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AimThe 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.MethodsDetails 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.Results112 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.ConclusionsRepeat 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.

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.

The response of human epidermal growth factor receptor2 (HER2)- positive breast cancer (BC) patients to anti-HER2 targeted therapy is significant. However, the response is not uniform and a proportion of HER2-positive patients do not respond. This study aims to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2status between pre- and post-treatment specimens in HER2-positive BC patients. The study group comprised 500 BC patients treated with neoadjuvant chemotherapy (NACT) and/or neoadjuvant anti-HER2 therapy and surgery who had tumours that were 3+ or 2+ with HER2 immunohistochemistry (IHC). HER2 IHC 2+ tumours were classified into five groups by fluorescence in situ hybridisation (FISH) according to the 2018 ASCO/CAP guidelines of which Groups 1, 2 and 3 were considered HER2amplified. Pathological complete response (pCR) was more frequent in HER2 IHC 3+ tumours than in HER2 IHC 2+/HER2amplified tumours, when either in receipt of NACT alone (38% versus 13%; p= 0.22) or neoadjuvant anti-HER2 therapy (52% versus 20%; p< 0.001). Multivariate logistic regression analysis showed that HER2 IHC 3+ and histological grade 3 were independent predictors of pCR following neoadjuvant anti-HER2 therapy. In the HER2 IHC 2+/HER2amplified tumours or ASCO/CAP FISH Group 1 alone, ER-negativity was an independent predictor of pCR following NACT and/or neoadjuvant anti-HER2 therapy. In the current study, 22% of HER2-positive tumours became HER2-negative by IHC and FISH following neoadjuvant treatment, the majority (74%) HER2 IHC 2+/HER2amplified tumours. Repeat HER2 testing after neoadjuvant treatment should therefore be considered.

Programmable nuclease-based genome editing technologies, including the clustered, regularly interspaced, short palindromic repeats (CRISPR)/Cas9 system, are becoming an essential component of many applications ranging from agriculture to medicine. However, fundamental limitations currently prevent the widespread, safe, and practical use of genome editors, especially for human disease interventions. These limitations include off-target effects, a lack of control over editing activity, suboptimal DNA repair outcomes, insufficient target conversion, and inadequate delivery performance. This perspective focuses on the potential for biological chemistry to address these limitations such that newly developed genome editing technologies can enable the broadest range of potential future applications. Equally important will be the development of these powerful technologies within a relevant ethical framework that emphasizes safety and responsible innovation.

This review examines the characteristics, candidates for, and future prospects of the transoral vestibular approach to the thyroid.

AimFibroepithelial lesions (FELs) of the breast span a morphological continuum including lesions where distinction between cellular fibroadenoma (FA) and benign phyllodes tumour (PT) is difficult. The distinction is clinically important with FAs managed conservatively while equivocal lesions and PTs are managed with surgery. We sought to audit core biopsy diagnoses of equivocal FELs by digital pathology and to investigate whether digital point counting is useful in clarifying FEL diagnoses.MethodScanned slide images from cores and subsequent excisions of 69 equivocal FELs were examined in a multicentre audit by eight pathologists to determine the agreement and accuracy of core needle biopsy (CNB) diagnoses and by digital point counting of stromal cellularity and expansion to determine if classification could be improved.ResultsInterobserver variation was high on CNB with a unanimous diagnosis from all pathologists in only eight cases of FA, diagnoses of both FA and PT on the same CNB in 15 and a ‘weak’ mean kappa agreement between pathologists (k=0.36). ‘Moderate’ agreement was observed on CNBs among breast specialists (k=0.44) and on excision samples (k=0.49). Up to 23% of lesions confidently diagnosed as FA on CNB were PT on excision and up to 30% of lesions confidently diagnosed as PT on CNB were FA on excision. Digital point counting did not aid in the classification of FELs.ConclusionAccurate and reproducible diagnosis of equivocal FELs is difficult, particularly on CNB, resulting in poor interobserver agreement and suboptimal accuracy. Given the diagnostic difficulty, and surgical implications, equivocal FELs should be reported in consultation with experienced breast pathologists as a small number of benign FAs can be selected out from equivocal lesions.

