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1.  Sentinel node biopsy in early breast cancer at the Hospital Comarcal La Linea (Spain) 
ecancermedicalscience  2013;7:353.
Objective
Our objective was to determine the identification and the percentage of false negatives in sentinel node biopsies in patients with early breast cancer at the Hospital La Línea (Spain), during the period between November 2007 and September 2010.
Methods
We collected 50 patients with early breast cancer, without clinical and ultrasonographic involvement of axillary nodes, from November 2007 to September 2010. We used the vital dye in the first 20 patients and the combined technique of vital dye and albumin labelled with technetium 99 in the other 30 patients. The site of injection for patients using blue dye was subdermal for palpable tumours and periareolar for non-palpable tumours. The technique of injection with the radioisotope for patients for palpable and most non-palpable tumours was the periareolar technique. We used albumin labelled with technetium 99. In seven patients with non-palpable tumours, we used the sentinel node occult lesion localisation (SNOLL) technique. The sentinel node biopsy was examined during surgery, with the frozen section examination and imprint as follows: the sentinel node was cut in three transversal sections along the axis and five frozen sections of each portion were done at a distance of 60 μm each; in total, 15–20 frozen sections and three imprints were done for each sentinel node. The axillary dissection was completed in the first 17 patients, and we performed total axillary dissection on the remaining patients if the sentinel node was positive for metastasis.
Results
The sentinel nodes were identified in 49 of 50 patients (98%). The patient in whom we did not identify the sentinel node was a patient in the combined technique. The number of nodes identified in the patients with vital dye was one sentinel node, and with the combined technique, it was two sentinel nodes. The false-negative rate was 8% (four patients); the micrometastasis was the principal factor of the false-negative rate (p < 0.05). The cases of false negatives were present at the beginning of the study with the use of the blue dyes; this factor was statistically significant (p < 0.05). The tumour size, the vascular invasion, and the periganglionar adipose tissue invasion were statistically significant for the presentation of axillary metastasis (p < 0.05).
Conclusion
This study shows that the micrometastasis and the use of vital dye were the principal factors for the presentation of the false-negative rate. The size of the tumour, the vascular invasion, and the periganglionar adipose tissue invasion were statistically significant for the appearance of the axillary metastasis.
doi:10.3332/ecancer.2013.353
PMCID: PMC3779590  PMID: 24066019
early breast cancer; axillary staging; sentinel node biopsy; SNOLL; micrometastasis
2.  Sentinel lymph node mapping in early breast cancer — Our experience 
Background
The axillary lymph node status is the most important determinant of prognosis in patients with breast cancer. Sentinel lymph node (SLN) biopsy is a safe alternative for axillary clearance with an equal efficacy limiting the morbidity caused by axillary clearance.
Patient and methods
From May 1996 till September 2009, 523 clinically node negative, early breast cancer patients attending our clinic at All India Institute of Medical Sciences were included in the study. They underwent sentinel lymph node biopsy by either combined technique or blue dye alone. All patients irrespective of the axillary status underwent axillary lymph node dissection (ALND).
Results
Of 523 patients, 267 underwent combined technique of sentinel node mapping and 256 underwent blue dye technique alone. The identification rate of sentinel lymph node was 94.3% (253/267) for combined technique and 87.8% (225/256) for blue dye alone. Of 523 patients SLN was identified in 478 patients. The identification rate was 91.3%. The sensitivity = 91.5% (141/154), false negative = 8.4% (13/154), negative predictive value = 96.14% (324/337), and accuracy being 97.2% (465/478).
Conclusion
Sentinel node mapping is a simple and safe technique of identifying the axillary node involvement. Sentinel lymph node biopsy is associated with less arm oedema and shoulder morbidity compared to ALND. However, the results of long term effects of sentinel node approach on tumor recurrence or patient survival are awaited.
doi:10.1007/s13193-010-0012-z
PMCID: PMC3421000  PMID: 22930619
Sentinel lymph node biopsy; Axillary lymph node dissection; Axillary node sampling; Lymphatic mapping; Early breast cancer; Immuohistochemistry
3.  A prospective comparative study to assess the contribution of radioisotope tracer method to dye-only method in the detection of sentinel lymph node in breast cancer 
BMC Surgery  2013;13:13.
Background
Metastasis in the axillary lymph nodes is the most important known prognostic factor for breast cancer. We aimed to investigate the contribution of the radioisotope tracer method to the dye-only method by performing sentinel lymph node biopsy on the same patient group during a single surgical session.
Methods
Forty-two patients who underwent operations in our clinic from February 2010 to October 2011 and with masses of <5 cm and clinically and radiologicallly negative axilla (T1-2 N0) were prospectively included in this study. After paraffin examination results were obtained, the numbers and metastatic states of the lymph nodes that were unidentifiable during surgery (although they were stained) but were detected by a gamma probe, lymph nodes that were only stained, lymph nodes that were only radioactive (hot), and lymph nodes that were both stained and radioactive (stained-hot) were determined in all patients. In patients who underwent axillary lymph node dissection, the total numbers of lymph nodes removed and their metastatic states were determined separately.
Results
At least one blue-stained sentinel lymph node was identified in all patients during the blue-stained lymph node detection stage. The average number of sentinel nodes removed at this stage was 2.1 ± 1.1. In the second surgical stage (the stage in which nodes with axillary counts were investigated with the gamma probe) in these 41 patients, at least one additional hot node was removed, or at least one of the nodes that was removed because it was blue was also hot. In addition to the lymph nodes removed in the dye stage, 34 hot lymph nodes were excised from 21 patients. Overall, the average number of hot lymph nodes removed was 2.9 ± 1.5. In all patients, subsequent frozen sections and histopathological examinations were 100% concordant with the sentinel lymph nodes that were removed; the stained sentinel lymph nodes that were removed first did not affect the decision to perform axillary dissection.
Conclusion
The results of our study indicate that performing sentinel lymph node biopsy with dye only is sufficient and as effective as the combined method.
doi:10.1186/1471-2482-13-13
PMCID: PMC3679879  PMID: 23617459
Breast cancer; Axilla; Sentinel lymph node; Blue-dye; Radionuclide
4.  Tc-99m Diphosphonate as a Potential Radiotracer to Detect Sentinel Lymph Nodes in Patients with Breast Cancer 
Purpose
To evaluate the potential of Tc-99m diphosphonate as a tracer for sentinel lymph node biopsy in breast cancer.
