Biomedical subjects
Publications and source records attributed to P Davaris.
Connective tissue nevi are benign hamartomas that usually appear as widespread, multiple, papular, skin lesions. They are subdivided into collagen, elastin, proteoglycans and mixed type, depending on their particular histopathologic features, and they often appear as a component of Buschke-Ollendorff Syndrome.
We examined the outcome of patients who developed breast cancer after curative chemotherapy (CHOP) for aggressive non-Hodgkin's lymphoma (NHL) in comparison to the outcome of a retrospectively selected matched-pair group of patients with de novo breast cancer, and evaluated the role of drug resistance-related protein (MDR, MRP, LRP) expression in breast cancer tissue. Twenty-two patients presented with breast cancer (BC) in complete remission after CHOP for NHL. The median age was 62 (49-70) years, each had high/intermediate grade B-cell NHL treated with 6 courses of CHOP, and were in complete remission. These patients were compared to a matched-pair group of de novo BC patients selected from our database over the same time period. Breast cancer tissue was stained by immunohistochemistry for drug resistance proteins LRP, MRP, and MDR. Breast cancer developed after a median of 26 (9-49) months of NHL diagnosis; breast tumor grades 1-2 were seen in 12, and grade 3 in 10 patients; 15 were negative and 7 weakly positive for estrogen and progesterone receptors. Twelve patients were stage IIIA/B, and 10 stage IV and were treated with conventional chemotherapy regimens. All progressed early in liver (n=13), brain (n=9), lung (n=6), bone (n=8), lymph nodes (n=7) and soft tissue (n=5), and received second-line chemotherapy with mitomycin-C + vinblastine or taxanes. The overall survival was 11.8 (6-26) months (p<0.01). Time from NHL to breast cancer development was 19 (14-27) months in patients with positive drug resistance proteins (group A), and 37 (26-56) months in patients with 1 or 2 positive resistance proteins (group B) (p<0.001). In patients with stage IIIA/B disease, there was no difference between the examined and control matched-pair group in median TTP, but there was in overall survival (OS) (23 vs 36 months, p=0.029). In advanced disease, there were more responders in the control vs the examined group (p=0.07). Patients in the control matched-pair group had more prolonged OS when compared to group A patients who developed BC in <24 months from NHL to BC (p=0.017). We conclude that breast cancer developing shortly after a complete response in NHL, is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of drug resistance mechanisms concerning MDR, MRP and LRP indicates that most of these patients have BC that overexpress these proteins leading to the suggestion that these mechanisms might be a part of the aggressive disease phenotype and partially explain the poor outcome.
AIMS: The aim of this study is to identify prognostic factors influencing survival in patients with gastrointestinal stromal tumors (GISTs) and to identify a mathematical model that can predict lifetime expectation. METHODS: One hundred and two patients with GISTs, were followed retrospectively for a median period of 32 months (from 1 to 82 months). Complete follow-up data were available in 72 cases. All tumors were surgically resected and examined by conventional light microscopy, immunohistochemistry and image analysis. The tumors' location, size, histologic characteristics, immunophenotype, proliferative activity index (assessed by proliferating cell nuclear antigen (PCNA) and Ki-67 immunoreactivity) and the apoptotic markers bcl-2 and bax, were considered as potential prognostic factors and were correlated with patient survival. RESULTS: Tumor size >8 cm (p<0.03), presence of necrosis (p<0.02), number of mitoses >5/10 HPF (p<0.01), metastasis (p<0.001), and PCNA index >10% (p<0.004) were significant predictors of poor survival. Bcl-2 protein (p<0.0007) was a favorable prognostic indicator. If all tumors were treated as of uncertain malignant potential, the following mathematic model named GISTs Prognostic Index (GPI), could be formed by the linear regression technique: GPI exp=(49.6 months-Status of metastasis x 22.9185-Size in cm x 0.6801+bcl-2 expression% x 0.2569) (r(2)=0.67) (Prob>F=0.0001). CONCLUSIONS: Tumors' size, necrosis, mitoses, metastasis and PCNA index are independent poor prognosticators, while bcl-2 protein is associated with favorable prognosis. An interesting equation for survival in patient with GISTs has been reported.
