Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial.

BACKGROUND: In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial. METHODS: This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133. FINDINGS: Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p<0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events. INTERPRETATION: The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR. FUNDING: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health.

Glass and Alchemy in Early Modern Europe: An Analytical Study of Glassware from the Oberstockstall Laboratory in Austria.

Glass distillation equipment from an early modern alchemical laboratory was analyzed for its technology of manufacture and potential origin. Chemical data show that the assemblage can be divided into sodium-rich, colorless distillation vessels made with glass from Venice or its European imitation, and potassium-rich dark-brown non-specialized forms produced within the technological tradition of forest glass typical for central and north-western Europe. These results complete our understanding of the supply of technical apparatus at one of the best-preserved alchemical laboratories and highlight an early awareness of the need for high-quality instruments to guarantee the successful outcome of specialized chemical operations. This study demonstrates the potential of archaeological science to inform historical research around the practice of early chemistry and the development of modern science.

Current Trends in the Oncologic and Surgical Managements of Breast Cancer in Women with Implants: Incidence, Diagnosis, and Treatment.

UNLABELLED: Breast augmentation is the most common cosmetic surgery in the United States, and thousands of augmented patients develop breast cancer each year. The possible effects of implants on cancer incidence, diagnosis, and treatment usually generate a disarming confusion. The present paper represents an update of the more recent oncologic and surgical strategies, aiming to support plastic and general surgeons in such challenging aspects. Several aspects of breast cancer management in augmented women are investigated, including (1) risk estimation and cancer characteristics, stage at diagnosis, and prognosis; (2) cancer diagnosis with clinical examination, mammography, ultrasound, and magnetic resonance imaging; (3) cancer treatment including breast conservation, intraoperative radiotherapy, sentinel node biopsy and mastectomy, and reconstruction. A brief resume of recommendations and conclusions is suggested, elucidating correct trends in the oncologic management of augmented patients and refusing well-established misconceptions: (1) breast augmentation does not increase the risk of breast cancer incidence, and it does not influence the prognosis; (2) possible risks exist in cancer detection due to technical difficulties; (3) sentinel lymph node detection is feasible; (4) intraoperative radiotherapy represents a good chance for conserving treatment; (5) immediate reconstruction with submuscular-subfascial implants is the most common procedure after mastectomy, and biological substitutes could support this procedure. Breast clinicians should be alerted because of high expectations of this subgroup of patients, accustomed to emphasize the aesthetic result. LEVEL OF EVIDENCE V: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Global cancer surgery: delivering safe, affordable, and timely cancer surgery.

Surgery is essential for global cancer care in all resource settings. Of the 15.2 million new cases of cancer in 2015, over 80% of cases will need surgery, some several times. By 2030, we estimate that annually 45 million surgical procedures will be needed worldwide. Yet, less than 25% of patients with cancer worldwide actually get safe, affordable, or timely surgery. This Commission on global cancer surgery, building on Global Surgery 2030, has examined the state of global cancer surgery through an analysis of the burden of surgical disease and breadth of cancer surgery, economics and financing, factors for strengthening surgical systems for cancer with multiple-country studies, the research agenda, and the political factors that frame policy making in this area. We found wide equity and economic gaps in global cancer surgery. Many patients throughout the world do not have access to cancer surgery, and the failure to train more cancer surgeons and strengthen systems could result in as much as US $6.2 trillion in lost cumulative gross domestic product by 2030. Many of the key adjunct treatment modalities for cancer surgery--e.g., pathology and imaging--are also inadequate. Our analysis identified substantial issues, but also highlights solutions and innovations. Issues of access, a paucity of investment in public surgical systems, low investment in research, and training and education gaps are remarkably widespread. Solutions include better regulated public systems, international partnerships, super-centralisation of surgical services, novel surgical clinical trials, and new approaches to improve quality and scale up cancer surgical systems through education and training. Our key messages are directed at many global stakeholders, but the central message is that to deliver safe, affordable, and timely cancer surgery to all, surgery must be at the heart of global and national cancer control planning.

Milestones in breast cancer treatment.