Methods
Lymphoscintigraphs of 35 patients (50.9 ± 10.2 years) with breast cancer were acquired after administering a subareolar intradermal injection of Tc-99m diphosphonate 18 h before surgery. Static images were taken within 15 min (early phase) and 15 h after injection (delayed phase). The lymphoscintigraphic identification rate was defined as the percentage of subjects studied with visible foci at axillae. Sentinel lymph node biopsies were performed using a gamma probe and by blue dye injection. Any node that was radioactive or stained with blue dye was labeled as a sentinel lymph node. Lymph nodes without radioactivity or blue dye staining were defined as non-sentinel lymph nodes. The intraoperative identification rate was defined as the percentage of patients with a radioactive sentinel lymph node. Percentages of lymphoid cells expressing S-100, CD83, and CD1a were compared.
Results
The lymphoscintigraphic identification rate was 94.3% (33/35) during the early phase and 96.9% (31/32) during the delayed phase, whereas the intraoperative identification rate was 94.3% (33/35). The mean percentages of lymphoid cells that stained positively for S-100 or CD83 were lower in sentinel lymph nodes than in non-sentinel lymph nodes (1.5% vs. 9.0% for S-100, and 4.5% vs. 9.3% for CD83, respectively, p = 0.0286). The mean percentages of lymphoid cells in sentinel lymph nodes and non- sentinel lymph nodes expressing CD1a were 3.3% and 7.0%, respectively (p = ns).
Conclusions
Tc-99m diphosphonate can reliably detect regional lymph nodes in breast cancer.
doi:10.1007/s13139-009-0002-7
PMCID: PMC4042961  PMID: 24899939
Tc-99m diphosphonate; Sentinel node; Breast cancer
5.  Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial 
The lancet oncology  2010;11(10):927-933.
Summary
Background
Sentinel node surgery was designed to minimize side effects of lymph node surgery but still offer outcomes equivalent to axillary dissection. The aims of NSABP Protocol B-32 were to determine whether sentinel node resection in breast cancer patients achieves the same survival and regional control as axillary dissection but with fewer side effects.
Methods
5611 women with invasive breast cancer were randomly assigned to sentinel node resection plus axillary dissection (Group 1) or to sentinel node resection alone with axillary dissection only if sentinel nodes were positive (Group 2). Random assignment was done at the NSABP Biostatistical Center and accomplished via using a biased coin minimization approach. Stratification variables were age at entry (≤ 49,≥ 50), clinical tumor size (≤ 2.0 cm, 2.1 – 4 cm, ≥ 4.1 cm), and surgical plan (lumpectomy, mastectomy). Sentinel node resection was done using blue dye and radioactive tracer. As pre-specified in the protocol, analyses of endpoint data were performed according to the randomized group assignments on patients who were assessed at the time of randomization as having pathologically negative sentinel nodes (3989 patients). The endpoint analyses were performed on all such patients who had follow-up information regardless of their eligibility status (3986 patients). The primary endpoint for the study was overall survival. All deaths regardless of cause were included. The mean time on study for the 3986 sentinel node-negative patients with follow-up information was 95.6 months (range: 70.1 – 126.7 months).
Findings
A total of 309 deaths were reported in the 3986 sentinel node-negative patients with follow-up information. Log-rank comparison of overall survival in Groups 1 and 2 yielded an unadjusted hazard ratio of 1.20 (95% confidence interval [CI]; 0.96 –1.50, P = 0.12). Eight-year Kaplan-Meier estimates for overall survival are 91.8% in Group 1 and 90.3% in Group 2. Treatment comparisons for disease-free survival yielded an unadjusted hazard ratio of 1.05 (95% CI: 0.90 – 1.22, P=0.54). Eight-year Kaplan-Meier estimates for disease-free survival are 82.4% in Group 1 and 81.5% in Group 2. There were 8 regional node recurrences as first events in Group 1 and 14 in Group 2 (P=0.22). Patients are continuing follow up for longer term evaluation of survival and regional control.
Interpretation
Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the sentinel node is negative, sentinel node surgery alone with no further axillary dissection is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes.
doi:10.1016/S1470-2045(10)70207-2
PMCID: PMC3041644  PMID: 20863759
sentinel node; breast cancer; randomized trial; survival; axillary dissection
6.  Impact of non-axillary sentinel node biopsy on staging and treatment of breast cancer patients 
British Journal of Cancer  2002;87(7):705-710.
The purpose of this study was to evaluate the occurrence of lymphatic drainage to non-axillary sentinel nodes and to determine the implications of this phenomenon. A total of 549 breast cancer patients underwent lymphoscintigraphy after intratumoural injection of 99mTc-nanocolloid. The sentinel node was intraoperatively identified with the aid of intratumoural administered patent blue dye and a gamma-ray detection probe. Histopathological examination of sentinel nodes included step-sectioning at six levels and immunohistochemical staining. A sentinel node outside level I or II of the axilla was found in 149 patients (27%): internal mammary sentinel nodes in 86 patients, other non-axillary sentinel nodes in 44 and both internal mammary and other non-axillary sentinel nodes in nineteen patients. The intra-operative identification rate was 80%. Internal mammary metastases were found in seventeen patients and metastases in other non-axillary sentinel nodes in ten patients. Staging improved in 13% of patients with non-axillary sentinel lymph nodes and their treatment strategy was changed in 17%. A small proportion of clinically node negative breast cancer patients can be staged more precisely by biopsy of sentinel nodes outside level I and II of the axilla, resulting in additional decision criteria for postoperative regional or systemic therapy.
British Journal of Cancer (2002) 87, 705–710. doi:10.1038/sj.bjc.6600359 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600359
PMCID: PMC2364267  PMID: 12232750
breast cancer; lymphoscintigraphy; sentinel node; staging
7.  Breast cancer (non-metastatic) 
BMJ Clinical Evidence  2007;2007:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage IIIB)? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/ fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole breast radiotherapy plus breast conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ, radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery, but may not improve survival.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation or trastuzumab (in women who overexpress HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours, but adverse effects begin to outweigh benefit after 5 years of treatment. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4-6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality, but may increase mortality in node-negative women. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear.Adjuvant taxoid regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.Chemotherapy alone, while widely used, does not improve survival in women with locally advanced breast cancer.
PMCID: PMC2943780  PMID: 19450345
8.  Contraindications of sentinel lymph node biopsy: Áre there any really? 
Background
One of the most exciting and talked about new surgical techniques in breast cancer surgery is the sentinel lymph node biopsy. It is an alternative procedure to standard axillary lymph node dissection, which makes possible less invasive surgery and side effects for patients with early breast cancer that wouldn't benefit further from axillary lymph node clearance. Sentinel lymph node biopsy helps to accurately evaluate the status of the axilla and the extent of disease, but also determines appropriate adjuvant treatment and long-term follow-up. However, like all surgical procedures, the sentinel lymph node biopsy is not appropriate for each and every patient.
