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C Brambilla

Publications and source records attributed to C Brambilla.

At least 37 records · Page 2Linked to original sources
PubMed2002

[Bronchial obstruction and the ideopathic hyper-eosinophilic syndrome].

The idiopathic hyper-eosinophilic syndrome is defined as a peripheral blood eosinophilia greater than 1.5 x 10(9)/litre present for at least 6 months and associated with visceral involvement. It may only be accepted after carefully excluding the other common or rare causes of hyper-eosinophilia and should remain a diagnosis of exclusion. The associated visceral lesions are multiple and non-specific. Among these neurological, digestive, dermatological and cardiac manifestations are the most frequently described. Whereas pleuro-pulmonary involvement is also common, asthma is rarely reported. We report a case of ideopathic hyper-eosinophilic syndrome presenting as asthma. This was secondary to eosinophilic infiltration of the bronchial mucosa as demonstrated by cytological examination of induced sputum.

Adult↗
PubMed2002

[Effect of diesel particles on allergic inflammatory response: cellular targets and molecular mechanisms].

The prevalence of allergic diseases has increased in industrialized western countries, and several hypotheses have been proposed to explain this rise. Besides the classical "hygiene theory" associated with improvements in living standards, a role for atmospheric pollution has been suggested, but this has as yet not been proven by epidemiological studies. By contrast, the impact of pollutants on the allergic inflammatory response is well documented. In this context, the effects of diesel exhaust particles and their organic extracts are the best known. In both human and animal studies, it has been demonstrated that diesel exhaust particles can cause an augmentation of respiratory symptoms, which are associated with the development of mucosal inflammation, an increase in airways resistance, and the development of non-specific bronchial hyper-reactivity. The mechanisms of these airway modifications are better understood. Diesel exhaust particles interfere with several inflammatory cell-types, involved in the regulation of the immune response. Diesel particles act in synergy with antigens to selectively amplify the production of specific IgE, TH2 cytokines, chemokines, and to increase the expression of adhesion molecules. Diesel particles modify antigen presentation by the macrophage, and facilitate its interaction with T cell. Finally, diesel exhaust particles enhance mast cell and basophil histamine release, and might influence fibrotic bronchial remodeling. In essence, these data argue for an important role of such small respirable particles in the pathophysiology and, probably also, the epidemiological modification of allergic disease.

Animals↗
PubMed2001

Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease. METHODS: We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV(1)] 46.8% of predicted, FEV(1)/forced vital capacity [FVC] 54.6%, and postsalbutamol reversibility 5.4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV(1) before and after use of a bronchodilator. Analyses were by intention to treat. FINDINGS: Cilomilast 15 mg twice daily significantly improved FEV(1) compared with placebo (mean 130 mL vs -30 mL [95% CI 90-240] at week 6, p<0.0001). FVC and peak expiratory flow were also improved (p=0.001 and p<0.0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups. INTERPRETATION: Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Distinct pattern of E2F1 expression in human lung tumours: E2F1 is upregulated in small cell lung carcinoma.

The transcription factor E2F1 is a key component of cell cycle that acts to transactivate genes required for S phase entry. Thus, it plays an important role in cellular proliferation, oncogenesis and differentiation. In order to investigate its potential implication in human lung carcinogenesis, we studied E2F1 protein expression by Western blotting and immunohistochemistry in a series of 58 human lung tumours of all histological types. We showed that E2F1 product was overexpressed in 92% (24/26) of small cell lung carcinoma (SCLC) and in 50% (5/10) of large cell neuroendocrine carcinoma (LCNEC) whereas it was undetectable in 90% (10/11) of adenocarcinoma and 82% (9/11) of squamous carcinoma when compared to corresponding normal lung. No amplification was found but an increase in E2F1 mRNA expression was detected in 75% (18/24) of SCLC overexpressing E2F1 product. In these tumours and in contrast with NSCLC, upregulation of E2F1 product was associated with its nuclear accumulation and with overexpression of several of its target-genes. Moreover, E2F1 overexpression in NE lung tumours was significantly associated with a high KI67 index (P<0.0001) as well as a Bcl-2:Bax ratio >1 (P<0.001). Overall, these results demonstrate a distinct pattern of E2F1 expression in human lung tumours and suggest that its deregulation could be involved in the carcinogenesis of SCLC.