Various morphometric characteristics of microvessels, highlighted by means of anti-CD34 immunohistochemical staining, were evaluated in the bone marrow of 52 patients with chronic myeloid leukemia (CML) in chronic phase, in relation to several clinicopathologic parameters. Twenty control bone marrows and 15 cases of CML in blastic phase were also studied. Microvessel density (MVD), total vascular area (TVA) and several size- and shape-related parameters were quantitated in the region of most intense vascularization using image analysis. Overall, the group of chronic phase CML had higher MVD and size-related parameters and more branching microvessels than controls. Blastic phase was characterized by increased numbers of microvessels with a rounder shape and smaller caliber than chronic phase. A positive correlation emerged between marrow fibrosis and MVD as well as between white blood cell counts and rounder vessel sections. No relationship existed between microvascular parameters and Hasford or Sokal prognostic scores. In univariate analysis, overall and progression-free survival were adversely affected by MVD, size-related parameters, increased platelet count, age and spleen size. Multivariate analysis indicated that microvessel area was related to progression-free survival, whereas both MVD and area were significant prognosticators of overall survival, even when Hasford or Sokal scores are introduced into the model. Our data suggest that changes in angiogenic parameters may participate in the conversion of normal marrow to CML and ultimately to blastic transformation. More importantly, MVD and microvessel caliber are significant predictors of patient survival and progression.
The expression of mitosin, a novel proliferation-associated molecule was evaluated immunohistochemically in a consecutive series of 47 patients with primary intracranial benign and atypical meningiomas. Mitosin expression was correlated with proliferation markers Ki-67 (MIB-1), proliferating cell nuclear antigen (PCNA), topoisomerase IIalpha (TopoIIalpha) and mitotic index, as well as with standard clinicopathological parameters and patient outcome. Seven tumors recurred (14.8%) following gross total resection, within a follow-up period ranging from 21 to 108 months (median 60 months). The higher proliferation indices were obtained with mitosin and PCNA and the lower ones with TopoIIalpha. Mitosin labeling index (LI) ranged from 0.1 to 57% (median 3%), with a significant overlapping of values between grades. A significant positive correlation was shown between mitosin LI on the one hand and Ki-67 LI (p < 0.001), or the mitotic index (p = 0.027) on the other. The incidence of recurrence was higher in cases with a mitosin LI higher than 3% (p = 0.048). Univariate analysis disclosed mitosin LI (p = 0.033) along with the mitotic index (p = 0.024) and tumor size (p = 0.028) as significant predictors of shortened recurrence-free survival. In multivariate analysis, the labeling indices of mitosin (p = 0.035) and Ki-67 (p = 0.032), along with tumor size, were shown to provide independent prognostic information, beyond that obtained by standard clinical and pathological parameters. However, as indicated by factor analysis, the prognostic information yielded by mitosin was superior to that provided by the remaining proliferation markers (p = 0.041). We conclude that mitosin immunohistochemical expression, although failing to discriminate between benign and atypical meningiomas, may be of use as a novel cell proliferation marker and as a predictor of tumor recurrence.
Loss of basement membrane integrity during neoplastic invasion may have some direct prognostic significance, which is worth investigating. We studied 151 cases of colorectal adenocarcinomas retrospectively. The aim of the study was to investigate the immunohistochemical expression as well as the distribution of laminin and collagen IV within the basement membranes of cancer cell formations. The results were related to histological grade of malignancy (I, II or III) and Dukes' staging of all tumours as well as to 3-year survival status in 52 patients. Using the immunostaining method of strept ABComplex/HRP and appropriate monoclonal or polyclonal antibodies, we assessed the continuity, the discontinuity of the distribution or the total loss of structural basement membrane components alongside the infiltrating borders of each tumour. The results were evaluated statistically. Either a considerable degree of discontinuity or a total loss of basement membrane components was more common in moderately and poorly differentiated adenocarcinomas (p = 0.002 and p = 0.005 for collagen IV and laminin, respectively) and they seemed to be adversely associated with survival status (p = 0.066 and p = 0.014 for collagen IV and laminin, respectively). Interestingly, no association with the stage of disease was noticed. The results of this study reinforce the value of laminin and collagen IV as possible prognostic factors independently to tumour stage. The total loss or considerable discontinuity of the basement membranes of cancerous cells can be considered as indicators of tumour aggressiveness.
