INTEND II randomized clinical trial of intraoperative duct endoscopy in pathological nipple discharge.

BACKGROUND: The majority of lesions resulting in pathological nipple discharge are benign. Conventional surgery is undirected and targeting the causative lesion by duct endoscopy may enable more accurate surgery with fewer complications. METHODS: Patients requiring microdochectomy and/or major duct excision were randomized to duct endoscopy or no duct endoscopy before surgery. Primary endpoints were successful visualization of the pathological lesion in patients randomized to duct endoscopy, and a comparison of the causative pathology between the two groups. The secondary endpoint was to compare the specimen size between groups. RESULTS: A total of 68 breasts were studied in 66 patients; there were 31 breasts in the duct endoscopy group and 37 in the no-endoscopy group. Median age was 49 (range 19-81) years. Follow-up was 5·4 (i.q.r. 3·3-8·9) years in the duct endoscopy group and 5·7 (3·1-9·0) years in no-endoscopy group. Duct endoscopy had a sensitivity of 80 (95 per cent c.i. 52 to 96) per cent, specificity of 71 (44 to 90) per cent, positive predictive value of 71 (44 to 90) per cent and negative predictive value of 80 (52 to 96) per cent in identifying any lesion. There was no difference in causative pathology between the groups. Median volume of the surgical resection specimen did not differ between groups. CONCLUSION: Diagnostic duct endoscopy is useful for identifying causative lesions of nipple discharge. Duct endoscopy did not influence the pathological yield of benign or malignant diagnoses nor surgical resection volumes. Registered as INTEND II in CancerHelp UK clinical trials database (https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-changes-inside-the-breast-ducts-of-women-who-have-nipple-discharge).

Clostridium butyricum partially regulates the development of colitis-associated cancer through miR-200c.

Colitis-associated cancer (CAC), one form of colorectal cancer (CRC),is an increasing concern worldwide. Both diagnosis and current therapy are challenging and bottlenecked. The aim of this study is to investigate novel mechanisms by which the therapeutic C. butyricum regulates colitis-induced oncogenesis. Mouse models of CAC were established with 2,4,6-Trinitrobenzenesulfonic acid (TNBS)and azoxymethane (AOM), following by biochemical, clinical and histological analysis. The integrity of epitheliumwas examined by electron microscopy (EM). The epithelial barrier function was evaluated with Ussing chamber. Real time PCR and fluorescent in situ hybridization (FISH) were performed to characterize the effect of C. butyricum on miR-200c; cell proliferation assays (MTT) were performed to study the role ofC. butyricum on epithelial cell proliferation mediated by miR-200c inhibitor; finally, we quantified the proinflammatory cytokines TNF-α and interleukin (IL)-12 by real time PCR. C. butyricum ameliorates clinical, histological and biochemical manifestations in colitis-induced CAC models. Further mechanistic studies demonstrated that C. Butyricum could lengthen epithelial microvillus and increase TER by decreasing the transepithelial permeability. We also showed that C. butyricum facilitates the expression of miR-200c, by which increase the proliferation rate. Finally, we found that C. butyricum can regulate the production of proinflammatory cytokines TNF-α and IL-12 through miR-200c. C. butyricum may regulate epithelial barrier function through miR-200c, then to be involved in the process of inflammation-associated cancers.

In vivo study of the surgical anatomy of the axilla.

BACKGROUND: Classical anatomical descriptions fail to describe variants often observed in the axilla as they are based on studies that looked at individual structures in isolation or textbooks of cadaveric dissections. The presence of variant anatomy heightens the risk of iatrogenic injury. The aim of this study was to document the nature and frequency of these anatomical variations based on in vivo peroperative surgical observations. METHODS: Detailed anatomical relationships were documented prospectively during consecutive axillary dissections. Relationships between the thoracodorsal pedicle, course of the lateral thoracic vein, presence of latissimus dorsi muscle slips, variations in axillary and angular vein anatomy, and origins and branching of the intercostobrachial nerve were recorded. RESULTS: Among a total of 73 axillary dissections, 43 (59 per cent) revealed at least one anatomical variant. Most notable variants included aberrant courses of the thoracodorsal nerve in ten patients (14 per cent)--three variants; lateral thoracic vein in 12 patients (16 per cent)--four variants; bifid axillary veins in ten patients (14 per cent); latissimus dorsi muscle slips in four patients (5 per cent); and variants in intercostobrachial nerve origins and branching in 26 patients (36 per cent). The angular vein, a subscapular vein tributary, was found to be a constant axillary structure. CONCLUSION: Variations in axillary anatomical structures are common. Poor understanding of these variants can affect the adequacy of oncological clearance, lead to vascular injury, compromise planned microvascular procedures and result in chronic pain or numbness from nerve injury. Surgeons should be aware of the common anatomical variants to facilitate efficient and safe axillary surgery.

