Time trends (2006-2015) of quality indicators in EUSOMA-certified breast centres.

AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast centres to establish minimum standards and ensure specialist multidisciplinary care. Prospectively collected anonymous information on primary breast cancer cases diagnosed and treated in the units is transferred annually to a central EUSOMA data warehouse for continuous monitoring of quality indicators (QIs) to improve quality of care. Units have to comply with the EUSOMA Breast Centre guidelines and are audited by peers. The database was started in 2006 and includes over 110,000 cancers from breast centres located in Germany, Switzerland, Belgium, Austria, The Netherlands, Spain, Portugal and Italy. The aim of the present study is assessing time trends of QIs in EUSOMA-certified breast centres over the decade 2006-2015. MATERIALS AND METHODS: Previously defined QIs were calculated for 22 EUSOMA-certified breast centres (46122 patients) during 2006-2015. RESULTS: On the average of all units, the minimum standard of care was achieved in 8 of 13 main EUSOMA QIs in 2006 and in all in 2015. All QIs, except removal of at least 10 lymph nodes at axillary clearance and oestrogen receptor-negative tumours (T > 1 cm or N+) receiving adjuvant chemotherapy, improved significantly in this period. The desirable target was reached for two QIs in 2006 and for 7 of 13 QIs in 2015. CONCLUSION: The EUSOMA model of audit and monitoring QIs functions well in different European health systems and results in better performance of QIs over the last decade. QIs should be evaluated and adapted on a regular basis, as guidelines change over time.

The requirements of a specialist Breast Centre.

INTRODUCTION: In recognition of the advances and evidence based changes in clinical practice that have occurred in recent years and taking into account the knowledge and experience accumulated through the voluntary breast unit certification programme, Eusoma has produced this up-dated and revised guidelines on the requirements of a Specialist Breast Centre (BC). METHODS: The content of these guidelines is based on evidence from the recent relevant peer reviewed literature and the consensus of a multidisciplinary team of European experts. The guidelines define the requirements for each breast service and for the specialists who work in specialist Breast Centres. RESULTS: The guidelines identify the minimum requirements needed to set up a BC, these being an integrated Breast Centre, dealing with a sufficient number of cases to allow effective working and continuing expertise, dedicated specialists working with a multidisciplinary approach, providing all services throughout the patients pathway and data collection and audit. It is essential that the BC also guarantees the continuity of care for patients with advanced (metastatic) disease offering treatments according to multidisciplinary competencies and a high quality palliative care service. The BC must ensure that comprehensive support and expertise may be needed, not only through the core BC team, but also ensure that all other medical and paramedical expertise that may be necessary depending on the individual case are freely available, referring the patient to the specific care provider depending on the problem. CONCLUSIONS: Applying minimum requirements and quality indicators is essential to improve organisation, performance and outcome in breast care. Efficacy and compliance have to be constantly monitored to evaluate the quality of patient care and to allow appropriate corrective actions leading to improvements in patient care.

Results of a national training programme in sentinel lymph node biopsy for breast cancer.

BACKGROUND: New Start, a structured, validated, multidisciplinary training programme in sentinel lymph node biopsy (SLNB), was established to allow the introduction and rapid transfer of appropriate knowledge and technical skills to ensure safe and competent practice across the UK. METHODS: Multidisciplinary teams attended a theory/skills laboratory course, following which they performed 30 consecutive SLNBs, either concurrently with their standard axillary staging procedure (training model A) or as stand-alone SLNB (training model B). SLNB was performed according to a standard protocol using the combined technique of isotope ((99m) Tc-labelled albumin colloid) and blue dye. An accredited New Start trainer mentored the first five procedures in the participant's hospital, or all 30 if stand-alone. Validation standards for model A and B were a localization rate of at least 90 per cent. In addition, for model A only, in which a minimum of ten patients were required to be node-positive, a false-negative rate (FNR) of 10 per cent or less was required. RESULTS: From October 2004 to December 2008, 210 SLNB-naive surgeons, in 103 centres, performed 6685 SLNB procedures. The overall sentinel lymph node (SLN) localization rate was 98·9 (95 per cent confidence interval 98·6 to 99·1) per cent (6610 of 6685) and the FNR 9·1 (7·9 to 10·5) per cent (160 of 1757). The FNR was related to nodal yield, ranging from 14·8 per cent for one node and declining to 9·7, 6·6, 4·7 and 4·1 per cent for two, three, four and more than four SLNs respectively. No learning curve was identified for localization or FNR. CONCLUSION: The programme successfully trained a wide range of UK breast teams to perform safe SLNB and suggested that a standard injection protocol and structured multidisciplinary training can abolish learning curves.