The article presents an obituary for scholar of modern Spain and American Historical Association (AHA) member Carolyn P. Boyd.

Pleomorphic lobular carcinoma is regarded as a biologically aggressive variant of invasive lobular carcinoma of the breast. However, there is no consensus on the definition and whether this subtype adds useful information to histological grade. Two-hundred and two grade 2 or grade 3 invasive lobular carcinomas were studied. Tumours were categorised according to the components of histological grade: tubules, pleomorphism and mitoses. Pleomorphic lobular carcinoma was defined as a carcinoma with a lobular growth pattern and marked nuclear pleomorphism (pleomorphism 3). Breast cancer-specific survival was used in analysis of prognosis. Grade 3 pleomorphic lobular carcinomas (tubules 3, pleomorphism 3, mitoses 2 and tubules 3, pleomorphism 3, mitoses 3) had a worse prognosis than grade 2 (tubules 3, pleomorphism 2, mitoses 1) carcinomas. Grade 2 lobular carcinomas with marked nuclear pleomorphism (tubules 3, pleomorphism 3, mitoses 1) had a similar prognosis to grade 2 carcinomas with moderate pleomorphism (tubules 3, pleomorphism 2, mitoses 1). Survival was associated with mitotic score, but not with nuclear pleomorphism on both univariate and multivariate analysis. A non-classical growth pattern was seen more frequently in all subgroups with marked nuclear pleomorphism and was associated with worse survival. Histological grade and nodal status were independent of prognostic factors. This study shows that histological grade (in particular the mitotic component) in invasive lobular carcinomas is of prognostic importance, but pleomorphic type does not provide useful additional prognostic information.

Pleomorphic lobular carcinoma is regarded as a biologically aggressive variant of invasive lobular carcinoma of the breast. However, there is no consensus on the definition and whether this subtype adds useful information to histological grade. Two-hundred and two grade 2 or grade 3 invasive lobular carcinomas were studied. Tumours were categorised according to the components of histological grade: tubules, pleomorphism and mitoses. Pleomorphic lobular carcinoma was defined as a carcinoma with a lobular growth pattern and marked nuclear pleomorphism (pleomorphism 3). Breast cancer-specific survival was used in analysis of prognosis. Grade 3 pleomorphic lobular carcinomas (tubules 3, pleomorphism 3, mitoses 2 and tubules 3, pleomorphism 3, mitoses 3) had a worse prognosis than grade 2 (tubules 3, pleomorphism 2, mitoses 1) carcinomas. Grade 2 lobular carcinomas with marked nuclear pleomorphism (tubules 3, pleomorphism 3, mitoses 1) had a similar prognosis to grade 2 carcinomas with moderate pleomorphism (tubules 3, pleomorphism 2, mitoses 1). Survival was associated with mitotic score, but not with nuclear pleomorphism on both univariate and multivariate analysis. A non-classical growth pattern was seen more frequently in all subgroups with marked nuclear pleomorphism and was associated with worse survival. Histological grade and nodal status were independent of prognostic factors. This study shows that histological grade (in particular the mitotic component) in invasive lobular carcinomas is of prognostic importance, but pleomorphic type does not provide useful additional prognostic information.

Accurate assessment of estrogen receptor (ER) and progesterone receptor (PR) status of breast cancers is essential for selecting patients for endocrine treatment. This study aimed to compare immunohistochemistry for these markers using the pharmDx system and standard methods.

Dentists are self‐selected for visual and kinesthetic learning preferences. Watching another practitioner perform treatment can be incredibly didactic, both before and after learning the procedure. This missing part of dental education has the capacity to play a tremendous role in dental education for all levels of practitioner. Dental students in their clinical years begin to realize the meaning of dentistry as a practice, a set of skills that are never perfected. Abundant evidence demonstrates that cycling between observation and practice enhances procedural learning and retention, yet this mechanism is vastly underused in dental education. Collaborative treatment paradigms, wherein the able student assists a more experienced practitioner, can create mentorship. Learning potentially esoteric information or subtle nuances of clinical acumen is facilitated by the contextual framework of the clinical environment and is strengthened by emotional attachments through interpersonal interactions. In this article, we explore the evidence surrounding mentorship and clinical observation both before and after students are given the responsibilities of patient care, which together recapitulate clinical apprenticeship. Finally, we present examples of how apprenticeship can be brought back to dental education, including evaluation of a clinical assisting program that we implemented and explanation of a hypothetical faculty‐student practice partnership model.