Modern treatment started in the 1880s with Halsted's mastectomy. The next milestone-a century later-was breast-conserving surgery, with equivalent survival but better esthetic outcomes than mastectomy. Sentinel node biopsy, introduced in the 1990s, was a milestone that permitted avoidance of axillary dissection if the sentinel node was disease-free. Chemotherapy was established for early breast cancer in the 1980s and its efficacy continues to improve; however side effects remain a concern, particularly since chemotherapy does not benefit most patients. External whole breast irradiation was introduced with conservative surgery, as it reduces recurrences. By the 2000s, 3-week regimens had been shown equivalent to standard 6-week regimens-easing pressure on patients and radiation centers. Intraoperative partial breast irradiation is potentially more beneficial as it permits complete local treatment in a single session; however, trials show that patients must be very carefully selected. From the 1990s irradiation technology was combined with imaging and computer technologies to produce equipment that directs radiation to more precisely defined target volumes, allowing increased dose to the target and markedly reduced dose to nearby tissues. Irradiation systems are evolving rapidly but are being implemented without data on long-term morbidity or efficacy, while costs rise steeply. The first targeted treatment was tamoxifen, a selective estrogen receptor inhibitor. Since its widespread use starting in the 1980s, tamoxifen has saved the lives or prolonged the survival of millions with estrogen-positive disease; it is cheap and has limited (but not negligible) side effects. The same cannot be said of newer targeted treatments like trastuzumab and pertuzumab, which, although effective against human epidermal growth factor receptor 2-positive cancer, come with important side effects and huge costs. Breast cancer mortality is declining in rich countries, but treatments have become more demanding and more expensive, so the outlook for the increasing numbers of women worldwide who develop the disease is uncertain.

Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data.

BACKGROUND: Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence. METHODS: We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. RESULTS: We analysed data for 83,399 women with 306,617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56-0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0·58, 0·51-0·66; p<0·0001 vs 25%, 0·75, 0·61-0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47-2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59-0·73), but only a small effect for non-vertebral fractures (0·93, 0·87-0·99). INTERPRETATION: For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. FUNDING: Cancer Research UK.

Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial.

BACKGROUND: Intraoperative radiotherapy with electrons allows the substitution of conventional postoperative whole breast irradiation with one session of radiotherapy with the same equivalent dose during surgery. However, its ability to control for recurrence of local disease required confirmation in a randomised controlled trial. METHODS: This study was done at the European Institute of Oncology (Milan, Italy). Women aged 48-75 years with early breast cancer, a maximum tumour diameter of up to 2·5 cm, and suitable for breast-conserving surgery were randomly assigned in a 1:1 ratio (using a random permuted block design, stratified for clinical tumour size [<1·0 cm vs 1·0-1·4 cm vs ≥1·5 cm]) to receive either whole-breast external radiotherapy or intraoperative radiotherapy with electrons. Study coordinators, clinicians, and patients were aware of the assignment. Patients in the intraoperative radiotherapy group received one dose of 21 Gy to the tumour bed during surgery. Those in the external radiotherapy group received 50 Gy in 25 fractions of 2 Gy, followed by a boost of 10 Gy in five fractions. This was an equivalence trial; the prespecified equivalence margin was local recurrence of 7·5% in the intraoperative radiotherapy group. The primary endpoint was occurrence of ipsilateral breast tumour recurrences (IBTR); overall survival was a secondary outcome. The main analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01849133. FINDINGS: 1305 patients were randomised (654 to external radiotherapy and 651 to intraoperative radiotherapy) between Nov 20, 2000, and Dec 27, 2007. After a medium follow-up of 5·8 years (IQR 4·1-7·7), 35 patients in the intraoperative radiotherapy group and four patients in the external radiotherapy group had had an IBTR (p<0·0001). The 5-year event rate for IBRT was 4·4% (95% CI 2·7-6·1) in the intraoperative radiotherapy group and 0·4% (0·0-1·0) in the external radiotherapy group (hazard ratio 9·3 [95% CI 3·3-26·3]). During the same period, 34 women allocated to intraoperative radiotherapy and 31 to external radiotherapy died (p=0·59). 5-year overall survival was 96·8% (95% CI 95·3-98·3) in the intraoperative radiotherapy group and 96·9% (95·5-98·3) in the external radiotherapy group. In patients with data available (n=464 for intraoperative radiotherapy; n=412 for external radiotherapy) we noted significantly fewer skin side-effects in women in the intraoperative radiotherapy group than in those in the external radiotherapy group (p=0·0002). INTERPRETATION: Although the rate of IBTR in the intraoperative radiotherapy group was within the prespecified equivalence margin, the rate was significantly greater than with external radiotherapy, and overall survival did not differ between groups. Improved selection of patients could reduce the rate of IBTR with intraoperative radiotherapy with electrons. FUNDING: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, and Umberto Veronesi Foundation.

Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial.