AIMS: alpha-Catenin is a member of the E-cadherin-catenin family of adhesion molecules whose role is essential for the function of the E-cadherin complex. In this study, we have evaluated the expression of alpha-catenin but also of the other catenins (beta-, gamma- and p120-catenin) and E-cadherin in invasive breast cancer and statistically analysed these expressions with known clinicopathological parameters, c-erbB-2 oncoprotein expression and patient survival. METHODS AND RESULTS: Abnormal E-cadherin and beta-catenin expression, especially loss of expression, was associated with lobular histological type of breast carcinomas (P=0.03 and P=0.01, respectively). Abnormal E-cadherin and alpha-catenin expression was associated with high histological grade ductal carcinomas (P=0.01 and P=0.03, respectively). Abnormal E-cadherin and beta-catenin expression was correlated with lymph node metastases (P=0.02 and P=0.05, respectively), while abnormal alpha- and beta-catenin were correlated with the advanced stage of the disease (P=0.04 and P=0.05, respectively). Abnormal p120-catenin expression was associated with loss of PR (P=0.008). Survival analysis demonstrated a statistically significant association between abnormal alpha-catenin expression and poor patient survival (P=0.02). When survival analysis was performed according to the different patterns of abnormal expression, statistically significant associations were seen between cytoplasmic alpha- and beta-catenin expression and poor survival (P=0.006 and P=0.04, respectively). CONCLUSIONS: alpha-Catenin, especially its cytoplasmic expression, seems to be a more sensitive prognostic marker than the other members of the E-cadherin complex in invasive breast cancer.
Astrocytic brain tumours, particularly malignant astrocytomas, are recognized to be highly vascular neoplasms with potent angiogenic activity. Recent research has shown that quantification of microvessel density (MVD), as a measure of the degree of angiogenesis, constitutes a strong prognostic indicator in patients with astrocytomas. However, the significance of other morphometric aspects of microvessel network has not been tested so far. In this report, histological sections from 70 astrocytomas (grades II to IV), immunostained for CD34, were evaluated by image analysis for the quantification of MVD, total vascular area (TVA), and microvascular branching, as well as several morphometric parameters related to vessel size or shape. Minor axis length increased with grade (P = 0.045) but MVD and TVA presented a peak in grade III (P = 0.033 and P < 0.001, respectively). Size and shape related parameters affected survival in univariate analysis of grade IV and grades II/III, respectively. In multivariate analysis, only branching counts, along with age and grade, were the independent predictors of survival. Although MVD, TVA and branching counts were adversely related to disease-free survival in grades II and III (univariate analysis), only TVA remained statistically significant in multivariate analysis. It is concluded that TVA and branching counts are prognostically more informative than MVD for patients with diffuse astrocytic tumours.
