The role of the early social environment on Epstein Barr virus infection: a prospective observational design using the Millennium Cohort Study.

Epstein-Barr virus (EBV) is a highly prevalent herpesvirus linked to infectious mononucleosis and several malignancies. This paper aims to study the association between children's early life social environment at 9 months and EBV infection at 3 years of age. METHODS: We used data on children included in the UK Millennium Cohort Study. We described the social environment using area-level and material factors as well as socioeconomic position (SEP) at 9 months. EBV was measured at 3 years of age (n = 12 457). RESULTS: Lower rates of EBV infection were observed in children living in towns and rural areas compared with those living in cities. Lower SEP and overcrowding in the household increased the odds of being infected. Children whose parents were social tenants were more likely to be infected than homeowners. In the overall model, the strength of the association between material factors and EBV infection weakened. CONCLUSIONS: We showed that early life material deprivation was associated with a higher risk of EBV infection among 3-year-olds. Children living in more deprived social conditions may be more likely to become EBV carriers at an earlier age.

Early-childhood BMI trajectories: evidence from a prospective, nationally representative British cohort study.

BACKGROUND AND OBJECTIVES: By age 5, 20% of British children are classed as overweight or obese, suggesting that early childhood is crucial for lifelong body mass index (BMI) trajectories. In this paper, we identify latent trajectories of early-childhood BMI from ages 3 to 11 years. Given the current context of growing socio-economic inequalities in childhood and adult overweight and obesity, we examine the socio-economic characteristics and mechanisms during pregnancy and infancy which underscore these trajectories. SUBJECT AND METHODS: We use a nationally representative, prospective cohort study of 9699 children born in 2000-2002, living in the United Kingdom shortly after birth, with complete information on height and weight (measured by an interviewer) at ages 3, 5, 7 and 11. Trajectories of BMI are calculated using latent growth mixture models. Multinomial models characterize these trajectories by their socio-economic profiles and mechanisms during pregnancy and infancy. RESULTS: Four trajectories were identified: two separate trajectories where BMI remains within a normal range (85% of the sample), an overweight trajectory (14.4%), and an obese trajectory (3.1%). No 'declining BMI' or late-onset groups were found. The obese group is already distinct from the other trajectories by age 3. The overweight group diverges from the normal groups around age 5. Strong socio-economic inequalities emerged; for the obese group, part of this disadvantage is mediated through early mechanisms such as pregnancy smoke and not initiating breastfeeding. CONCLUSIONS: This study provides strong evidence for the idea that childhood BMI trajectories develop early, especially for children who will follow an obese trajectory. Strong socio-economic patterns in these trajectories suggest that the observed trend in growing inequalities may be rooted in early life. Mediating mechanisms for the obese appear to be in the pregnancy and infant period, further research should explore mechanisms occurring around age 5 when the overweight trajectory diverges.

FOXN1 mutation abrogates prenatal T-cell development in humans.

BACKGROUND: The transcription factor FOXN1 is implicated in the differentiation of thymic and skin epithelial cells, and alterations in it are responsible for the Nude/SCID phenotype. During a genetic counselling programme offered to couples at risk in a community where a high frequency of mutated FOXN1 had been documented, the identification of a human FOXN1(-/-) fetus gave the unique opportunity to study T cell development in utero. RESULTS: Total blockage of CD4(+) T cell maturation and severe impairment of CD8(+) cells were documented. Evaluation of the variable-domain ß-chain (Vß) families' usage among T lymphocytes revealed that the generation of T cell receptor (TCR) diversity occurred to some extent in the FOXN1(-/-) fetus, although it was impaired compared with the control. A few non-functional CD8(+) cells, mostly bearing TCRγδ in the absence of CD3, were found. DISCUSSION: FOXN1 is crucial for in utero T cell development in humans. The identification of a limited number of CD8(+) cells suggests an extrathymic origin for these cells, implying FOXN1-independent lymphopoiesis.

Why does birthweight vary among ethnic groups in the UK? Findings from the Millennium Cohort Study.

