Angiosarcoma arising in the capsule of a mammary silicone implant.

A 40-year-old woman with silicone implants inserted 21 years before presented with sudden onset of painful right breast swelling. Clinical examination revealed a firm swollen breast with appearance of old bruising. Ultrasound showed fluid around the implant. Cytology of the fluid showed cells with large pleomorphic nuclei with prominent nucleoli including elongated forms and very occasional vacuoles. The cell block also contained small fragments with atypical spindle cells around slit-like spaces that were positive for CD31 and CD34. MRI showed a 25 mm serpiginous area of enhancement on the inner aspect of the fibrous capsule with haematoma between the capsule and the implant. The capsule and adjacent area were excised. Histology showed angiosarcoma extending from the inner aspect of the capsule into the cavity around the implant. The location of the tumour on the inner aspect of the capsule is the same site that breast implant associated anaplastic large cell lymphomas arise and suggests a possible causal link between the implant and the angiosarcoma. This case emphasises the value of cytological assessment of fluid around breast implants and the role of cell blocks and immunohistochemistry.

Machine learning-based prediction of breast cancer growth rate in vivo.

BACKGROUND: Determining the rate of breast cancer (BC) growth in vivo, which can predict prognosis, has remained elusive despite its relevance for treatment, screening recommendations and medicolegal practice. We developed a model that predicts the rate of in vivo tumour growth using a unique study cohort of BC patients who had two serial mammograms wherein the tumour, visible in the diagnostic mammogram, was missed in the first screen. METHODS: A serial mammography-derived in vivo growth rate (SM-INVIGOR) index was developed using tumour volumes from two serial mammograms and time interval between measurements. We then developed a machine learning-based surrogate model called Surr-INVIGOR using routinely assessed biomarkers to predict in vivo rate of tumour growth and extend the utility of this approach to a larger patient population. Surr-INVIGOR was validated using an independent cohort. RESULTS: SM-INVIGOR stratified discovery cohort patients into fast-growing versus slow-growing tumour subgroups, wherein patients with fast-growing tumours experienced poorer BC-specific survival. Our clinically relevant Surr-INVIGOR stratified tumours in the discovery cohort and was concordant with SM-INVIGOR. In the validation cohort, Surr-INVIGOR uncovered significant survival differences between patients with fast-growing and slow-growing tumours. CONCLUSION: Our Surr-INVIGOR model predicts in vivo BC growth rate during the pre-diagnostic stage and offers several useful applications.

Surgical management of ductal carcinoma in situ of the breast: A large retrospective study from a single institution.

BACKGROUND: Management of breast ductal carcinoma in situ (DCIS) has various approaches with distinct institutional specific practice. Here, we review DCIS management in a single institution with emphasize on re-operation rates and outcome. METHODS: Breast ductal carcinoma in situ cases diagnosed at the Nottingham Breast Institute between 1987 and 2017 were identified (n = 1249). Clinicopathological data were collected. Cases were histologically reviewed, and different factors associated with primary operation selection, re-excision, presence of residual tumor in the re-excision specimens, use of radiotherapy and ipsilateral recurrences were analyzed. RESULTS: 34% of DCIS patients were initially treated by mastectomy and were more frequently symptomatic, of high nuclear tumor grade, size >40 mm, and associated with comedo necrosis and Paget's disease of the nipple. Further surgery was due to involved or narrow surgical margins. Residual tumor tissue was detected in 53% of the re-excision specimens. Re-excision rates of patients treated with breast-conserving surgery (BCS) were reduced from approximately 70% to 23%, and the final mastectomy rates decreased from 60% to 20%. Changes in surgical practice with acceptance of smaller excision margins and more frequent use of local radiotherapy have led to a significant decrease not only in the re-excision rate but also in the final mastectomy rate together with non-significant reduction in 5- and 10-year local recurrence rates. CONCLUSION: Although BCS is increasingly the preferred primary surgical option for DCIS management, a proportion of low-risk DCIS patients continue to undergo re-excision surgery or completion mastectomy. Despite acceptance of smaller margins, recurrence rate is decreasing.

Accuracy of GE digital breast tomosynthesis vs supplementary mammographic views for diagnosis of screen-detected soft-tissue breast lesions.