Activation of telomerase, present in the vast majority of all human cancers, is associated with elongation of chromosomal telomeres and consequent cell immortalization. Telomere length homeostasis is a dynamic process governed by the negative feedback mechanism of the telomeric repeat binding factor 1 (TRF1) which inhibits the action of telomerase in telomerase-positive cells. In an attempt to investigate markers of tumour growth as possible prognostic indicators in laryngeal cancer, we studied the expression of TRF1 and of the proliferation marker Ki67 on 96 invasive squamous carcinomas of the larynx. A standard three step immunoperoxidase staining method was applied on paraffin sections incubated with appropriate polyclonal antibodies. The percentages of Ki67- and TRF1-immunopositive cancerous cells were calculated by image analysis. Univariate and multivariate statistical analysis of the staining results were performed in order to detect any association of the examined immunomarkers with the tumours' classical clinicopathological variables including nuclear morphometric features as well as with patients' disease-free survival. Ki67 immunostaining was positively linked with advanced patients' age, nodal involvement as well as presence of early recurrence. No relation was found between proliferative fraction and TRF1 immunoexpression. TRF1 was expressed in 55.2% of all cases and was positively linked only to tumour size. Multivariate statistical analysis revealed the presence of lymph nodal metastasis and Ki67 immunopositivity index > or = 20% as significant predictors of relapse. Increased Ki67 immunostaining appears to be a promising marker of tumour aggressiveness in laryngeal cancer. After one point at the tumour's natural history, the maintenance of tumour growth does not seem to depend on cell proliferation but on TRF1 immunoexpression. Whether the latter can be used for the identification of immortalized cells in every-day practice is worth investigating.
The objective of this study is to investigate whether image cytometry is a sensitive and specific method for the differential diagnosis of equivocal cells in routine cytology of effusion smears. One hundred four effusion smears were studied from routine cytologic material. Cytologically 56 (53.8%) of the smears were classified as malignant, 26 (24%) as suspicious and 22 (21.1%) as benign. Two morphometric variables (nuclear major axis length and nuclear area) of the nuclei were measured by an image analysis system. Higher values for the area were found for malignant rather than benign and suspicious cells (p < 0.0005 and p < 0.005 respectively). The same result was extracted for the nuclear major axis length values (p < 0.0005 and p < 0.0005 respectively). Values of nuclear major axis length and nuclear area didn't differ significantly between benign and suspicious cells (p = 0.071 and p = 0.066 respectively). The results show that the range of the values for suspicious cells is closer to the range of the benign cells. Cytomorphometry of the effusion smear cells may provide important information for the differentiation of atypical mesothelial cells from malignant adenocarcinoma cells.
The aim of this study was to investigate the nuclear and angiogenetic profile in different types of thyroid neoplasms and to make any possible statistical comparison between the different nuclear morphometric and angiogenetic parameters, in order to search for new diagnostic and prognostic criteria. Sixty two cases of thyroid neoplasms were classified as follows: 31 papillary carcinomas, 10 follicular neoplasms (5 adenomas and 5 carcinomas), 5 undifferentiated carcinomas, 6 Huerthle-cell carcinomas and 10 medullary carcinomas. Using an image analysis system, six nuclear morphometric and eight angiogenetic variables were measured for each case. Concerning nuclear morphometric variables, statistical differences were found mainly between undifferentiated and overall subtypes of differentiated carcinomas, as well as between follicular adenomas and carcinomas. Concerning angiogenesis variables, statistical differences were found only in the vessel's minor axis length between undifferentiated and overall subtypes of differentiated carcinomas, between MVD of follicular adenomas and carcinomas respectively, as well as between MVD of medullary carcinoma and follicular cell carcinomas generally. In conclusion nuclear morphometry and quantitation of angiogenesis could offer two additional parameters in the distinction between follicular adenomas and carcinomas. However, they cannot serve as absolute diagnostic criteria since they are only based on statistical differences. From a prognostic point of view, nuclear morphometry may have some relevance as far as follicular-cell neoplasms are concerned since the more aggressive anaplastic carcinomas have a distinct morphometric profile. Moreover, our study revealed differences in the angiogenetic profile between medullary and follicular cell carcinomas.