BACKGROUND: Birthweight varies according to ethnic group, but it is not clear why such differences exist. We examine the contribution of socioeconomic, maternal and behavioural factors to differences in mean birthweight and the prevalence of low birthweight across ethnic groups. METHODS: Data from the nationally representative UK Millennium Cohort Study (n = 16,157) on White, Indian, Pakistani, Bangladeshi, Black Caribbean and Black African infants were analysed. Cohort members were born in 2000-02, and data on birthweight, maternal, infant, behavioural and socioeconomic factors were collected by home interviews. RESULTS: Indian, Pakistani and Bangladeshi infants were 280-350 g lighter, and 2.5 times more likely to be low birthweight compared with White infants. Black Caribbean infants were 150 g and Black African infants 70 g lighter compared with White infants, and Black Caribbean and Black African infants were 60% more likely to be low birthweight compared with White infants. For Black Caribbean, Black African, Bangladeshi and Pakistani infants, socioeconomic factors were important in explaining birthweight differences and, for Indian and Bangladeshi infants, maternal and infant factors were important in explaining birthweight differences. CONCLUSION: Future policies aimed at reducing inequalities in birthweight must pay attention to the different socioeconomic and culturally-related profiles of ethnic minority groups in the UK.

[The ketogenic diet in infantile refractory epilepsy: electroclinical response, complications and secondary effects]. / Dieta cetogénica en la epilepsia refractaria infantil: respuesta electroclínica, complicaciones y efectos secundarios.

INTRODUCTION: The ketogenic diet (KD) was developed after observation that prolonged starvation might lead to the seizures stopping. Due to is efficacy and safety, KD plays an important part in the management of children with refractory epilepsy. OBJECTIVES: To show the clinical anticonvulsant response of KD, the electroencephalographic changes, the need for strict methodology to enhance the success of the treatment, and evaluation of the side effects and complications observed. PATIENTS AND METHODS: After being started on a protocol of a classical ketogenic diet, 13 patients aged between 1 and 19 years were prospectively evaluated for an average period of 22 months. All had different types of refractory epilepsy according to Schmidt's scores, as modified by Aicardi. RESULTS: There was over 50% reduction in the number of crises of 84.5% of the children. Complete control was attained in 30.8%. The electroencephalographic recordings showed improvement in 100% of the children. The families involved reported a 58.8% reduction in the side effects observed. During treatment the serum cholesterol rose in 72.7% of the children, 36.4% complained of constipation, 27.3% had a brief period of anorexia and there was symptomatic metabolic acidosis during intercurrent infection and renal lithiasis in one patient. CONCLUSION: The clinical and electroencephalographic improvement and minimal side-effects seen confirm that KD is beneficial in refractory epilepsy in children.

[The electroencephalographic evolution of a group of patients on a ketonic diet]. / Evolución electroencefalográfica de un grupo de pacientes en dieta cetogénica.

INTRODUCTION: A ketogenic diet is an old method for the treatment of resistant epilepsy in children, which has been revived in recent years because of its proven efficacy. OBJECTIVE: To correlate electroencephalographic findings and clinical changes observed in a group of patients on the classical ketogenic diet, to determine the validity of the electroencephalogram in following-up treatment. PATIENTS AND METHODS: We made a prospective evaluation of 11 patients aged between 1 and 19 years for an average period of 22 months. The patients had different types of resistant epilepsy according to Schmidt's score as modified by Aicardi, with a sleep encephalogram prior to treatment and 3, 6, 12 and 24 months later, after following the protocol of the classical ketogenic diet. RESULTS: The sleep encephalograph recordings showed changes in all patients. In 9% of cases they became normal, there was great improvement in 45.45% and some improvement in 45.45%. No patient had worsening of the recording. There was over 50% reduction in the number of seizures seen in 72.7% of the children and complete control was achieved in 27.3%. CONCLUSIONS: Normalization or improvement of sleep encephalogram recordings was correlated with improvement in seizures. Electroenchephalogram follow-up is a useful method for prediction of response to treatment with a ketogenic diet.

TAG-72 expression and clinical outcome in primary breast cancer.

Clinical data of 92 patients with primary breast carcinomas previously analysed for the pattern of immunohistochemical expression of three distinct carbohydrate epitopes of the TAG-72 molecule were reviewed. The clinical outcome of the patients after a median follow-up of 66 months was determined in 84 out of 92 patients. Clinicopathological characteristics of the tumours and clinical outcome of the patients were correlated with the TAG-72 epitope expression. TAG-72 was expressed more frequently in patients aged more than 50 years and in tumours of larger size, with lymph nodes metastasis, with low differentiation and with high proliferative activity. A statistical correlation was found with more advanced stages of the disease (35.7% vs 60% in stage I and in stage II-III, respectively, p=0.03). Disease-free survival and overall survival were estimated by the Kaplan-Meier method. The survival of the patients with tumours expressing TAG-72 was not statistically different from that of patients with tumours without TAG-72 expression. These data suggest that TAG-72 expression is associated with clinicopathological parameters of aggressiveness in primary breast cancer, but it does not appear to affect the clinical outcome of the patients.

