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N Cascinelli

Publications and source records attributed to N Cascinelli.

At least 19 recordsLinked to original sources

Optical imaging and automated melanoma detection: questions and answers.

Early detection and prompt excision of cutaneous melanoma is of paramount importance to improve patient survival, and the clinician should be aware of the clinical features that suggest the presence of a malignant lesion. The clinical diagnosis is mainly based on observation of the colour and shape of a given skin lesion. Unfortunately, evaluation of a pigmented lesion is to a large extent subjective and is closely related to the experience of the clinician. To overcome this problem, optical imaging techniques using different instrumentation (i.e. colour video camera, epiluminescence microscopy, reflectance spectrophotometry) and computer image analysis have been proposed in an attempt to provide quantitative measurements in an objective and reproducible fashion. The different procedures employed to perform the diagnosis automatically all have a common denominator: mimicking the eye and the brain of the clinician by image processing and computerized analysis programs, respectively. Sensitivity and specificity data reported in the literature suggest that the computer-based diagnosis of melanoma does not greatly differ from the diagnostic capability of an expert clinician, and is independent of the optical acquisition method employed to analyse the lesions. Most of the computer-processed morphometric variables useful in automated diagnosis are not recognizable nor can be objectively evaluated by the human eye, except that of lesion dimension. However, several questions should be answered before assessing the actual usefulness, including the potential and limitations, of computer-based diagnostic procedures. The purpose of this study was to briefly review the different kinds of instrumentation being used to diagnose melanoma, and to raise questions and whenever possible provide answers in an attempt to establish whether there will be a future for these computerized systems.

Automation↗

Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial.

BACKGROUND: Less than half of patients with melanoma that has spread to local draining regional lymph nodes (stage III melanoma) live with no disease for 5 years or longer after surgery. We aimed to see whether interferon alpha-2a increased survival prospects in these patients. METHODS: 444 patients from 23 centres in the WHO Melanoma Programme had complete lymphadenectomy for pathologically proven regional nodal spread of melanoma and were randomly assigned to receive either 3 MU subcutaneously of recombinant interferon alpha-2a three times a week for 3 years, or to observation alone after surgery. Patients were stratified by centre, nodes with macroscopic or microscopic melanoma, number of affected nodes, and nodal metastatic spread. Treatment was continued for 3 years or until first sign of relapse. FINDINGS: 424 patients entered the study. 5-year disease-free survival of those who had surgery plus interferon alpha-2a was 27.5% (95% CI 21.7-33.6); for those who received surgery alone, survival was 28.4% (22.5-34.6) (p=0.50). Neither Kaplan-Meier cumulative survival rates, nor multivariate analysis of survival, showed a difference between those who had surgery and interferon alpha-2a (35%, 95% CI 29-42) and those who had surgery alone (37%, 31-44). INTERPRETATION: Patients with melanoma that has spread to the local draining regional lymph nodes tolerate well 3 MU of interferon alpha-2a given subcutaneously three times a week for 3 years, but this treatment does not improve either disease-free or overall survival.

Adolescent↗

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Adolescent↗

Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

Humans↗

Axillary lymph node staging in breast cancer by 2-fluoro-2-deoxy-D-glucose-positron emission tomography: clinical evaluation and alternative management.