The distribution of glucocorticoid receptor in subcellular fractions of brain cortex and hippocampus, two regions rich in glucocorticoid receptor, has revealed its presence in nuclei, cytosol, mitochondria, synaptosomes, and synaptosomal mitochondria. The identification of glucocorticoid receptor has been accomplished both by Western blotting using antibodies recognizing the carboxy and the amino terminus of the glucocorticoid receptor and by immunogold electron microscopy using the same anti-glucocorticoid receptor antibodies. Antibody-glucocorticoid receptor interaction is abolished by preincubation of each antibody with its competing peptide. In addition to the intact 95-kDa glucocorticoid receptor in all fractions, lower molecular weight glucocorticoid receptor fragments have been also detected by Western blotting. The presence of glucocorticoid receptor in brain mitochondria supports the concept of a direct action of glucocorticoids on mitochondrial gene transcription, parallel to the established primary actions of the hormones on nuclear gene transcription, as a mechanism of coordinate regulation of respiratory enzyme biosynthesis by steroid hormones.
BACKGROUND: The aim of this observational study is to examine cases of upper respiratory atresia, in an effort to seek pathogenetic evidence suggestive of either a primary defect in embryogenesis or of a secondary etiology. METHODS: Archival material of 412 fetal and perinatal autopsies with congenital malformations was reviewed in an effort to identify infants with complete upper airway obstruction without tracheoesophageal (TE) communication. Histological sections of the upper and lower respiratory tract were examined, seeking evidence of previous amniotic fluid or meconium aspiration, indicated by the presence of amniotic squamous epithelial cells, lanugo hair, or bile-stained meconium in the airways. Immunohistochemical stain for epithelial membrane antigen (EMA) and high-molecular-weight cytokeratin (CK1) were used to identify amniotic fluid and keratinizing squamous epithelial cells. RESULTS: Eight infants with upper airway obstruction were identified, three of them without a TE communication. Two of the latter, one infant with multiple atresia born at 34 weeks gestation and another with tracheal atresia born at 32 weeks, presented evidence of amniotic fluid aspiration in their lungs. CONCLUSIONS: Evidence of amniotic fluid aspiration in the above two cases indicates that there had been a previous patency of the upper respiratory pathway, since the absence of a TE fistula excludes any communication with the oronasal cavity. This implicates a secondary pathogenesis for at least some cases of upper airway obstruction.
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BACKGROUND AND PURPOSE: We have recently shown that hypoxaemic reperfusion, after an ischaemic brain insult, improves neurological outcome and decreases lipid peroxidation. In the present study, we investigated the effect of hypoxaemic reperfusion on brain histopathological changes. METHODS: Sixteen pigs subjected to a 10-min global cerebral ischaemia were either hypoxaemically (PaO2 = 35 mmHg, hypoxaemic reperfusion (HR) group, n = 8) or hyperoxaemically (PaO2 > 300 mmHg, control (C) group, n = 8) reperfused. The brains were removed 24 h after reperfusion and six neuropathological abnormalities were evaluated blindly and scored semi-quantitatively (0: normal to 3: severe injury) on eight representative regions of the brain. The overall cumulative score of the abnormalities and their regional prevalence, as well as the neurological outcome, were compared between the two groups. RESULTS: The neuronal degeneration, assessed in terms of cumulative score (P = 0.002) and regional prevalence (P = 0.025 to P = 0.041), was lower in the HR group than in the C group. Spongy degeneration attained statistically significant difference only in cerebellum (P = 0.002) and inflammation only in hippocampus (P = 0.046) but the difference in the cumulative score of these abnormalities was not statistically significant. The difference of the three neurological assessments over time was statistically significant between the two groups, i.e. after resuscitation (P = 0.001), at 8 h (P = 0.006) and at 24 h (P = 0.001) after reperfusion. CONCLUSIONS: Hypoxaemic reperfusion during resuscitation from a severe global ischaemic cerebral insult is associated with statistically significantly fewer histopathological changes of the brain than in controls. This is associated with a superior neurological outcome.