Multicentric breast cancer: clonality and prognostic studies.

Clonality of multicentric breast cancer has traditionally been difficult to assess. We aimed to assess this using analysis of TP53 status (expression and mutation status). These results were then incorporated into an analysis of prognostic factors in multicentric tumours in a 10-year follow up study. Clonal status of multicentric breast cancer foci (n = 88 foci) was determined by immunohistochemical and molecular studies of TP53 in a total of 40 patients. Prognostic factors from these patients were also compared with 80 age- and stage-matched controls with unicentric breast cancer from the Royal Marsden NHS Foundation Trust Breast Cancer Database. Our results indicate that multicentric breast cancer foci were polyclonal within an individual patient in at least 10 patients (25%) with respect to immunohistochemical staining and in four patients (10%) with respect to abnormal band shifts on single strand conformational polymorphism (SSCP) molecular analysis. No individual variable was predictive of multicentric or unicentric disease. However, there was a worse overall survival in the multicentric breast cancer patients in whom at least two cancer foci stained positively on TP53 immunohistochemistry compared with the matched control group (P = 0.04). In conclusion, these results suggest that a proportion of multicentric breast cancer foci are polyclonal with respect to TP53 status and that TP53 over-expression predicts for a poorer prognosis in multicentric breast cancer.

Nipple-sparing mastectomy.

BACKGROUND: Although effective local control is the primary goal of surgery for breast cancer, the long-term aesthetic outcome is also important. Nipple-sparing mastectomy aims to address this, but there is no consensus on its clinical application. Evidence relating to oncological safety, surgical technique and early data on aesthetic outcome was reviewed. METHODS: The review was based on a PubMed search using the terms 'nipple-sparing' or 'subcutaneous mastectomy' and 'breast cancer'. RESULTS: Large pathological studies report occult nipple involvement with cancer in 5.6-31 per cent, reflecting variation in inclusion criteria. Recent clinical series with careful patient selection report local recurrence in less than 5 per cent of patients. The incidence of cancer in the retained nipple after risk-reducing mastectomy is less than 1 per cent. Nipple necrosis rates range up to 8 and 16 per cent for total and partial necrosis respectively. Variations in outcome result from differences in extent of resection, placement of incisions and type of breast reconstruction. CONCLUSION: Nipple-sparing mastectomy is an acceptable technique for women undergoing risk-reducing mastectomy. In the therapeutic setting, it may be offered to patients with smaller tumours far from the nipple and favourable pathological features. Women should be counselled about nipple necrosis and the potential for local recurrence.

Complete excision with narrow margins provides equivalent local control to wider excision in breast conservation for invasive cancer.

Background: Society of Surgical Oncology and American Society for Radiation Oncology guidelines define clear margins in breast-conserving therapy (BCT) as 'no ink on tumour', in contrast to the attainment of margins of at least 1 mm widely practised in the UK. The primary aim of this study was to explore clinical, surgical and tumour-related factors associated with local recurrence after BCT, with a secondary aim of assessing the impact of margin re-excision on the risk of local recurrence. Methods: Patient demographics, surgical details, tumour characteristics and local recurrence were recorded for consecutive women with BCT undergoing surgery between January 1997 and January 2007. Margins were defined as clear (greater than 1 mm), close (less than 1 mm but no ink on tumour), reaches (ink on tumour) and clear after re-excision. Results: A total of 1045 women of median age 54 (range 18-86) years were studied. Median follow-up was 89 (range 4-196) months. Local recurrence occurred in 52 patients (5·0 per cent). Ink on tumour was associated with local recurrence (hazard ratio (HR) 4·86, 95 per cent c.i. 1·49 to 15·79; P = 0·009). Risk of local recurrence was the same for close and clear margins (HR 1·03, 0·40 to 2·62; P = 0·954). In women with involved margins, re-excision was still associated with an increased local recurrence risk (HR 2·50, 1·32 to 4·72; P = 0·005). Oestrogen receptor negativity increased risk (HR 2·28, 1·28 to 4·06; P = 0·005). Conclusion: Adequately excised margins, even when under 1 mm, provide equivalent outcomes to wider margins in BCT. Achieving complete excision at primary surgery achieves the lowest rates of local recurrence.