Investigation of anaphylactic reaction after patent blue V dye injection.

BACKGROUND: Patent blue dye V (PBV) is in widespread use for sentinel node biopsy in breast cancer and melanoma. At present, the best diagnostic approach in investigating possible anaphylaxis due to PBV is not defined. METHOD: We reviewed our experience of patients and the cases reported in the literature that developed an anaphylactic reaction after injection of PBV and suggest a diagnostic protocol. From May 2006 to April 2009 six patients were known to the Cardiff anaesthetics department to have suffered a severe anaphylactic reaction after injection of PBV. We amalgamated the results of the investigations of our patients with those of 42 case reports published in the literature during the last 10 years. RESULTS: Of 40 patients with a documented allergy history 31 patients did not have a past medical history of allergy. The median interval between PBV administration and allergic reaction was 15 min (range 1 min-180 min). Of 20 patients with hypotension 18 received inotropes. 4 patients had a fall in blood pressure as their sole symptom. 23 patients had urticaria or other allergic skin manifestations, 8 had blue wheals. 5 patients had bronchospasm. 2 patients had a cardiac arrest. They were successfully resuscitated. The median dose of PBV was 2 ml (range 0.5 ml-5 ml). Tryptase levels were elevated in 14 of 26 tested patients. Skin prick testing was positive in 24 of 30 tested patients. Intradermal testing was positive in all 13 tested patients. CONCLUSION: Most patients experiencing a severe allergic reaction to PBV have no past medical history of allergy. The value of formal allergy skin testing for PBV-related allergy lies in excluding other agents as the causative factor to avoid their exposure in the future.

Axillary node staging by ultrasonography and fine-needle aspiration cytology in patients with breast cancer.

BACKGROUND: This study evaluated the role of axillary ultrasonography (AUS) and fine-needle aspiration cytology (FNAC) in preoperative staging of the axilla in patients with invasive breast cancer. METHODS: Between October 2006 and March 2009, 502 patients scheduled to undergo surgery for invasive breast cancer had preoperative AUS. All patients with suspicious nodes on ultrasonography underwent FNAC, and those with positive cytology proceeded directly to axillary node clearance. Patients with normal findings on AUS or negative cytology underwent sentinel node biopsy (SNB). RESULTS: A total of 137 (27.3 per cent) of 502 patients had axillary node metastases on final histology. Thirty-nine (28.5 per cent) node-positive patients were identified by AUS-FNAC and spared unnecessary SNB. AUS-FNAC had a sensitivity of 28.5 per cent and a specificity of 100 per cent for detecting axillary nodal metastases. AUS-FNAC findings were normal in all 15 patients with nodal micrometastases and in 11 patients with isolated tumour cells on histopathology. The sensitivity of AUS-FNAC had a positive correlation with invasive tumour size (odds ratio 1.03) and grade (odds ratio 2.80). CONCLUSION: Preoperative AUS-FNAC avoided unnecessary SNB in 28.5 per cent of node-positive patients and in 7.8 per cent of patients overall.

Adverse reactions to patent blue V dye - The NEW START and ALMANAC experience.