Carcinoma, Small Cell↗
PubMed2001

Human ARF binds E2F1 and inhibits its transcriptional activity.

The INK4a/ARF locus which is frequently inactivated in human tumours encodes two different tumour suppressive proteins, p16(INK4a) and ARF. p16(INK4a) is a major component of the RB pathway. ARF is part of an ARF-mdm2-p53 network that exerts a negative control on hyperproliferative signals emanating from oncogenic stimuli. Among these is the transcription factor E2F1, a final effector of the RB pathway, that induces ARF expression. Recent data suggest that ARF function is not restricted to the p53 pathway. However, ARF target(s) implicated in this p53-independent function remains to be identified. We show that ARF is able to inhibit the proliferation of human cell lines independently of their p53 status. In this context, we demonstrate that ARF interacts physically with E2F1 and inhibits its transcriptional activity. Moreover, we show that mdm2 is required for the modulation of E2F1 activity by ARF. Beside the well-known p53 and mdm2 partners, these results identify E2F1 as a new ARF target. Thus, ARF can be viewed as a dual-acting tumour suppressor protein in both the p53 and RB pathways, further emphasizing its role in tumour surveillance.

ADP-Ribosylation Factors↗
PubMed2001

Early lung leukocyte infiltration, HLA and adhesion molecule expression predict chronic rejection.

Obliterative bronchiolitis remains the main cause of graft dysfunction and death after 1 year. Defined by an irreversible airway obstruction, bronchiolitis obliterans syndrome is usually recognized in the advanced stage of the disease, with histological evidence of fibrotic damage. Fibrosis represents the end-stage of an inflammatory process, leading to the postulate that chronic lung graft dysfunction is preceded by cellular and molecular events. This study was performed during the first year following lung transplantation, in the absence of histological or functional criteria of chronic rejection. Transbronchial biopsies from eight lung allografts were examined. Four developed a bronchiolitis obliterans syndrome (Group I), and 4 had good outcomes (Group II) at 2 years. Using immunohistochemistry, the aim of the study was to correlate early immunological events with graft outcomes at 2 years. An up-regulation of HLA class I antigen (P = 0.0001), an overexpression of Ki-67 (P = 0.006) on bronchial epithelium, and graft infiltration by CD45+, CD25+ cells (P = 0.003) were significantly associated with the development of chronic rejection. An overexpression of numerous adhesion molecules was observed. However, only very late antigen-4 had a discriminative value (P = 0.04), preceding chronic graft dysfunction. Our results suggest that graft dysfunction is associated with early molecular and cellular events, and raises the possibility that a fibroproliferative disorder is initiated shortly after transplantation. The recognition of such early immunological markers might facilitate improved graft management and prognosis.

Adolescent↗
PubMed2001

Phase I/II study of gemcitabine in association with vinorelbine for metastatic breast cancer.

BACKGROUND: Gemcitabine (G) and vinorelbine (V) have favorable safety profile and antitumor activity in metastatic breast cancer. To exploit their different mechanism of action and lack of overlapping toxicity, we performed a phase I and II study of G and V in combination. PATIENTS AND METHODS: Fifty-three patients with metastatic breast cancer were treated. In the dose-finding phase, seven cohorts of patients (22 women) received increasing doses to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination. Patients recruited in the phase II portion of the study (31 women) received the dose level immediately below the one defined as MTD (i.e., G 1200 mg/m2, V 30 mg/m2, on day 1 and day 8, every 3 weeks). RESULTS: Dose escalation was discontinued at G 1400mg/m2 and V 30 mg/m2 because of toxic death due to thrombocytopenia and CNS hemorrage. No other limiting toxicities were observed, and tolerability was similar at all dose levels studied in the escalation portion of the study. The main toxicity was granulocytopenia of grade 3/4 in 36 and 48% of the patients on phase I and II respectively, without episodes of neutropenic fever. Thrombocytopenia was uncommon. Other side effects were usually mild to moderate. In 46 evaluable patients, the response rate was 24% (complete response 7%, partial response 17%). Disease stabilization was observed in further 17%. The median duration of response was 12 months (range 5-14) and the median survival was 20 months (range 1 to 45+). CONCLUSIONS: G and V, on day 1 and 8 of 3-weekly cycles, can safely be administered to patients with metastatic breast cancer at the dose of 1200 and 30 mg/m2, respectively. The antitumor activity of G and V in combination was similar to that reported when using either drug as single agent.

