopaste, in group 2 with a compound intracanal medicament, and in group 3 with placebo. Patients determined their pain rate and percussion sensitivity on Heft-parker VAS diagram, before the first appointment and 24 hours and 7 days after that. RESULTS: Spontaneous pain and Percussion sensitivity score averages of 24 hours after the first appointment in group 1 and group 2 were less than group 3, which indicates statistically significant difference between these groups. There was no statistically significant difference between these groups after 7 days neither on spontaneous pain nor percussion sensitivity. CONCLUSIONS: Odontopaste® and compound intracanal medicaments resulted in statistically significant reduction in postoperative pain and percussion sensitivity after 24 hours, but there was no statistically significant difference after 7 days with placebo.