OBJECTIVE: To compare the accuracy of standard supplementary views and GE digital breast tomosynthesis (DBT) for assessment of soft-tissue mammographic abnormalities. METHODS: Women recalled for further assessment of soft-tissue abnormalities were recruited and received standard supplementary views (typically spot compression views) and two-view GE DBT. The added value of DBT in the assessment process was determined by analysing data collected prospectively by radiologists working up the cases. Following anonymization of cases, there was also a retrospective multireader review. The readers first read bilateral standard two-view digital mammography (DM) together with the supplementary mammographic views and gave a combined score for suspicion of malignancy on a five-point scale. The same readers then read bilateral standard two-view DM together with two-view DBT. Pathology data were obtained. Differences were assessed using receiver operating characteristic analysis. RESULTS: The study population was 342 lesions in 322 patients. The final diagnosis was malignant in 113 cases (33%) and benign/normal in 229 cases (67%). In the prospective analysis, the performance of two-view DM plus DBT was at least equivalent to the performance of two-view DM and standard mammographic supplementary views-the area under the curve (AUC) was 0.946 and 0.922, respectively, which did not reach statistical significance. Similar results were obtained for the retrospective review-AUC was 0.900 (DBT) and 0.873 (supplementary views), which did not reach statistical significance. CONCLUSION: The accuracy of GE DBT in the assessment of screen detected soft-tissue abnormalities is equivalent to the use of standard supplementary mammographic views. ADVANCES IN KNOWLEDGE: The vast majority of evidence relating to the use of DBT has been gathered from research using Hologic equipment. This study provides evidence for the use of the commercially available GE DBT system demonstrating that it is at least equivalent to supplementary mammographic views in the assessment of soft-tissue screen-detected abnormalities.

Screen-detected malignant breast lesions diagnosed following benign (B2) or normal (B1) needle core biopsy diagnoses.

UNLABELLED: Breast needle core biopsy (NCB) is now a standard diagnostic procedure in the triple assessment of screen detected breast lesions. However, unlike fine needle aspiration (FNA) cytology, information on the miss rate including false-negative diagnoses (FN) of malignancy (benign 'B2' or normal 'B1' NCB with a malignant outcome) is limited. METHODS: A large series of NCBs (121,742) performed over an 8-year period has been studied to assess the frequency and causes of missing a malignant diagnosis on NCB and to evaluate their impact on patients' management in the screening service. RESULTS: During the period of this study, 50,691 were diagnosed as B2 and 9599 were diagnosed as B1. Of those, 779 B2 and 919 B1 were diagnosed as malignant on the subsequent surgical specimens, respectively, giving a FN rate of 3.0%. However when year of diagnosis was taken into consideration, we found that during the period 1999-2001, the FN rate for B2 was 2.7% while the miss rate for B1 was 4.0%. This showed marked improvement over time to reach a figure of 0.5% and 0.5% for B2 and B1, respectively, during the period 2005-2007. On detailed review of cases from a single screening region diagnosed during the last 3 years (2005-2008), 14 cases (0.17% of all NCBs) with malignant surgery were diagnosed as B2 (seven cases; FN rate 0.19%) and B1 (seven cases; B1 biopsy rate from cancer 0.19%). In these cases, NCB was unsatisfactory, there was a discrepancy between radiological abnormalities and histological findings with recommendation for excision or suspicious/malignant cytological diagnosis on concurrent FNA material. Therefore, our results indicate that the malignancy miss rate on NCB is rare and FN NCB diagnoses had no impact on patient management.

A woman living with osteoarthritis: A case report.

Osteoarthritis is a common condition that is typically associated with older adults. Other causes of osteoarthritis, such as those cases resulting from childhood Perthes disease, can affect younger people and frequently have a major impact on the lives of those affected. This case report describes the experiences of one patient with osteoarthritis, using examples of her poetry to illustrate her social, psychological and emotional transformation.

Potentiation of ATP- and bradykinin-induced [Ca2+]c responses by PTHrP peptides in the HaCaT cell line.

In the epidermis, local and systemic factors including extracellular nucleotides and parathyroid hormone-related protein (PTHrP) regulate keratinocyte proliferation and differentiation. Extracellular nucleotides increase proliferation via activation of P2 receptors and induction of calcium transients, while endoproteases cleave PTHrP, resulting in fragments with different cellular functions. We investigated the effects of adenosine 5'-triphosphate (ATP) alone and in combination with synthetic PTHrP peptides on calcium transients in HaCaT cells. ATP induced calcium transients, while PTHrP peptides did not. C-terminal and mid-molecule PTHrP peptides (1-100 pM) potentiated ATP-induced calcium transients independently of calcium influx. 3-Isobutyl-1-methylxanthine potentiated ATP-induced calcium transients, suggesting that a cyclic monophosphate is responsible. Cyclic AMP is not involved, but cyclic GMP is a likely candidate since the protein kinase G inhibitor, KT5823, inhibited potentiation. Co-stimulation with ATP and either PTHrP (43-52) or PTHrP (70-77) increased proliferation, suggesting that this is important in the regulation of cell turnover and wound healing and may be a mechanism for hyperproliferation in skin disorders such as psoriasis. Finally, PTHrP fragments potentiated bradykinin-induced calcium transients, suggesting a role in inflammation in the skin. Since PTHrP is found in many normal and malignant cells, potentiation is likely to have a wider role in modulating signal transduction events.

Influence of mammographic parenchymal pattern in screening-detected and interval invasive breast cancers on pathologic features, mammographic features, and patient survival.

