Background. The Nod-Like-Receptor-Protein-3 (NLRP3) inflammasome and the Interleukin-6 (IL-6) pathways are central mechanisms of the inflammatory response in myocardial reperfusion injury. Expanding our knowledge about the inflammasome signaling axis is important to improve treatment options. In a cross-sectional study, we aimed to study presence, localization, and genetic expression of inflammasome- and IL-6- signaling-related proteins in coronary thrombi and circulating leukocytes from ST-elevation myocardial infarction (STEMI) patients, with relation to myocardial injury and time from symptoms to PCI. Methods. Intracoronary thrombi were aspirated from 33 STEMI patients. Blood samples were drawn. mRNA of Toll-Like-Receptor-4 (TLR4), NLRP3, caspase 1, Interleukin-1β (IL1-β), Interleukin-18 (IL-18), IL-6, IL-6-receptor (IL-6R), and glycoprotein 130 (gp130) were isolated from thrombi and circulating leukocytes and relatively quantified by RT-PCR. A part of each thrombus was embedded in paraffin for histology and immunohistochemistry analyses. Results. Genes encoding the 8 markers were present in 76-100% of thrombi. Expression of TLR4 in thrombi significantly correlated to troponin T ( r = 0.455 , p = 0.013 ), as did NLRP3 ( r = 0.468 , p = 0.024 ). Troponin T correlated with expression in circulating leukocytes of TLR4 ( r = 0.438 , p = 0.011 ), NLRP3 ( r = 0.420 , p = 0.0149 ), and IL-1β ( r = 0.394 , p = 0.023 ). IL-6R expression in thrombi correlated significantly to troponin T ( r = 0.434 , p = 0.019 ), whereas gp130 was inversely correlated ( r = − 0.398 , p = 0.050 ). IL-6 in circulating leukocytes correlated inversely to troponin T ( r = − 0.421 , p = 0.015 ). There were no significant correlations between genes expressed in thrombi and time from symptom to PCI. Conclusions. The inflammasome signaling pathway was actively regulated in coronary thrombi and in circulating leukocytes from patients with STEMI, in association with myocardial damage measured by troponin T. This supports the strategy of medically targeting this pathway in treating myocardial infarction and contributes to sort out optimal timing and targets for anti-inflammatory treatment. The study is registered at clinicaltrials.gov with identification number NCT02746822.

Background Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are considered important both in atherosclerosis and remodeling after acute myocardial infarction (AMI). We aimed to study genetic expression and presence of MMP-2, MMP-9, TIMP-1, TIMP-2 and the extracellular MMP-inducer (EMMPRIN) in coronary thrombi. Circulating levels and genetic expression in circulating leukocytes were also assessed, and relations to degree of myocardial injury measured by troponin T and time from symptom to PCI were explored. Expression of cell markers were also analyzed, indicating relations to cell types.Methods Intracoronary thrombi were aspirated from 33 patients with ST-elevation myocardial infarction (STEMI). Blood samples with Pax-gene tubes were drawn at end of PCI and the next day. RNA was isolated from thrombi and leukocytes, and genes were relatively quantified by RT-PCR. Each thrombus was preserved for histology and immunohistochemistry analyzes. ResultsGenes coding for the five markers were present in 84-100% of thrombi and immunohistochemically stained in 96-100%. Expression of TIMP-1 in thrombi and in leukocytes correlated significantly to peak troponin T (r = 0.393 P = 0.026, r = 0.469 P = 0.006, respectively). No significant correlations between genes expressed in thrombi and time from symptom to PCI were observed. TIMP-1 was connected mainly to monocytes/ macrophages in the thrombi.Conclusion MMP-2, MMP-9, TIMP-1, TIMP-2 and EMMPRIN were highly expressed in human coronary thrombi. The correlation between troponin T and the expression of TIMP-1 both in thrombi and in leukocytes at time of PCI indicates that TIMP-1 plays a role in myocardial damage early post-MI.

Purpose To correlate MRI morphological response patterns with histopathological tumor regression grading system based on tumor cellularity in locally advanced breast cancer (LABC)-treated neoadjuvant with third-generation aromatase inhibitors. Methods Fifty postmenopausal patients with ER-positive/HER-2-negative LABC treated with neoadjuvant letrozole and exemestane given sequentially in an intra-patient cross-over regimen for at least 4 months with MRI response monitoring at baseline as well as after at least 2 and 4 months on treatment. The MRI morphological response pattern was classified into 6 categories: 0/complete imaging response; I/concentric shrinkage; II/fragmentation; III/diffuse; IV/stable; and V/progressive. Histopathological tumor regression was assessed based on the recommendations from The Royal College of Pathologists regarding tumor cellularity. Results Following 2 and 4 months with therapy, the most common MRI pattern was pattern II (24/50 and 21/50, respectively). After 4 months on therapy, the most common histopathological tumor regression grade was grade 3 (21/50). After 4 months an increasing correlation is observed between MRI patterns and histopathology. The overall correlation, between the largest tumor diameter obtained from MRI and histopathology, was moderate and positive (r = 0.50, P-value = 2e-04). Among them, the correlation was highest in type IV (r = 0.53). Conclusion The type II MRI pattern “fragmentation” was more frequent in the histopathological responder group; and types I and IV in the non-responder group. Type II pattern showed the best endocrine responsiveness and a relatively moderate correlation between sizes obtained from MRI and histology, whereas type IV pattern indicated endocrine resistance but the strongest correlation between MRI and histology.

