Impact analysis of rotavirus vaccination in various geographic regions in Western Europe.

BACKGROUND: Universal mass vaccination (UMV) against rotavirus has been implemented in many but not all European countries. This study investigated the impact of UMV on rotavirus incidence trends by comparing European countries with UMV: Belgium, England/Wales and Germany versus countries without UMV: Denmark and the Netherlands. METHODS: For this observational retrospective cohort study, time series data (2001-2016) on rotavirus detections, meteorological factors and population demographics were collected. For each country, several meteorological and population factors were investigated as possible predictors of rotavirus incidence. The final set of predictors were incorporated in negative binomial models accounting for seasonality and serial autocorrelation, and time-varying incidence rate ratios (IRR) were calculated for each age group and country separately. The overall vaccination impact two years after vaccine implementation was estimated by pooling the results using a random effects meta-analyses. Independent t-tests were used to compare annual epidemics in the pre-vaccination and post-vaccination era to explore any changes in the timing of rotavirus epidemics. RESULTS: The population size and several meteorological factors were predictors for the rotavirus epidemiology. Overall, we estimated a 42% (95%-CI 23;56%) reduction in rotavirus incidence attributable to UMV. Strongest reductions were observed for age-groups 0-, 1- and 2-years (IRR 0.47, 0.48 and 0.63, respectively). No herd effect induced by UMV in neighbouring countries was observed. In all UMV countries, the start and/or stop and corresponding peak of the rotavirus season was delayed by 4-7 weeks. CONCLUSIONS: The introduction of rotavirus UMV resulted in an overall reduction of 42% in rotavirus incidence in Western European countries two years after vaccine introduction and caused a change in seasonal pattern. No herd effect induced by UMV neighbouring countries was observed for Denmark and the Netherlands.

Updated cost-effectiveness and risk-benefit analysis of two infant rotavirus vaccination strategies in a high-income, low-endemic setting.

BACKGROUND AND OBJECTIVE: Since 2013, a biennial rotavirus pattern has emerged in the Netherlands with alternating high and low endemic years and a nearly 50% reduction in rotavirus hospitalization rates overall, while infant rotavirus vaccination has remained below 1% throughout. As the rotavirus vaccination cost-effectiveness and risk-benefit ratio in high-income settings is highly influenced by the total rotavirus disease burden, we re-evaluated two infant vaccination strategies, taking into account this recent change in rotavirus epidemiology. METHODS: We used updated rotavirus disease burden estimates derived from (active) surveillance to evaluate (1) a targeted strategy with selective vaccination of infants with medical risk conditions (prematurity, low birth weight, or congenital conditions) and (2) universal vaccination including all infants. In addition, we added herd protection as well as vaccine-induced intussusception risk to our previous cost-effectiveness model. An age- and risk-group structured, discrete-time event, stochastic multi-cohort model of the Dutch pediatric population was used to estimate the costs and effects of each vaccination strategy. RESULTS: The targeted vaccination was cost-saving under all scenarios tested from both the healthcare payer and societal perspective at rotavirus vaccine market prices (€135/child). The cost-effectiveness ratio for universal vaccination was €51,277 at the assumed vaccine price of €75/child, using a societal perspective and 3% discount rates. Universal vaccination became cost-neutral at €32/child. At an assumed vaccine-induced intussusception rate of 1/50,000, an estimated 1707 hospitalizations and 21 fatal rotavirus cases were averted by targeted vaccination per vaccine-induced intussusception case. Applying universal vaccination, an additional 571 hospitalizations and <  1 additional rotavirus death were averted in healthy children per vaccine-induced intussusception case. CONCLUSION: While universal infant rotavirus vaccination results in the highest reductions in the population burden of rotavirus, targeted vaccination should be considered as a cost-saving alternative with a favorable risk-benefit ratio for high-income settings where universal implementation is unfeasible because of budget restrictions, low rotavirus endemicity, and/or public acceptance.

Health-care providers' perspectives on childhood cancer treatment in Manado, Indonesia.