Microbial community and short-chain fatty acid profile in gastrointestinal tract of goose.

Goose is an economically important herbivore waterfowl supplying nutritious meat and eggs, high-quality liver fat, and feathers. However, biogeograhpy of the gut microbiome of goose remains limited. The aim of this study was to investigate the microbiota inhabiting 7 different gastrointestinal locations (proventriculus, gizzard, duodenum, jejunum, ileum, cecum, and rectum) of 180-day-old geese and the short-chain fatty acids (SCFA) of their metabolites based on 16S rRNA gene sequences and gas chromatography, respectively. Consequently, 3,886,340 sequences were identified into 29 phyla and 359 genera. Proteobacteria, Firmicutes, Bacteroidetes, Cyanobacteria, and Actinobacteria were the major phyla, in which Bacteroidetes (28%) and Fusobacteria (0.8%) in the cecum were significantly higher than those in other sections (∼4.4 and 0.1%, respectively). In addition, Cyanobacteria in the gizzard (4.9%) was significantly higher than those in other gut sections except the proventriculus (2.4%). At the genus level, Bacteroides was the most dominant group in the cecum at 23.7%, which was much more than those in the 6 other sections (less than 4.6%). Moreover, Faecalibacterium and Butyricicoccus were significantly high in the cecum (P < 0.05). Results of SCFA showed that acetic and butyric acids in the cecum were significantly higher than those in the 6 other sections (P < 0.05); this result was consistent with the high abundance of Bacteroides, Faecalibacterium, Prevotella, and Butyricicoccus in the cecum. Additionally, isobutyric, isovaleric, and valeric acids were found only in the cecum. The different microbial compositions among the 7 gastrointestinal locations might be a cause and consequence of gut functional differences. All these results could offer some information for future study of the relationship between gastrointestinal microbiota and the ability of fiber utilization and adaptability.

A comparative proteinomic analysis of nipple aspiration fluid from healthy women and women with breast cancer.

This pilot study examines the feasibility of nipple aspiration to distinguish women with breast cancer from healthy women using surface-enhanced laser desorption ionisation time-of-flight mass spectrometry (SELDI-TOF/MS). Nipple aspiration fluid (NAF) was collected from each breast in 21 women newly diagnosed with unilateral breast cancer and 44 healthy women. No differences were found when proteomic profiles of NAF from the cancer-bearing breast and the contralateral non-cancerous breast were compared. In contrast, 9 protein peaks were significantly different between the cancer-bearing breast compared with healthy women and 10 peaks were significantly different between the contralateral healthy breast and healthy women (P<0.05). These data suggest that invasive breast cancer may result in a field change across both breasts and that proteomic profiling of NAF may have more value in breast cancer risk assessment than as a diagnostic or screening tool.

Breast implant associated anaplastic large cell lymphoma: The UK experience. Recommendations on its management and implications for informed consent.

BACKGROUND: Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare, Non-Hodgkin lymphoma arising in the capsule of breast implants. BIA-ALCL presents as a recurrent effusion and/or mass. Tumours exhibit CD30 expression and are negative for Anaplastic Lymphoma Kinase (ALK). We report the multi-disciplinary management of the UK series and how the stage of disease may be used to stratify treatment. METHODS: Between 2012 and 2016, 23 cases of BIA-ALCL were diagnosed in 15 regional centres throughout the UK. Data on breast implant surgeries, clinical features, treatment and follow-up were available for 18 patients. RESULTS: The mean lead-time from initial implant insertion to diagnosis was 10 years (range: 3-16). All cases were observed in patients with textured breast implants or expanders. Fifteen patients with breast implants presented with stage I disease (capsule confined), and were treated with implant removal and capsulectomy. One patient received adjuvant chest-wall radiotherapy. Three patients presented with extra-capsular masses (stage IIA). In addition to explantation, capsulectomy and excision of the mass, all patients received neo-/adjuvant chemotherapy with CHOP as first line. One patient progressed on CHOP but achieved pathological complete response (pCR) with Brentuximab Vedotin. After a mean follow-up of 23 months (range: 1-56) all patients reported here remain disease-free. DISCUSSION: BIA-ALCL is a rare neoplasm with a good prognosis. Our data support the recommendation that stage I disease be managed with surgery alone. Adjuvant chemotherapy may be required for more invasive disease and our experience has shown the efficacy of Brentuximab as a second line treatment.