BACKGROUND: Surgical removal of axillary lymph node and histologic examination for metastases are used to determine whether adjuvant treatment is necessary for patients with breast cancer. Axillary lymph node dissection (ALND) is a costly procedure associated with various side effects, and 80% or more of patients with tumors of 20 mm or less are lymph node negative and might avoid ALND. In this study, we evaluated whether an alternative, noninvasive method--i.e., positron emission tomography (PET) with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-- could be used to determine axillary lymph node status in patients with breast cancer. METHODS: One hundred sixty-seven consecutive patients with breast cancers of 50 mm or less (range = 5-50 mm; mean = 21 mm) scheduled for complete ALND were studied preoperatively with FDG-PET, and then PET and pathology results from ALND were compared. All statistical tests were two-sided. RESULTS: The overall sensitivity, specificity, and accuracy of lymph node staging with PET were 94.4% (PET detected 68 of 72 patients with axillary involvement; 95% confidence interval [CI] = 86.0% to 98.2%), 86.3% (82 of 95 patients without axillary involvement; 95% CI = 77.8% to 91.9%), and 89.8% (150 of 167 patients with breast cancer; 95% CI = 84.2% to 93.6%), respectively. Positive- and negative-predictive values were 84.0% (68 patients with histologically positive lymph nodes of 81 patients with positive FDG-PET scan; 95% CI = 74.2% to 90.5%) and 95.3% (82 patients with histologically negative lymph nodes of 86 patients with negative FDG-PET scan; 95% CI = 88.2% to 98.5%), respectively. When PET results for axillary metastasis were analyzed by tumor size, the diagnostic accuracy was similar for all groups (86.0%-94.2%), with higher sensitivity for tumors of 21-50 mm (98.0%) and higher specificity for tumors of 10 mm or less (87.8%), and the range was 93.5%-97.3% for negative-predictive values and 54.5%-94.1% for positive-predictive values. Among the 72 patients with axillary involvement, PET detected three or fewer metastatic lymph nodes in 27 (37.5%) patients, about 80% of whom had no clinically palpable axillary lymph nodes. CONCLUSIONS: Noninvasive FDG-PET appears to be an accurate technique to predict axillary status in patients with breast cancer and thus to identify patients who might avoid ALND. These results should be confirmed in large multicenter studies.

Adult↗

Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables.

PURPOSE: There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. PATIENTS AND METHODS: Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach. The end points considered were relapse-free survival (RFS) and cause-specific survival (CSS). RESULTS: Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status. In particular regarding HER2 status, Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors, respectively. CONCLUSION: CMF treatment showed a clinical benefit in the considered subgroups, defined according to HER2 and other tumor variables status. Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment.

Aged↗

Do patients with tumor-positive sentinel nodes constitute a homogeneous group?

From January 1993 to May 2000, 1062 patients with primary cutaneous melanoma and no evidence of clinically detectable regional node metastases underwent sentinel node (SN) dissection to microscopically define the tumor status of the regional lymph nodes. A total of 1165 biopsies were performed. The SN identification rate was 89.6%. In 62.2% of the cases, only one SN was detected; 26.4% of patients had two SNs; and 11.4% had three or more SNs. Analysis of survival indicated that the tumor status of the nodes was the most important prognostic factor. Breslow's thickness had a significant impact on survival in tumors 4 mm or thicker, and ulceration dropped to a borderline-significant P value. To assess the tumor burden in positive SNs, all slides for patients at the Istituto Nazionale Tumori and S. Pio X Hospital were reviewed. Of 658 patients in this series, 90 had positive SNs. Eighteen of these patients had evidence of metastasis in other nodes. Of the remaining 72 with a single tumor-involved SN, 62% had a single metastatic deposit. Preliminary data from this study indicate that several subgroups may be identified among patients with positive nodes, but adequate analysis of survival requires a larger number of patients and a multicenter study.

Female↗

Impact of clinical trials on the treatment of melanoma.

Today the role of clinical trials is being challenged and it seems that this investigative tool does not keep in step with the rhythms imposed by the progress of scientific knowledge and the expectations of the public and media. From the 1970's to the 1990's, however, clinical trials have been the most important way for clinical researchers to find answers to therapeutic questions.

Humans↗

A new American Joint Committee on Cancer staging system for cutaneous melanoma.

The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria. The committee members represent most of the major cooperative groups and cancer centers worldwide with a special interest in melanoma; the committee also collectively has had clinical experience with over 40,000 patients. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion, to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 4) an upstaging of all patients with Stage I,II, and III disease when a primary melanoma is ulcerated; 5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into Stage III disease; and 6) a new convention for defining clinical and pathologic staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. The AJC Melanoma Staging Committee invites comments and suggestions regarding this proposed staging system before a final recommendation is made.

Biopsy↗

Sentinel lymph node biopsy in cutaneous melanoma: the WHO Melanoma Program experience.