BACKGROUND: Childhood cancer survival in low-income countries is low. OBJECTIVE: Our study investigated health-care providers' perspectives on childhood cancer treatment in Indonesia. Their health beliefs and attitudes toward parental financial difficulties, protocol adherence, parental education, and communication were explored. METHODS: A self-administered questionnaire was filled in by 222 health-care providers (156 doctors, 51 nurses, 6 social workers, 9 administrators) RESULTS: Health of children with cancer is beyond doctor's control and determined by luck, fate or God according to 35% of health-care providers, 30% were uncertain about this statement, and 35% disagreed. Combination of chemotherapy and alternative treatment is best to achieve cure according to 15% of health-care providers, 50% were uncertain, and 35% disagreed. Prosperous parents adhere better with treatment (67%). Doctors adhere better with cancer treatment for prosperous patients (55%). When dealing with poor families, less elaborate explanation is given (62%), more difficult vocabulary is used (49%), and less cooperation is offered (46%). Reasons for non-adherence with treatment protocol were as follows: financial difficulties parents (82%), side-effects (77%), lack of motivation parents (75%), and inadequate drugs supply at pharmacy (70%). Information about cancer and treatment makes parents more afraid or depressed about future, and parents prefer not to know according to 27% of health-care providers, 20% were uncertain, and 53% disagreed. Communication with parents is hindered by differences in status and social hierarchical structures (83%). CONCLUSIONS: Health-care providers' beliefs about childhood cancer treatment are characterized by much uncertainty and contradiction. This likely affects adherence of health-care providers, parents, and childhood cancer treatment outcome.

Variations in diagnostic and therapeutic procedures in a multicentre, randomized clinical trial (EORTC 10853) investigating breast-conserving treatment for DCIS.

AIMS: To evaluate the diagnostic and therapeutic procedures which were followed in a European Organization for Research and Treatment of Cancer (EORTC) randomized clinical trial investigating the role of radiotherapy in breast-conserving treatment (BCT) for ductal carcinoma in situ (DCIS) of the breast. METHODS: The medical files of 824 of the 1010 randomized patients (82%) were reviewed during site visits to 30 participating institutes. RESULTS: Large variations occurred, particularly in the surgical procedures and histopathological work-up which were performed. Important risk factors like tumour size and margin status were poorly quantified in the medical files. CONCLUSIONS: These findings emphasize the need for establishing uniform guidelines for diagnostic and therapeutic procedures for DCIS, and for clearly defined risk factors for recurrence after BCT for DCIS. Because of its randomized nature, the main question of the trial, i.e. the effect of radiotherapy on the risk of local recurrence, will not be influenced by variation. The risk of local recurrence in itself, and hence the success of BCT for DCIS, may however be influenced by the quality of the initial procedures that were conducted.

Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials.

PURPOSE: Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments. PATIENTS AND METHODS: The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%). RESULTS: There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P <.01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P <.01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P <.01). CONCLUSION: Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.

Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial.

BACKGROUND: Breast-conserving therapy (BCT) has been shown to be as effective as mastectomy in the treatment of tumors 2 cm or smaller. However, evidence of its efficacy, over the long term, in patients with tumors larger than 2 cm is limited. From May 1980 to May 1986, the European Organization for Research and Treatment of Cancer carried out a randomized, multicenter trial comparing BCT with modified radical mastectomy for patients with tumors up to 5 cm. In this analysis, we investigated whether the treatments resulted in different overall survival, time to distant metastasis, or time to locoregional recurrence. METHODS: Of 868 eligible breast cancer patients randomly assigned to the BCT arm or to the modified radical mastectomy arm, 80% had a tumor of 2.1-5 cm. BCT comprised lumpectomy with an attempted margin of 1 cm of healthy tissue and complete axillary clearance, followed by radiotherapy to the breast and a supplementary dose to the tumor bed. The median follow-up was 13.4 years. All P values are two-sided. RESULTS: At 10 years, there was no difference between the two groups in overall survival (66% for the mastectomy patients and 65% for the BCT patients; P =.11) or in their distant metastasis-free rates (66% for the mastectomy patients and 61% for the BCT patients; P =.24). The rate of locoregional recurrence (occurring before or at the same time as distant metastasis) at 10 years did show a statistically significant difference (12% of the mastectomy and 20% of the BCT patients; P =. 01). CONCLUSIONS: BCT and mastectomy demonstrate similar survival rates in a trial in which the great majority of the patients had stage II breast cancer.

Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast is a disorder that has become more common since it may manifest as microcalcifications that can be detected by screening mammography. Since selected women with invasive cancer can be treated safely with breast conservation therapy it is paradoxical that total mastectomy has remained the standard treatment for DCIS. We did a randomised phase III clinical trial to investigate the role of radiotherapy after complete local excision of DCIS. METHODS: Between 1986 and 1996, women with clinically or mammographically detected DCIS measuring less than or equal to 5 cm were treated by complete local excision of the lesion and then randomly assigned to either no further treatment (n=503) or to radiotherapy (n=507; 50 Gy in 5 weeks to the whole breast). The median duration of follow-up was 4.25 years (maximum 12.0 years). All analyses were by intention to treat. FINDINGS: 500 patients were followed up in the no further treatment group and 502 in the radiotherapy group. In the no further treatment group 83 women had local recurrence (44 recurrences of DCIS, and 40 invasive breast cancer). In the radiotherapy group 53 women had local recurrences (29 recurrences of DCIS, and 24 invasive breast cancer). The 4-year local relapse-free was 84% in the group treated with local excision alone compared with 91% in the women treated by local excision plus radiotherapy (log rank p=0.005; hazard ratio 0.62). Similar reductions in the risk of invasive (40%, p=0.04) and non-invasive (35%, p=0.06) local recurrence were seen. CONCLUSIONS: Radiotherapy after local excision for DCIS, as compared with local excision alone, reduced the overall number of both invasive and non-invasive recurrences in the ipsilateral breast at a median follow-up of 4.25 years.

Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. European Organization for Research and Treatment of Cancer.

PURPOSE: To evaluate both qualitative and quantitative scoring methods for the cosmetic result after breast-conserving therapy (BCT), and to compare the usefulness and reliability of these methods. METHODS AND MATERIALS: In EORTC trial 22881/10882, stage I and II breast cancer patients were treated with tumorectomy and axillary dissection. A total of 5318 patients were randomized between no boost and a boost of 16 Gy following whole-breast irradiation of 50 Gy. The cosmetic result was assessed for 731 patients in two ways. A panel scored the qualitative appearance of the breast using photographs taken after surgery and 3 years later. Digitizer measurements of the displacement of the nipple were also made using these photographs in order to calculate the breast retraction assessment (BRA). The cosmetic results after 3-year follow-up were used to analyze the correlation between the panel evaluation and digitizer measurements. RESULTS: For the panel evaluation the intraobserver agreement for the global cosmetic score as measured by the simple Kappa statistic was 0.42, considered moderate agreement. The multiple Kappa statistic for interobserver agreement for the global cosmetic score was 0.28, considered fair agreement. The specific cosmetic items scored by the panel were all significantly related to the global cosmetic score; breast size and shape influenced the global score most. For the digitizer measurements, the standard deviation from the average value of 30.0 mm was 2.3 mm (7.7%) for the intraobserver variability and 2.6 mm (8.7%) for the interobserver variability. The two methods were significantly, though moderately, correlated; some items scored by the panel were only correlated to the digitizer measurements if the tumor was not located in the inferior quadrant of the breast. CONCLUSIONS: The intra- and interobserver variability of the digitizer evaluation of cosmesis was smaller than that of the panel evaluation. However, there are some treatment sequelae, such as disturbing scars and skin changes, that can not be evaluated by BRA measurements. Therefore, the methods of cosmetic evaluation used in a study must be chosen in a way that balances reliability and comprehensiveness.

Long-term functional morbidity after mild hyperthermic isolated limb perfusion with melphalan.