Methods
In this article we review the absolute and relative contraindications of the procedure in respect to clinically positive axilla, neoadjuvant therapy, tumor size, multicentric and multifocal disease, in situ carcinoma, pregnancy, age, body-mass index, allergies to dye and/or radio colloid and prior breast and/or axillary surgery.
Results
Certain conditions involving host factors and tumor biologic characteristics may have a negative impact on the success rate and accuracy of the procedure. The overall fraction of patients unsuitable or with multiple risk factors that may compromise the success of the sentinel lymph node biopsy, is very small. Nevertheless, these patients need to be successfully identified, appropriately advised and cautioned, and so do the surgeons that perform the procedure.
Conclusion
When performed by an experienced multi-disciplinary team, the SLNB is a highly effective and accurate alternative to standard level I and II axillary clearance in the vast majority of patients with early breast cancer.
doi:10.1186/1477-7819-5-10
PMCID: PMC1797176  PMID: 17261174
9.  Testing the Feasibility of Intra-Operative Sentinel Lymph Node Touch Imprint Cytology 
INTRODUCTION
Sentinel lymph node biopsy is emerging as the new standard for axillary staging in breast cancer. Intra-operative assessment of the sentinel lymph nodes allows immediate completion of axillary dissection during the same anaesthetic. This project was a quality assurance practice to establish feasibility, time-to-report, as well as accuracy of performing intra-operative assessment of sentinel lymph nodes using touch imprint cytology in our centre.
PATIENTS AND METHODS
This prospective audit included 146 sentinel lymph nodes from 74 consecutive patients with invasive breast cancer. All patients underwent axillary sentinel lymph node biopsy using combined blue dye and radiocolloid technique. Results of intra-operative touch imprint cytology using haematoxylin and eosin staining were compared with the definitive histopathology results.
RESULTS
Mean time to report touch imprint cytology was 25.7 ± 6.4 min (range, 15–40 min). Histopathology demonstrated metastasis in 25 sentinel nodes from 17 (23%) patients. Intra-operative touch imprint cytology detected 15 nodes in 11 patients, giving a sensitivity of 60% (nodes) and 66.7% (patients) and specificity of 99.2% (nodes) and 98.2% (patients) based on the number of nodes and patients involved, respectively. Touch imprint cytology failed to show metastatic involvement in 10 nodes from 6 patients; of these, five nodes had micrometastasis (< 2 mm) and the other five had macrometastasis. One touch imprint cytology positive node contained isolated tumour cells only. Using intra-operative touch imprint cytology made a change in treatment of 11(14.9%) patients, and spared second axillary procedure in 7 (9.4%) patients.
CONCLUSIONS
Intra-operative sentinel lymph node assessment using touch imprint cytology is feasible within a busy NHS practice. We now offer touch imprint cytology to patients following appropriate counselling.
doi:10.1308/003588409X391758a
PMCID: PMC2749406  PMID: 19344553
Touch imprint cytology; Sentinel lymph node; Breast cancer
10.  Quantitative Measurement of Melanoma Spread in Sentinel Lymph Nodes and Survival 
PLoS Medicine  2014;11(2):e1001604.
In this study, Klein and colleagues investigated the impact of minimal cancer sentinel lymph node spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival. The authors found that cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death and the best predictor of outcome was a model based on combined quantitative effects of DCCD, tumor thickness, and ulceration.
Please see later in the article for the Editors' Summary
Background
Sentinel lymph node spread is a crucial factor in melanoma outcome. We aimed to define the impact of minimal cancer spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival.
Methods and Findings
We analyzed 1,834 sentinel nodes from 1,027 patients with ultrasound node-negative melanoma who underwent sentinel node biopsy between February 8, 2000, and June 19, 2008, by histopathology including immunohistochemistry and quantitative immunocytology. For immunocytology we recorded the number of disseminated cancer cells (DCCs) per million lymph node cells (DCC density [DCCD]) after disaggregation and immunostaining for the melanocytic marker gp100. None of the control lymph nodes from non-melanoma patients (n = 52) harbored gp100-positive cells. We analyzed gp100-positive cells from melanoma patients by comparative genomic hybridization and found, in 45 of 46 patients tested, gp100-positive cells displaying genomic alterations. At a median follow-up of 49 mo (range 3–123 mo), 138 patients (13.4%) had died from melanoma. Increased DCCD was associated with increased risk for death due to melanoma (univariable analysis; p<0.001; hazard ratio 1.81, 95% CI 1.61–2.01, for a 10-fold increase in DCCD + 1). Even patients with a positive DCCD ≤3 had an increased risk of dying from melanoma compared to patients with DCCD = 0 (p = 0.04; hazard ratio 1.63, 95% CI 1.02–2.58). Upon multivariable testing DCCD was a stronger predictor of death than histopathology. The final model included thickness, DCCD, and ulceration (all p<0.001) as the most relevant prognostic factors, was internally validated by bootstrapping, and provided superior survival prediction compared to the current American Joint Committee on Cancer staging categories.
Conclusions
Cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death. A model based on the combined quantitative effects of DCCD, tumor thickness, and ulceration predicted outcome best, particularly at longer follow-up. If these results are validated in an independent study, establishing quantitative immunocytology in histopathological laboratories may be useful clinically.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Because the skin contains many different cell types, there are many types of skin cancer. The most dangerous type—melanoma—develops when mutations occur in melanocytes, the cells that produce the pigment melanin. Less than 5% of skin cancers are melanomas, but melanoma causes most skin cancer deaths. Early signs of melanoma are a change in the appearance of a mole (a pigmented skin blemish) or the development of a new and unusual pigmented lesion. If these signs are noticed and the melanoma is diagnosed before it has spread from the skin into nearby lymph nodes and other tissues, surgery often provides a cure. For advanced melanomas, the outlook is generally poor, although novel therapies may prolong a patient's life.
Why Was This Study Done?