BACKGROUND: We report the experience of the World Health Organization (WHO) Melanoma Program concerning sentinel lymph node (SLN) biopsy for detecting patients with occult regional nodal metastases to submit to selective regional node dissection. METHODS: From February 1994 to August 1998, in 12 centers of the WHO Melanoma Program, 892 SLN biopsies were performed in 829 patients with clinical stage I melanoma (male: 370; female: 459; median age: 50 years old). The location of the primary melanoma was as follows: trunk 35%; lower limbs, 45%; upper limbs, 18%; and head and neck, 2%. Blue dye injection for SLN identification was performed in all cases; preoperative lymphoscintigraphy was done in 440 patients, and an intra-operative probe for a radio-guided biopsy was used in 141 cases. Overall, the SLN identification rate was 88%. In 68% of the patients, only one SLN was identified, whereas two and three or more SLN were detected in 24% and 8% of the remaining cases, respectively. RESULTS: Overall SLN positivity rate was 18%. Intra-operative frozen section examination was performed in 39% of the cases and was helpful in detecting occult localizations only in 47% of the positive SLNs. Distribution of positive cases by primary thickness was as follows: < 1mm: 2%; 1-1.99 mm: 7%; 2-2.99 mm: 13%; and > or = 3 mm: 31%. Positive nonsentinel lymph nodes were found in 22% of cases with positive SLN submitted for selective dissection. No complications due to the procedure were registered. Of 710 patients who were evaluated, 40 (6%) presented a regional nodal relapse after a negative SLN biopsy and underwent a delayed therapeutic dissection. From the 710 enrolled cases, 638 (88.5%) were alive without evidence of disease at the time of this writing. A multivariate analysis showed SLN status as one of the most significant prognostic factors (P = .000) along with thickness (P = .001) and ulceration (P = .015) of primary tumor. CONCLUSIONS: These data confirm the feasibility and safety of the SLN technique for selecting patients to submit to a radical node dissection. The data represent the basis for a future trial by the WHO Melanoma Program in this field to evaluate the most appropriate surgical approach for treating patients with occult regional nodal metastases.

Adolescent↗

What is the most promising strategy for the treatment of metastasizing melanoma?

The treatment of patients with metastasizing melanoma, still one of the most deadly diseases in modern medicine, ranks among the greatest challenges that a clinician has to face. Metastatic melanoma also is one of the most profound sources of clinical frustration, since it provides far more ultimately defeating experiences than clinical victories. At the same time, the fascinating biology of melanoma has invited the study of this neuroectodermal tumor as a model system for dissecting many of the key problems of modern oncology, ranging from molecular oncogenesis via the controls of tumor proliferation, apoptosis, invasion, metastasis, and angiogenesis to tumor immunosurveillance and tumor drug resistance. Together with the dire need to develop more effective treatment modalities for improving both life expectancy and quality of life of affected patients, this has made metastatic melanoma a favorite model for the exploration of innovative strategies for tumor management. Encouragingly, many of these have already generated very promising results in animal models. However, this impressive level of research progress in conquering melanoma in the animal room contrasts rather pitifully with the actual progress made on the ward. This CONTROVERSIES feature, therefore, critically and soberly reviews the state of the art of treating metastatic melanoma today (distinguishing between nodal and distant metastases), and sharply defines unresolved or comparatively neglected key problems. In addition, this feature highlights several novel, provocative, hitherto underappreciated, yet potentially promising treatment approaches that deserve systematic exploration. Hopefully, this will offer further inspiration for the design and pursuit of innovative anti-melanoma strategies off-the-beaten-track.

Humans↗

Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis.