AIMS: To assess long-term functional morbidity in patients entered in the prospective randomized EORTC trial investigating the role of adjuvant isolated limb perfusion (ILP) with melphalan for high-risk primary melanoma. METHODS: In 65 patients (ILP 36, wide excision only 29), limb circumference and joint mobility measurements were performed on the treated and the contralateral limb after a mean interval of 48 months after primary treatment. The two treatment groups were comparable regarding age, sex distribution, percentage of skin grafts or regional lymph-node dissections, and interval between primary treatment and physical measurements. RESULTS: None of the patients had severe complaints of the treated limb at the time of analysis. The ankle suffered most from ILP, with a statistical significant restricted extension in approximately 40% of the perfused patients. Abduction of the shoulder was minimally affected in treated upper limbs, probably as a result from the formation of scar tissue after axillary lymph-node dissection. Although no significant differences could be demonstrated in the circumference of upper or lower limbs, atrophy was seen in 24% of perfused lower limbs. Of the five perfused patients who developed oedema, four had also undergone a regional lymph-node dissection. CONCLUSION: This risk of long-term functional morbidity should be weighed against the possible advantages of ILP in patients with limb melanoma or sarcoma.

Low risk of locoregional recurrence of primary breast carcinoma after treatment with a modification of the Halsted radical mastectomy and selective use of radiotherapy.

BACKGROUND: The purpose of the current study was to evaluate the locoregional recurrence rate after treatment of patients with operable breast carcinoma with a modification of the Halsted radical mastectomy and the selective use of radiotherapy and to identify risk factors for locoregional recurrence. METHODS: Between 1979-1987, 691 consecutive patients underwent mastectomy after a negative biopsy of the axillary apical lymph nodes. The median age of the patients was 59 years (range, 26-89 years). The clinical tumor size was < 2 cm in 72 patients, 2-5 cm in 387 patients, and >5 cm in 169 patients; 16 patients had a T4 tumor. Surgery was comprised of a modification of the Halsted radical mastectomy, including at least part of the pectoralis major muscle and the entire pectoralis minor muscle, in 573 patients; 303 patients had positive axillary lymph nodes. Adjuvant radiotherapy to the chest wall and regional lymph nodes was given to 74 patients, whereas an additional 414 patients underwent irradiation to the internal mammary and medial supraclavicular lymph nodes. The median follow-up was 91 months. RESULTS: The actuarial overall survival rate was 82% at 5 years and 63% at 10 years. The 10-year chest wall and regional lymph node control rates, including patients with prior distant failures, were 95% and 94%, respectively. The only two significant prognostic factors for locoregional recurrence on multivariate analysis were lymph node status and pathologic tumor size. CONCLUSIONS: Excellent locoregional control can be achieved with a modified technique of radical mastectomy in patients with negative apical biopsy and the selective use of comprehensive radiotherapy. These results may serve as a reference outcome for comparison with other locoregional treatment strategies.

Prognosis after treatment for loco-regional recurrence after mastectomy or breast conserving therapy in two randomised trials (EORTC 10801 and DBCG-82TM). EORTC Breast Cancer Cooperative Group and the Danish Breast Cancer Cooperative Group.

The aim of this study was to investigate and compare the prognosis after treatment for loco-regional recurrences (LR) after (modified) radical mastectomy (MRM) or breast conserving therapy (BCT), in terms of overall survival and time to subsequent LR, in patients originally treated in two European randomised trials. In EORTC trial 10801 and DBCG trial 82-TM, 1,807 patients with stage I and II breast cancer were randomised to receive MRM or BCT from 1980 to 1989. All patients with a LR in these trials were analysed for survival and time to subsequent LR after salvage treatment. Of these, 133 patients had their LR as a first event, the majority within 5 years after initial treatment. The prognostic significance for survival and time to subsequent LR after salvage treatment was analysed in uni-, and multivariate analyses for a number of original tumour- and recurrence-related variables. After salvage treatment of LR after MRM or BCT, actuarial survival curves and the actuarial locoregional control curves were similar. The 5-year survival rates were 58% and 59% and the 5-year subsequent loco-regional control rates 62% and 63%, respectively. In a multivariate analysis, pN category (P = 0.03), pT category (P = 0.01) and vascular invasion (P = 0.02) of the primary tumour were the only independent prognostic factors for survival, whereas extensive LR (P < 0.001), interval < or = 2 years (P < 0.002) and pN+ at primary treatment (P = 0.004) were significant predictive factors for time to subsequent LR. The type of original treatment (MRM or BCT) did not have any prognostic impact. It is concluded that the survival and time to subsequent LR after treatment for an early loco-regional recurrence after MRM or BCT was similar in these two European randomised trials. This suggests that both after MRM and BCT an early LR is an indicator of a biologically aggressive tumour; early loco-regional relapse carries a poor prognosis and salvage treatment only cures a limited number of patients, whether treated by MRM or BCT originally.