BACKGROUND: Blue dye with or without isotope has been widely used to identify the sentinel lymph node(s) in breast cancer. Patent blue V is used in the UK while its isomer isosulfan blue is used in the US. The allergic potential of isosulfan blue is well documented (1.4% adverse reactions) but that of patent blue V is less clearly defined. METHODS: In this paper we review the adverse reactions of patent blue V in 7,917 patients who participated in the NEW START training programme and the ALMANAC trial. All patients underwent sentinel lymph node biopsy for breast carcinoma using patent blue V in combination with (99m)Tc-albumin colloid. RESULTS: In total, 72 of 7,917 (0.9%) patients experienced adverse reactions : non-allergic reactions were observed in 4 (0.05%) patients, 23 (0.3%) patients had minor grade I allergic skin reactions (urticaria, blue hives, pruritus, or generalised rash) and 16 (0.2%) had grade II reactions (transient hypotension/bronchospasm/laryngospasm). Severe Grade III reactions (severe hypotension requiring vasopressor support and/or change/abandoning of planned procedure and/or HDU/ITU admission) were noted in 5 (0.06%) patients. The type of adverse reaction was not specified in 24 (0.3%) patients. No mortality was recorded. CONCLUSION: The allergic potential of patent blue V dye compares favourably with isosulfan blue however both the surgeon and anaesthetist need to be alert to the risk of allergic reactions.

ONCOPOOL - a European database for 16,944 cases of breast cancer.

ONCOPOOL is a retrospectively compiled database of primary operable invasive breast cancers treated in the 1990s in 10 European breast cancer Units. Sixteen thousand and nine hundred and forty four cases were entered, with tumours less than 5 cm diameter in women aged 70 or less (mean age 55). DATA: Data were date of birth, mode of diagnosis, pathology (size, lymph node status, grade, type, lympho-vascular invasion and hormone receptor) and therapies and outcome measures: first local, regional or distant recurrences, contralateral primary, date and cause of death. TUMOUR CHARACTERISTICS: Mean diameter 1.8 cm, 66% lymph node negative, 24% 1-3 lymph nodes involved and 10% had 4 or more involved. Grade 1, 29%; Grade 2, 41%; and Grade 3, 30%. Polynomial relationships were established between grade, stage and size. Seventy-five percent were oestrogen receptor (ER) positive. ER closely related to grade. OUTCOMES: Overall Survival was 89% at 5 years from diagnosis, 80% 10 years and 73% 15 years; Breast Cancer-Specific survivals were 91%, 84% and 79%. Survival strongly related to the Nottingham Prognostic Index (NPI). Cases detected at screening had 84% 10-year survival, those presenting symptomatically 76%. ER positive cases treated with adjuvant hormone therapy had a reduction in risk of death of 13% over those not receiving adjuvant therapy (p=0.000). ER negative cases treated with chemotherapy showed a risk reduction of 23% over those not receiving chemotherapy (p=0.000).

Cost-effectiveness analysis of anastrozole vs tamoxifen in adjuvant therapy for early stage breast cancer in the United Kingdom: the 5-year completed treatment analysis of the ATAC ('Arimidex', Tamoxifen alone or in combination) trial.

Results from the completed treatment analysis of the ATAC (Arimidex, Tamoxifen alone or in combination) trial indicated that anastrozole was significantly superior to tamoxifen in terms of efficacy and safety in the adjuvant treatment of postmenopausal women with hormone receptor-positive (HR+) early breast cancer. On the basis of these results, this study estimated the cost-effectiveness of anastrozole vs tamoxifen, from the perspective of the UK National Health Service (NHS). A Markov model was developed using the 5-year completed treatment analysis from the ATAC trial (ISRCTN18233230), as well as data obtained from published literature and expert opinion. Resource utilisation data and associated costs (2003-4 UK pound) were compiled from standard sources and expert opinion. Utility scores for a number of health states were obtained from a cross-sectional study of 26 representative patients using the standard gamble technique. The utility scores were then inserted into the model to obtain cost per quality adjusted life-year (QALY) gained. Costs and benefits were discounted at recommended annual rates of the UK Treasury (3.5%). Modelled for 25 years, anastrozole, relative to generic tamoxifen, was estimated to result in 0.244 QALYs gained per patient at an additional cost of pound4315 per patient). The estimated incremental cost-effectiveness of anastrozole compared with tamoxifen was pound17 656 per QALY gained. There was a greater than 90% probability that the cost-effectiveness of anastrozole was below pound30 000 per QALY gained and of the order of 65% that it was below pound20 000 per QALY gained. The results were robust to all parameters tested in sensitivity analysis. Compared with commonly accepted thresholds, anastrozole is a cost-effective alternative to generic tamoxifen in adjuvant treatment of postmenopausal women with HR+ early breast cancer from the UK NHS perspective.