BACKGROUND: For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, axillary dissection might be overtreatment. We designed IBCSG trial 23-01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm. METHODS: In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov, NCT00072293. FINDINGS: Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6-7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five [corrected] regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4-91·2) in the group without axillary dissection and 84·4% (80·7-88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55-1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3-4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection. INTERPRETATION: Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival. FUNDING: None.

Conservative mastectomy: extending the idea of breast conservation.

Conservative mastectomy is a surgical technique to remove breast glandular tissue without disruption to the appearance of the breast. The main contraindication to this operation is involvement of the nipple-areola complex. Preservation of a healthy nipple does not affect long-term survival rates. Intraoperative retroareolar biopsy and accurate removal of all mammary tissue are mainstays to guarantee oncological safety of the technique. A complication, however infrequent, is nipple necrosis, which can be treated successfully by local excision. Several breast reconstructive techniques are used during conservative mastectomy and aesthetic results are good in most cases.

The Archaeology of Alchemy and Chemistry: Past, Present, and Ideas for the Future.

The materials and practices of chymical procedures have become key sources of information among science historians, opening up channels for cross-disciplinary dialogue. This is especially true with regard to material culture-based disciplines such as archaeology whose bottom-up approach offers significant contributions to the new historiography of science. Parallel to this trend, some archaeological scientists who specialise in reconstructing past technologies have begun to address questions concerning the production and circulation of scientific knowledge, and have focused as well on the contributions of artists/artisans to the development of natural philosophical theories. This essay charts the history of this archaeology of alchemy and chemistry and its development as a sub-discipline of archaeological science. By mapping this history, from an initial period with a focus on metallurgy to current trends, it demonstrates how the archaeology of alchemy and chemistry both mirrors and, at the same time, feeds the broadening scope of the historiography of science. After surveying the most relevant works and highlighting the key contributions that archaeologists have brought to a discourse related to the creation of scientific knowledge, the essay also offers a series of ideas related to materials awaiting comprehensive study that will further strengthen methodological synergies across disciplines.

Can we avoid axillary dissection in the micrometastatic sentinel node in breast cancer?

There is considerable interest in foregoing axillary dissection (AD) when the sentinel node (SN) is positive in early breast cancer, particularly when involvement is minimal (micrometastases or isolated tumor cells). To address this issue we analyzed outcomes in patients with a single micrometastatic SN who did not receive AD. We selected 377 consecutive patients treated at the European Institute of Oncology between 1999 and 2007 for invasive breast cancer. Classical and competing risks survival analyses were performed to estimate prognostic factors for axillary recurrence, first events and overall survival. Median age was 53 years (range 26-80); median follow-up was 5 years (range 1-9). Most (91.8%) patients received conservative surgery; 209 (55.4%) had only one SN (range 1-8). Five-year overall survival was 97.3%. There were 10 local events, 2 simultaneous local and axillary events, 6 axillary recurrences and 12 distant events. The cumulative incidence of axillary recurrence was 1.6% (95% CI 0.7-3.3). By multivariable analysis, tumor size and grade were significantly associated with axillary recurrence. The high five-year survival and low cumulative incidence of axillary recurrence in this cohort provide justification for the increasingly common practice of foregoing AD in women with minimal SN involvement, and suggest in particular that AD can safely be avoided in women with small, low-grade tumors. Nevertheless, a subset of patients might be at high risk of developing overt axillary disease and efforts should be made to identify such patients by ancillary analyses of the results of ongoing or recently published clinical trials.

Repeating conservative surgery after ipsilateral breast tumor reappearance: criteria for selecting the best candidates.

BACKGROUND: Mastectomy is still considered the treatment of first choice in patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) and whole-breast radiotherapy. METHODS: We retrospectively evaluated 161 patients with invasive IBTR who underwent a second BCS in order to describe prognosis, determine predictive factors of outcome, and select the subset of patients with the best local control. Median follow-up after IBTR was 81 months. RESULTS: Median age at IBTR was 53 years. Five-year overall survival after IBTR was 84 % (95 % confidence interval [CI] 78-89). Five-year cumulative incidence of a second local event after IBTR was 29 % (95 % CI 22-37). At the multivariate analysis, IBTR size >2 cm and time to relapse ≤48 months significantly increased the risk of local reappearance (hazard ratio [HR] 3.3, 95 % CI 1.6-7.0; and HR 1.9, 95 % CI 1.1-3.5). The 5-year cumulative incidence of a further local reappearance of the tumor after repeating BCS was 15.2 % in the patients with IBTR ≤2 cm and time to IBTR >48 months, 31.2 % in the patients with IBTR ≤2 cm and time to IBTR ≤48 months, and 71.2 % in patients with IBTR >2 cm (P < 0.001). CONCLUSIONS: The best candidates for a second BCS are those with small (≤2 cm) and late (>48 months) IBTR. The information about the risk of a further local reappearance after repeating BCS should be shared with the patients in the decision making process.