When a person is diagnosed with melanoma, it is important to “stage” the tumor. Knowing the extent and severity of the melanoma helps oncologists plan treatments and estimate their patients' likely outcomes. The detection of isolated melanoma cells in sentinel lymph nodes (the nodes to which cancer cells are most likely to spread from a primary tumor) is included in melanoma staging recommendations. However, finding rare tumor cells in sentinel lymph node biopsies by examining the tissue requires the analysis of many slides from each node removed from the patient and is extremely time-consuming. In this study, the researchers investigate the predictive value of a quantitative immunocytological assay that involves disaggregation of the sentinel node and detection of disseminated cancer cells (DCCs) by immunostaining for gp100 (a marker for melanoma cells). They also use this new assay to examine the effect of increasing numbers of DCCs on melanoma-specific survival.
What Did the Researchers Do and Find?
The researchers used routine histopathology and immunocytology to analyze 1,834 sentinel lymph nodes from 1,027 patients with melanoma who underwent sentinel lymph node biopsy at one German hospital. For immunocytology, the researchers recorded the number of gp100-positive cells per million lymph node cells (the DCC density). During follow-up, 138 patients (13.4%) died from melanoma. The results indicated that increased DCC density was associated with an increased risk of death due to melanoma. Specifically, every 10-fold increase in DCC density + 1 was associated with a near doubling of the risk of death from melanoma (a hazard ratio of 1.81). Even patients with three or fewer gp100-positive cells per million lymph node cells had an increased risk of dying from melanoma compared to patients with no gp100-positive cells (hazard ratio 1.63). When other predictors of outcome such as age and primary tumor location were taken into account, DCC density was a stronger predictor of death than histopathology. Finally, a survival model that included tumor thickness, tumor ulceration, and DCC density provided survival prediction superior to that of a model based on the current standard staging recommendations.
What Do These Findings Mean?
These findings show that quantification of cancer cell dissemination from melanomas to sentinel lymph nodes is feasible and can be combined with other characteristics of the primary tumor to provide an accurate prediction of outcomes for individual patients with melanoma. Notably, the new prediction model identifies a group of patients at high risk of progression for whom the current clinical standard underestimates the risk of death. These patients may benefit from adjuvant therapies, so the new analysis presented in this study may help to stratify patients for clinical trials. Importantly, quantitative immunocytology and the new model, although internally validated in this study, need to be validated in an independent group of patients before they can be considered for routine clinical use. If external validation is successful, quantitative immunocytology, which is much less labor-intensive than histopathology, has the potential to change the routine clinical care of patients with melanoma and probably with other solid tumors, conclude the researchers.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001604.
The US National Cancer Institute provides information for patients and professionals on melanoma, cancer staging, and sentinel lymph node biopsy (in English and Spanish)
The nonprofit organization American Cancer Society provides information in several languages on cancer and how it develops and specific information on melanoma, including the AJCC system for staging and personal stories
The UK National Health Service Choices website includes an introduction to cancer and a page on melanoma that includes personal stories
The nonprofit organization Cancer Research UK provides basic information about cancer and detailed information on melanoma
doi:10.1371/journal.pmed.1001604
PMCID: PMC3928050  PMID: 24558354
11.  Sentinel lymph node biopsy for breast cancer patients using fluorescence navigation with indocyanine green 
Background
There are various methods for detecting sentinel lymph nodes in breast cancer. Sentinel lymph node biopsy (SLNB) using a vital dye is a convenient and safe, intraoperatively preparative method to assess lymph node status. However, the disadvantage of the dye method is that the success rate of sentinel lymph node detection depend on the surgeon's skills and preoperative mapping of the sentinel lymph node is not feasible. Currently, a vital dye, radioisotope, or a combination of both is used to detect sentinel nodes. Many surgeons have reported successful results using either method. In this study we have analyzed breast lymphatic drainage pathways using indocyanine green (ICG) fluorescence imaging.
Methods
We examined the lymphatic courses, or lymphatic vessels, in the breast using ICG fluorescence imaging, and applied this method to SLNB in patients who underwent their first operative treatment for breast cancer between May 2006 and April 2008. Fluorescence images were obtained using a charge coupled device camera with a cut filter used as a detector, and light emitting diodes at 760 nm as a light source. When ICG was injected into the subareola and periareola, subcutaneous lymphatic vessels from the areola to the axilla became visible by fluorescence within a few minutes. The sentinel lymph node was then dissected with the help of fluorescence imaging navigation.
Results
The detection rate of sentinel nodes was 100%. 0 to 4 states of lymphatic drainage pathways from the areola were observed. The number of sentinel nodes was 3.41 on average.
Conclusions
This method using indocyanine green (ICG) fluorescence imaging may possibly improve the detection rate of sentinel lymph nodes with high sensitivity and compensates for the deficiencies of other methods. The ICG fluorescence imaging technique enables observation of breast lymph vessels running in multiple directions and easily and accurately identification of sentinel lymph nodes. Thus, this technique can be considered useful.
doi:10.1186/1477-7819-9-157
PMCID: PMC3269998  PMID: 22132943
sentinel lymph node biopsy; breast cancer; indocyanine green; fluorescence imaging
12.  Sentinel lymph node biopsy under fluorescent indocyanin green guidance: Initial experience 
Objective:
Sentinel lymph node biopsy can be applied by using either blue dye or radionuclide method or both in breast cancer. Fluorescent imaging with indocyanine green is a new defined method. This study evaluates the applicability of sentinel lymph node biopsy via fluorescent indocyanine green.
Material and Methods:
IC-VIEW (Pulsion Medical Systems AG, Munich, Germany) infrared visualization system was used for imaging. Two mL of indocyanine green was injected to visualize sentinel lymph nodes. After injection, subcutaneous lymphatics were traced and sentinel lymph nodes were found with simultaneous imaging. Sentinel lymph nodes were excised under fluorescent light guidance, and excised lymph nodes were examined histopathologically. Patients with sentinel lymph node metastases underwent axillary dissection.
Results:
Four patients with sentinel lymph node biopsy due to breast cancer were included in the study. Sentinel lymph nodes were visualized with indocyanine green in all patients. The median number of excised sentinel lymph node was 2 (2–3). Two patients with lymph node metastasis underwent axillary dissection. No metastasis was detected in lymph nodes other than the sentinel nodes in patients with axillary dissection. There was no complication during and after the operation related to the method.
Conclusion:
According to our limited experience, sentinel lymph node biopsy under fluorescent indocyanine green guidance, which has an advantage of simultaneous visualization, is technically feasible.
doi:10.5152/UCD.2015.2832
PMCID: PMC4771427  PMID: 26985159
Fluorescent light; indocyanine green; sentinel lymph node biopsy
13.  Cardiac Arrest after Patent Blue V Injection for Sentinel Lymph Node Biopsy in Breast Cancer 
Breast Care  2010;5(6):411-413.