Clinical outcome and service implications of screening women at increased breast cancer risk from a family history.

INTRODUCTION: The value of special screening for women at moderate breast cancer risk with a family history of breast cancer remains controversial. Little is known about recall rates, false negative outcomes and the impact on clinical service. Despite this, surveillance programmes within breast units have been established in the United Kingdom. PATIENTS AND METHODS: In our institution, screening of women at moderate (lifetime risk, 17-30%) and high risk (>30%) consisted of annual clinical examination and mammography from the age of 35 years. The active study period ran for four months and each patient was followed through a further screening cycle (whole study period), providing information on interval cancers and detection at the subsequent screen. RESULTS: One thousand one hundred and thirty-two women attended for their incident screen: 137 at high risk, 803 at moderate risk and 192 at standard risk. The median age at cancer diagnosis in the moderate risk group was 54 (range, 45-68) years and the high-risk group 51 (46-52) years, compared to 63 (45-69) years in the standard risk group. Seven cancers were diagnosed during the four-month active study period. Two patients were diagnosed with interval cancers and eight at the next screen, giving a cancer incidence in the whole study period of 17/1132 (1.5%). Thirteen patients had invasive cancer and four had ductal carcinoma in situ (DCIS) The median invasive tumour size was 15 had (range, 7-28)mm and the median DCIS size was 4 (2-30)mm. 10/13 (76.9%) invasive cancers were < or =20mm and 2/13 patients (15.4%) with invasive cancer were lymph node positive. The sensitivity and specificity of mammography were 85.7% and 98.8%, respectively. The mammogram recall rate was 27.6 per 1000. The benign to malignant surgery ratio was 8:17. CONCLUSION: Screening women at increased breast cancer risk is effective. Early detection and recall rates are comparable to that of older women attending the British National Breast Screening Programme.

Wire localisation biopsy of non-palpable breast lesions: reasons for unsuccessful excision.

Surgical excision following needle-wire localization of nonpalpable, mammographically detected breast lesions is a very valuable diagnostic and therapeutic procedure. No further treatment is usually required after establishing an accurate histological benign diagnosis of indeterminate lesions on preoperative assessment. On the other hand, ductal carcinoma in-situ (DCIS) and early invasive cancer, properly excised, may sometimes require further management depending on specific histologic findings. An uncommon problem of this procedure is the failure to identify, localize or excise the breast lesion. In this review article, factors that contribute to the failed needle localization procedure are presented.

HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer.

In experimental models, human epidermal growth factor receptor-2 (HER-2) amplification leads to estrogen independence and tamoxifen resistance in estrogen receptor (ER)-positive human breast cancer cells. Some but not all reports suggest an association between HER-2 positivity and hormone independence in breast cancer patients. This study aimed to evaluate the antiproliferative effects of endocrine therapy in HER-2-positive/ER-positive primary human breast cancer. The effect on proliferation (Ki67) of hormone therapy was assessed at 2 weeks and/or 12 weeks in biopsies from 115 primary breast cancers with ER-positive tumors. The patients took part in one of 3 neoadjuvant trials of hormonal therapy with a SERM (tamoxifen or idoxifene) or an aromatase inhibitor (anastrozole or vorozole). HER-2 status was assessed by immunocytochemistry and fluorescence in situ hybridization (FISH). Fifteen patients were defined as HER-2 positive by both immunohistochemistry and FISH, with the remaining 100 patients HER-2 negative. Geometric mean Ki67 levels were substantially higher in HER-2-positive than HER-2-negative tumors (27.7% versus 11.5%, respectively; P = 0.003). In HER-2-negative patients, Ki67 was reduced by 62 and 71% at 2 and 12 weeks, respectively (P < 0.0001 for both), but HER-2-positive patients showed no significant fall. The proportional change in Ki67 was significantly different between HER-2-positive and -negative patients (P = 0.014 at 2 weeks; P = 0.047 at 12 weeks). Mean ER levels were lower in the HER-2-positive patients (P = 0.06) but the change in Ki67 was impeded even in those with high ER. Apoptotic index was reduced by 30% at 2 weeks in the HER-2-negative group. However, there were no statistically significant differences in apoptotic index between the groups. It is concluded that ER-positive/HER-2-positive primary breast carcinomas show an impeded antiproliferative response to endocrine therapy that nonetheless may vary between individual treatments. This together with high baseline proliferation is likely to translate to poor clinical response.