Evidence-based management of Mastalgia: a meta-analysis of randomised trials.

Several agents have been utilised for therapy of mastalgia based on data from small trials. No meta-analysis of trials on mastalgia exists. We have conducted a meta-analysis on trials on mastalgia published in the English language. Study was restricted to randomised controlled trials comparing Bromocriptine, Danazol, Evening primrose oil (EPO) and Tamoxifen with placebo. The analysis was carried out on the REVMAN statistical package. Weighted mean difference in the pain score in favour of Bromocriptine was -16.31(95% CI -26.35 to -6.27). Danazol produced a significant benefit with a mean pain score difference -20.23(95% CI -28.12 to -12.34). EPO did not offer any advantage over placebo in pain relief, mean pain score difference being -2.78 (95% CI -7.97 to 2.40). Tamoxifen achieved a relative risk (RR) of pain relief of 1.92 (95% CI 1.42-2.58). Tamoxifen is associated with least side effects and should be the drug of first choice.

The role of growth differentiation factor-9 (GDF-9) and its analog, GDF-9b/BMP-15, in human breast cancer.

BACKGROUND: There has been a recent surge of interest in the role of growth differentiation factors and other bone morphogenic proteins in the development and spread of cancer. In this study we have provided evidence that highlights the significance of growth and differentiation factor-9a (GDF-9a) and GDF-9b (bone morphogenic protein-15, BMP-15) in breast cancer development and progression. METHODS: Primary breast cancer samples (n = 109) and matched background tissues from same patients (n = 33) were processed for frozen section and RNA extraction. Frozen sections from matched tissues were immunostained with GDF-9a and GDF-9b antibodies. Staining intensity was analyzed by computer image analysis. RNA was reverse transcribed and quantified before analysis by quantitative polymerase chain reaction (Q-PCR). Results were expressed as number of transcripts (standardized by beta-actin). The data were compared with the clinical outcome of the disease. The biological effects of the molecule were studied using in vitro assays after forced expression in breast cancer cells. RESULTS: Highly aggressive breast cancer cells did not express GDF-9a. On forced expression of GDF-9a, breast cancer cells became less invasive. These laboratory findings were analyzed against the clinical information. Primary breast cancer samples with good predicted prognosis had a significantly higher level of GDF-9a than in samples with poor predicted prognosis (P = .004). Patients who remained disease-free at the end of a 10-year follow-up had significantly higher levels of both GDF-9a and GDF-9b in their tissue than those with poor clinical outcome (P = .001 and .014, respectively). CONCLUSION: Growth differentiation factor-9 family expressed in breast cancer has an inhibitory effect on the progression of human breast cancer.

Expression of the WASP verprolin-homologues (WAVE members) in human breast cancer.

BACKGROUND: The WASP family proteins have been indicated to play a vital role in the formation of membrane protrusions required for cell locomotion. WAVE proteins are an important subfamily that also plays a crucial role in actin polymerisation, which is vital to cell migration. However, not much is known about the clinical significance of this subfamily in cancers. We report, for the first time, the expression of the WAVE molecules, at protein and mRNA levels, in human breast cancer. MATERIALS AND METHODS: The expression of the 3 WAVE molecules at the mRNA and protein levels in a cohort of 122 human breast cancers and 32 normal breast tissues were analysed and correlated with the patients' pathological and clinical information as well as outcome (120 months follow-up). RESULTS: All 3 WAVE molecules were detected in mammary tissues. WAVE2 transcripts were expressed in high levels in all breast tumours. Over-expression of WAVE2 was seen in node-positive cases as well as in moderately and poorly differentiated tumours. Also, high levels of WAVE2 expression were associated with death due to disease (p = 0.02) at follow-up. No distinct associations were found between the WAVE1 and WAVE3 transcripts and the breast cancer cells.

Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency.

Although idiopathic humoral immunodeficiencies are arbitrarily classified into specific antibody deficiency (SAD) or common variable immunodeficiency (CVID), this distinction does not accurately predict the risk of the bronchiectasis, one of the major long-term clinical complications in these patients. In this study, clinical complications were compared with laboratory markers of cellular and humoral immunity in fifty-five consecutive patients (27 children and 28 adults) attending regional immunology clinics in Manchester, United Kingdom. Reduced CD19(+)CD27(+)IgD(-) B cell percentage but not serum immunoglobulin levels or classification of patients into SAD and CVID was associated with a significantly higher prevalence of bronchiectasis (OR 0.4 (0.2-0.8), P = 0.001), splenomegaly (OR 0.2 (0.1-0.5), P = 0.001) and autoimmunity (OR 0.4 (0.2-0.7), P = 0.003). We conclude that in patients with idiopathic humoral immunodeficiencies assessment of B cell switching more accurately predicts clinical prognosis than either classification of patients into SAD and CVID or serum immunoglobulin concentrations.

Total and serotype-specific pneumococcal antibody titres in children with normal and abnormal humoral immunity.

A heptavalent pneumococcal conjugate vaccine (PCV-7) protects children against invasive pneumococcal disease. The aim of this study was to evaluate immunoglobulin subclass and serotype-specific pneumococcal antibody responses to vaccination in children with a history of recurrent or severe bacterial infections. Pneumococcal IgG, IgG1, IgG2 titres were assayed by ELISA, and nine serotype concentrations measured using a nonaplex bead assay in 145 children investigated for recurrent or severe infections. Children mounted an exclusively IgG1 response after vaccination with two doses of PCV-7 and a dose of 23 valent pneumococcal polysaccharide vaccine (PPV-23), with pneumococcal IgG2 antibody titres remaining low to negligible. Measurement of serotype-specific responses demonstrated that although PCV-7 specific serotype responses increased significantly post-vaccination, specific IgG against two of the serotypes not covered by PCV-7 but only by PPV-23 remained low. We conclude that in contrast to antibody response to natural infection with Pneumococcus or pneumococcal polysaccharide vaccines which are often of a IgG2 subclass, responses in children after PCV-7 are of IgG1 subclass. Serotype-specific IgG were useful in determining the protection against specific pneumococcal strains, and showed that the PPV-23 did not broaden protection against non-PCV-7 serotypes.

Intraoperative evaluation of axillary sentinel lymph nodes using touch imprint cytology and immunohistochemistry. Part II. Results.

AIM: In order to operate selectively on positive axillae during the initial operative session for early breast cancer, an accurate and rapid intraoperative method to examine an axillary node sample (ANS) or a sentinel node biopsy (SNB) is required. The aim of this study was to determine the feasibility and accuracy of Immunohistochemistry (IHC)-stained touch imprints in detecting metastatic axillary nodes intraoperatively. MATERIAL AND METHODS: Four hundred and thirty-two axillary nodes from 52 patients (23 axillary node clearance (ANC), 15 ANS and 14 SNB) were bisected, imprinted and stained with anti-cytokeratin 19 IHC. Results were compared with those of routine haematoxylin and eosin (H&E)-stained sections. RESULTS: IHC imprints detected 32 positive nodes from 12 patients. H&E sections detected 31 positive nodes from 11 patients. IHC imprints missed metastases in three nodes and missed the diagnosis of positive axillae in two patients. H&E missed metastases in four nodes and missed the diagnosis of positive axillae in 3 patients. On a node-basis, sensitivities were 91.4 and 88.5%, negative predictive values (NPV) were 99.2 and 99.0% and overall accuracies were 99.3 and 99.1% for IHC imprints and H&E sections, respectively. On a patient-basis, sensitivities were 85.7 and 78.5%, NPVs were 95.2 and 93.1% and overall accuracies were 96.1 and 94.2% for IHC imprints and H&E sections respectively. There were no false positives. Interpretation of the results by a non-histopathologist was concordant with that of a histopathologist. Results might be obtained within 30-45 min depending on the number of examined nodes. CONCLUSION: Intraoperative IHC staining of touch imprints of axillary sentinel nodes is feasible and is a reliable method for evaluating axillary nodes. Slides can be reliably interpreted by a trained non-histopathologist.