Summary
Background
Sentinel lymph node biopsy (SLNB) is a widely accepted method to determine lymph node status in for instance breast cancer, cervical cancer, or cutaneous melanomas. Although injection of blue dyes facilitates successful detection of sentinel nodes, they have also been shown to cause adverse reactions.
Case Report
A 62-year-old female patient was referred to the surgical department of the Atrium Medical Centre with a suspicious lesion located in the right breast, detected during population-based screening. Immediately after injection of patent blue V, the patient developed tachycardia on top of preexisting supraventricular tachycardia and showed an instant drop in blood pressure, after which cardiac arrest occurred. These clear symptoms of anaphylactic shock required prompt treatment, and the patient was treated accordingly.
Conclusions
Anaphylactic shock after injection of patent blue V remains a serious adverse event and warrants awareness. Immediate action with ephedrine, antihistamines, and subsequently corticosteroids can stabilize the patient. Tc-99m, isosulphan blue, and methylene blue can alternatively be used for SLNB, although also not without side effects.
doi:10.1159/000322658
PMCID: PMC3076355  PMID: 21494408
Sentinel node; Patent blue; Anaphylactic shock; Breast cancer
14.  Contrast enhanced ultrasound of sentinel lymph nodes 
Journal of Ultrasonography  2013;13(52):73-81.
Sentinel lymph nodes are the first lymph nodes in the region that receive lymphatic drainage from a primary tumor. The detection or exclusion of sentinel lymph node micrometastases is critical in the staging of cancer, especially breast cancer and melanoma because it directly affects patient's prognosis and surgical management. Currently, intraoperative sentinel lymph node biopsies using blue dye and radioisotopes are the method of choice for the detection of sentinel lymph node with high identification rate. In contrast, conventional ultrasound is not capable of detecting sentinel lymph nodes in most cases. Contrast enhanced ultrasound with contrast specific imaging modes has been used for the evaluation and diagnostic work-up of peripherally located suspected lymphadenopathy. The method allows for real-time analysis of all vascular phases and the visualization of intranodal focal “avascular” areas that represent necrosis or deposits of neoplastic cells. In recent years, a number of animal and human studies showed that contrast enhanced ultrasound can be also used for the detection of sentinel lymph node, and may become a potential application in clinical routine. Several contrast agents have been used in those studies, including albumin solution, hydroxyethylated starch, SonoVue®, Sonazoid® and Definity®. This review summarizes the current knowledge about the use of ultrasound techniques in detection and evaluation of sentinel lymph node.
doi:10.15557/JoU.2013.0006
PMCID: PMC4613570  PMID: 26675994
contrast enhanced ultrasound; sentinel lymph node; breast cancer; melanoma; preoperative staging; microbubble contrast agents
15.  Partial axillary lymph node dissection inferior to the intercostobrachial nerves complements sentinel node biopsy in patients with clinically node-negative breast cancer 
BMC Surgery  2015;15:79.
Background
The practice of breast cancer diagnosis and treatment in China varies to that in western developed countries. With the unavailability of radioactive tracer technique for sentinel lymph nodes biopsy (SLNB), using blue dye alone has been the only option in China. Also, the diagnosis of breast malignant tumor in most Chinese centres heavily relies on intraoperative instant frozen histology which is normally followed by sentinel lymph nodes mapping, SLNB and the potential breast and axillary operations in one consecutive session. This practice appears to cause a high false negative rate (FNR) for SLNB. The present study aimed to investigate the impact of the current practice in China on the accuracy of SLNB, and whether partial axillary lymph node dissection (PALND), dissection of lymph nodes inferior to the intercostobrachial nerve (ICBN), was a good complementary procedure following SLNB using blue dye.
Methods
289 patients with clinically node-negative breast cancer were identified and recruited. Tumorectomy, intraoperative instant frozen histological diagnosis, SLNB using methylene blue dye, and PALND or complete axillary node dissection (ALND) were performed in one consecutive operative session. The choice of SLNB only, SLNB followed by PALND or by ALND was based on the pre-determined protocol and preoperative choice by the patient. Clinical parameters were analyzed and survival analysis was performed.
Results
37 % patients with clinically negative nodes were found nodes positive. 59 patients with positive SLN underwent ALND, including 47 patients with up to two positive nodes which were all located inferior to the ICBN. 9 patients had failed SLNB and underwent PALND. Among them, 3 (33.3 %) patients were found to have one metastatic node. 149 patients showed negative SLNB but chose PALND. Among them, 30 (20.1 %), 14 (9.4) and 1 (0.7 %) patients were found to have one, two and three metastatic node(s), respectively. PALND detected 48 (30.4 %) patients who had either failed SLNB or negative SLNB to have additional positive nodes. All the patients with up to two positive nodes had their nodes located inferior to the ICBN. The FNR of SLNB was 43 %. The accuracy rate was 58 %. The follow-up ranged 12–33 months. The incidence of lymphedema for SLNB, PALND, and ALND was 0 %, 0 %, and 25.4 %, respectively (P < 0.005). The disease-free survivals for SLNB, PALND, and ALND groups were 95.8 %, 96.8 %, and 94.9 %, respectively (p > 0.05).
Conclusions
Under the circumstances of current practice in China, PALND is a good complementary procedure following SLNB in clinically node-negative breast cancer.
doi:10.1186/s12893-015-0067-4
PMCID: PMC4486390  PMID: 26123412
16.  Sentinel lymph node biopsy: technique validation at the Setúbal Medical Centre, Portugal 
ecancermedicalscience  2009;3:124.
Aims:
To evaluate the accuracy of sentinel lymph node biopsy in breast cancer patients at this institution, using combined technetium-99m (99mTc) sulphur colloid and patent blue vital dye.
Methods:
From March 2007 to July 2008, 50 patients with a tumour of less than 3 cm and with clinically negative axillary lymph nodes underwent sentinel lymph node biopsy (SLNB), followed by axillary lymph node dissection (ALND). Sub-areolar 99mTc sulphur colloid injection was performed the day before surgery, and patent blue vital dye was also injected sub-areolarly at least 5 minutes before surgery. Sentinel lymph node was identified during the surgical procedure, using a gamma probe and direct vision. All sentinel nodes underwent frozen section analysis. Later haematoxylin and eosin staining and immunohistochemical analysis were performed. Finally, SLNB was compared with standard ALND for its ability to accurately reflect the final pathological status of the axillary nodes.