OBJECTIVE: The aim of our study was to assess the effect of mammographic parenchymal pattern on patient survival, mammographic features, and pathologic features of breast cancer in a screened population. MATERIALS AND METHODS: We classified the parenchymal pattern (according to BI-RADS) of 759 screened women who presented with a screening-detected (n = 455) or interval (n = 304) invasive breast cancer. Pathologic details (tumor size, histologic grade, lymph node stage, vascular invasion, and histologic type) and mammographic appearances were recorded. Breast cancer-specific survival was ascertained, with a median follow-up of 9.0 years. RESULTS: An excess of interval cancers was seen in women with dense breasts (p < 0.0001). Screening-detected (but not interval) tumors were significantly smaller in fatty breasts (p = 0.014). Tumor grade, lymph node stage, vascular invasion, and histologic type did not vary significantly with mammographic parenchymal pattern in screening-detected or interval cancers. Screening-detected cancers in fatty breasts were more likely to appear as indistinct (p = 0.003) or spiculated (p = 0.002) masses in contrast to cancers in dense breasts, which more commonly appeared as architectural distortions (p < 0.0001). No significant breast cancer-specific survival difference was seen by mammographic parenchymal pattern for screening-detected cancers (p = 0.75), interval cancers (p = 0.82), or both groups combined (p = 0.12). CONCLUSION: The prognosis of screened women presenting with breast cancer is unrelated to dense mammographic parenchymal pattern despite an excess of interval cancers and larger screening-detected tumors in this group. These data support the mammographic screening of women with dense parenchymal patterns.

Human keratinocytes release ATP and utilize three mechanisms for nucleotide interconversion at the cell surface.

Nucleotide activation of P2 receptors is important in autocrine and paracrine regulation in many tissues. In the epidermis, nucleotides are involved in proliferation, differentiation, and apoptosis. In this study, we have used a combination of luciferin-luciferase luminometry, pharmacological inhibitors, and confocal microscopy to demonstrate that HaCaT keratinocytes release ATP into the culture medium, and that there are three mechanisms for nucleotide interconversion, resulting in ATP generation at the cell surface. Addition of ADP, GTP, or UTP to culture medium elevated the ATP concentration. ADP to ATP conversion was inhibited by diadenosine pentaphosphate, oligomycin, and UDP, suggesting the involvement of cell surface adenylate kinase, F(1)F(0) ATP synthase, and nucleoside diphosphokinase (NDPK), respectively, which was supported by immunohistochemistry. Simultaneous addition of ADP and GTP elevated ATP above that for each nucleotide alone indicating that GTP acts as a phosphate donor. However, the activity of NDPK, F(1)F(0) ATP synthase or the forward reaction of adenylate kinase could not fully account for the culture medium ATP content. We postulate that this discrepancy is due to the reverse reaction of adenylate kinase utilizing AMP. In normal human skin, F(1)F(0) ATP synthase and NDPK were differentially localized, with mitochondrial expression in the basal layer, and cell surface expression in the differentiated layers. We and others have previously demonstrated that keratinocytes express multiple P2 receptors. In this study we now identify the potential sources of extracellular ATP required to activate these receptors and provide better understanding of the role of nucleotides in normal epidermal homeostasis and wound healing.

Human keratinocytes express multiple P2Y-receptors: evidence for functional P2Y1, P2Y2, and P2Y4 receptors.

Extracellular nucleotides are agonists at the family of receptors known as the P2 receptors, and in keratinocytes the P2Y2 subtype is known to elevate the intracellular free calcium concentration (Cai) and stimulate proliferation. In this study, we have investigated the presence of other functional members of the P2Y subgroup in both normal human keratinocytes and the HaCaT cell line. Using reverse transcription polymerase chain reaction, the expression of mRNA for P2Y1, P2Y2, P2Y4, and P2Y6 receptors was demonstrated in HaCaT cells and differentiated and undifferentiated normal human keratinocytes. Cai was monitored in response to a panel of P2Y receptor agonists. To couple mobilized Cai to a downstream cellular response, cell proliferation was also addressed. In both cell types, adenosine 5'-triphosphate and uridine 5'-triphosphate induced Cai transients of approximately equal duration, magnitude, and shape, confirming the presence of functional P2Y2 receptors. In HaCaT cells, additional characteristic responses were observed in a subpopulation of cells; adenosine 5'-triphosphate failed to elevate Cai in some cells responding to uridine 5'-triphosphate, indicating the presence of P2Y4 receptors, whereas the P2Y1-specific agonist 2-methylthio-5'-adenosine diphosphate was, again, only effective in a small subpopulation. Uridine 5'-diphosphate was ineffective, indicating the absence of functional P2Y6 receptors. Adenosine 5'-triphosphate and uridine 5'-triphosphate equally promoted cell growth in normal human keratinocytes in comparison with the control. In HaCaT cells, adenosine 5'-triphosphate, uridine 5'-triphosphate, and adenosine 5'-diphosphate significantly increased proliferation in comparison to the controls, with a 30% higher response to uridine 5'-triphosphate than with adenosine 5'-triphosphate. These data demonstrate that multiple P2Y receptors (P2Y1, P2Y2, and P2Y4 subtypes) are differentially involved in the regulation of proliferation in human keratinocytes and therefore may be important in wound healing.