Measurement of neovascularization is an independent prognosticator of survival in node-negative breast cancer patients with long-term follow-up.

We measured neovascularization, epidermal growth factor receptor, and c-erbB-2 expression in a consecutive series of 233 surgically resected axillary lymph node-negative breast cancer patients with a long-term follow-up to define the usefulness of these parameters as independent prognostic indicators of overall survival (OAS). Microvessel count (MVC), as a measure of neovascularization, was determined using a monoclonal antibody against human factor VIII-related antigen. The median MVC of 20 (range, 4-76) was used as a cutoff value for discriminating between low and high vascularized tumors. Epidermal growth factor receptor and c-erbB-2 expression were evaluated by immunohistochemistry. Tumors were considered positive if >10% of the cells showed specific membrane staining. OAS curves were estimated by the Kaplan-Meier method. The independent prognostic effect of each variable was determined with the Cox proportional hazards model. High MVC (P = 0.04), high nuclear grade (P = 0.005), and high S-phase (P = 0.02) significantly affected OAS at univariate analysis. In a Cox multivariate analysis, the characteristics with an independent prognostic effect on OAS were: MVC (relative hazard, 2.12; 95% confidence interval, 1.18-3.81; P = 0.01) and nuclear grade (relative hazard, 2.83; 95% confidence interval, 1.12-7.17; P = 0.01). These results demonstrate that quantification of neovascularization adds useful independent prognostic information on survival in node-negative breast cancer patients with long-term follow-up.

Mammary hamartomas: an immunohistochemical study of ten cases.

Ten cases of breast hamartomas were reviewed; the patients' age ranged from 31 to 55 (mean 40.4, median 39). All cases presented with a palpable, sometimes tender, lump. The typical mammographic feature was a well defined, round to lens shaped, variable dense mass, occasionally surrounded by a thin radiolucent zone. All hamartomas were unilateral (4 in the right and 6 in the left breast, respectively) and no recurrence occurred after local excision. The tumor size ranged from 5 to 150 mm (mean 54 mm). Histologically all hamartomas were composed of a typical fibrous, adipose and glandular tissue combination. Immunohistochemically there was a strong positivity for cytokeratin and epithelial membrane antigen in the epithelial cells, a positive finding for vimentin and muscle-specific actin in stromal and myoepithelial cells, and for S-100 protein in myoepithelial cells. Vessels endothelial cells were immunoreactive for Factor VIII. Immunohistochemical analysis of hormone receptors completed on formaldehyde-fixed paraffin-embedded specimens, showed estrogen and progesterone receptors positivity in 9 cases and estrogen positive progesterone negative receptors in one case. In all cases the receptorial positivity was limited to the epithelial elements. These data revealed that 1) breast hamartoma is a benign, tumor-like lesion, histologically dissimilar from other lesions such as fibroadenoma and pseudoangiomatous hyperplasia; and 2) hamartoma tissue is influenced by hormones like the surrounding normal breast parenchyma.

[Benign lesions of the breast]. / Lesioni benigne della mammella.

Benign lesions represent the most frequent lesions of the breast. Such lesions often onset with nodules or palpable masses simulating a breast cancer. In uncertain cases, an excisional biopsy may be at the same time a diagnostic and a therapeutic solution. A high percentage (40%) of the diagnosed lesions belongs to fibrocystic disease. A remaining 50% can be shared among tumor-like lesions, inflammatory lesions or benign tumors like fibroadenomas. Only in the 10% of palpable breast masses, biopsy reveals a breast cancer. The role of the pathologist is strictly related to the surgeon's one. Clinically benign lesions may be excised throughout a biopsy performed under local anesthesia. Clinically uncertain lesion must be evaluated by a fine needle aspiration biopsy (FNAB), nevertheless in some cases the doubt may persist. In such cases an excisional biopsy performed while the patient is under general anesthesia may finally solve the question. In case of breast malignancies the intervention can be enlarged as described for cancer.

