Weekday on-weekend off oral capecitabine: a phase I study of a continuous schedule better simulating protracted fluoropyrimidine therapy.

BACKGROUND: Although protracted intravenous 5-fluorouracil is superior to bolus regimens in terms of tumour exposure to the drug during DNA synthesis as well as activity and safety, the oral fluoropyrimidine capecitabine is administered intermittently. In this phase I study, we investigated an alternative, dose-intense continuous regimen. MATERIALS AND METHODS: Oral capecitabine was administered twice daily continuously with weekend breaks, in patients with advanced solid tumours refractory to standard therapy. Dose escalation proceeded from 1,331 to 2,510 mg/m(2) daily. Dose limiting toxicity (DLT) consisted of any grade-3 or 4 adverse event except for alopecia and skin toxicity resolving within 7 days. RESULTS: Twenty-five heavily pretreated patients participated in the study. No DLT occurred in the first four cohorts. Two out of four patients developed grade III diarrhoea in the fourth week of capecitabine at 2,510 mg/m(2) (DLT). The most common toxic episodes during all cycles of treatment were grade 1-2 fatigue, skin erythema, abdominal cramps, nausea, constipation and neutropenia. Disease regression was seen in three and stabilisation with clinical benefit in ten patients (clinical benefit response 54%). Pharmacokinetic studies of capecitabine and metabolites in four patients at 2,250 mg/m(2 )daily showed rapid absorption, short plasma half-lives with the exception of FBAL and absence of accumulation or conversion saturation during the course of therapy. At this dose, administered dose intensity in eight patients was 99.3% of the planned one. CONCLUSIONS: Weekday on-weekend off capecitabine maximizes cytotoxic impact on tumour cells during S-phase by safely simulating protracted fluoropyrimidine therapy at a recommended dose (2,250 mg/m(2)) close to that of the intermittent schedule and clearly higher than the continuous one of 1,331 mg/m(2).

Dermatofibrosarcoma protuberans occuring in a child.

Dermatofibrosarcoma protuberans (DFSP) usually occurs in adults, however it can also occur in infancy and childhood. Diagnosis of DFSP in children is quite difficult given the rarity of the tumor and its variegated appearance. The behavior of this neoplasm is of borderline or intermediate malignancy with a high rate of recurrence but limited metastatic potential. We present the case of an eleven-year old boy who presented with a slightly raised, not tender lesion on his right shoulder. It had appeared two years before as a red-brown plaque and since then it had gradually grown to a nodule. An excisional biopsy was performed, and the diagnosis of DFSP was made based on the histological and immunohistochemical findings.

Cell cycle proteins in laryngeal cancer: role in proliferation and prognosis.

A study of laryngeal carcinomas was performed in order to analyze (a) the expression of p53/p21, cyclin D1/cyclin E, p21/p27 (b) the relation of normal and abnormal protein expression, with the proliferation status, as determined by the expression of Ki67 and PCNA and (c) the correlation of our findings with prognosis. We performed a retrospective analysis of 57 cases of squamous cell carcinomas of the larynx. We applied monoclonal antibodies against p53, p21, p27, cyclin D1, cyclin E, Ki67 and PCNA, using streptavidin-biotin method. Analysis of the p53/p21 proteins, revealed abnormalities in 25/37 cases (67.57%), while 12/37 (32.43%) cases displayed normal phenotype (p53-/p21-). Analysis of cyclins revealed overexpression in 17/48 cases (35.42), while the majority 31/48(64.58%) displayed normal phenotype (cyclin D1-/cyclin E-). Concerning CDKIs expression, the majority 30/50(60%) presented high levels of both inhibitors (p21+/p27+). Cases with simultaneous overexpression of CDKIs demonstrated significantly higher levels of Ki67 protein (p = 0.05). Analysis of p53/p21, cyclin D/cyclin E, p21/p27 patterns showed no association between the presence of one or two alterations and prognosis. In conclusion, we demonstrated that p53 tumor suppressor pathway is frequently disrupted in laryngeal cancer. Furthermore, levels of CDKIs, although they act as cell cycle activity blockers, are not reliable markers for the estimation of laryngeal neoplastic cells growth fraction.

Immunohistochemical expression of cathepsin D in laryngeal epithelial lesions: correlation with CD44 expression, p53 and Rb status and proliferation associated indices.

Clinical studies in several tumour types have shown a strong correlation between cathepsin D expression and tumour progression. Immunohistochemical staining for cathepsin D (clone D13A) was performed in paraffin embedded-tissues from 39 invasive squamous cell carcinomas, 13 in situ carcinomas, 35 cases of dysplasia, 10 papillomas and 17 cases of keratosis. The association between cathepsin D expression and CD44, p53, Rb proteins and proliferation indices (Ki-67, PCNA) was assessed by univariate analysis. Cathepsin D was highly positive in the groups of carcinomas compared to other lesions (p < 0.0001). A statistically significant correlation of cathepsin D expression with CD44 expression was observed in invasive cancers (p = 0.037). The relationship of cathepsin D immunoreactivity with p53, Rb and proliferation indices was insignificant. The results show that cathepsin D is expressed in a higher proportion of cancerous lesions of the larynx than in non cancerous or premalignant lesions, a fact which suggests that cathepsin D may be involved in laryngeal tumour cell growth process.