Staphylococcus lugdunensis is a coagulase-negative Staphylococcus (CoNS), and part of the normal skin flora. The bacterium is an emerging pathogen that, unlike other CoNS, resembles coagulase-positive Staphylococcus aureus infections in virulence, tissue destruction, and clinical course. We report a fatal case following minor surgery. The frequency of S. lugdunensis infections has probably been underestimated and under-reported in the past as few clinical laboratories routinely identify coagulase-negative Staphylococci.

Background Axillary lymph node (LN) metastasis is one of the most important predictors of recurrence and survival in breast cancer, and accurate assessment of LN involvement is crucial. Determining extent of residual disease is key for surgical planning after neoadjuvant therapy. The aim of the study was to evaluate the diagnostic reliability of MRI for nodal disease in locally advanced breast cancer patients treated with neoadjuvant endocrine therapy (NET). Methods Thirty-three clinically node-positive locally advanced breast cancer patients who underwent NET and surgery were prospectively enrolled. Two radiologists reviewed the axillary nodes at 3 separate time points MRI examinations at baseline (before the first treatment regimen), interim (following at least 2 months after the first cycle and prior to crossing-over), and preoperative (after the final administration of therapy and immediately before surgery). According to LN status after surgery, imaging features and diagnostic performance were analyzed. Results All 33 patients had a target LN reduction, the greatest treatment benefit from week 8 to week 16. There was a positive correlation between the maximal diameter of the most suspicious LN measured by MRI and pathology during and after NET, being highest at therapy completion (r = 0.6, P ≤ .001). Mean and median differences of maximal diameter of the most suspicious LN were higher with MRI than with pathology. Seven of 33 patients demonstrated normal posttreatment MRI nodal status (yrN0). Of these 7 yrN0, 3 exhibited no metastasis on final pathology (ypN0), 2 ypN1 and 2 ypN2. Reciprocally, MRI diagnosed 3 cases of ypN0 as yrN + . Diffusion -weighted imaging (DWI) was the only axillary node characteristic significant when associated with pathological node status (χ2(4) = 8.118, P = .072). Conclusion Performance characteristics of MRI were not completely sufficient to preclude surgical axillary staging. To our knowledge, this is the first study on MRI LN assessment following NET in locally advanced breast cancer, and further studies with larger sample sizes are required to consolidate the results of this preliminary study. Trial Registration Institutional Review Board approval was obtained (this current manuscript is from a prospective, open-label, randomized single-center cohort substudy of the NEOLETEXE trial). NEOLETEXE, a phase 2 clinical trial, was registered on March 23rd, 2015 in the National trial database of Norway and approved by the Regional Ethical Committee of the South-Eastern Health Region in Norway; registration number: REK-SØ-84–2015.

Objective The purpose of this study was to investigate and classify the molecular subtypes of high-grade ductal carcinoma in situ (DCIS) and identify possible high-risk subtypes. The heterogenicity of DCIS with variable clinical and histopathological presentations has been recognized. Nevertheless, only histopathological grading and diameter are currently implemented in clinical decision-making following the diagnosis of DCIS. The molecular subtypes of DCIS and their IHC surrogate markers have not been defined in conventional treatment guidelines and recommendations. We applied the definitions of molecular subtypes according to the IHC surrogate markers defined for IBC and subclassified high-grade DCIS, accordingly. Methods Histopathological specimens were collected, revised, and regraded from 494 patients diagnosed with DCIS between 1996 and 2018. Other in situ and papillary lesions observed in breast biopsies were excluded from this study. 357 high-grade DCIS cases were submitted to IHC analysis. The markers investigated were ER, PR, HER2, and Ki67. Results 45 cases were classified as grade 1, 19 as grade 2, and 430 as grade 3. Sixty patients with high-grade DCIS had an additional invasive component in the surgical specimen. Thirty-three patients were diagnosed with recurrent DCIS or invasive cancer (minimum one year after their primary DCIS diagnosis). The proportions of luminal A and luminal B HER2-negative subtypes varied depending on whether 2011 or 2013 St. Gallen Consensus Conference guidelines were adopted. Luminal A was the most prevalent subtype, according to both classifications. The luminal B HER2-positive subtype was found in 22.1% of cases, HER2-enriched subtype in 21.8%, and TPN subtype in 5.6%. There were strong indications that HER2-enriched subtype was significantly more frequent among DCIS with invasive component (p = 0.0169). Conclusions High-grade DCIS exhibits all the molecular subtypes previously identified in IBC, but with a somewhat different distribution in our cohort. HER2-enriched subtype is substantially related to the presence of an invasive component in DCIS; consequently, it is regarded as a high-risk entity.