Angiogenesis is essential for tumour growth and important in metastasis and for prognosis in invasive carcinoma of the breast. Two patterns of increased vascularity have been shown in mammary ductal carcinoma in situ(DCIS): a cuff of vessels close to the involved ducts, and vessels in the interductal stroma. Inflammation may potentially promote angiogenesis by release of angiogenic factors and digestive enzymes. A correlation has previously been found between the intensity of perivascular inflammation and stromal vascularity in DCIS, but no strong relationship has been observed between inflammation and angiogenesis in invasive carcinoma. Tumour angiogenesis is regulated by a number of angiogenic factors, including thymidine phosphorylase (platelet‐derived endothelial cell growth factor), which is expressed at high levels in macrophages. Using immunohistochemical methods, thymidine phosphorylase expression and vascularity have been studied in DCIS (n= 34) and invasive carcinoma (n= 32). Stromal vascularity in DCIS was associated with thymidine phosphorylase expression in the perivascular inflammatory cells and in the cytoplasm of carcinoma cells. In invasive carcinoma, no relationship was found between vascularity and thymidine phosphorylase expression in either the carcinoma or the inflammatory cells. This study suggests that thymidine phosphorylase expression in both inflammatory and carcinoma cells may contribute to one of the patterns of vascularity in DCIS, but not in invasive disease. Copyright © 1999 John Wiley & Sons, Ltd.

Angiogenesis is essential for tumour growth and important in metastasis and for prognosis in invasive carcinoma of the breast. Two patterns of increased vascularity have been shown in mammary ductal carcinoma in situ (DCIS): a cuff of vessels close to the involved ducts, and vessels in the interductal stroma. Inflammation may potentially promote angiogenesis by release of angiogenic factors and digestive enzymes. A correlation has previously been found between the intensity of perivascular inflammation and stromal vascularity in DCIS, but no strong relationship has been observed between inflammation and angiogenesis in invasive carcinoma. Tumour angiogenesis is regulated by a number of angiogenic factors, including thymidine phosphorylase (platelet-derived endothelial cell growth factor), which is expressed at high levels in macrophages. Using immunohistochemical methods, thymidine phosphorylase expression and vascularity have been studied in DCIS (n = 34) and invasive carcinoma (n = 32). Stromal vascularity in DCIS was associated with thymidine phosphorylase expression in the perivascular inflammatory cells and in the cytoplasm of carcinoma cells. In invasive carcinoma, no relationship was found between vascularity and thymidine phosphorylase expression in either the carcinoma or the inflammatory cells. This study suggests that thymidine phosphorylase expression in both inflammatory and carcinoma cells may contribute to one of the patterns of vascularity in DCIS, but not in invasive disease. Copyright © 1999 John Wiley & Sons, Ltd.

Angiogenesis is essential for tumour growth and important in tumour metastasis and prognosis. Vascular endothelial growth factor (VEGF) stimulates endothelial proliferation in vitroand angiogenesis in vivo. VEGF expression has been correlated with high vascularity in tumours, including carcinoma of the breast. This study investigated VEGF expression and vascularity of invasive lobular (n=10) and invasive ductal carcinoma (n=28), and pure ductal carcinoma in situof the breast (n=33). VEGF protein expression was studied with immunohistochemistry and VEGF mRNA with in situhybridization. Vascular density was assessed on sections stained for von Willebrand factor. There was more expression of both VEGF protein (P=0·006) and mRNA (P=0·002) in invasive ductal than in invasive lobular carcinoma. VEGF protein (rs=0·32, P=0·047) and mRNA (rs=0·56, P=0·04) correlated with vascular density in invasive ductal carcinoma. In invasive lobular carcinoma, vascular density did not correlate with VEGF mRNA (rs=0·15, P=0·35) and was inversely related to VEGF protein (rs=−0·57, P=0·04). There were no significant differences in vascular density between the two types of invasive carcinoma, suggesting that VEGF is important in angiogenesis in invasive ductal carcinoma, but that other angiogenic factors are important in invasive lobular carcinoma. Although VEGF protein was frequently expressed in ductal carcinoma in situ, no relationship was found between VEGF and the two patterns of angiogenesis previously described. © 1998 John Wiley & Sons, Ltd.