Angiotropic large cell lymphoma.

A 67 year old man developed "status epilepticus" and died with acute respiratory failure. An autopsy and concomitant histological examination, revealed intravascular infiltrate of lymphoid cells throughout the body. Immunohistochemical studies showed intense positive staining for leukocyte common antigen (LCA), L26 and CD20 and negative staining for Factor VIII- related antigen, and CD5, demonstrated that the neoplastic cells were of B-cell lineage.

Expression of cyclin-dependent kinases inhibitors p21(WAF1) and p27(KIP1) in benign, premalignant and malignant laryngeal lesions. correlation with cell cycle regulatory proteins.

BACKGROUND: Cell cycle progression and transition of cells from the first gap phase (G1) to the DNA replication phase (S) depend on a finely tuned balance between the levels of cyclins, cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs). MATERIALS AND METHODS: We analyzed 57 squamous cell invasive carcinomas of the larynx, 10 in situ carcinomas, 56 cases of dysplasia, 11 papillomas and 26 keratosis. We investigated: a) the immunohistochemical expression of CDKIs, p21 and p27, b) any possible relation between normal and abnormal immunoprofiles of these proteins and p53 protein and proliferation status as determined by the expression of Ki67 and PCNA, and c) their presence in pre-malignant and malignant laryngeal lesions. RESULTS: Expression of p21 and p27 was observed in 58.9% and 89.5% of the laryngeal carcinomas, respectively. High levels of p21 were significantly correlated with increased cyclin D (p=0.001), cyclin E (p<0.001) and Ki67 (p<0.001), while increased expression levels of p27 were associated with p53 accumulation (p=0.02) and with increased proliferation status as expressed by Ki67 (p=0.05). CONCLUSION: Due to the increased expression levels of CDKIs in laryngeal carcinomas, we suggest the existence of a mechanism by which tumor cells tolerate the inhibitory effect of these proteins on cell cycle progression.

An epidemiologic study of acute coronary syndromes in northwestern Greece.

Acute coronary syndromes (ACS) represent the most common cause of morbidity and mortality in the Western world. Relative epidemiologic data for Greece, a Mediterranean country, are sparse. The aim of the study was to determine the incidence and the clinical presentations of ACS. Over a 1-year period we conducted a prospective, population-based survey of ACS cases in an isolated area of northwestern (NW) Greece with 170,000 inhabitants. Every patient living in the study area, aged <80 years, without history of coronary artery disease, who presented with symptoms suspicious for ACS and was hospitalized for at least 24 hours was eligible for inclusion in the study. For sudden cardiac deaths, relative information was obtained from the autopsy report or the physician who documented death. Additional information regarding timing and associated conditions was obtained from relatives. The diagnosis and classification of the studied cases was performed according to World Health Organization and European Society of Cardiology criteria. The authors identified 352 patients (265 men, 87 women, mean age 62.5 +/-10 and 68 +/-9.5 years, respectively) with first-appeared ACS (174 non-ST elevation, 105 ST elevation, 73 sudden cardiac deaths). Fifty-six patients with other forms of ischemic heart disease (stable angina, heart failure, and silent ischemia) were not included in the analysis. Moreover, 154 patients with chest pain and normal appearing EGG at rest, normal values for enzymes (CK, troponin), and negative exercise testing, as well as 77 patients with normal findings from coronary angiography studies, were also excluded. The annual incidence for the age group of 30-79 was 39/10,000 inhabitants (60.6 for men and 19 for women). The incidence of ACS increased with age in both sexes and was higher in men even after the age of 70. About one third of the ACS and half of the sudden cardiac deaths occurred in the age group of 70-79. Only 3 patients were successfully resuscitated. ACS are common in this area of NW Greece and the majority of them present in a form amenable to therapeutic manipulations. Twenty percent of patients died suddenly, and a very small percentage of these were successfully resuscitated. Preventive measures and acute management facilities need to be improved, even in a Mediterranean country where the incidence of ischemic heart disease is relatively lower than in northern European countries.

Expression of the cell-cycle regulatory proteins (cyclins D1 and E) in endometrial carcinomas: correlations with hormone receptor status, proliferating indices, tumor suppressor gene products (p53, pRb), and clinicopathological parameters.