Is mammography overused in male patients?

There is no agreed protocol for the use of mammography in evaluating the male breast. As a result, the tendency is to use the mammography more often than required. In order to define the role of mammography in men, we carried out a retrospective analysis of all male patients referred to the breast clinic with a history of breast lump between January 2001 and December 2003. The impact of mammography in the evaluation of male breast cancer cases was studied. A total of 220 male patients were referred to the breast clinic during this period. Of these, 134 men had a mammographic examination, with majority (96%) being performed prior to their consultation with the breast clinician as per the clinic protocol. Nine patients under the age of 35 years also had a mammographic evaluation. There were 4 cases of breast cancer diagnosed during this period. Breast cancer was suspected in all patients on clinical examination and was confirmed by biopsy. Breast cancer in men can be suspected on clinical examination in the majority of cases. Mammography appears unnecessary in most men and should not be used as a routine imaging procedure. One should consider imaging only those with clinically suspicious breast lumps to avoid unnecessary imaging particularly in young male patients.

Molecular and cellular mechanisms of lymphangiogenesis.

Lymphangiogenesis is the growth and formation of new lymphatic vessels. It occurs in normally developing tissues and in pathological processes like inflammation, wound healing, lymphoedema and in cancer. New molecular markers that are specific to the lymphatic endothelium include: podoplanin, prox-1 and LYVE-1. The molecular mechanisms of lymphangiogenesis are not clear, but vascular endothelial growth factors (VEGF-C and VEGF-D) within tumours may simulate endothelial cells within tumour tissues to grow and generate new lymphatics. We report the current knowledge of molecular and cellular mechanisms of lymphangiogenesis.

Interleukin 7 upregulates vascular endothelial growth factor D in breast cancer cells and induces lymphangiogenesis in vivo.

BACKGROUND: Interleukin (IL) 7 is known to stimulate growth of breast cancer cells in vitro. It has been recently associated with node-positive tumours and with poor survival in breast cancer. The effects of IL-7 on the lymphangiogenic properties of breast cancer cells were explored. METHODS: The effects of IL-7 on the expression of vascular endothelial growth factors (VEGFs) in MDA MB-231, MCF-7 and BT-483 cells were analysed by reverse transcriptase-polymerase chain reaction and western blotting. An in vivo lymphangiogenesis model using nude mice was developed. The newly generated microtubules were stained with anti-von Willebrand factor and anti-LYVE-1 (lymphatic vessel endothelial hyaluronan receptor) antibodies. RESULTS: All VEGFs (VEGF-A, -B, -C and -D) were expressed in breast cancer cells, but at different levels. IL-7 increased the expression of VEGF-D at both mRNA and protein levels in MCF-7 and MDA MB-231 cells. In the in vivo model, IL-7 significantly induced the formation of lymphatic LYVE-1-positive, but not vascular von Willebrand factor-positive, microtubules (P = 0.021 versus sections without IL-7). CONCLUSION: IL-7 induced the lymphangiogenic properties of breast cancer cells, probably by upregulation of VEGF-D. This might have a significant impact on the lymphatic spread of breast cancer.

Clinical relevance of multiple sentinel nodes in patients with breast cancer.