Sensory change of the reconstructed breast envelope after skin-sparing mastectomy.

BACKGROUND: Comprehensive studies of somatosensory change following breast reconstruction are limited. We investigated altered sensation quantitatively and qualitatively in patients undergoing mastectomies for cancer treatment and unaffected individuals who had risk-reducing mastectomies (RRM) for cancer predisposing genes. METHODS: Women attending breast clinic review at Royal Marsden Hospital, London were invited to participate. Sensory testing was performed a minimum of 1 year after surgery. Quantitative assessment of light touch and temperature sensation was performed at six points on the breast mound using Semmes-Weinstein monofilaments and temperature regulated droplets. Subjective sensibility of pain, tingling and pleasurable sensation was assessed using a four-point Likert scale questionnaire. RESULTS: 181 breast envelopes were examined, 77 following mastectomy for cancer, 68 after RRM and 36 controls. Partial sensation was maintained with normal light touch in at least 1 quadrant in 57% following surgery. Preserved sensation was highest in the medial breast mound (p = 0.001). On qualitative assessment 74% reported significant loss of pleasurable sensation and 9% reported chronic pain. No difference in light touch and temperature sensation was noted in cancer versus RRM groups but loss of pleasurable sensation was more frequent in the former. Radiotherapy did not affect sensory change post-mastectomy. Following nipple sparing mastectomies, 47% retained normal touch sensation in the preserved areola and nipple. CONCLUSION: Breast sensibility is significantly impaired following mastectomy and reconstruction but sensory loss is partial in the majority of women. Patients should be informed of these adverse post-operative effects to facilitate an informed decision if there is a surgical choice other than mastectomy as a surgical option.

Aesthetic and oncologic outcomes after one-stage immediate breast reconstruction using a permanent biodimensional expandable implant.

INTRODUCTION: Immediate breast reconstruction (IBR) with implants is the commonest method of reconstructive surgery after mastectomy. With careful patient selection, a stable implant pocket can be created at the primary operation to decrease the likelihood of further surgery to adjust the reconstructed side. One-stage IBR is cost effective but failed procedures requiring early revision may be costly as permanent expanders are expensive. METHODS: Data were prospectively collected on all women undergoing a planned one-stage immediate breast reconstruction between 1997 and 2010. All patients had a Style 150 implant (Allergan, Marlow, UK). Descriptive statistics, Kaplan-Meier plots and, where applicable, Cox Proportional Hazards Regression was used to compare outcomes between groups. RESULTS: 249 planned one-stage IBRs were performed in 193 women, median age 45 years (range 20-77) with median follow-up of 101 months (range 27-159 months). 18/193 (9%) patients required implant exchange at 12 months and 66% of patients maintained their original implants at the time of census. Implant assisted latissimus appears to be robust even when radiotherapy was delivered. Disease free survival and breast cancer mortality were as expected for the breast cancer stage treated. CONCLUSION: With careful patient selection, one-stage implant IBR using a definitive anatomical expandable implant provides good long term reconstruction and safe oncologic outcome. Direct to implant decision algorithms may be influenced by future developments in acellular dermal matrix technology, but the ability to create a single-stage stable implant pocket with good surgical technique should not be forgotten.

Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer?

PURPOSE: This retrospective analysis aimed to identify whether breast cancer patients receiving radiotherapy alone following a complete clinical remission (cCR) to neoadjuvant chemotherapy had a worse outcome than those treated with surgery. PATIENTS AND METHODS: One hundred thirty-six patients who had achieved a cCR to neoadjuvant chemotherapy for early breast cancer were identified from a prospectively maintained database of 453 patients. Of these, 67 patients had undergone surgery as their primary locoregional therapy, and 69 patients had radiotherapy alone. Outcome was assessed in relation to local recurrence-free survival, disease-free survival, and overall survival. RESULTS: Median follow-up was 63 months in the surgery group and 87 months in the no surgery group. Prognostic characteristics were well balanced between the two groups. For surgery and no surgery, respectively, there were no significant differences in disease-free survival or overall survival (5-year, 74% v 76%; 10-year, 60% v 70%, P =.9) between the two groups. There was a nonsignificant trend toward increased locoregional-only recurrence for the no surgery group (21% v 10% at 5 years; P =.09), but no long-term failures of local control. Patients in the no surgery group who also achieved an ultrasound complete remission had a 5-year local recurrence rate of only 8%. CONCLUSION: In patients achieving a cCR to neoadjuvant chemotherapy, radiotherapy alone achieve survival rates as good as with surgery, but with higher local recurrence rates. Ultrasound may identify a low recurrence rate subgroup for assessing no surgery in a prospective trial.