OBJECTIVE: To evaluate the impact of breast carcinoma (T1-2N0) surgery without axillary dissection on axillary and distant relapses, and to evaluate the usefulness of a panel of pathobiologic parameters determined from the primary tumor, independent of axillary nodal status, in planning adjuvant treatment. METHODS: In a prospective nonrandomized pilot study, 401 breast cancer patients who underwent breast surgery without axillary dissection were accrued from January 1986 to June 1994. At surgery, all patients were clinically node-negative and lacked evidence of distant metastases after clinical or radiologic examination. A precise 4-month clinical and radiologic follow-up was performed to detect axillary or distant metastases. Patients with clinical evidence of axillary nodal relapse were considered for surgery as salvage treatment. Biologic characteristics of primary carcinomas were investigated by immunohistochemistry, and four pathologic and biologic parameters (size, grading, laminin receptor, and c-erbB-2 receptor) were analyzed to determine a prognostic score. RESULTS: The 5-year follow-up of these patients revealed a low rate of nodal relapses (6.7%), particularly for T1a and T1b patients (2% and 1.7%, respectively), whereas T1c and T2 patients showed a 10% and 18% relapse rate, respectively. Surgery was a safe and feasible salvage treatment without technical problems in all 19 cases of progressive disease at the axillary level. The low rate of distant metastases in T1a and T1b groups (<6%) increased to 15% in T1c and 34% in T2 patients. Analyzing the primary tumor with respect to the panel of pathologic and biologic parameters was predictive of metastatic spread and therefore can replace nodal status information for planning adjuvant treatment. CONCLUSIONS: Middle-term follow-up shows that the rate of axillary relapse in this patient population is lower than expected, suggesting that only a minimal number of microembolic nodal metastases become clinically evident. Avoidance of axillary dissection has a negligible effect on the outcome of T1 patients, particularly in T1a and T1b tumors with no palpable nodes, because the rate of axillary node relapse is very low for both. In T1 breast carcinoma, postsurgical therapy should be considered on the basis of biologic characteristics rather than nodal involvement. The authors' prognostic score based on the primary tumor identified patients who required postsurgical treatment, providing a practical alternative to axillary status for deciding on adjuvant treatment. Conversely, in the T2 group, the high rate of salvage surgery for axillary relapses, which is expected in tumors larger than 2.5 cm or 3.0 cm, represents a limit for avoiding axillary dissection. Preoperative evaluation of axillary nodes for modification of surgical dissection in this subgroup would be more useful more than in T1 breast cancer because of the high risk. Complete dissection is feasible without technical problems if precise follow-up detects progressive axillary disease.

Aged↗

Which kinds of lymph node metastases can FDG PET detect? A clinical study in melanoma.

UNLABELLED: The purposes of this study were to establish the diagnostic accuracy of FDG PET for lymph node metastases and to determine the smallest detectable volume of disease. METHODS: Using FDG PET, we preoperatively studied 56 lymph node basins in 38 patients with a clinical or instrumental diagnosis of lymph node metastases from melanoma. All lymph node basins underwent node dissection. The FDG PET results were compared with the postoperative histopathology results. PET images were obtained using a GE 4096 WB scanner, after injection of a mean activity of 496 MBq (range, 366-699 MBq) of FDG. RESULTS: The efficacy of FDG PET in the diagnosis of involved lymph node basins was good. Sensitivity was 95% (35/37); specificity, 84% (16/19); accuracy, 91% (51/56); positive predictive value, 92% (35/38); and negative predicative value, 89% (16/18). Metastases were shown histologically in 114 of 647 surgically removed lymph nodes. FDG PET detected 100% of metastases > or = 10 mm, 83% of metastases 6-10 mm, and 23% of metastases < or = 5 mm. Moreover, FDG PET had high sensitivity (> or = 93%) only for metastases with more than 50% lymph node involvement or with capsular infiltration. CONCLUSION: Our study shows that FDG PET has a reasonable sensitivity and specificity for detecting the presence or absence of lymph node metastases in patients with melanoma. However, even if able to detect small volumes of subclinical macroscopic disease, FDG PET cannot detect subclinical microscopic disease with acceptable sensitivity. The specificity of FDG PET is good, but some false-positive results may occur.

Adult↗

Vaccination of melanoma patients with interleukin 4 gene-transduced allogeneic melanoma cells.