Experimental studies suggest that cyclin D1 is a potential oncogene but in clinical studies of invasive breast cancer, overexpression of cyclin D1 is found to be associated with oestrogen receptor (ER) expression and low histological grade, both markers of good prognosis. Immunohistochemistry has been used to examine the relationship between cyclin D1 expression and differentiation in 36 cases of ductal carcinoma in situ(DCIS) and the interrelationship between expression of cyclin D1, its associated protein product of the retinoblastoma gene (pRb), and ER, in this group of cases. The expression of these markers has also been examined in nine cases of atypical ductal hyperplasia (ADH) and these results have been compared with the levels of expression seen in DCIS. Cyclin D1 overexpression was found in 23/36 (64 per cent) cases of DCIS and, in contrast to invasive carcinoma, there was no relationship with either differentiation or ER expression. The level of pRb expression was significantly associated with cyclin D1 expression (rS=0·49, P=0·001) and only two cases (6 per cent) were pRb‐negative. There was no association between pRb and differentiation of DCIS or ER status. In contrast to DCIS, only one case of ADH showed overexpression of cyclin D1 (Mann–Whitney U‐test, P=0·02). All cases of ADH were ER‐positive and showed moderate pRb staining, similar to that seen in well‐differentiated DCIS. These results provide further evidence that overexpression of cyclin D1 plays a role early in carcinogenesis. © 1998 John Wiley & Sons, Ltd.

Several recent studies suggest that vascular density may be an independent prognostic indicator in invasive carcinoma of the breast. Increased vascularity has also been shown in ductal carcinoma in situ (DCIS). The prognostic significance of the inflammatory infiltrate in mammary carcinoma is more controversial, but it could affect angiogenesis by releasing angiogenic factors and digesting matrix. Vascularity and inflammation have been studied in 41 examples of pure DCIS, classified using the method of Holland et al. Immunohistochemistry was performed with antibodies to von Willebrand factor, CD3, CD8, CD45RO, CD45RA, CD20, CD68, and c-erbB-2. The main pattern of inflammation was clusters of B and T cells situated either adjacent to involved ducts or in the interductal stroma. Typically, these clusters were around vessels with plump endothelium suggestive of high endothelial venules. A less prominent pattern was a diffuse stromal infiltrate of macrophages and T cells. There were two patterns of increased vascularity associated with DCIS: necklaces of vessels close to the involved ducts and vessels arranged diffusely in the interductal stroma. Each pattern of inflammation and of vascularity was graded semi-quantitatively. Increased stromal vascularity was associated with the perivascular clusters of inflammation; both were associated with c-erbB-2 expression and extent of the DCIS. Necklaces of vessels were associated with the diffuse inflammation. Perivascular inflammation and c-erbB-2 (but neither pattern of vascularity) were associated with poor differentiation of the DCIS. Thus, different patterns of inflammation are associated with different patterns of vessels. The clusters of B and T cells may be recruited via high endothelial venules induced by the DCIS. Cytokines released by the DCIS and/or the inflammatory cells (clusters or diffuse) may stimulate the two patterns of new vessel formation. © 1997 John Wiley & Sons, Ltd.

Experimental studies suggest that cyclin D1 is a potential oncogene but in clinical studies of invasive breast cancer, overexpression of cyclin D1 is found to be associated with oestrogen receptor (ER) expression and low histological grade, both markers of good prognosis. Immunohistochemistry has been used to examine the relationship between cyclin D1 expression and differentiation in 36 cases of ductal carcinoma in situ (DCIS) and the interrelationship between expression of cyclin D1, its associated protein product of the retinoblastoma gene (pRb), and ER, in this group of cases. The expression of these markers has also been examined in nine cases of atypical ductal hyperplasia (ADH) and these results have been compared with the levels of expression seen in DCIS. Cyclin D1 overexpression was found in 23/36 (64 per cent) cases of DCIS and, in contrast to invasive carcinoma, there was no relationship with either differentiation or ER expression. The level of pRb expression was significantly associated with cyclin D1 expression (rS=0·49, P=0·001) and only two cases (6 per cent) were pRb-negative. There was no association between pRb and differentiation of DCIS or ER status. In contrast to DCIS, only one case of ADH showed overexpression of cyclin D1 (Mann–Whitney U-test, P=0·02). All cases of ADH were ER-positive and showed moderate pRb staining, similar to that seen in well-differentiated DCIS. These results provide further evidence that overexpression of cyclin D1 plays a role early in carcinogenesis. © 1998 John Wiley & Sons, Ltd.