Adult↗
PubMed2001

Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34betaE12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung.

Basaloid carcinoma (BC) and large-cell neuroendocrine carcinoma (LCNEC) are 2 recently recognized variants of large-cell lung carcinomas that may overlap in their morphology, and are discriminated by expression of neuroendocrine markers in LCNEC. Because thyroid transcription factor 1 (TTF-1) is expressed in lung adenocarcinomas but not in squamous cell carcinomas (SCC), and 34betaE12 recognizes a set of high-molecular-weight cytokeratins characteristic of basal stem cells, we hypothesized that these 2 markers could help in distinguishing BC from LCNEC. Immunostaining for TTF-1 was detected in 40.9% of pure LCNEC but in no BC or basaloid variant of SCC. In contrast, immunoreactivity for 34betaE12 was shown in all BC and basaloid variant of SCC but in only 1 LCNEC. Bouin fixation was less efficient than formalin in the immunodetection of both markers for its well-known deleterious effect on antigen preservation. Specificity of TTF-1 for LCNEC (100%) and that of 34betaE12 for BC (98.3%) exceeded that of NE markers for distinction of these 2 entities. These data show that TTF-1 and 34betaE12, in association with specific neuroendocrine markers, represent a useful panel of antibodies in differentiating carcinomas presenting with a solid pattern, palisading, or pseudorosettes, the expression of TTF-1 excluding the diagnosis of BC, and staining with 34betaE12 excluding pure LCNEC.

Carcinoma, Large Cell↗
PubMed2001

[Allergic bronchopulmonary aspergillosis disclosing mucoviscidosis].

In predisposed patients, allergic bronchopulmonary aspergillosis (ABPA) can arise from aspergillus bronchial colonization. We report the case of a young woman who presented with a right basal pneumonia, ground glass opacities and mediastinal adenopathies on CT scan. Biological, radiological and clinical criteria, as well as an history of childhood asthma, allowed the initial diagnosis of ABPA. However, the unusual coexistence of an additional infection with Pseudomonas Aeruginosa evoked the diagnosis of cystic fibrosis, confirmed by a sweat test and genetic analysis. Under corticosteroid and antifungal therapy and antibiotics, the clinical and radiological evolution was favourable but immuno-allergic sensitisation persisted. The ABPA-cystic fibrosis association is not rare with an estimated prevalence of 2% to 11% according to previous studies. This variability is partly explained by the difficulty of the diagnosis due to confounding clinical, radiological, and biological signs between ABPA and cystic fibrosis. Many predictive development factors of ABPA in the context of cystic fibrosis have been reported, including respiratory function, personal or familial atopy, colonization with Pseudomonas Aeruginosa and age. As in non cystic fibrosis patients, the treatment requires systemic corticotherapy and itraconazole. ABPA is still often under diagnosed and should be evoked in the context of cystic fibrosis.