[Serum anti-HIV IgA in seropositive patients and in subjects at risk of HIV infection]. / IgA sieriche anti-HIV in pazienti sieropositivi ed in soggetti a rischio di infezione da HIV.

To detect the presence of anti-HIV IgA in HIV infected subjects and in seronegative subjects at risk of infection, we assessed a Western Blot using nitrocellulose strips with HIV separated proteins. We tested at least 2 different serum samples from 9 anti-HIV positive subjects (Group A), 9 anti-HIV negative subjects at risk of infection (Group B) and 9 controls (Group C). One subject in Group B became anti-HIV positive during the observation. Anti-HIV IgA were detected in all patients of Group A, in 66.6% of patients of Group B and in no patient of Group C. The subject who seroconverted during the observation showed positivity for IgA anti-HIV in both serum samples, while anti-HIV IgG became detectable only on the second serum sample. A newborn from a seropositive mother showed maternal anti-HIV IgG on the first 2 out of 3 serum samples while showed anti-HIV IgA positivity on the third sample only. This child is still anti-HIV negative.

[Polymerase chain reaction (PCR) for the detection of HIV proviral DNA (pDNA) in subjects at risk of infection]. / Polymerase chain reaction (PCR) per la determinazione di DNA provirale (pDNA) di HIV in soggetti a rischio di infezione.

To detect HlV proviral DNA in lymphocytes from subjects at risk of acquiring HIV infection, we assessed a Polymerase Chain Reaction Assay using the SK38 and SK39 primers for the amplification and the SK19 probe for the hybridization. The detection of amplified HIV-DNA was obtained by a new colorimetric method, the DNA enzyme immunoassay (DEIA). The PCR we performed allowed to detect HIV-pDNA in lymphocytes of 13 out of 64 subjects at risk of acquiring HIV infection. Seven of these 13 became anti-HIV positive during a follow up of 8 months.

[HIV Antigens as complement fixing circulating immune complexes]. / Antigeni di HIV in immunocomplessi circolanti fissanti il complemento.

To detect HIV antigens in circulating complement fixing immune complexes (ICs) we assessed an ELISA using wells of microtitre plates coated with F(ab)2 anti-C3b and monoclonal antibodies anti-HIV gp120 and anti-HIV p24. We tested 24 anti-HIV positive subjects (Group A), 10 anti-HIV negative subjects at risk of acquiring HIV infection (Group B), 20 normal controls (Group C) and 2 seroconversion panels. We found HIV antigens in ICs in all sera from seroconversion panels, in 25.5% of sera from subjects in Group A, in 28.6% of sera from subjects in Group B and in no serum from subjects in Group C. A subject in Group B acquired HIV infection during the observation. HIV antigens in ICs by our assay were detected 8 months before Anti-HIV and Ag by commercial ELISA.

An unusual, recurring breast tumor with features of eccrine spiradenoma: a case report.

A new case of breast tumor with features of eccrine spiradenoma is described. This neoplasm is exceedingly rare, because only two cases, arising in breast parenchima, have been previously reported. The patient was a 43-year-old woman and she experienced three local recurrences at 7, 20, and 30 months from the first excision. No distant metastases were observed. Microscopically, the tumor was circumscribed and showed a lobulated pattern. Neoplastic lobules consisted of packed, monotonous, basaloid epithelial cells with round to ovoid nuclei and scant cytoplasm. At the periphery, the lobules were delimitated by smaller cells with dark nuclei. Immunohistochemical reactivity in tumoral cells was found for both cytokeratin and epithelial membrane antigen; vimentin, muscle-specific actin, glial fibrillary acidic protein, S-100 protein, and carcinoembryonal antigen were all negative. Furthermore, the lesion showed a diffuse positivity for estrogen and progesterone receptors and a high growth fraction labelled by MIB-1 (Ki-67) antibody. These findings, in conjunction with the deep location of the tumor, suggest an origin of the neoplasm from the breast epithelium. Because of a potential local aggressive behavior, the excision of a wide rim of uninvolved breast tissue is recommended.

c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases.