Endothelial adhesion molecules in breast cancer invasion into the vascular and lymphatic systems.

AIMS: It is well recognised that intravasation of tumour cells into the vasculature and/or lymphatics is a key stage in the metastatic process. It is also clear that very little is known about the mechanisms underlying this event. In this review, we will focus on cell surface molecules that may be instrumental in mediating the attachment of tumour cells, and in particular breast carcinoma cells, to the lymphatic and microvascular endothelia and discuss the therapeutic and prognostic value in targeting these receptors in metastatic disease. METHODS: A literature search was carried out from PubMed for indexed articles and reviews. Websites containing information on gene expression profiles were located using standard web browser search functions. For articles containing gene expression data, relevant information was frequently located in supplementary tables or in associated websites. FINDINGS: The search yielded a very large number of indexed published articles and websites. Important major reports and studies were reviewed, screened and tracked for other relevant publications. The most important articles were analysed and discussed. CONCLUSIONS: The lack of knowledge as to the mechanism by which tumour cells intra-vasate into the vasculature and/or lymphatics is perhaps not surprising given the lack of suitable models with which to investigate tumour cell intravasation. However, recent advances in the identification of molecular markers of angiogenic and lymphangiogenic endothelium, the development of techniques to image tumour cells in vivo and a better understanding of the architecture of these vessels is beginning to offer hope that this least well understood event in the metastatic process is becoming more amenable to study.

Continued axillary sampling is unnecessary and provides no further information to sentinel node biopsy in staging breast cancer.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) has become increasingly accepted as a diagnostic method to stage the axilla in breast cancer, selecting women with a positive sentinel node for completion axillary clearance. As SLNB became established, many surgeons supplemented SLNB to sample a minimum of four lymph nodes, on the assumption that the four-node technique is supported by randomised trial data. We hypothesised that the practice of undirected sampling to supplement SLNB adds little information to the status of the residual axilla. METHODS: One hundred and sixty-five patients with early breast cancer were studied. Following successful identification of the sentinel node, 84 women had completion axillary dissection and 81 women had an axillary sample with at least four nodes available for pathological assessment. RESULTS: Following successful identification of the sentinel node in 165 patients, the false negative rate (FNR) was 2/44=4.5% (95% CI 0.6-15.5), sensitivity 42/44=95.5% (84.5-99.4) and negative predictive value (NPV) 121/123=98.4% (94.2-99.8). In the axillary dissection cohort, the FNR was 2/26=7.7% (0.9-25.1), sensitivity 24/26=92.3% (74.9-99.1) and NPV 58/60=96.7% (88.5-100). In the axillary sample group, the FNR was 0/18=0% (0-18.5), sensitivity 18/18=100% (81.5-100) and NPV 63/63=100% (94.3-100). The SLNB was the only positive node in 12/26 (46.2%) in the axillary dissection group and 10/18 (55.6%) in the axillary sampling group. There was no patient in the axillary sampling group where the sample node was positive and the sentinel node negative. CONCLUSION: Once SLNB is validated within the multidisciplinary unit, undirected sampling of the axilla following identification of the sentinel node(s) is unnecessary. The additional sampling of non-sentinel nodes has no role to play either in the assessment of a potential false negative SLNB nor as predictive information on the status of the residual axillary nodes.

The incidence of breast cancer from screening women according to predicted family history risk: Does annual clinical examination add to mammography?

