Multicentre study of the risk of invasive cancer and use of sentinel node biopsy in women with a preoperative diagnosis of ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) in the breast that is diagnosed by biopsy implies a risk of upstaging to invasive carcinoma (IC) on final pathology. These patients require a sentinel lymph node biopsy (SLNB) for axillary staging. A two-stage procedure is not always feasible and precise selection of patients who should be offered SLNB is crucial. The aims were: to determine the rate of upstaging, and use of redundant and required SLNB in women with a preoperative diagnosis of DCIS; and to identify patient and tumour characteristics that increase the risk of upstaging. METHODS: Patients with DCIS treated between 2008 and 2016 were identified using Orbit operation planning system software, and those suitable for the study were selected based on review of the medical records. Upstaging rates and proportions of redundant and required SLNBs were calculated. Associations between clinicopathological characteristics and upstaging were analysed using univariable and multivariable logistic regression analyses. RESULTS: Of 1368 patients initially identified, 975 women with a preoperative diagnosis of DCIS were included in the study. Tumours in 246 of these patients (25·2 per cent) were upstaged to IC. Redundant SLNB was performed in 392 of 975 women (40·2 per cent). Forty-four patients (4·5 per cent) with a final diagnosis of IC were not offered SLNB and thus potentially undertreated. In adjusted analysis, DCIS size, palpability and mass formation identified by breast imaging were associated with increased risk of upstaging. The Van Nuys classification was not associated with upstaging. CONCLUSION: Most patients with IC on final pathology underwent SLNB, but a considerable number of patients with DCIS had a redundant SLNB. Lesion size, palpability and mass formation, but not Van Nuys classification group, are suggested risk factors for upstaging.

ANTECEDENTES: El carcinoma ductal in situ (ductal carcinoma in situ, DCIS) de mama que se diagnostica mediante biopsia implica un riesgo de infraestadiaje de un carcinoma invasivo (invasive carcinoma, IC) en la anatomía patológica final. Estas pacientes requieren una biopsia del ganglio linfático centinela (sentinel lymph node biopsy, SLNB) para la estadificación axilar. Dado que un procedimiento en dos etapas no siempre es factible, la selección precisa de pacientes a las que se debe ofrecer SLNB es crucial. El objetivo del estudio era determinar la tasa de infraestadiaje inicial y el uso repetido/requerido de SLNB en mujeres con un diagnóstico preoperatorio de CDIS. Además, se identificarán las características del paciente y del tumor que aumentan el riesgo de necesidad de re-estadificación. MÉTODOS: Un total de 1.368 mujeres con DCIS tratadas entre 2008-2016 fueron identificadas utilizando el programa informático de la planificación de las intervenciones hospitalarias. Después de la revisión de los registros médicos, se incluyeron 975 pacientes en la cohorte del estudio. Se calcularon las tasas de infraestadiaje y la proporción del uso repetido/requerido de SLNB. Las asociaciones entre las características clinicopatológicas y la necesidad de re-estadificación se analizaron mediante análisis de regresión logística univariable y multivariable. RESULTADOS: De 975 pacientes diagnosticados inicialmente de DCIS, 246 (25,2%) fueron re-estadiados a IC. Se realizó SLNB repetidas en 392 (40,2%) de estos pacientes. En 44 pacientes (4,5%) con un diagnóstico final de IC no se les ofreció la SLNB y, por lo tanto, pudieron estar potencialmente infratratados. En el análisis ajustado, el tamaño del DCIS, la palpabilidad y la presencia de una masa en las imágenes radiológicas de la mama se asociaron con un mayor riesgo de necesidad de re-estadificación por infraestadiaje inicial. La clasificación de Van Nuys no se asoció con la re-estadificación. CONCLUSIÓN: La mayoría de pacientes con IC en la patología final se sometieron a SLNB, sin embargo, un número considerable de pacientes con DCIS se sometieron a SLNB repetidas. El tamaño de la lesión, la palpabilidad y la presencia de masa, aunque no el grupo de clasificación de Van Nuys, se consideran factores de riesgo relacionados con infraestadiaje inicial y necesidad de re-estadificación final.

Radioactive seed localisation of non-palpable lymph nodes - A feasibility study.