Results:
The sentinel lymph node (SLN) was identified in 48 of 50 patients (96%). The number of sentinel lymph nodes ranged from one to four (mean 1.48) and non-sentinel nodes ranged from seven to 27 (mean 14.33). Of the 48 patients with successfully identified SLNs, 29.17% (14/48) were histologically positive. Sensivity of the SLN to predict axilla was 93.75%; accuracy was 97.96%. The SLN was falsely negative in one patient—6.25% (1/16).
Conclusions:
The SLNB represents a major advance in the surgical treatment of breast cancer as a minimally invasive procedure predicting the axillary lymph node status. This validation study demonstrates the accuracy of the SLNB and its reasonable false negative rate when performed in our institute. It can now be used as the standard method of staging in patients with early breast cancer at this institution.
doi:10.3332/ecancer.2008.124
PMCID: PMC3224010  PMID: 22275996
17.  Sentinel nodes identified by computed tomography-lymphography accurately stage the axilla in patients with breast cancer 
BMC Medical Imaging  2013;13:42.
Background
Sentinel node biopsy often results in the identification and removal of multiple nodes as sentinel nodes, although most of these nodes could be non-sentinel nodes. This study investigated whether computed tomography-lymphography (CT-LG) can distinguish sentinel nodes from non-sentinel nodes and whether sentinel nodes identified by CT-LG can accurately stage the axilla in patients with breast cancer.
Methods
This study included 184 patients with breast cancer and clinically negative nodes. Contrast agent was injected interstitially. The location of sentinel nodes was marked on the skin surface using a CT laser light navigator system. Lymph nodes located just under the marks were first removed as sentinel nodes. Then, all dyed nodes or all hot nodes were removed.
Results
The mean number of sentinel nodes identified by CT-LG was significantly lower than that of dyed and/or hot nodes removed (1.1 vs 1.8, p <0.0001). Twenty-three (12.5%) patients had ≥2 sentinel nodes identified by CT-LG removed, whereas 94 (51.1%) of patients had ≥2 dyed and/or hot nodes removed (p <0.0001). Pathological evaluation demonstrated that 47 (25.5%) of 184 patients had metastasis to at least one node. All 47 patients demonstrated metastases to at least one of the sentinel nodes identified by CT-LG.
Conclusions
CT-LG can distinguish sentinel nodes from non-sentinel nodes, and sentinel nodes identified by CT-LG can accurately stage the axilla in patients with breast cancer. Successful identification of sentinel nodes using CT-LG may facilitate image-based diagnosis of metastasis, possibly leading to the omission of sentinel node biopsy.
doi:10.1186/1471-2342-13-42
PMCID: PMC4028847  PMID: 24321242
Sentinel node; Breast cancer; Computed tomography; Lymphography; Staging
18.  Breast cancer (non-metastatic) 
BMJ Clinical Evidence  2011;2011:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage 3B)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole-breast radiotherapy plus breast-conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ (DCIS), radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery. The role of tamoxifen added to radiotherapy for DCIS remains unclear because of conflicting results.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation, or trastuzumab (in women who over-express HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4 to 6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear. Adjuvant taxane-based regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.We don't know if chemotherapy alone improves survival in women with locally advanced breast cancer as we found few trials.
PMCID: PMC3217212  PMID: 21718560
19.  Sentinel lymph node biopsy of the internal mammary chain in breast cancer 
Routine removal of the internal mammary chain (IMC) sentinel node in breast cancer patients remains a subject of discussion. The aim of this study was to determine the impact of routinely performed IMC sentinel node biopsy on the systemic and locoregional treatments plan. All patients with biopsy proven breast cancer who underwent a sentinel node procedure between 2002 and 2011 were included in a prospective database. In cases of IMC drainage, successful exploration of the IMC (i.e., sentinel node removed) and surgical complications were registered. If the removed sentinel node contained malignant cells we determined if this altered the treatment plan when practising the current guidelines. In total, 119 of the 493 included patients showed IMC drainage on lymphoscintigraphy. Exploration of the IMC was performed in 107 (89 %) patients; in 86/107 (80 %) exploration was successful. In 14/107 patients (13 %) the IMC sentinel node was tumor positive. Macro and micro metastases were found in eight and six patients, respectively. In the group of patients who underwent surgical exploration of the IMC, systemic treatment was changed in none, radiotherapy treatment in 13/107 patients (11 %). Routine sentinel node biopsy of the IMC does not alter the systemic treatment. Radiotherapy treatment is altered in a small proportion of the patients; however, solid scientific evidence for this adjustment is lacking.
doi:10.1007/s10549-012-2086-5
PMCID: PMC3401492  PMID: 22678155
Sentinel lymph node biopsy; Internal mammary chain; Breast cancer; Post-operative treatment
20.  Sentinel lymphnode biopsy in early breast cancer using methylene blue dye and radioactive sulphur colloid — a single institution Indian experience 
The Indian Journal of Surgery  2008;70(3):111-119.
Background
Axillary lymph node dissection is an established procedure in breast cancer staging. However, it is associated with unpleasant side effects. A promising alternative to assess axillary lymph node status in early breast cancer patients is Sentinel Lymph Node Biopsy (SLNB). Isosulfan blue has traditionally been the dye used to identify the Sentinel Lymph Node (SLN). This article is a validation study of SLNB using methylene blue dye and radioactive sulphur colloid in early breast cancer Indian patients.
Materials & Methods
With written informed consent, 100 patients with cytology or biospy proven carcinoma breast, clinical stage T1/ T2 N0 M0, underwent SLNB using combination of methylene blue dye & radioactive technetium 99m sulphur colloid as a part of validation study from June 2003 to February 2006. After validation study, from March 2006 to February 2007, 35 patients have undergone SLNB followed by complete axillary clearance in only those patients with SLNB being positive for metastases.
Results
In all 100 patients of the validation study SLN was identified. Total number of cases with positive axillary nodes was 27, out of which SLN was only positive node for metastases in 69% of cases. The overall sensitivity, specificity, positive predictive valve and negative predictive valve of SLNB 96.2%, 100%, 100% and 98.6% respectively with false negative rate of 3.7%. In subsequent 35 patients who underwent SLNB followed by complete axillary clearance, SLNs was identified in all the cases.
Conclusions
SLNB is effective in early breast cancer patients of Indian population. SLNB using combination of methylene blue dye and radio-active Tc99m sulphur colloid can stage the axilla with high accuracy & low risk of false negativity in early breast cancer patients.
doi:10.1007/s12262-008-0033-9
PMCID: PMC3452444  PMID: 23133037
Sentinel lymph node biopsy; Methylene blue dye; Tc99m radioactive sulfur colloid; Early breast cancer; Indian patients
21.  The impact of previous para-areolar incision in the upper outer quadrant of the breast on the localization of the sentinel lymph node in a canine model 
Clinics  2011;66(8):1413-1418.