The Old Ashmolean Museum and Oxford's Seventeenth-Century Chymical Community: A Material Culture Approach To Laboratory Experiments.

Towards the end of the seventeenth century, Oxford's chymical community came together in the Ashmolean Museum. Founded in 1683, the institution was part of Oxford University and home to the first official chair of chymistry in the country, with practical teaching directed by Robert Plot in the basement laboratory. The information at our disposal is scarce and Plot did not leave us detailed accounts of his laboratory work. However, a large assemblage of ceramic crucibles and distillation apparatus was recovered from the site where the laboratory once operated, an invaluable material perspective on the experimental agenda of one of the most important chymical laboratories in early modern Europe. The scientific analysis of the materials indicates that the work focused on technological innovation in the fields of glassmaking, specialised pottery, and zinc metallurgy, and shows how the laboratory kept close contact with some renowned artisan-entrepreneurs of the time. We argue that material culture offers an informative perspective on chymical practice in and beyond Oxford. The results provide fresh insight into the Old Ashmolean Museum, an institution that grew out of the Baconian spirit, where doing chymistry meant working at the intersection of artisanal and scholarly worlds.

Influence of margin status on outcomes in lobular carcinoma: experience of the European Institute of Oncology.

OBJECTIVE: We analyzed 382 patients with pure lobular carcinoma treated up to 2002 with sufficient follow-up to draw prognostic conclusions, all treated by conservative surgery. Our aim was to evaluate the influence of margin status on outcomes with a view assessing the appropriateness of conservative surgery in this breast cancer subtype. METHODS: We assessed locoregional relapse, distant metastasis, contralateral breast cancer, breast cancer-related event free survival, disease-free survival and overall survival according to margin status categorized as at least 10 mm versus less than 10 mm (usually considered negative). RESULTS: The proportions of patients with less than 10 mm margins varied significantly with age (P = 0.02), menopausal status (P = 0.006), and tumor size (P = 0.02) but no other characteristic was significantly related to margin status. As regards unfavorable events during follow-up, none differed significantly between at least 10 mm and less than 10 mm margin groups. In particular, there were 11 (3.7%) local relapses in the same quadrant in at least 10 mm margin group compared to 4 (4.6%) in the less than 10 mm margin group, and 7 (2.4%) ipsilateral breast cancers in the 10 mm or more margin group but none in the less than 10 mm group. These findings indicate that minimal residual disease as evidenced by margins less than 10 mm is eradicated by radiotherapy (backed up in selected cases by reexcision, which in this series was always conservative). The rate of contralateral breast cancer was low at 2.9% indicating that prophylactic contralateral mastectomy is not justified. CONCLUSIONS: We conclude that the surgical approach and criteria for adjuvant hormonal and systemic treatment in lobular carcinoma should be the same as for ductal carcinoma, provided that adequate preoperative investigations exclude extensive multifocal and contralateral disease.

The management of ductal intraepithelial neoplasia (DIN): open controversies and guidelines of the Istituto Europeo di Oncologia (IEO), Milan, Italy.

The management of ductal intraepithelial neoplasia (DIN) has substantially changed over the past 30 years, as its incidence has increased (from 2-3% to more than 20%), mainly due to the widespread use of mammography screening. This article describes not only the more widespread theoretical concepts on DIN but also the differences in the practical applications of the theory between different countries, different oncology specialists, and different cancer centers. Papers related to the international multicentre-randomized trials and retrospective studies were analyzed. We include articles and papers published between 1993 and 2010 related to patients with DIN, and abstracts and reports from MEDLINE and other sources were indentified. The standard of care for DIN consists of (a) breast conservative surgery (mastectomy is still indicated in large lesions--masses or microcalcifications--in about 30% of cases); (b) radiotherapy (RT) after conservative surgery, and (c) medical treatment in estrogen receptors-positive patients. However, most studies have shown significant differences between theory and practical application. Moreover, there are differences regarding (a) the indications of sentinel lymph node biopsy, (b) the definition and identification of low-risk DIN subgroups that can avoid RT and tamoxifen, and (c) the research into new alternative drugs in adjuvant medical therapy. A general agreement on the best management of DIN does not exist as yet. New large trials are needed in order to define the best management of DIN patients which is (in most respects) still complex and controversial.