BACKGROUND: Radioactive seed localisation (RSL) is a preoperative localisation method using a small titanium seed containing iodine-125. The method is increasingly applied for localising non-palpable lesions in the treatment of breast cancer. We believe that RSL has the potential to be used in various surgical specialties. The aim of this feasibility study was to test RSL as a preoperative localisation of non-palpable lymph nodes. METHODS: Between November 24, 2015 and October 26, 2016, 15 patients with suspicious lymph nodes on imaging were included in the study. The lymph nodes were located in the axillary region (n = 9), the head and neck region (n = 5) and the inguinal region (n = 1). The seeds were placed in the centre of the lymph node, in the capsule or just outside the capsule guided by ultrasound. During surgery, incision and localisation of the lymph nodes were performed based on the auditory signal of the gamma probe. After excision, lymph nodes including iodine seeds were sent for pathologic examination and the seeds were returned to the Department of Nuclear Medicine. RESULTS: The non-palpable lymph nodes were all successfully marked using ultrasound. The lymph nodes were successfully localised and excised during surgery, and the procedure was performed without complications in the majority of the cases. CONCLUSION: Localisation of suspicious non-palpable lymph nodes using RSL is feasible. RSL may ease the surgical procedure, minimise trauma to the surrounding tissue and ultimately benefit the patient. Future prospective studies are necessary to determine the further use of RSL within different surgical specialties.

A predictive tool to estimate the risk of axillary metastases in breast cancer patients with negative axillary ultrasound.

BACKGROUND: Sentinel node biopsy (SNB) is the "gold standard" in axillary staging in clinically node-negative breast cancer patients. However, axillary treatment is undergoing a paradigm shift and studies are being conducted on whether SNB may be omitted in low-risk patients. The purpose of this study was to evaluate the risk factors for axillary metastases in breast cancer patients with negative preoperative axillary ultrasound. METHODS: A total of 1,395 consecutive patients with invasive breast cancer and SNB formed the original patient series. A univariate analysis was conducted to assess risk factors for axillary metastases. Binary logistic regression analysis was conducted to form a predictive model based on the risk factors. The predictive model was first validated internally in a patient series of 566 further patients and then externally in a patient series of 2,463 patients from four other centers. All statistical tests were two-sided. RESULTS: A total of 426 of the 1,395 (30.5 %) patients in the original patient series had axillary lymph node metastases. Histological size (P < 0.001), multifocality (P < 0.001), lymphovascular invasion (P < 0.001), and palpability of the primary tumor (P < 0.001) were included in the predictive model. Internal validation of the model produced an area under the receiver operating characteristics curve (AUC) of 0.731 and external validation an AUC of 0.79. CONCLUSIONS: We present a predictive model to assess the patient-specific probability of axillary lymph node metastases in patients with clinically node-negative breast cancer. The model performs well in internal and external validation. The model needs to be validated in each center before application to clinical use.

Cross-validation of three predictive tools for non-sentinel node metastases in breast cancer patients with micrometastases or isolated tumor cells in the sentinel node.

BACKGROUND: We cross-validated three existing models for the prediction of non-sentinel node metastases in patients with micrometastases or isolated tumor cells (ITC) in the sentinel node, developed in Danish and Finnish cohorts of breast cancer patients, to find the best model to identify patients who might benefit from further axillary treatment. MATERIAL AND METHOD: Based on 484 Finnish breast cancer patients with micrometastases or ITC in sentinel node a model has been developed for the prediction of non-sentinel node metastases. Likewise, two separate models have been developed in 1577 Danish patients with micrometastases and 304 Danish patients with ITC, respectively. The models were cross-validated in the opposite cohort. RESULTS: The Danish model for micrometatases was accurate when tested in the Finnish cohort, with a slight change in AUC from 0.64 to 0.63. The AUC of the Finnish model decreased from 0.68 to 0.58 when tested in the Danish cohort, and the AUC of the Danish model for ITC decreased from 0.73 to 0.52, when tested in the Finnish cohort. The Danish micrometastatic model identified 14-22% of the patients as high-risk patients with over 30% risk of non-sentinel node metastases while less than 1% was identified by the Finish model. In contrast, the Finish model predicted a much larger proportion of patients being in the low-risk group with less than 10% risk of non-sentinel node metastases. CONCLUSION: The Danish model for micrometastases worked well in predicting high risk of non-sentinel node metastases and was accurate under external validation.

International multicenter tool to predict the risk of four or more tumor-positive axillary lymph nodes in breast cancer patients with sentinel node macrometastases.

Recently, many centers have omitted routine axillary lymph node dissection (ALND) after metastatic sentinel node biopsy in breast cancer due to a growing body of literature. However, existing guidelines of adjuvant treatment planning are strongly based on axillary nodal stage. In this study, we aim to develop a novel international multicenter predictive tool to estimate a patient-specific risk of having four or more tumor-positive axillary lymph nodes (ALN) in patients with macrometastatic sentinel node(s) (SN). A series of 675 patients with macrometastatic SN and completion ALND from five European centers were analyzed by logistic regression analysis. A multivariate predictive model was created and validated internally by 367 additional patients and then externally by 760 additional patients from eight different centers. All statistical tests were two-sided. Prevalence of four or more tumor-positive ALN in each center's series (P = 0.010), number of metastatic SNs (P < 0.0001), number of negative SNs (P = 0.003), histological size of the primary tumor (P = 0.020), and extra-capsular extension of SN metastasis (P < 0.0001) were included in the predictive model. The model's area under the receiver operating characteristics curve was 0.766 in the internal validation and 0.774 in external validation. Our novel international multicenter-based predictive tool reliably estimates the risk of four or more axillary metastases after identifying macrometastatic SN(s) in breast cancer. Our tool performs well in internal and external validation, but needs to be further validated in each center before application to clinical use.

