Dataset for reporting of the invasive carcinoma of the breast: recommendations from the International Collaboration on Cancer Reporting (ICCR).

BACKGROUND AND OBJECTIVES: Current national or regional guidelines for the pathology reporting on invasive breast cancer differ in certain aspects, resulting in divergent reporting practice and a lack of comparability of data. Here we report on a new international dataset for the pathology reporting of resection specimens with invasive cancer of the breast. The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organizations. METHODS AND RESULTS: The established ICCR process for dataset development was followed. An international expert panel consisting of breast pathologists, a surgeon, and an oncologist prepared a draft set of core and noncore data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalized and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for invasive cancer of the breast is intended to promote high-quality, standardized pathology reporting. Its widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve the management of invasive breast cancer patients.

Expression of Cathepsin D in early-stage breast cancer and its prognostic and predictive value.

PURPOSE: Cathepsin D is a proteolytic enzyme that is normally localized in the lysosomes and is involved in the malignant progression of breast cancer. There are conflicting results regarding Cathepsin D significance as prognostic and predictor marker in breast cancer. This study aimed to evaluate the expression and prognostic significance of Cathepsin D in early-stage breast cancer. METHODS: Expression of Cathepsin D was assessed by immunohistochemical staining of tissue microarrays, in a large well-characterized series of early-stage operable breast cancer (n = 954) from Nottingham Primary Breast Carcinoma Series between the period of 1988 and 1998 who underwent primary surgery. Correlation of Cathepsin D expression with clinicopathological parameters and prognosis was evaluated. RESULTS: Cathepsin D expression was positive in 71.2% (679/954) of breast cancer tumours. Positive expression of Cathepsin D was significantly associated with high histological grade (p = 0.007), pleomorphism (p = 0.002), poor Nottingham Prognostic Index (NPI) score (p < 0.002), recurrence (p = 0.005) and distant metastasis (p < 0.0001). Kaplan-Meier analysis showed that Cathepsin D expression was significantly associated with shorter breast cancer-specific survival (p = 0.001), higher risk of recurrence (p = 0.001) and distant metastasis (p < 0.0001). ER-positive tumours expressing Cathepsin D and treated with tamoxifen demonstrated a significantly higher risk of distant metastasis. CONCLUSION: Cathepsin D expression significantly predicts poor prognosis in breast cancer and is associated with variables of poor prognosis and shorter outcome. The strong association of Cathepsin D with aggressive tumour characteristics and poor outcomes warrants further research of its potential as a therapeutic target The results also suggest a possible interaction between Cathepsin D and tamoxifen therapy in ER-positive breast cancer which needs further investigation to elucidate the underlying mechanisms.

A dedicated structured data set for reporting of invasive carcinoma of the breast in the setting of neoadjuvant therapy: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: The International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations, is an initiative aimed at providing a unified international approach to reporting cancer. ICCR recently published new data sets for the reporting of invasive breast carcinoma, surgically removed lymph nodes for breast tumours and ductal carcinoma in situ, variants of lobular carcinoma in situ and low-grade lesions. The data set in this paper addresses the neoadjuvant setting. The aim is to promote high-quality, standardised reporting of tumour response and residual disease after neoadjuvant treatment that can be used for subsequent management decisions for each patient. METHODS: The ICCR convened expert panels of breast pathologists with a representative surgeon and oncologist to critically review and discuss current evidence. Feedback from the international public consultation was critical in the development of this data set. RESULTS: The expert panel concluded that a dedicated data set was required for reporting of breast specimens post-neoadjuvant therapy with inclusion of data elements specific to the neoadjuvant setting as core or non-core elements. This data set proposes a practical approach for handling and reporting breast resection specimens following neoadjuvant therapy. The comments for each data element clarify terminology, discuss available evidence and highlight areas with limited evidence that need further study. This data set overlaps with, and should be used in conjunction with, the data sets for the reporting of invasive breast carcinoma and surgically removed lymph nodes from patients with breast tumours, as appropriate. Key issues specific to the neoadjuvant setting are included in this paper. The entire data set is freely available on the ICCR website. CONCLUSIONS: High-quality, standardised reporting of tumour response and residual disease after neoadjuvant treatment are critical for subsequent management decisions for each patient.

Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

Performance of a novel spectroscopy-based tool for adjuvant therapy decision-making in hormone receptor-positive breast cancer: a validation study.

PURPOSE: Digistain Index (DI), measured using an inexpensive mid-infrared spectrometer, reflects the level of aneuploidy in unstained tissue sections and correlates with tumor grade. We investigated whether incorporating DI with other clinicopathological variables could predict outcomes in patients with early breast cancer. METHODS: DI was calculated in 801 patients with hormone receptor-positive, HER2-negative primary breast cancer and ≤ 3 positive lymph nodes. All patients were treated with systemic endocrine therapy and no chemotherapy. Multivariable proportional hazards modeling was used to incorporate DI with clinicopathological variables to generate the Digistain Prognostic Score (DPS). DPS was assessed for prediction of 5- and 10-year outcomes (recurrence, recurrence-free survival [RFS] and overall survival [OS]) using receiver operating characteristics and Cox proportional hazards regression models. Kaplan-Meier analysis evaluated the ability of DPS to stratify risk. RESULTS: DPS was consistently highly accurate and had negative predictive values for all three outcomes, ranging from 0.96 to 0.99 at 5 years and 0.84 to 0.95 at 10 years. DPS demonstrated statistically significant prognostic ability with significant hazard ratios (95% CI) for low- versus high-risk classification for RFS, recurrence and OS (1.80 [CI 1.31-2.48], 1.83 [1.32-2.52] and 1.77 [1.28-2.43], respectively; all P < 0.001). CONCLUSION: DPS showed high accuracy and predictive performance, was able to stratify patients into low or high-risk, and considering its cost and rapidity, has the potential to offer clinical utility.

Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

The amino acid transporter SLC7A11 expression in breast cancer.

Breast cancer (BC), characterized by its diverse molecular profiles and clinical outcomes, presents a significant challenge in the development of effective therapeutic strategies. Metabolic reprogramming, a defining characteristic of cancer, has emerged as a promising target for novel therapies. SLC7A11, an amino acid transporter that facilitates cysteine uptake in exchange for glutamate, plays a crucial role in sustaining the altered metabolism of cancer cells. This study delves into the comprehensive analysis of SLC7A11 at the genomic, transcriptomic, and protein levels in extensive BC datasets to elucidate its potential role in different BC subtypes. SLC7A11 gene copy number and mRNA expression were evaluated using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1,980) and Breast Cancer Gene Expression Miner (n = 4,712). SLC7A11 protein was assessed using immunohistochemistry in a large BC cohort (n = 1,981). Additionally, The Cancer Genome Atlas (TCGA) dataset was used to explore SLC7A11 DNA methylation patterns using MethSurv (n = 782) and association of SLC7A11 mRNA expression with immune infiltrates using TIMER (n = 1,100). High SLC7A11 mRNA and SLC7A11 protein expression were significantly associated with high tumor grade (p ≤ .02), indicating a potential role in cancer progression. Interestingly, SLC7A11 copy number gain was observed in HER2+ tumors (p = .01), suggesting a subtype-specific association. In contrast, SLC7A11 mRNA expression was higher in the basal-like/triple-negative (TN; p < .001) and luminal B tumors (p = .02), highlighting its differential expression across BC subtypes. Notably, high SLC7A11 protein expression was predominantly observed in Estrogen Receptor (ER)-negative and Triple Negative (TN) BC, suggesting a role in these aggressive subtypes. Further analysis revealed that SLC7A11 was positively correlated with other amino acid transporters and enzymes associated with glutamine metabolism, implying a coordinated role in metabolic regulation. Additionally, SLC7A11 gene expression was positively associated with neutrophil and macrophage infiltration, suggesting a potential link between SLC7A11 and tumor immunity. Our findings suggest that SLC7A11 plays a significant role in BC metabolism, demonstrating differential expression across subtypes and associations with poor patient outcomes. Further functional studies are warranted to elucidate the precise mechanisms by which SLC7A11 contributes to BC progression and to explore its potential as a therapeutic target.