OBJECTIVES:
This paper discusses the influence of a para-areolar incision in the upper outer quadrant of the breast on the location of the sentinel lymph node in a canine model.
METHODS:
The sentinel lymph node was marked with technetium-99, which was injected into the subareolar skin of the cranial breast. After the marker had migrated to the axilla, an arcuate para-areolar incision was performed 2 cm from the nipple in the upper outer quadrant. Patent blue dye was then injected above the upper border of the incision. At the marked site, an axillary incision was made, and the sentinel lymph node was identified by gamma probe and/or by direct visualization of the dye. The agreement between the two injection sites and the two sentinel lymph node identification methods was determined. Our sample group consisted of 40 cranial breasts of 23 adult females of the species Canis familiaris. The data were analyzed by using the McNemar test and by determining the kappa agreement coefficient.
RESULT:
Our findings showed that in 95% of the breasts, the sentinel lymph node was identified by the injection of technetium-99 m into the subareolar region, and in 82% of the cases, the sentinel lymph node was identified by the injection of patent blue dye above the upper border of the incision. The methods agreed 82% of the time.
CONCLUSIONS:
Previous para-areolar incisions in the upper outer quadrant did not interfere significantly with the biopsy when the dye was injected above the upper border of the incision.
doi:10.1590/S1807-59322011000800018
PMCID: PMC3161221  PMID: 21915493
Breast cancer; Gamma probe; Sentinel node; Animal model; Oncologic surgery
22.  The importance of pre-operative axillary ultrasound and intra-operative sentinel lymph node frozen section analysis in patients with early breast cancer – a 3-year study 
INTRODUCTION
To ensure appropriate axillary surgery is performed at a single operation, we have sought to identify patients with involved nodes who might progress directly to axillary dissection.
PATIENTS AND METHODS
We evaluated pre-operative ultrasound of the axilla and intra-operative frozen section of sentinel lymph nodes over a 3-year period. Patients with clinical early breast cancer underwent axillary ultrasound. Abnormal nodes were defined as a cortex > 2.5 mm, loss of high echogenic medulla, and morphological changes. Any axilla containing a lymph node considered abnormal had ultrasound-directed fine needle aspiration (FNA) performed. Patients with positive cytology proceeded directly to axillary dissection. Patients with negative cytology and those with normal ultrasound proceeded to sentinel four-node biopsy using Patent Blue dye alone. A single sentinel node was evaluated by intra-operative frozen section.
RESULTS
A total of 311 patients underwent pre-operative ultrasound successfully, identifying 115 (77%) patients of the total 150 who were found to have positive lymph nodes. Overall, 196 patients underwent sentinel lymph node biopsy analysis intra-operatively. Of the 11 false negative cases in which the lymph node was found to be positive postoperatively, eight cases showed the single tested sentinel node contained cancer that was recognised on postoperative staining but not frozen section. In six, the deposit in the sentinel node was a micrometastasis. Three cases were found to contain cancer in the ‘non-sentinel' node; in all, this was micrometastatic disease.
CONCLUSIONS
This study confirms the value of pre-operative ultrasound and intra-operative frozen section examination of axillary nodes. Only 3.5% of patients required two operations.
doi:10.1308/003588411X12851639108196
PMCID: PMC3293300  PMID: 21144229
Ultrasound; Frozen section; Sentinel lymph node; Breast cancer
23.  Dual-Modality Photoacoustic and Ultrasound Imaging System for Noninvasive Sentinel Lymph Node Detection in Patients with Breast Cancer 
Scientific Reports  2015;5:15748.
The detection of regional lymph node metastases is important in cancer staging as it guides the prognosis of the patient and the strategy for treatment. Sentinel lymph node biopsy (SLNB) is an accurate, less invasive alternative to axillary lymph node dissection. The sentinel lymph node hypothesis states that the pathological status of the axilla can be accurately predicted by determining the status of the first lymph nodes that drain from the primary tumor. Physicians use radio-labeled sulfur colloid and/or methylene blue dye to identify the SLN, which is most likely to contain metastatic cancer cells. However, the surgical procedure causes morbidity and associated expenses. To overcome these limitations, we developed a dual-modality photoacoustic and ultrasonic imaging system to noninvasively detect SLNs based on the accumulation of methylene blue dye. Ultimately, we aim to guide percutaneous needle biopsies and provide a minimally invasive method for axillary staging of breast cancer.
doi:10.1038/srep15748
PMCID: PMC4625171  PMID: 26510774
24.  Intraoperative frozen section assessment of sentinel lymph nodes in the operative management of women with symptomatic breast cancer 
Background
Maximisation of the potential of sentinel lymph node biopsy as a minimally invasive method of axillary staging requires sensitive intraoperative pathological analysis so that rates of re-operation for lymphatic metastases are minimised. The aim of this study was to describe the test parameters of the frozen section evaluation of sentinel node biopsy for breast cancer compared to the gold standard of standard permanent pathological evaluation at our institution.
Methods
The accuracy of intraoperative frozen section (FS) of sentinel nodes was determined in 94 consecutive women undergoing surgery for clinically node negative, invasive breast cancer (37:T1 disease; 43:T2; 14:T3). Definitive evidence of lymphatic spread on FS indicated immediate level II axillary clearance while sentinel node "negativity" on intraoperative testing led to the operation being curtailed to allow formal H&E analysis of the remaining sentinel nodal tissue.
Results
Intraoperative FS correctly predicted axillary involvement in 23/30 patients with lymphatic metastases (76% sensitivity rate) permitting definitive surgery to be completed at the index operation in 87 women (93%) overall. All SN found involved on FS were confirmed as harbouring tumour cells on subsequent formal specimen examination (100% specificity and positive predictive value) with 16 patients having additional non-sentinel nodes found also to contain tumour. Negative Predictive Values were highest in women with T1 tumours (97%) and lessened with more local advancement of disease (T2 rates: 86%; T3: 75%). Of those with falsely negative FS, three had only micrometastatic disease.
Conclusion
Intraoperative FS reliably evaluates the status of the sentinel node allowing most women complete their surgery in a single stage. Thus SN can be offered with increased confidence to those less likely to have negative axillae hence expanding the population of potential beneficiaries.
doi:10.1186/1477-7819-6-69
PMCID: PMC2443144  PMID: 18582366
25.  Receptor-Defined Subtypes of Breast Cancer in Indigenous Populations in Africa: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(9):e1001720.