A human melanoma line genetically modified to release interleukin 4 (IL-4) was utilized to immunize advanced melanoma patients in order to elicit or increase a specific anti-melanoma immune response, which may affect distant lesions. Twelve metastatic melanoma patients were injected subcutaneously at least three times with 5 x 10(7) IL-4 gene-transduced and irradiated allogeneic melanoma cells per dose. Both systemic and local toxicities were mild, consisting of transient fever and erythema, swelling, and induration at the vaccination site. Two mixed but not complete or partial clinical responses were recorded. To assess the immune response of vaccinated patients, both serological and cell-mediated activities were evaluated. Antibodies to alloantigens could be detected in 2 of 11 patients tested. Mixed tumor-lymphocyte cultures were performed, utilizing autologous and allogeneic HLA-A2-matched melanoma lines as simulators and targets. A significant increase in IFN-gamma release was detected in 7 of 11 cases when postvaccination lymphocytes were stimulated by the untransduced allomelanoma cells. However, induction of a specific recognition of autologous melanoma cells by PBLs was obtained after vaccination in only one of six cases studied. This response involved the melanoma peptide Melan-A/MART-1(27-35) that was recognized in an HLA-A2-restricted fashion. These results indicate that vaccination with allogeneic melanoma cells releasing IL-4 locally can expand a T cell response against antigen(s) of autologous, untransduced tumor, although in a minority of patients.

Adult↗

Fluctuation of HER2 expression in breast carcinomas during the menstrual cycle.

The hormonal milieu at time of tumor surgery seems to have a significant impact on survival in premenopausal breast cancer patients. Indeed, surgery performed during the follicular phase of the menstrual cycle was suggested to correlate with a poor prognosis. To investigate the relationship between prognosis and menstrual cycle at time of surgery, we analyzed the expression of some markers associated with tumor aggressiveness, such as the hormone receptors, HER2, p53, Bcl2, and cathepsin D in breast carcinomas obtained from 198 premenopausal women who underwent surgery during different phases of the menstrual cycle. HER2 overexpression was found to fluctuate in hormone receptor-positive tumors. In actual fact, 20% of the tumors removed during the follicular phase scored HER2-positive, versus 8% of those removed during the luteal phase. Similarly, a number of hormone receptor-positive tumor specimens, obtained from the same patients during follicular and luteal phases, were scored HER2-positive when the sample was removed during the follicular phase and HER2-negative when removed in the luteal phase. Southern blot analysis of the HER2 gene indicated that, in hormone receptor-positive cases, the overexpression of HER2 is often not associated with gene amplification. The finding that overexpression of the HER2 gene, associated with tumor aggressiveness, can fluctuate according to the hormonal milieu may explain the increased survival of patients operated during the luteal phase. It is also relevant to the selection and treatment of patients most likely to benefit from anti-HER2 antibody therapy.

Adult↗

Pathobiologic identification of two distinct breast carcinoma subsets with diverging clinical behaviors.

Many different pathological and biological variables which characterize breast carcinomas have been found to be associated. The aim of this work was to analyze the complex relationship among these parameters. The pathologic, biologic, and clinical characteristics of a series of primary breast carcinomas from 676 patients were retrospectively investigated. Multiple correspondence analysis of 13 factors revealed clustering of eight pathobiologic variables, that is histologic grade, necrosis, lymphoid infiltration, number of mitoses, c-erbB-2 overexpression, p53, progesterone receptor, and bcl2 expression. An index for each tumor calculated on the basis of these eight factors served to distinguish two different tumor phenotypes, designated A and B. Phenotype A is represented by tumors sharing most of the biologic features of normal breast tissues: indeed, these tumors are characterized by a relatively high degree of differentiation, low proliferation, no necrosis or leukocyte infiltration, and no gene alterations. By contrast, phenotype B is quite divergent from the normal tissue because of its poor differentiation, high proliferation, frequent gene alterations and evidence of a host immune reaction. As regards the disease progression, these two subsets showed marked differences: phenotype A tumors had a low recurrence rate per year that remained constant over time and affected more frequently elderly patients, whereas group B tumors showed high aggressivity in the first years after surgery followed by a low long-term recurrence rate and were more frequently seen in younger patients. These data suggest that breast carcinoma consists of two different subsets that can be identified on the basis of pathobiologic features.

Adult↗