Long-term outcomes in two adult siblings with Fucosidosis - Diagnostic odyssey and clinical manifestations.

Fucosidosis (OMIN# 230000) is a rare lysosomal storage disorder (LSDs) caused by mutations in the FUCA1 gene, leading to alpha-L-fucosidase deficiency; it is inherited as an autosomal recessive trait. Fucosidosis represents a disease spectrum with a wide variety of clinical features, but most affected patients have slow neurologic deterioration. Many patients die young and the long-term clinical outcomes in adult patients are poorly documented. Here, we report the long-term follow up of two Caucasian siblings, a 31-year-old man and 25-year-old woman. We describe the clinical, biochemical, radiological and genetic findings in two siblings affected by Fucosidosis and the differences between them after 19-years follow up. The dermatological features of the younger sibling have been reported previously by Bharati et al. (2007). Both patients have typical features of Fucosidosis, such as learning difficulties, ataxia, and angiokeratomas with differing severity. Case 1 presents severe ataxia with greater limitation of mobility, multiple dysostoses, angiokeratomas on his limbs, retinal vein enlargement and increased tortuosity in the eye and gastrointestinal symptoms. Biochemical analysis demonstrated a deficiency of alpha-fucosidase in leucocytes. Case 2 has a greater number of angiokeratomas and has suffered three psychotic episodes. The diagnosis of Fucosidosis was confirmed in cultured skin fibroblast at the age of 12 years. Molecular analysis of the FUCA1 gene showed a heterozygous mutation c.998G > A p.(Gly333Asp), with a pathogenic exon 4 deletion in the other allele in both patients. Conclusion. Fucosidosis presents a wide clinical heterogeneity and intrafamilial variability of symptoms. Psychosis and gastrointestinal symptoms have not been reported previously in Fucosidosis.

Unravelling transcriptomic complexity in breast cancer through modulation of DARPP-32 expression and signalling pathways.

DARPP-32 is a key regulator of protein-phosphatase-1 (PP-1) and protein kinase A (PKA), with its function dependent upon its phosphorylation state. We previously identified DKK1 and GRB7 as genes with linked expression using Artificial Neural Network (ANN) analysis; here, we determine protein expression in a large cohort of early-stage breast cancer patients. Low levels of DARPP-32 Threonine-34 phosphorylation and DKK1 expression were significantly associated with poor patient prognosis, while low levels of GRB7 expression were linked to better survival outcomes. To gain insight into mechanisms underlying these associations, we analysed the transcriptome of T47D breast cancer cells following DARPP-32 knockdown. We identified 202 differentially expressed transcripts and observed that some overlapped with genes implicated in the ANN analysis, including PTK7, TRAF5, and KLK6, amongst others. Furthermore, we found that treatment of DARPP-32 knockdown cells with 17ß-estradiol or PKA inhibitor fragment (6-22) amide led to the differential expression of 193 and 181 transcripts respectively. These results underscore the importance of DARPP-32, a central molecular switch, and its downstream targets, DKK1 and GRB7 in breast cancer. The discovery of common genes identified by a combined patient/cell line transcriptomic approach provides insights into the molecular mechanisms underlying differential breast cancer prognosis and highlights potential targets for therapeutic intervention.

Role of Akt/Protein Kinase B in Cancer Metastasis.