Several recent studies suggest that vascular density may be an independent prognostic indicator in invasive carcinoma of the breast. Increased vascularity has also been shown in ductal carcinoma in situ(DCIS). The prognostic significance of the inflammatory infiltrate in mammary carcinoma is more controversial, but it could affect angiogenesis by releasing angiogenic factors and digesting matrix. Vascularity and inflammation have been studied in 41 examples of pure DCIS, classified using the method of Holland et al. Immunohistochemistry was performed with antibodies to von Willebrand factor, CD3, CD8, CD45RO, CD45RA, CD20, CD68, and c‐erbB‐2. The main pattern of inflammation was clusters of B and T cells situated either adjacent to involved ducts or in the interductal stroma. Typically, these clusters were around vessels with plump endothelium suggestive of high endothelial venules. A less prominent pattern was a diffuse stromal infiltrate of macrophages and T cells. There were two patterns of increased vascularity associated with DCIS: necklaces of vessels close to the involved ducts and vessels arranged diffusely in the interductal stroma. Each pattern of inflammation and of vascularity was graded semi‐quantitatively. Increased stromal vascularity was associated with the perivascular clusters of inflammation; both were associated with c‐erbB‐2 expression and extent of the DCIS. Necklaces of vessels were associated with the diffuse inflammation. Perivascular inflammation and c‐erbB‐2 (but neither pattern of vascularity) were associated with poor differentiation of the DCIS. Thus, different patterns of inflammation are associated with different patterns of vessels. The clusters of B and T cells may be recruited via high endothelial venules induced by the DCIS. Cytokines released by the DCIS and/or the inflammatory cells (clusters or diffuse) may stimulate the two patterns of new vessel formation. © 1997 John Wiley & Sons, Ltd.

Angiogenesis is essential for tumour growth and important in tumour metastasis and prognosis. Vascular endothelial growth factor (VEGF) stimulates endothelial proliferation in vitro and angiogenesis in vivo. VEGF expression has been correlated with high vascularity in tumours, including carcinoma of the breast. This study investigated VEGF expression and vascularity of invasive lobular (n=10) and invasive ductal carcinoma (n=28), and pure ductal carcinoma in situ of the breast (n=33). VEGF protein expression was studied with immunohistochemistry and VEGF mRNA with in situ hybridization. Vascular density was assessed on sections stained for von Willebrand factor. There was more expression of both VEGF protein (P=0·006) and mRNA (P=0·002) in invasive ductal than in invasive lobular carcinoma. VEGF protein (rs=0·32, P=0·047) and mRNA (rs=0·56, P=0·04) correlated with vascular density in invasive ductal carcinoma. In invasive lobular carcinoma, vascular density did not correlate with VEGF mRNA (rs=0·15, P=0·35) and was inversely related to VEGF protein (rs=−0·57, P=0·04). There were no significant differences in vascular density between the two types of invasive carcinoma, suggesting that VEGF is important in angiogenesis in invasive ductal carcinoma, but that other angiogenic factors are important in invasive lobular carcinoma. Although VEGF protein was frequently expressed in ductal carcinoma in situ, no relationship was found between VEGF and the two patterns of angiogenesis previously described. © 1998 John Wiley & Sons, Ltd.

Presents several letters to the editor on articles and topics discussed in previous issues. Commendation for the report published in the December 2004 issue on the recent conference on "Race and Human Variation"; Warning related to the archive restoration with reference to the article "Making Technology Work for You" published in the January 2005 issue of the journal.