BACKGROUND: Indiscriminate removal of axillary nodes may not be justified as it may potentially worsen the morbidity of the sentinel lymph node biopsy (SNB) procedure. This study examined the factors associated with removal of multiple sentinel lymph nodes and determined whether there was an upper threshold for the number of sentinel nodes that should be removed. METHODS: A total of 803 patients with breast cancer underwent successful SNB using peritumoral injection of (99m)Tc-labelled albumin colloid and Patent Blue V dye. SNB was followed by standard axillary treatment at the same operation in all patients. RESULTS: The mean number of sentinel nodes removed per procedure was 2.2 (range 1-9). Multiple sentinel nodes (mean 2.9, range 2-9) were found in 501 patients (62.4 per cent). The false-negative rate in patients who had one sentinel node harvested was 10 per cent, compared with 1 per cent in patients who had three or more nodes removed (P = 0.010). Factors associated with finding multiple sentinel nodes were age less than 50 years (P = 0.004), low body mass index (P < 0.001), tumour in the outer half of the breast (P = 0.013), sentinel node visualization on lymphoscintigraphy (P < 0.001) and an interval of 12 h or less between radioisotope injection and SNB (P = 0.014). For 99.6 per cent of node-positive tumours, metastasis was detected within the first four sentinel nodes removed. CONCLUSION: The identification of multiple sentinel nodes, when present, reduced the false-negative rate. These data suggested that removal of more than four nodes was unnecessary.

Lymphangiogenesis and its role in cancer.

In many tumour types, lymphatic vasculature serves as a major route for tumour metastasis. The dissemination of malignant cells to the regional lymph nodes is an early step in the progression of many solid tumours and is an important determinant of prognosis. Lymphangiogenesis (formation of new lymphatic vessels) is thought to be crucial for cancer cells to metastasise to the regional lymph nodes. However research in this important process has been neglected largely due to the lack of molecular markers specific to the lymphatic endothelium. Recently, several specific markers have been identified including LYVE-1, podoplanin and prox-1. Although the biology of lymphangiogeneis, particularly its regulation, is still far from clear, it is now well established that tumours are lymphangiogenic i.e. they could induce the generation of their own lymphatics and metastasise to the regional lymph nodes. It is thought that the interruption of the main signalling pathways involved in this process could help to prevent lymphatic spread of many tumours. Furthermore, understanding the molecular mechanisms in lymphangiogenesis might help to develop new therapeutic strategies against cancer lymphatic spread. Here, we reviewed the literature in regards to the biology of lymphangiogenesis, its molecular regulation, lymphatic markers and the significance in human solid tumours.

Predictors of non-sentinel lymph node metastasis in breast cancer patients.

In many patients, the sentinel lymph node (SLN) is the sole site of regional nodal metastasis. This subgroup of patients would not be expected to benefit from completion axillary lymph node dissection (CALND). This study evaluated the factors that may determine the likelihood of additional positive nodes in the axilla in the presence of sentinel node metastasis. A total of 618 breast cancer patients underwent SLN biopsy based on lymphoscintigraphy, intraoperative gamma probe detection, and blue dye mapping using 99mTc-nanocolloid and Patent Blue V injected peritumourally. This was followed by standard axillary node clearance at the same operation. Of the 201 patients with a positive SLN, 105 (52%) patients had no further positive nodes in the axilla, 96 (48%) patients had additional metastasis in non-sentinel lymph nodes (NSLN) upon CALND. In patients with a positive SLN, increasing tumour size and tumour grade significantly increased the frequency of additional positive nodes on univariate analysis. The number of SLNs removed and the number of negative SLNs were significant negative predictors. Increasing tumour burden in the sentinel nodes (determined by the number of positive SLNs) was significantly associated with increasing likelihood of positive NSLNs. Multivariate analysis revealed that the rest of the axilla is more likely to be positive if there are more positive than negative SLNs removed and more likely to be negative otherwise. A group of cases from one centre (Cardiff) were subjected to further detailed analysis. Tumour burden in the positive SLN was assessed by measuring the size of metastasis, percentage replacement of the SLN by tumour and by documenting extracapsular extension (ECE) around the SLN. Of the 64 patients with a positive SLN, 34 (53%) patients had no further positive nodes in the axilla, 30 patients (47%) had additional metastasis in NSLNs upon CALND. Increasing tumour burden in the SLN was associated with additional positive nodes in the axilla. Multivariate analysis revealed that size of the SLN metastasis is the most important predictor of involvement of only the SLN. Overall, in patients with a positive SLN, the difference in the number of positive and negative SLNs removed and size of the metastasis in the SLN, all predicted the frequency of additional positive nodes.