Metastasis is a critical step in the process of carcinogenesis and a vast majority of cancer-related mortalities result from metastatic disease that is resistant to current therapies. Cell migration and invasion are the first steps of the metastasis process, which mainly occurs by two important biological mechanisms, i.e., cytoskeletal remodelling and epithelial to mesenchymal transition (EMT). Akt (also known as protein kinase B) is a central signalling molecule of the PI3K-Akt signalling pathway. Aberrant activation of this pathway has been identified in a wide range of cancers. Several studies have revealed that Akt actively engages with the migratory process in motile cells, including metastatic cancer cells. The downstream signalling mechanism of Akt in cell migration depends upon the tumour type, sites, and intracellular localisation of activated Akt. In this review, we focus on the role of Akt in the regulation of two events that control cell migration and invasion in various cancers including head and neck squamous cell carcinoma (HNSCC) and the status of PI3K-Akt pathway inhibitors in clinical trials in metastatic cancers.

Should a borderline negative HER2 result in a core biopsy of invasive carcinoma of the breast have HER2 assessment repeated in the excision specimen?

AIM: The 2015 UK guidelines for HER2 assessment in breast cancer recommended repeat assessment if the core biopsy was scored as 2+ on HER2 immunohistochemistry (IHC) with borderline negative in situ hybridisation (ratio of number of HER2 to chromosome 17 centromere copies of 1.8-1.99). This case series aimed to assess the value of such repeat assessment in the surgical specimen, in particular the proportion that were HER2 positive. METHODS: Details of biopsies with 2+ IHC and borderline negative in situ hybridisation were extracted from a database. The results of repeat HER2 testing in the surgical specimen for this cohort study were then obtained. RESULTS: 112 patients with no preoperative treatment had repeat assessment: 4 were 3+ and 16 were 2+ amplified. Of 14 with preoperative chemotherapy, 1 was 3+ and 4 were 2+ amplified. All the 2+ amplified carcinomas had a HER2 to chromosome 17 ratio less than 4, in 50% the ratio was between 2.0 and 2.2, and in 50% the HER2 copy number was less than 4. CONCLUSIONS: Repeat assessment yielded 4% 3+ results and 14% 2+ amplified carcinomas but with low level amplification. These results suggest that retesting of borderline negative HER2 cases should be optional and no longer mandatory.

Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes.

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.

Second opinion (external specialist referral) practice of breast pathology: the Nottingham experience.

AIMS: Breast pathology is a challenging field, and discrepancies in diagnoses exist and can affect patient management. This study aims to review a breast referral practice and assess the pattern and frequency of breast lesions sent for an external expert review and evaluate potential impacts on patients' care. METHODS AND RESULTS: Seven hundred and forty cases that were referred to Nottingham City Hospital for a second opinion between 2019 and 2022 which have slides and reports were retrieved and reviewed. Reasons for referral, initial diagnosis, proffered specialist opinion and any discrepancy or potential impacts of management were assessed. The most frequent entities were papillary lesions (19%), fibroepithelial lesions (17%), invasive carcinomas that were sent for confirmation of the invasive diagnosis or subtyping of the invasive tumour (17%), intraductal epithelial proliferation with atypia (9%) and spindle cell lesions (8%). Other entities included biphasic tumours such as adenomyoepithelioma, as well as vascular and nipple lesions. Few cases were sent for prognostic classification or comments on the management, and in occasional cases no initial diagnosis was offered. After reviewing the cases by the expert pathologists, the initial diagnosis was confirmed or one of the suggested diagnoses was preferred in 79% of cases, including 129 cases (17%) in which the opinion resulted minor changes in the management. Significant changes in the classification of lesions were made in 132 cases (18%) which resulted in significant change in the patient management recommendation. In 14 cases (2%) a final classification was not possible, and further specialist opinion was obtained. Comments on the differential diagnosis and advice on further patient management were provided in most cases. CONCLUSIONS: This study demonstrates the value of external referral of challenging, rare and difficult to classify breast lesions. It also highlights the most common breast lesions that are likely to be challenging, and specialist opinion can refine their classification to improve patient care.