Cancer screening in the elderly.

Population-based cancer screening is effective only for a few tumour types. For these categories the screening programs have upper age limits. Arguments are provided for why population-based cancer screening is contraproductive in the elderly, even for cancers with a high incidence in old age.

Identification and biopsy of the sentinel lymph node in breast cancer.

AIMS: To examine the hypothesis that lymphatic dissemination in breast cancer occurs sequentially. METHODS: Thirty patients with clinically localized adenocarcinoma were studied. Patent blue dye was administered into the tumour at the beginning of a modified radical mastectomy or segmental mastectomy with en bloc axillary lymph-node dissection (ALND). In the removed specimen, blue-stained lymphatic channels were dissected from the primary tumour to the first draining lymph node(s) (sentinel node(s)). RESULTS: Identification of a sentinel node (SN) was successful in 26 patients (87%). In 10 patients the SN was tumour-positive. In six of these patients, the SN was the only tumour-positive node. There was no incidence of 'skip' metastasis. CONCLUSIONS: This study confirms the sequential nature of lymphatic dissemination. When confirmed in vivo, these data may lead to a substantial reduction of the need for ALND without compromising survival and regional control and without loss of prognostic and staging information.

Breast-conserving therapy vs mastectomy in early-stage breast cancer: a meta-analysis of 10-year survival.

BACKGROUND: The randomized trials comparing breast-conserving therapy (BCT), i.e., surgery and radiation to the breast, with mastectomy in early-stage breast cancer use a variety of protocols. Meta-analysis may assist in understanding the impact of these differences on survival. PURPOSE: To evaluate the possible variations of the relative efficacy of BCT and mastectomy in terms of overall survival according to tumor size, nodal status, and use of adjuvant radiation therapy. METHODS: The most recent published results and, where available, updated patient-level data from randomized controlled trials of BCT and mastectomy for early-stage breast cancer were combined in a meta-analysis using a random effects model. Pooled survival rates and odds ratios were generated according to subgroups of nodal status and tumor size. Five- and 10-year odds ratios were also determined according to adjuvant radiation protocol. RESULTS: The pooled odds ratio comparing 10-year survival for BCT and mastectomy was 0.91. The odds ratios comparing the two treatment regimens were not significant after grouping according to tumor size and nodal status. When more than 50% of node-positive patients in both the mastectomy and BCT arms received adjuvant radiation, both arms had similar survival rates. When less than 50% of node-positive patients in both arms received adjuvant nodal radiation, the odds ratio was 0.69, and patients receiving BCT had a survival advantage. CONCLUSIONS: Patients allocated to BCT have survival rates at least as high as patients allocated to mastectomy. When all protocols were combined, nodal status and tumor size did not significantly alter the relative survival rates. However, under some conditions, particularly for node-positive patients, BCT may confer a relative survival advantage over mastectomy. In particular, mastectomy without adjuvant radiation appears to be inferior to BCT for node-positive patients.

Value of laboratory tests in monitoring acute regional toxicity after isolated limb perfusion.