Sentinel lymph node biopsy in multicentric breast cancer: five-year results in a large series from a single institution.

PURPOSE: This study was designed to present the 5-year results of patients with multicentric breast cancer who underwent sentinel lymph node biopsy (SLNB) in a single institution. METHODS: Between June 1999 and December 2007, 337 patients with multicentric breast cancer and a clinically negative axilla underwent lymphatic mapping by a single periareolar/peritumoral (n = 306) or a double peritumoral or subdermal injection (n = 31) of (99m)Tc-HSA nanocolloids. The sentinel lymph node (SLN) was evaluated by intraoperative frozen section and axillary dissection was performed only in cases of positive SLNB. RESULTS: The median age of the patients was 48 (range, 22-81) years. The mean number of hot spots identified was 1.4 in the whole series, 1.3 in patients who received a single injection, and 1.7 in those who received a double injection (P < 0.001). The mean number of removed SLNs was 1.7 (median, 1; range, 1-7) with an identification rate of 100%. A total of 138 patients with negative SLNB (n = 134) or isolated tumor cells in the SLN (n = 4) did not receive completion axillary lymph node dissection (CALND). In these latter patients, a total of 27 events (19.5%) occurred with 3 patients (2.2%) developing axillary recurrences after a median follow-up of 5 years (range, 17-134 months). CONCLUSIONS: Axillary lymph node reappearance was infrequent among patients with multicentric breast cancer, having negative SLNB and no CALND. We recommend SLNB as the standard procedure for nodal staging in patients with multicentric breast cancer and a clinically negative axilla.

Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study.

OBJECTIVE: Sentinel node biopsy (SNB) is widely used to stage the axilla in breast cancer. We present 10-year follow-up of our single-institute trial designed to compare outcomes in patients who received no axillary dissection if the sentinel node was negative, with patients who received complete axillary dissection. METHODS: From March 1998 to December 1999, 516 patients with primary breast cancer up to 2 cm in pathologic diameter were randomized either to SNB plus complete axillary dissection (AD arm) or to SNB with axillary dissection only if the sentinel node contained metastases (SN arm). RESULTS: The 2 arms were well-balanced for number of sentinel nodes found, proportion of positive sentinel nodes, and all other tumor and patient characteristics. About 8 patients in the AD arm had false-negative SNs on histologic analysis: a similar number (8, 95% CI: 3-15) of patients with axillary involvement was expected in SN arm patients who did not receive axillary dissection; but only 2 cases of overt axillary metastasis occurred. There were 23 breast cancer-related events in the SN arm and 26 in the AD arm (log-rank, P = 0.52), while overall survival was greater in the SN arm (log-rank, P = 0.15). CONCLUSIONS: Preservation of healthy lymph nodes may have beneficial consequences. Axillary dissection should not be performed in breast cancer patients without first examining the sentinel node.

Nonpalpable breast carcinomas: long-term evaluation of 1,258 cases.

INTRODUCTION: In recent decades, a steady improvement in imaging diagnostics has been observed together with a rising adherence to regular clinical breast examinations. As a result, the detection of small clinically occult (nonpalpable) lesions has progressively increased. At present in our institution some 20% of the cases are treated when nonpalpable. The aim of the present study is to analyze the characteristics and prognosis of such tumors treated in a single institution. METHODS: The analysis focused on 1,258 women who presented at the European Institute of Oncology with a primary clinically occult carcinoma between 2000 and 2006. All patients underwent radioguided occult lesion localization (ROLL), axillary dissection when appropriate, whole breast radiotherapy, or partial breast intraoperative irradiation and received tailored adjuvant systemic treatment. RESULTS: Median age was 56 years. Imaging showed a breast nodule in half of the cases and a breast nodule accompanied by microcalcifications in 9%. Microcalcifications alone were present in 17.1% of the cases, whereas suspicious opacity, distortion, or thickening represented the remaining 24.6%. Most tumors were characterized by low proliferative rates (68.9%), positive estrogen receptors (92.3%), and non-overexpressed Her2/neu (91.3%). After a median follow-up of 60 months, we observed 19 local events (1.5%), 12 regional events (1%), and 20 distant metastases (1.6%). Five-year overall survival was 98.6%. CONCLUSIONS: Clinically occult (nonpalpable) carcinomas show very favorable prognostic features and high survival rates, showing the important role of modern imaging techniques.