In a systematic review and meta-analysis, Isabel dos Santos Silva and colleagues estimate the prevalence of receptor-defined subtypes of breast cancer in North Africa and sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Breast cancer is the most common female cancer in Africa. Receptor-defined subtypes are a major determinant of treatment options and disease outcomes but there is considerable uncertainty regarding the frequency of poor prognosis estrogen receptor (ER) negative subtypes in Africa. We systematically reviewed publications reporting on the frequency of breast cancer receptor-defined subtypes in indigenous populations in Africa.
Methods and Findings
Medline, Embase, and Global Health were searched for studies published between 1st January 1980 and 15th April 2014. Reported proportions of ER positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor-2 positive (HER2+) disease were extracted and 95% CI calculated. Random effects meta-analyses were used to pool estimates. Fifty-four studies from North Africa (n = 12,284 women with breast cancer) and 26 from sub-Saharan Africa (n = 4,737) were eligible. There was marked between-study heterogeneity in the ER+ estimates in both regions (I2>90%), with the majority reporting proportions between 0.40 and 0.80 in North Africa and between 0.20 and 0.70 in sub-Saharan Africa. Similarly, large between-study heterogeneity was observed for PR+ and HER2+ estimates (I2>80%, in all instances). Meta-regression analyses showed that the proportion of ER+ disease was 10% (4%–17%) lower for studies based on archived tumor blocks rather than prospectively collected specimens, and 9% (2%–17%) lower for those with ≥40% versus those with <40% grade 3 tumors. For prospectively collected samples, the pooled proportions for ER+ and triple negative tumors were 0.59 (0.56–0.62) and 0.21 (0.17–0.25), respectively, regardless of region. Limitations of the study include the lack of standardized procedures across the various studies; the low methodological quality of many studies in terms of the representativeness of their case series and the quality of the procedures for collection, fixation, and receptor testing; and the possibility that women with breast cancer may have contributed to more than one study.
Conclusions
The published data from the more appropriate prospectively measured specimens are consistent with the majority of breast cancers in Africa being ER+. As no single subtype dominates in the continent availability of receptor testing should be a priority, especially for young women with early stage disease where appropriate receptor-specific treatment modalities offer the greatest potential for reducing years of life lost.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Breast cancer is the commonest female tumor in Africa and death rates from the disease in some African countries are among the highest in the world. Breast cancer begins when cells in the breast acquire genetic changes that allow them to grow uncontrollably and to move around the body. When a breast lump is found (by mammography or manual examination), a few cells are collected from the lump (a biopsy) to look for abnormal cells and to test for the presence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) on the cells. The hormones estrogen and progesterone promote the growth of normal breast cells and of ER+ and PR+ breast cancer cells. HER2 also controls the growth of breast cells. The receptor status of breast cancer is a major determinant of treatment options and prognosis (likely outcome). ER+ tumors, for example, are more receptive to hormonal therapy and have a better prognosis than ER− tumors, whereas HER2+ tumors, which make large amounts of HER2, are more aggressive than HER2− tumors. Breast cancer is treated by surgically removing the lump or the whole breast (mastectomy) if the tumor has already spread, before killing any remaining cancer cells with chemotherapy or radiotherapy. In addition, ER+, PR+, and HER2+ tumors are treated with drugs that block these receptors (including tamoxifen and trastuzumab), thereby slowing breast cancer growth.
Why Was This Study Done?
ER+ tumors predominate in white women but the proportion of ER+ tumors among US-born black women is slightly lower. The frequency of different receptor-defined subtypes of breast cancer in indigenous populations in Africa is currently unclear but policy makers need this information to help them decide whether routine receptor status testing should be introduced across Africa. Because receptor status is a major determination of treatment options and outcomes, it would be more important to introduce receptor testing if all subtypes are present in breast cancers in indigenous African women and if no one subtype dominates than if most breast cancers in these women are ER+. In this systematic review (a study that uses pre-defined criteria to identify all the research on a given topic) and meta-analysis (a statistical approach that combines the results of several studies), the researchers examine the distribution of receptor-defined breast cancer subtypes in indigenous populations in Africa.
What Did the Researchers Do and Find?
The researchers identified 54 relevant studies from North Africa involving 12,284 women with breast cancer (mainly living in Egypt or Tunisia) and 26 studies from sub-Saharan Africa involving 4,737 women with breast cancer (mainly living in Nigeria or South Africa) and used the data from these studies to calculate the proportions of ER+, PR+, and HER2+ tumors (the number of receptor-positive tumors divided by the number of tumors with known receptor status) across Africa. The proportion of ER+ tumors varied markedly between studies, ranging between 0.40 and 0.80 in North Africa and between 0.20 and 0.70 in sub-Saharan Africa. Among prospectively collected samples (samples collected specifically for receptor-status testing; studies that determined the receptor status of breast cancers using stored samples reported a lower proportion of ER+ disease than studies that used prospectively collected samples), the overall pooled proportions of ER+ and triple negative tumors were 0.59 and 0.21, respectively.
What Do These Findings Mean?
Although these findings highlight the scarcity of data on hormone receptor and HER2 status in breast cancers in indigenous African populations, they provide new information about the distribution of breast cancer subtypes in Africa. Specifically, these findings suggest that although slightly more than half of breast cancers in Africa are ER+, no single subtype dominates. They also suggest that the distribution of receptor-defined breast cancer subtypes in Africa is similar to that found in Western populations. The accuracy of these findings is likely to be affected by the low methodological quality of many of the studies and the lack of standardized procedures. Thus, large well-designed studies are still needed to accurately quantify the distribution of various breast cancer subtypes across Africa. In the meantime, the current findings support the introduction of routine receptor testing across Africa, especially for young women with early stage breast cancer in whom the potential to improve survival and reduce the years of life lost by knowing the receptor status of an individual's tumor is greatest.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001720.
This study is further discussed in a PLOS Medicine Perspective by Sulma i Mohammed
The US National Cancer Institute (NCI) provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer including an online booklet for patients
Cancer Research UK, a not-for profit organization, provides information about cancer; its detailed information about breast cancer includes sections on tests for hormone receptors and HER2 and on treatments that target hormone receptors and treatments that target HER2
Breastcancer.org is a not-for-profit organization that provides up-to-date information about breast cancer (in English and Spanish), including information on hormone receptor status and HER2 status
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
doi:10.1371/journal.pmed.1001720
PMCID: PMC4159229  PMID: 25202974

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