BACKGROUND: Severe limb toxicity following isolated limb perfusion (ILP) can lead to compartmental compression syndrome and severe rhabdomyolysis, occasionally necessitating amputation of the affected limb. We determined whether laboratory tests for muscle damage and inflammation could predict impending limb toxicity. METHODS: All 184 consecutive ILPs performed in our institute from 1988 to 1994 were included in this study. Creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT) and white blood cell (WBC) counts were determined on post-ILP days 1-4, 6, 8, and 15. RESULTS: "Late peak" CK patterns, characterised by a peak on or after the 5th post-perfusion day, were strongly associated with severe limb toxicity (p < 0.001). Severe toxicity did develop in 40% of the limbs when CK values exceeded 1000 IU/L on the 2nd to 5th post-ILP day (p < 0.001). There was a correlation between the peak CK and the individual grades of toxicity (r = 0.6, p < 0.001). Serum LDH and ASAT values peaked 2.9 and 3.4 days after the CK peak respectively. Severe limb toxicity was statistically significantly associated with higher WBC counts from the 2nd post-ILP day onwards. CONCLUSIONS: CK values exceeding 1000 IU/L after the 1st and WBC counts increasing after the 2nd post-ILP day could be predictors of impending limb toxicity. These patients should be observed closely for signs of compartmental compression syndrome and severe rhabdomyolysis.

[The relationship between health gain and effort in mass screening for breast cancer]. / De verhouding tussen gezondheidswinst en inspanningen bij bevolkingsonderzoek naar borstkanker.

Mass screening for breast cancer reduces the mortality of this disease. In the Netherlands, with a very high incidence of breast cancer, a well organized health care system and a stable economic prosperity, the decision taken to implement nationwide breast cancer screening for the female population aged 50-70 years appears well-founded. The first data indeed suggest a reduction of breast cancer in the coming years. The effects of screening as such will be difficult to evaluate since the programme leads also to optimalization of breast cancer treatment in general. Other factors, such as adjuvant therapy, may have a beneficial effect on breast cancer mortality, reducing the yield of the screening proper. This and the non-negligible negative aspects should not be hidden from the public. Continuous evaluation and quality control, not only in mammography techniques and reading, but also in the treatment of the detected cases, are essential for a successful screening programme.

The benefits of participation in clinical trials.

This editorial marks a change of editors for the trials section. It is intended to encourage surgeons to participate in clinical trials work. The recruitment of patients into clinical trials with strict protocols and quality control may be expected to lead to better outcomes. Well-conducted trials may also add to our understanding of tumour biology and the role of prognostic markers, and may lead to the standardization of definitions and medical terminology. This will help us to overcome uncertainties in current treatment protocols.

[Identification of the sentinel node in patients with breast carcinoma]. / Identificatie van de schildwachtklier bij patiënten met mammacarcinoom.

OBJECTIVE: To investigate the hypothesis that lymphatic metastasis of breast cancer progresses in a sequential fashion, and whether the first lymph node on a direct drainage pathway (first-echelon node, sentinel node) can be identified in a mastectomy specimen. DESIGN: Descriptive analysis. SETTING: The Netherlands Cancer Institute (Antoni van Leeuwenhoek Hospital), Amsterdam, the Netherlands. METHODS: In 22 patients with clinically localized breast cancer and five with breast cancer and axillary lymphadenopathy, patent blue dye was administered preoperatively into the primary tumor. After mastectomy and axillary lymph node dissection, blue stained lymphatic channels were dissected down to the first draining lymph nodes. These sentinel nodes were removed from the specimen and examined separately for presence of metastatic disease. RESULTS: In 2/5 patients with palpable axillary metastases and in one patient with a tumour in the medial upper quadrant, no sentinel node was found. A total of 35 first-echelon nodes was identified in the 22 patients without palpable lymphadenopathy, on average 1.6 nodes per patient (range: 1-4). In 10 of these patients, metastatic tumour was found in the sentinel nodes. In 6 of these 10 patients, no metastatic disease was detected in the remaining axillary nodes. Metastasis was never found in the other axillary nodes if the sentinel node was disease-free. CONCLUSIONS: Dissemination of breast cancer to the axillary nodes appears to occur in a sequential fashion. Patent blue dye drains from the tumour in the breast to the axillary lymph nodes in mammary cancer patients. These blue nodes can be identified in the surgical specimen.