Persistent pain, sensory disturbances and functional impairment after immediate or delayed axillary lymph node dissection.

BACKGROUND: Patients treated with 2-step axillary lymph node dissection (ALND) may be at increased risk of nerve damage due to more challenging surgery than an ALND immediately after a sentinel lymph node biopsy (SLNB), and thus more at risk for persistent pain after breast cancer treatment (PPBCT). The aim of this study was to examine PPBCT, sensory disturbances and functional impairment in patients treated with a 2-step ALND compared to patients with an SLNB followed by an immediate ALND, and patients with ALND without a prior SLNB. METHODS: The study is a cross-sectional questionnaire study, comparing 2847 women treated with ALND in Denmark in 2005-2008. 196 patients treated with a 2-step ALND were compared with 1558 patients treated with an ALND after SLNB and 1093 with an ALND without a prior SLNB. RESULTS: Overall prevalence of PPBCT and sensory disturbances was high, with about 55% reporting PPBCT and 77% reporting sensory disturbances in all groups. No differences were found between the groups on prevalence and intensity of PPBCT (p = 0.92), sensory disturbances (p = 0.32), and functional consequences (p = 0.35). CONCLUSIONS: A 2-step ALND does not modify the risk of developing PPBCT compared to an immediate ALND.

Anticoagulant properties of rabbit lungs in tissue thromboplastin-induced intravascular coagulation.

This study was conducted in order to examine possible anticoagulant properties of the lungs during tissue thromboplastin-induced intravascular coagulation. Rabbit brain tissue thromboplastin (n = 17) or saline (n = 6 + 3) was infused above the right atrium (n = 11 + 3) of the heart or in the arcus aorta (n = 6) for a period of 120 min in non-pregnant New Zealand rabbits. Rabbits infused with tissue thromboplastin responded with significantly (p < 0.05) more excessive changes in a number of haemodynamic variables (heart rate, PaO2,PaCO2, blood pH etc.) compared with rabbits infused with saline. Similarly, the prothrombin time (p < 0.05) and the activated partial thromboplastin time (p < 0.05) were significantly more prolonged in rabbits receiving tissue thromboplastin compared with control animals. Also the concentration of blood platelets (p < 0.05), plasma fibrinogen (p < 0.05), antithrombin (p < 0.05), and protein C (p < 0.05) decreased significantly in thromboplastin-treated animals compared with control animals. In all these haemostatic variables there was a common trend that animals infused with tissue thromboplastin in the arcus aorta responded more excessively than animals infused in the right atrium of the heart, and these deviations were statistically significant for fibrinogen (p < 0.05) and prothrombin time (p < 0.05). Similarly, animals infused with tissue thromboplastin in the arcus aorta had an increased number of microthrombi in the lungs and kidneys compared with animals receiving tissue thromboplastin above the right atrium. As the lungs are the first pass organ when you infuse above the right atrium the results from this study suggest that the lungs play a key role in protecting the organism against excessive tissue thromboplastin-induced activation of coagulation.

Studies of the initial anticoagulant response in tissue-thromboplastin induced intravascular coagulation.

The very early anticoagulant response was analysed in non-pregnant female New Zealand rabbits infused with rabbit brain tissue thromboplastin for a period of 10 min (n = 6), 20 min (n = 6), and 30 min (n = 6). The rabbits infused with thromboplastin responded with a significant drop in mean arterial pressure (P < 0.05), an increase in blood PaO2 (P < 0.05) and a decrease in PaCO2 (P < 0.05), while control animals remained stable with respect to these variables. The thromboplastin-treated animals had an immediate drop in platelet count (P < 0.05), plasma fibrinogen (P < 0.05) and a prolongation in prothrombin time (P < 0.05) and activated partial thromboplastin time (P < 0.05). The concentrations in a number of proteins involved in the anticoagulant response (antithrombin, plasminogen, antiplasmin) as well as global fibrinolytic activity did not change significantly following 10, 20 and 30 min infusion of thromboplastin, while the concentration of protein C decreased continuously during the infusion periods (P < 0.05) to reach the lowest level (approximately 60%) in animals infused with thromboplastin for 30 min. The animals infused with tissue thromboplastin had microthrombi in 1-6% of the renal glomeruli, but the number of microthrombi did not differ significantly between animals infused for 10, 20 and 30 min. It is concluded that the protein C system may play a key role during the initial phase of intravascular coagulation and immediate activation of protein C may protect against excessive deposition of fibrin.