PURPOSE: We studied retrospectively the interaction between c-erbB2 overexpression and adjuvant tomoxifen in node-negative breast cancer patients enrolled in the Gruppo Universitario Napoletano 1 (GUN-1) trial. PATIENTS AND METHODS: c-erbB2, evaluated by immunohistochemistry in 145 of 173 patients randomly assigned to 2-year adjuvant tamoxifen or no further therapy, was considered overexpressed if greater than 10% of the cells showed specific membrane staining. The role of each prognostic variable and their independent effect were studied using the Cox model. Disease-free (DFS) and overall (OAS) survival curves were estimated by the Kaplan-Meier method. RESULTS: As of November 30, 1994, the median follow-up period was 12 years. c-erbB2 was overexpressed in 43 of 145 patients (29.7%), which directly correlated with tumor size and inversely with estrogen receptor (ER) level. At univariate analysis, overexpression of c-erbB2 did not affect either DFS or OAS; tamoxifen had a greater effect on reducing the risk of recurrence than of death. Addition of c-erbB2 to a multivariate Cox model that contained menopausal status, tumor size, nuclear grade, and treatment as covariates did not affect the significance of the model for DSF or OAS, whereas addition of the first-order interaction between c-erbB2 and tamoxifen was statistically significant both for DFS and OAS. The same result was obtained when the model contained ER status and ER-tamoxifen interaction. Indeed, adjuvant tamoxifen significantly prolonged DFS and OAS in c-erbB2-negative cases, whereas it had no effect on DFS and OAS in c-erbB2-positive patients. CONCLUSION: In early-stage breast cancer patients, overexpression of c-erbB2 is a marker of lack of efficacy of adjuvant tamoxifen.

A predictive index of axillary nodal involvement in operable breast cancer.

We investigated the association between pathological characteristics of primary breast cancer and degree of axillary nodal involvement and obtained a predictive index of the latter from the former. In 2076 cases, 17 histological features, including primary tumour and local invasion variables, were recorded. The whole sample was randomly split in a training (75% of cases) and a test sample. Simple and multiple correspondence analysis were used to select the variables to enter in a multinomial logit model to build an index predictive of the degree of nodal involvement. The response variable was axillary nodal status coded in four classes (N0, N1-3, N4-9, N > or = 10). The predictive index was then evaluated by testing goodness-of-fit and classification accuracy. Covariates significantly associated with nodal status were tumour size (P < 0.0001), tumour type (P < 0.0001), type of border (P = 0.048), multicentricity (P = 0.003), invasion of lymphatic and blood vessels (P < 0.0001) and nipple invasion (P = 0.006). Goodness-of-fit was validated by high concordance between observed and expected number of cases in each decile of predicted probability in both training and test samples. Classification accuracy analysis showed that true node-positive cases were well recognised (84.5%), but there was no clear distinction among the classes of node-positive cases. However, 10 year survival analysis showed a superimposible prognostic behaviour between predicted and observed nodal classes. Moreover, misclassified node-negative patients (i.e. those who are predicted positive) showed an outcome closer to patients with 1-3 metastatic nodes than to node-negative ones. In conclusion, the index cannot completely substitute for axillary node information, but it is a predictor of prognosis as accurate as nodal involvement and identifies a subgroup of node-negative patients with unfavourable prognosis.

c-erbB-2 expression in FNAB smears and matched surgical specimens of breast cancer.

Most of the data regarding the significance of c-erbB-2 oncogene expression as a prognostic marker in breast cancer have been generated in many large retrospective studies by retrieving the corresponding oncoprotein in archival paraffin embedded sections. Recently, employing fresh breast cancer cells obtained by means of fine-needle aspiration biopsy, we found a rate of c-erbB-2 positive breast tumors (58%) higher than that reported in paraffin-embedded tissue sections by others studies. The present analysis was undertaken to investigate the impact of routine tissue processing on the preservation of the c-erbB-2 immunoreactivity. This issue was addressed by assessing the relative rate of c-erbB-2 oncoprotein immunodetection on FNAB smears and matched surgical specimens of breast cancer. The expression of c-erbB-2 oncoprotein was evaluated using the alkaline phosphate-anti-alkaline phosphatase (APAAP) technique in 54 breast aspirates and corresponding surgical specimens of primary breast cancer. Twenty-six (48%) smears and 23 (43%) matched paraffin sections gave specific signal for c-erbB-2 oncoprotein. The slightly higher incidence of c-erbB-2 expression found on smears seems to be mainly due to the better antigen preservation in the fresh cytological preparations. We conclude that routine histological processing may affect c-erbB-2 immunoreactivity; therefore, in mounting prospective studies, it is advisable to assess c-erbB-2 status in fresh tissue. Moreover, the assessment of c-erbB-2 expression on aspirate samples may yield additional information to the pre-surgical prognostic evaluation of breast cancer diagnosed by FNAB.