Objective The purpose of this study was to investigate and classify the molecular subtypes of high-grade DCIS and identify possible high-risk subtypes. The heterogenicity of DCIS with variable clinical and histopathological presentations has been recognized. Nevertheless, only histopathological grading and diameter are currently implemented in clinical decision-making following the diagnosis of DCIS. The molecular subtypes of DCIS and their IHC surrogate markers have not been defined in conventional treatment guidelines and recommendations. We applied the definitions of molecular subtypes according to the IHC surrogate markers defined for IBC and subclassified high-grade DCIS, accordingly. Methods The histopathological specimens from 494 patients diagnosed with DCIS between 1996 – 2018, were collected, revised and regraded. Other in situ and papillary lesions of breast were excluded. 357 high-grade DCIS cases were submitted to IHC analysis. The investigated markers were ER, PR, HER2, and Ki-67. Results 45 were classified as grade 1, 19 as grade 2, and 430 as grade 3. 64 patients with high-grade DCIS had an additional invasive component in the surgical specimen. 33 patients were diagnosed with recurrent DCIS or invasive cancer (minimum one year after their primary DCIS diagnosis). The proportions of luminal A and luminal B HER2-negative subtypes varied depending on whether 2011 or 2013 St. Gallen Consensus Conference guidelines were adopted. Luminal A was the most prevalent subtype, according to both classifications. The luminal B HER2-positive subtype was found in 22.1% of cases, HER2-enriched subtype in 21.8%, and TPN subtype in 5.6%. HER2-enriched subtype was significantly more frequent among DCIS with invasive component (p = 0.0169). Conclusions High-grade DCIS exhibits all the molecular subtypes previously identified in IBC, but with a somewhat different distribution in our cohort. HER2-enriched subtype is substantially related to the existence of an invasive component in DCIS; consequently, it is regarded as a high-risk entity.

Background: Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group with variable clinical presentation. 70-80% of DCIS are classified as grade 3 (Van Nuys Classification). They are treated according to grade and extension of the lesion, as was the standard treatment for invasive breast cancer in the 1970`s. Molecular genetic studies of invasive breast carcinomas (BC) have defined a molecular subclassification. In routine diagnostics, we use surrogate markers like estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) as tools to stratify for treatment. The individual results of these surrogate markers have resulted in a complex treatment algorithm. In contrast, still all DCIS grade 3 are given the same treatment. Aim: To investigate the molecular subtypes of DCIS diagnosed at the Department of Pathology, Akershus University Hospital (Norway). Materials: 483 histological specimens of DCIS at Akershus University Hospital, Dep. of Pathology, during 1996-2018. All relevant background information was recorded. Methods: All histological sections have been reassessed, and the grading has been confirmed independently by two experienced pathologists. An eventual peritumoral inflammatory component was made note of. All grade 3 DCIS with representative paraffin blocks were submitted for immunohistochemistry (IHC). The investigated markers were ER, PR, Ki-67 and HER-2. Results: The age ranged from 33-90, with a mean and median of 57 years. 10.4% were grade 1, 3.9% as grade 2 and 85.7% as grade 3. The size of DCIS ranged from 0,5 to150 mm, with mean 28 mm and median of 20 mm. 64 patients had an invasive component, 51 of them with a size of <5 mm (pT1a), and 13 > 5 mm but < 10 mm (pT1b). 33 (6,8%) patients were diagnosed with a recurrent DCIS or cancer (minimum 1year after primary DCIS diagnosis). Six patients were deceased (1 was diagnosed with new ipsilateral DCIS 3 years later, 2 with cancer in the contralateral breast, 2 with cancer in ipsilateral breast and 1 with new DCIS in the ipsilateral breast). The preliminary results of immunohistochemical studies of 245 cases indicate: Luminal A: 30.7% (Ki-67 <14%), Luminal B: 42% (Ki-67> 14%) and non-luminal 27.3%. Around 33% of the non-luminal cases are expected to be triple negative. Histomorphologically, we have found peritumoral lymphoid cells in 31% of cases, and all of these (100%) are DCIS grade 3. Conclusions: The molecular subtypes identified in invasive breast carcinomas are all represented in DCIS G3 and further studies might reveal the possibility of a more adapted treatment algorithm, as in invasive BC. The peritumoral inflammatory cell infiltrates will be investigated in future studies. Citation Format: Hossein Schandiz, Daehoon Park, Yan Liu Kaiser, Marianne Lyngra, Ingrid Solvang Talleraas, Jürgen Geisler, Torill Sauer. A novel diagnostics approach to Ductal Carcinoma In Situ (DCIS) with potential impact on the therapeutic algorithms [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A015.