In breast cancer, mutations of predisposition genes such as BRCA-1/2 and other genes as yet uncharacterised are manifest in up to 10% of cases. Although the prior probability of the presence of a breast cancer predisposing gene can be calculated for individual women, there is no published evidence to justify predicted risk as a selection criteria for screening. This study aims to define which patient groups with a significant family history should be screened, and whether clinical examination is necessary in addition to mammography. The Claus model was used to predict breast cancer risk in women with a family history. Women were divided into two groups according to their predicted risk: group I consisted of women at standard risk (lifetime risk less than 1:6) and group II with moderate/high risk (lifetime risk greater than or equal to 1:6). Women were cancer-free at the point of entry, and screening consisted of annual clinical examination and mammography from the age of 35 years. This study consisted of 1500 women in group I and 1078 in group II. The period of observation was 5902.0 and 4327.8 women years, respectively. A total of 31 cancers were detected, 12 in group I and 19 in group II. The median age at diagnosis in group II was 45 years (range 26-66 years) compared with 54.5 years (range 38-63 years) in group I (P=0.03). The relative risk of developing breast cancer in group II was 2.6 (95% confidence interval (CI) 1.2-5.8). When compared with breast cancer incidence in the normal population, the standardised incidence ratio in group II was significantly higher at 2.8 (95% CI: 1.7-4.2). The standardised incidence ratio of women in group I was similar to that of the general population (1.1 (95% CI: 0.6-1.8)). A total of 26/31 (84%) cancers detected were palpable, of which 14 (54%) were not visible on mammography. Approximately one-third of all palpable cancers were detected at routine follow-up. Mammography correctly identified 17/31 cancers (55%), but 29% of these were not palpable. Family history screening programmes are effective and women should be selected for screening according to predicted risk. The younger age of diagnosis in group II justifies screening from an earlier age using both annual clinical examination and mammography.

Modulation of very late activation-2 laminin receptor function in breast cancer metastasis.

BACKGROUND: Very late activation-2 (VLA-2) is an integrin receptor for laminin that consists of an alpha 2- and a beta 1-subunit. In human breast cancer, down-regulation of VLA-2 expression is related to positive nodal status. The functional significance of altered integrin expression in individual patients has never been investigated. To test the hypothesis that less adhesive primary breast cancer cells were predisposed to metastasize, variation in VLA-2 modulation of cell attachment to laminin with nodal status was studied. METHODS: Integrin expression was measured by means of immunohistochemistry on cryostat sections. Primary breast cancer cells were isolated by enzymatic disaggregation and immunomagnetic separation. Cell adhesion to laminin was evaluated in an in vitro assay, and the effect of monoclonal antibodies against the component subunits of VLA-2 was assessed. RESULTS: Adhesion of primary breast cancer cells from women with positive nodes to laminin was significantly reduced compared with women with negative nodes (p < 0.001, Wilcoxon signed rank test). VLA-2 antibodies inhibited primary breast cancer cell attachment of women with negative nodes but not women with positive nodes. Strong adhesion to laminin was related to node-negative status (chi-squared, 16.33; p < 0.001) and to positive integrin expression (chi-squared, 31.54; p < 0.001). CONCLUSIONS: VLA-2-mediated adhesion of primary breast cancer cells to laminin differs with nodal status. Measurement of VLA-2 expression may thus be of clinical value as a prognostic indicator in the assessment of breast cancer.

Integrin expression in primary breast cancer and its relation to axillary nodal status.

BACKGROUND: Integrins are transmembrane receptors that modulate cell adhesion. Each is a heterodimer of varying alpha and beta subunits. In malignancy, loss of integrin expression may result in less adhesive cells more likely to metastasize. Our aim was to characterize the integrins in human breast tissue and to examine the relationship between integrin expression and nodal metastasis in breast cancer. METHODS: Cryostat sections from 12 benign and 61 malignant (50 ductal and 11 lobular) samples were stained by the avidin-biotin complex method with monoclonal antibodies to the beta 1, beta 3, beta 4, and beta 5 subfamilies. All slides were read by two independent assessors with consensus agreement. Integrin expression was compared to variables by using the chi-squared test with Yates' correction and multivariate analysis based on logistic regression. RESULTS: All integrin subunits studied were significantly reduced on breast cancer compared with benign cells (chi-squared test) but were not related to tumor differentiation. Loss of alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 6 beta 1, alpha v beta 1, and alpha v beta 5 were related to the presence of axillary metastasis. Independently the integrins were of limited clinical value as predictors of axillary spread. However, on multivariate analysis the combination of beta 1, alpha v, alpha 1, tumor size, and vascular invasion gave a cumulative overall accuracy in predicting nodal disease of 97%. CONCLUSIONS: Integrin expression is reduced in breast cancer and may explain tumor progression. Measuring the integrins might thus provide a means of selection for aggressive axillary treatment.