Adult↗
PubMed2000

Pulmonary pathology of Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare non-Langerhans' cell histiocytosis that may present with pulmonary symptoms. The condition seems to be nonfamilial and typically affects middle-aged adults. Radiographic and pathologic changes in the long bones are diagnostic, but patients often present with extraskeletal manifestations. Advanced pulmonary lesions are associated with extensive fibrosis that may lead to cardiorespiratory failure. The clinical, radiologic, and pathologic features of six patients with ECD with lung involvement are presented. The patients were three men and three women (mean age, 57). Five presented with progressive dyspnea, and one presented with diabetes insipidus. Open-lung biopsies showed histiocytic infiltrates in a lymphangitic pattern with associated fibrosis and lymphoplasmacytic inflammatory infiltrates. The histiocytes did not stain with periodic acid-Schiff. Immunoperoxidase studies performed on specimens from five of six patients showed that the histiocytes were positive for CD68 and Factor XIIIa and negative for CD1a. Specimens from two patients exhibited immunoreactivity for S-100 protein. Electron microscopy studies performed on specimens from two patients showed phagocytic lysosomes but no Birbeck granules. Clinical follow-up of up to 16 years was available. At the end of that time, five patients were dead of complications related to their disease; one patient remains alive 4 years after diagnosis but with severe respiratory compromise. ECD is a rare non-Langerhans' cell histiocytosis that may present as interstitial lung disease and resemble other pulmonary conditions, particularly usual interstitial pneumonitis and pulmonary Langerhans' cell histiocytosis. Recognition of this entity will allow better assessment of its true incidence, therapeutic options, and prognosis.

Adult↗
PubMed2000

NCAM (neural cell adhesion molecules) expression in malignant mesotheliomas.

Neural cell adhesion molecules (NCAM) are adhesion molecules expressed by neural and neuroendocrine tumors and a few biphasic tumors such as synovialosarcomas and breast phyllode tumors. To investigate NCAM expression in mesotheliomas, we studied 26 cases of epithelioid (n = 12), biphasic (n = 11), and sarcomatoid (n = 3) malignant mesotheliomas (MM), in comparison with normal mesothelium, and 50 primary non-small cell lung carcinomas (NSCLC) (25 adenocarcinomas [ADC] and 25 squamous cell carcinomas [SCC]), using electron microscopy as a gold standard for recognition of MM. NCAM reactivity using 123C3 antibody was compared with that of NE markers such as chromogranin A and synaptophysin. Although normal mesothelium remains negative, NCAM was expressed in 19 of 26 MM (73%) with a membranous staining on frozen or paraffin sections. In 6 of 12 epithelioid MM, the tumor cells expressed NCAM, whereas in 5 cases stromal fibroblasts showed a strong but focal staining. In 11 biphasic MM, 4 presented an NCAM reactivity of both epithelioid and spindle cell components, whereas in 7, only fusiform component was NCAM positive. Two of 3 sarcomatoid MM showed an NCAM expression. Chromogranin expression was never seen, whereas synaptophysin was noticed in 2 cases. No case of NSCLC showed membranous 123C3 staining, whereas 2 ADC weakly expressed synaptophysin. We conclude that NCAM expression in MM is reminiscent of its expression in mesoderm during fetal life and consistent with that reported in other biphasic tumors. These data show that NCAM expression occurs in 73% of MM, highly exceeding that observed in lung cancer.

Adenocarcinoma↗
PubMed1999

Biological markers as indicators of response to primary and adjuvant chemotherapy in breast cancer.

Interest in translational studies on breast cancer is presently devoted to identify biological predictors of treatment response. In patients with operable breast cancer, subjected to primary and adjuvant chemotherapy, we analyzed the predictivity on objective clinical response and relapse-free survival of biological markers related to different cellular aspects and functions. Tumour proliferative rate (evaluated as the (3)H-thymidine-labelling index, TLI), oestrogen and progesterone receptors (ER and PgR, evaluated by the dextran-coated-charcoal method), nuclear DNA ploidy and the immunocytochemical expression of p53, bcl-2 and bax proteins were determined before primary treatment, at the time of diagnosis, and after primary chemotherapy, at surgery. Objective clinical response was significantly related only to pre-treatment p53 expression or PgR status, with a higher rate for tumours not expressing than for those expressing p53 (94% vs. 72%), as well as for PgR-negative (PgR(-)) than for PgR-positive (PgR(+)) tumours (86% vs. 68%). In the overall series, 8-year clinical outcome was significantly related only to post-treatment steroid receptors. In particular, higher 8-year relapse-free survival rate was observed for patients with ER(-) or PgR(-) than for those with ER(+) (64% vs. 38%) or PgR(+) (53% vs. 37%) tumours. Such findings held true even within the sub-set of patients who received adjuvant post-operative chemotherapy, i.e., those with node-positive (N(+)) or ER(-)/node-negative (N(-)) tumours, among whom also rapid proliferation or the presence of apoptosis-favouring markers (bcl-2(-) or bax(+), singly and in association) on surgical specimens identified a sub-set of women who benefited from systemic treatment. The different biological markers were variously indicative of clinical outcome, with a predictivity on tumour shrinkage for p53 and PgR, detected before primary chemotherapy, and on long-term follow-up for ER, PgR and, to a lesser extent, TLI and apoptosis-modulating markers. Int. J. Cancer (Pred. Oncol.) 84:580-586, 1999.