Recent research has shown that neovascularization, quantitated by microvessel density (MVD), constitutes a strong prognostic indicator in patients with invasive urothelial carcinomas. These studies, however, have focused only on MVD as the only factor reflecting angiogenesis in transitional-cell carcinomas (TCCs). The objective of this report was to evaluate multiple morphometric microvascular characteristics besides MVD in superficial and muscle-invasive TCCs separately, to provide a better approach to the relationship between angiogenesis, clinicopathological parameters, and prognosis. Histologic sections from 115 TCCs [35 superficial (T1) and 80 muscle-invasive] were immunostained for CD31 and evaluated using image analysis for the quantitation of MVD, area, total vascular area, major axis length, minor axis length, perimeter, compactness, shape factor, and Feret diameter. Patients were followed-up until death (n=31) or for an average of 42.2 months (median 38.5 months). MVD increased with progressing T category (P=0.049) but area (P=0.033), major axis length (P=0.022), perimeter (P=0.043), and Feret diameter (P=0.042) were highest in T2 tumors. Area was the single independent predictor of adverse significance in T1 TCCs, whereas for muscle-invasive tumors, survival was independently predicted by MVD. Regarding disease-free survival in superficial tumors, the single significant independent parameter was compactness, whereas area was an independent favorable indicator of disease-free survival for patients with invasive TCCs. It is concluded that the prognostic significance of neovascularization is better assessed by area and shape-related morphometric characteristics, whereas MVD becomes influential only with regard to overall survival of patients with invasive tumors.
Precise quantitation of apoptotic cells in meningiomas is necessary to determine the role of apoptosis in tumor growth and recurrence. In this study, we investigated the incidence of baseline apoptosis in relation to p53 and bcl-2 protein expression, proliferation status as expressed by Ki-67, PCNA and mitotic counts, standard clinicopathological parameters and patients' outcome, in a series of 59 patients with primary intracranial benign and atypical meningiomas. Seven tumors recurred (11.9%) following complete surgical resection, within a follow-up period ranging from 21 to 108 months. Apoptotic fractions were quantified immunohistochemically by means of a novel monoclonal antibody recognizing exposed single-stranded (ss) regions in the DNA of apoptotic cells during heating. Tissues consisted of archival formalin-fixed paraffin-embedded meningioma specimens. The apoptotic index (AI) ranged from 0% to 2.90% (mean: 0.50%), increased with proliferative activity (p = 0.014), had lower values in transitional meningiomas (p = 0.001) and was unrelated to grade and p53 expression. Increased AI predominated among bcl-2 negative tumors (p = 0.041) and tended to be accompanied by a shortened recurrence-free survival, in univariate (p = 0.0407) as well as in multivariate analysis (p = 0.0405). These results implicate apoptotic rate in meningioma growth and recurrence and denote that assessment of apoptotic potential by means of anti-ssDNA monoclonal antibody provides valid prognostic information irrespective of other parameters.
Considering the recently stated suggestion of neovascularization being implicated in myelodysplastic syndromes (MDS) pathogenesis, we evaluated multiple morphometric microvascular characteristics in MDS, in relation to clinicopathologic factors and prognosis. Trephines from 50 newly diagnosed MDS patients were immunostained for factor VIII and compared to those from 20 controls, 10 chronic myelomonocytic leukemia (CMML) and 12 acute myeloid leukemia (AML) patients. Quantitation of microvessel density (MVD), area, total vascular area (TVA), major and minor axis length, perimeter, compactness, shape factor, Feret diameter, and the number of branching vessels was performed by image analysis. Overall, the MDS group had significantly higher MVD, TVA, minor axis and shape factor values and significantly lower compactness than the control group. AML was characterized by increased vascularity compared to MDS and CMML, as well as by the presence of flattened microvessels (lower values of shape factor). Hypercellular MDS showed higher MVD. RA/RARS displayed larger caliber vessels than RAEB, which explains the favorable prognostic effect of increased size-related parameters on progression and/or survival. Moreover, decreased compactness and MVD were independent predictors of longer progression-free survival. It is concluded that angiogenesis is involved in the conversion of normal marrow to MDS and ultimately to AML and that disease progression within MDS is accompanied by qualitative alterations of the microvascular network. Furthermore, size-related parameters affect survival, while shape-related parameters and MVD are more influential with regard to progression-free survival.