Preoperative diagnosis of ductal carcinoma in situ of the breast over a 24-year period.

AIMS: The method of diagnosis of ductal carcinoma in situ (DCIS) has changed since the 1980s. The aim of this audit was to assess changes in the preoperative diagnosis of DCIS since the introduction of needle core biopsy, particularly the proportion with a preoperative biopsy diagnosis of DCIS. METHODS AND RESULTS: The preoperative diagnoses of patients with a final diagnosis of DCIS in the surgical specimen were reviewed (i) in 809 patients who presented through breast screening from 1997 to 2021, and (ii) in all patients in 5 individual years at 5-year intervals from 2000 to 2020 (254 in total). For screening-detected DCIS the proportion with a preoperative diagnosis of DCIS increased from 75% to 98% over the study period. In a detailed analysis of all cases of DCIS in 5 separate years the proportion with a preoperative diagnosis of DCIS increased from 68% in 2000 to 96% in 2020. For high-grade DCIS the proportion increased from 87% to 97%, and for low- or intermediate-grade DCIS from 48% to 93%. The proportion of women who had vacuum-assisted biopsy increased from 7% in 2000 to 58% in 2015. There was a small increase in the number of biopsies that had basal cytokeratin and oestrogen receptor immunohistochemistry to aid diagnosis. CONCLUSION: There has been an increase in the preoperative diagnosis of DCIS, particularly of low- or intermediate-grade, over the last two decades. The increasing use of vacuum-assisted biopsy is likely to be a major contributory factor to this increase.

A retrospective analysis of ezrin protein and mRNA expression in breast cancer: Ezrin expression is associated with patient survival and survival of patients with receptor-positive disease.

INTRODUCTION: The cytoskeletal protein ezrin is upregulated in many cancer types and is strongly associated with poor patient outcome. While the clinical and prognostic value of ezrin has been previously evaluated in breast cancer, most studies to date have been conducted in smaller cohorts (less than 500 cases) or have focused on specific disease characteristics. The current study is the largest of its kind to evaluate ezrin both at the protein and mRNA levels in early-stage breast cancer patients using the Nottingham (n = 1094) and METABRIC (n = 1980) cohorts, respectively. RESULTS: High expression of ezrin was significantly associated with larger tumour size (p = 0.027), higher tumour grade (p < 0.001), worse Nottingham Prognostic Index prognostic group (p = 0.011) and HER2-positive status (p = 0.001). High ezrin expression was significantly associated with adverse survival of breast cancer patients (p < 0.001) and remained associated with survival in multivariate Cox-regression analysis (p = 0.018, hazard ratio (HR) = 1.343, 95% confidence interval (CI) = 1.051-1.716) when potentially confounding factors were included. High ezrin expression was significantly associated with adverse survival of patients whose tumours were categorised as receptor (oestrogen receptor (ER), progesterone receptor (PgR) or HER2) positive (p < 0.001) in comparison to those categorised as triple-negative breast cancer (p = 0.889). High expression of ezrin mRNA (VIL2) in the METABRIC cohort was also significantly associated with adverse survival of breast cancer patients (p < 0.001). CONCLUSION: Retrospective analyses show that ezrin is an independent prognostic marker, with higher expression associated with shortened survival in receptor-positive (ER, PgR or HER2) patients. Ezrin expression is associated with more aggressive disease and may have clinical utility as a biomarker of patient prognosis in early-stage breast cancer.

Class II composite restoration technique teaching: A randomised controlled crossover laboratory-based trial involving a novel ringless sectional matrix technique.