Apoptosis↗
PubMed1999

Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance.

Inactivation of the Rb pathway in non-small cell lung carcinoma (NSCLC) occurs mostly through inactivation of the cyclin-dependent kinase inhibitor p16(INK4A) and/or up-regulation of cyclin D1. In order to assess the frequency and the prognostic value of these abnormalities in NSCLC, immunohistochemical analysis of Rb, p16(INK4), and cyclin D1 has been performed on 168 cases of NSCLC including 77 squamous cell carcinomas, 43 adenocarcinomas, and 48 basaloid carcinomas. The reduced survival rate of basaloid carcinoma (stage I-II) compared with other histological types of NSCLC was confirmed (p = 0.008). Loss of protein expression of Rb and p16(INK4A) was observed in 12 per cent and 58 per cent of NSCLC cases respectively and cyclin D1 overexpression in 43 per cent. There was an inverse correlation between Rb and p16 expression ( p < 0.0001) and a direct correlation between Rb and cyclin D1 expression ( p = 0.0007). In univariate analysis, Rb-negative adenocarcinomas at stages I-II had a significantly shorter survival than Rb-positive cases ( p = 0.04) and stages I-II p16-positive cases had a shorter survival than p16-negative cases ( p = 0.02), which was more significant in basaloid carcinoma ( p = 0.003). p16 status retained its influence on survival in multivariate analysis at stage I-II for all cases ( p = 0.01) and for basaloid carcinoma ( p = 0.005). Cyclin D1 overexpression did not influence survival. Combined Rb/p16/cyclin D1 phenotypes in univariate analysis showed a shorter survival for Rb-negative/p16-positive/cyclin D1-negative tumours ( p = 0.002). These results, linked to previous data, indicate that the Rb pathway of G1 arrest is initially disrupted in the vast majority of NSCLCs (83 per cent), but could not confirm an unfavourable role for each individual event (p16(INK4A) loss or cyclin D1 up-regulation) in prognosis.

Adenocarcinoma↗
PubMed1999

Expression of vascular endothelial growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): correlation with angiogenesis and survival.