Differential immunohistochemical detection of transforming growth factor alpha, amphiregulin and CRIPTO in human normal and malignant breast tissues.

The expression of growth factors, such as transforming growth factor alpha (TGF alpha), amphiregulin (AR) and CRIPTO, a type-1 tyrosine-kinase growth factor receptor (erbB-2), and a tumor-suppressor gene (p53), that have been implicated in the development and/or the progression of breast cancer, was evaluated by immunohistochemistry in 100 human primary infiltrating breast carcinomas (IBC). AR and CRIPTO immunoreactivity was also assessed in 55 human breast ductal carcinomas in situ (DCIS). Within the 100 IBC, 80, 50, 73, 17, and 34 tumors expressed moderate to high levels of TGF alpha, AR, CRIPTO, erbB-2, and p53 respectively. In addition, AR and CRIPTO immunoreactivity were found in 11 and in 26 out of 55 DCIS respectively. In contrast, only 4, 3, and 2 out of 10 normal mammary-gland samples were weakly positive for TGF alpha, AR, and CRIPTO expression, respectively, whereas none was positive for erbB-2 or p53. Within the 100 IBC, expression of erbB-2 significantly correlated with high histologic and nuclear grading, with high growth fraction, and with estrogen-receptor (ER)- and progesterone-receptor (PgR)-negative tumors. A statistically significant correlation was also observed between p53 expression and high histologic grading, high growth fraction, and PgR-negative tumors. In contrast, no significant correlations were found between TGF alpha, AR, and CRIPTO immunoreactivity and various clinicopathological parameters, with the exception of a positive correlation between TGF alpha and ER expression. These data demonstrate that TGF alpha, AR, and CRIPTO expression are significantly increased in malignant mammary epithelium relative to normal epithelium. In particular, the differential expression of CRIPTO may serve as a potential tumor marker for breast carcinogenesis.

[Laboratory diagnosis of HIV infection]. / Diagnosi di laboratorio dell'infezione da HIV.

The diagnosis of HIV infection is generally lead using two different ELISAs to detect specific anti-HIV antibodies, the eventual reactivity must then be confirmed by a Western Blot The antibodies can be detected only 1-6 months after the infection; in fact in the earliest phases neither the antibodies, for their low titre, nor the specific antigens, for the antibodies could form immune complexes, can be detected by the achieved methods. Only the viral isolation can reveal the presence of the virus in this early phase, but the isolation must be conducted only in adequately safe laboratories (P3 laboratories). The only test able to replace the viral isolation is the Polymerase Chain Reaction (PCR). The PCR technique can be useful to reveal an HIV infection in its early phase and to monitor the infection progression and the efficacy of an antiretroviral treatment

Selecting high-risk early breast cancer patients: what to add to the number of metastatic nodes?

High-risk early breast cancer patients are usually identified by the number of metastatic axillary nodes. To study whether other easily and inexpensively detectable morphological factors are able to detect high-risk patients, we performed a retrospective analysis of tumor size, and skin/fascia and nipple invasion. The data consisted of 941 node-positive cases registered between 1978 and 1991. Tumour size, and skin/fascia and nipple invasion were closely associated with the number of metastatic nodes (chi 2 test). The number of metastatic nodes, tumour size, skin/fascia and nipple invasion significantly affected disease free survival (DFS) and overall survival (OS) at univariate analysis. These results were confirmed by multivariate analysis with a model containing the number of metastatic nodes, tumour diameter categories, skin/fascia invasion, nipple invasion and adjuvant therapy as covariates: all variables significantly and independently affected risk of relapse and of death. All the variables studied were prognostic, within individual nodal categories, for both DFS and OS. In conclusion, the number of metastatic nodes is not the only prognostic tool with which to select high-risk patients for new intensive adjuvant programmes. Tumour size, and skin/fascia invasion or nipple invasion, taken singly or combined, are valuable prognostic factors that can identify patients with few metastatic nodes and poor outcome. On the basis of our data, we believe that a reconsideration of the pT4 category within the pTNM classification is in order, that is, chest wall invasion should be substituted by fascia invasion, and combined skin/fascia invasion could be a subcategory of each class defined by tumour size.