INTRODUCTION: Objectives were to assess how different techniques (including a novel ringless sectional matrix approach) affect students' restorative outcomes, and their preferences for and preparedness to clinically implement new techniques with the aim of introducing appropriate techniques to the undergraduate curriculum. MATERIALS AND METHODS: Students performed two class II composite restorations in plastic teeth using two sectional matrix techniques (separating ring vs. without [ringless]), and two composite restorative techniques (incremental vs. injection-moulded bulk-fill). Restorations were assessed on multiple parameters which were combined to rate them as "good" or not. Online surveys assessed students' preferences for and preparedness to clinically implement new techniques. RESULTS: Contact area concavity (OR = 106, p < .001) and cervical marginal overhang (OR = 7.4, p < .001) were much more likely with the separating ring compared to the ringless sectional matrix technique. "Good" restorations were 29.5 times more likely when using ringless compared to separating ring techniques and 3.3 times more likely when using the injection-moulding bulk-fill compared to layered composite technique. A majority of students preferred the ringless to separating ring sectional matrix technique and the injection-moulding bulk-fill to layered composite technique. Large majorities felt prepared to implement the new techniques clinically with no or minimal guidance. CONCLUSIONS: A classic sectional matrix technique with separating ring resulted in a much greater occurrence of contact area concavity and cervical marginal overhang than a novel ringless approach. When allied with student preferences and clinical preparedness, inclusion of the novel ringless approach in the undergraduate curriculum can be supported alongside bulk-fill injection-moulding techniques.

An international unified approach to reporting and grading invasive breast cancer. An overview of the International Collaboration on Cancer Reporting (ICCR) initiative.

Standardised reporting of breast cancer key pathology data has become the norm in some parts of the world, but are based on national or regional guidelines that differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data internationally. The International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organizations, have recently produced a new international dataset for the pathology reporting of breast cancer, including resection specimens with invasive cancer and ductal carcinoma in situ (DCIS) of the breast. This initiative aims at providing an international unified approach to reporting cancer. The guidance was prepared by an international expert panel consisting of experienced breast pathologists, a surgeon, and an oncologist. The dataset includes core (essential) and noncore (optional) data items based on a critical review and discussion of current evidence. Commentary is provided for each data item to explain the rationale for selection, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. The process concludes with international public consultation, before ratification and publication on the free open access ICCR website, with a synoptic reporting guide. The key aim is to promote high-quality, standardised pathology reporting that can be used worldwide. Histological grade, tumour size, and oestrogen receptor status are used in this article to illustrate this process and the detail provided to support its inclusion.

UK recommendations for HER2 assessment in breast cancer: an update.

The last UK breast cancer (BC) human epidermal growth factor receptor 2 (HER2) testing guideline recommendations were published in 2015. Since then, new data and therapeutic strategies have emerged. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a focused update in 2018 that reclassified in situ hybridisation (ISH) Group 2 (immunohistochemistry (IHC) score 2+and HER2/chromosome enumeration probe 17 (CEP17) ratio ≥2.0 and HER2 copy number <4.0 signals/cell), as well as addressed other concerns raised by previous guidelines. The present article further refines UK guidelines, with specific attention to definitions of HER2 status focusing on eight key areas: (1) HER2 equivocal (IHC 2+) and assignment of the ASCO/CAP ISH group 2 tumours; (2) the definition of the group of BCs with low IHC scores for HER2 with emphasis on the distinction between IHC score 1+ (HER2-Low) from HER2 IHC score 0 (HER2 negative); (3) reporting cases showing HER2 heterogeneity; (4) HER2 testing in specific settings, including on cytological material; (5) repeat HER2 testing, (6) HER2 testing turnaround time targets; (7) the potential role of next generation sequencing and other diagnostic molecular assays for routine testing of HER2 status in BC and (8) use of image analysis to score HER2 IHC. The two tiered system of HER2 assessment remains unchanged, with first line IHC and then ISH limited to IHC equivocal cases (IHC score 2+) but emerging data on the relationship between IHC scores and levels of response to anti-HER2 therapy are considered. Here, we present the latest UK recommendations for HER2 status evaluation in BC, and where relevant, the differences from other published guidelines.