PURPOSE OF INVESTIGATION: This study aimed to investigate the immunohistochemical expression of cyclins D1 and E in normal, hyperplastic and neoplastic endometrium, and their correlation with proliferative activity and clinicopathological features. METHODS: We carried out immunohistochemical techniques on archived material of formalin-fixed paraffin-embedded tissues using the antibodies against the cyclins D1 and E, PR-ER, p53, Ki67 (MIB1) and pRb with the streptavidin-biotin-peroxidase method in a total of 20 cases of normal endometrium, 32 cases of hyperplastic endometrium and 66 cases of endometrial carcinomas. RESULTS: Cyclin D1 and E immunoreactivity was observed in the nuclei of tumour cells in 18.2% and 39.1%, respectively, of the cases of endometrial carcinomas. Cyclin D1 labelling index was not significantly correlated with any of the clinicopathologic parameters examined. However, there was a significant correlation between the cyclin E labelling index and histological grade of carcinoma (p = 0.00096), which increased significantly with histological grades of malignancy. We also detected a significant correlation between cyclin E and PCNA (p < 0.0001) as well as with the tumor suppressor genes p53 and pRb (p = 0.052 and 0.0002, respectively) in endometrioid endometrial carcinoma. CONCLUSION: Our results indicate that cyclin E overexpression may be involved in the development and/or proliferation and differentiation of human endometrioid endometrial carcinoma. Immunoexpression of cyclin D1 does not appear to be associated with cell-cycle progression in the benign or malignant endometrium.

E-cadherin adhesion molecule and syndecan-1 expression in various thyroid pathologies.

UNLABELLED: Cadherins and syndecans are transmembrane glycoproteins implicated in cell-cell and cell-matrix adhesion. Impairment of cadherin and syndecan mediated adhesion is likely to constitute one of the main factors leading to the reduced cell-cell and cell-matrix adhesion characteristics of tumor cells and play a pivotal role in the acquisition of invasive and metastatic proprieties by neoplastic epithelial cells. AIM: To elucidate the role and alterations of syndecan-1 expression in comparison with those of E-cadherin in normal and pathological thyroid glands (TG). METHODS: A total of 55 TG carcinomas, 40 TG adenomas, 40 cases of hyperplastic TG disorders and 20 cases of normal TG autopsy samples, were evaluated by immunohistochemistry. The staining intensity, and localization of syndecan-1 and E-cadherin in sequential sections were examined, and semi-quantified. RESULTS: Immunostaining of syndecan-1 and E-cadherin was strong in normal follicular TG epithelial cells, and located mainly in basolateral membrane. No significant change was seen in either molecule in hyperplastic TG disorders compared with TG adenomas. A significant reduction in expression of both syndecan-1 and E-cadherin was seen in well-differentiated TG carcinomas as compared with normal TG epithelium (p = 0.0001 and p = 0.032, respectively). Similarly, there was a significant reduction of both molecules expression in poorly differentiated and anaplastic TG carcinomas compared to well differentiated tumors (syndecan-1: p = 0.0037; and E-cadherin: p = 0.075). CONCLUSION: Decreased E-cadherin and syndecan-1 expression along with decreasing cellular differentiation may be involved in the complex mechanism of progression of TG pathology.

Expression of matrix metalloproteinase-9 (gelatinase B) in benign, premalignant and malignant laryngeal lesions.

The matrix metalloproteinases (MMPs) are a family of proteolytic zinc-containing enzymes, which are responsible for the breakdown of the extracellular matrix components in pathological and physiological conditions. They are involved in basement membrane disruption, stroma and blood vessel penetration, metastasis and more recently there is evidence that they participate in tumor growth and angiogenic events. Matrix metalloproteinase 2 and 9 (MMP 2 and 9) belong to the gelatinases, a subgroup of MMPs, and have the capacity to degrade the triple helix type IV collagen of basal lamina of the basement membrane. With the present study, we tried to demonstrate the expression of MMP-9 immunohistochemically, comparatively in benign, premalignant and malignant lesions of the larynx. We studied 154 laryngeal lesions including 55 squamous cell carcinomas, 8 in situ carcinomas, 54 cases of dysplasia (of low and intermediate grade), 13 papillomas and 24 cases of keratosis. Overexpression of MMP 9 was observed in 74.4% and 50% in invasive and in situ squamous cell carcinomas respectively. In dysplastic cases, in papillomas and in keratoses the percentage of overexpression was 62.9%, 61.53% and 54.16% respectively and the expression of MMP-9 was significantly higher in invasive squamous cell carcinomas compared to dysplasias (p=0.000004). Also significantly higher was the expression of MMP-9 in dysplastic cases compared to papillomas (p=0.023). The MMP-9 expression was related neither to survival nor to the other available clinicopathological parameters (tumor size, grade, clinical stage, lymph node status and patient age). In conclusion, our study indicates that the expression of MMP-9 is up-regulated in a stepwise fashion, with two main steps, the first one, when a dysplastic lesion evolves and the next one, when the dysplasia progresses to invasive carcinoma.