The formation of new vessels (angiogenesis) is essential for primary tumour growth and metastasis and is induced by several angiogenic factors, including vascular endothelial growth factor (VEGF). The microvascular density (MVD) in tumours was assessed and the expression of VEGF and its receptors VEGF-R1-Flt1 and VEGF-R2-KDR/Flk1 was investigated in the different cellular compartments in vivo, in order to establish their interrelationship and their prognostic influence. Immunohistochemical study of 69 stage I-II non-small cell lung carcinomas (NSCLCs) was performed on paraffin sections with CD34 antibody to estimate MVD, using a Chalkley eye-piece graticule and VEGF, VEGF-R1, and VEGF-R2 antibodies. There was strong expression of VEGF and its receptors in tumour cells, endothelial cells, and stromal fibroblasts. In tumour cells, the level of VEGF was correlated with that of VEGF-R1 ( p = 0. 018) but not that of VEGF-R2. In fibroblasts, high expression of VEGF was correlated with that of VEGF-R1 ( p = 0.0001) and VEGF-R2 ( p = 0.0001). In endothelial cells, expression of VEGF was correlated with that of VEGF-R1 ( p < 0.0001) and VEGF-R2 ( p = 0.04). The level of VEGF in fibroblasts was correlated with that of VEGF-R1 ( p = 0.0028) and VEGF-R2 ( p = 0.01) in endothelial cells. There was no correlation between the level of MVD and that of VEGF or VEGF-R1 or VEGF-R2. Neither the level of MVD, nor the level of expression of VEGF and VEGF receptors in any compartment influenced the patient's survival. In conclusion, although angiogenesis is essential for tumour growth, this study failed to demonstrate that MVD, VEGF, VEGF-R1, and VEGF-R2 are prognostic markers for stage I-II NSCLC. VEGF, however, might act as a direct autocrine growth factor for tumour cells via VEGF-R1 and angiogenesis could be promoted in a paracrine loop, where VEGF is produced by fibroblasts and tumour cells and then binds to endothelial cells via induced VEGF receptors. VEGF and its receptors thus appear as relevant therapeutic targets in NSCLC.

Adenocarcinoma↗
PubMed1999

Endovascular treatment of superior vena cava obstruction in patients with malignancies.

The aim of this study was to report our experience on the management of superior vena cava obstruction (SVCO) secondary to malignant disease, using endovascular procedures. Twenty-six patients with SVCO due to primary or secondary tumors of the lung or the mediastinum, or catheter inserted for treatment of an extra-thoracic neoplasm, had an endovascular therapy which consisted of stenting, angioplasty, thrombo-aspiration or local fibrinolysis. Immediately after the procedure, rapid relief of symptoms occurred in 24 (90 %) of the patients. The mean Kishi's score decreased from 5.5 to 0.96. Immediate complications included one death related to pericarditis bleeding following fibrinolysis. Three patients relapsed after 20 days, 4 months and 6 months, and needed a second stenting. At 6 months the primary patency rate was 83 % and the secondary patency rate was 89 %. Endovascular treatment of SVCOs is a simple and safe procedure to restore the patency of the superior vena cava in malignant SVCO. It should be indicated in most cases as first-line treatment and performed as early as possible.

Adult↗
PubMed1999

Comparative analysis of breast cancer recurrence risk for patients receiving or not receiving adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF). Data supporting the occurrence of 'cures'.

PURPOSE: To comparatively analyse the risk of recurrence at given times after surgery for breast cancer patients receiving or not receiving adjuvant CMF. PATIENTS AND METHODS: A total of 1452 node positive patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy for operable breast cancer, were examined. In 575 cases no further treatment was performed, whereas 877 pts were given 6 or 12 courses of adjuvant Cyclophosphamide, Methotrexate, Fluorouracil (CMF). The recurrence risk was estimated by the event-specific hazard rate for first failure and distant metastases, and, following Efron, hazard rates were fitted by logistic regression models. RESULTS: The hazard rate for first failure and distant metastases showed a double peaked pattern for both treated patients and controls, with a first major peak at about 18-24 months from surgery (early metastases), a second minor peak at the 5th-6th year, and a tapered plateau-like tail extending over 10 years from surgery (late metastases). As expected, the recurrence risk of CMF treated patients was lower than the corresponding risk of patients undergoing surgery only. However, the difference was highly evident for early recurrences, while it declined and disappeared afterwards. CONCLUSION: Our findings confirm previous reports on patients not receiving adjuvant chemotherapy, suggesting that the recurrence risk for operable breast cancer has a multipeak pattern. As far as CMF treated patients are concerned, the unchanged peak timing together with the early recurrence risk reduction in comparison to controls are much more consistent with the real nonappearance of some early recurrences (putatively 'cured' patients) than with the delay in their manifestation. As late relapsing patients seem to have at most marginal benefits from adjuvant CMF, ways to recognize patients doomed to have late recurrence and new ways for treating micrometastases resulting in late recurrences are required.

Antineoplastic Combined Chemotherapy Protocols↗