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P Heikkilä

Publications and source records attributed to P Heikkilä.

At least 19 recordsLinked to original sources
PubMed2006

Tumour-positive sentinel node findings in patients with ductal carcinoma in situ.

BACKGROUND: Our aim was to evaluate the prevalence of and risk factors for tumour-positive sentinel node (SN) findings in patients with ductal carcinoma in situ (DCIS). METHODS: Altogether 1,470 patients underwent sentinel node biopsy (SNB) between April 2001 and March 2005 in our unit. According to a histopathological review, 11 of them had microinvasive and 74 pure DCIS and were included in the study. RESULTS: Five patients (7%) with pure DCIS had SN metastases. Three of them had isolated tumour cells (ITC) only. Axillary clearance without further metastatic findings was performed in three patients. The median histological size of DCIS was larger, 50 (45-60) mm in patients with metastatic SN findings than the median of 18 (2-110) mm in those with tumour-negative SN, P=0.0103. All five patients with metastatic SN findings underwent mastectomy. Metastatic SN findings were detected in one (9%) patient with microinvasive DCIS. CONCLUSIONS: Metastatic SN findings in patients with pure DCIS may be a sign of missed invasion.

Adult↗
PubMed2006

Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides.

Cyclin A has in some studies been associated with poor breast cancer survival, although all studies have not confirmed this. Its prognostic significance in breast cancer needs evaluation in larger studies. Tissue microarray (TMA) technique allows a simultaneous analysis of large amount of tumours on a single microscopic slide. This makes a rapid screening of molecular markers in large amount of tumours possible. Because only a small tissue sample of each tumour is punched on an array, the question has arisen about the representativeness of TMA when studying markers that are expressed in only a small proportion of cells. For this reason, we wanted to compare cyclin A expression on TMA and on traditional large sections. Two breast cancer TMAs were constructed of 200 breast tumours diagnosed between 1997-1998. TMA slides and traditional large section slides of these 200 tumours were stained with cyclin A antibody and analysed by two independent readers. The reproducibility of the two readers' results was good or even very good, with kappa values 0.71-0.87. The agreement of TMA and large section results was good with kappa value 0.62-0.75. Cyclin A overexpression was significantly (P<0.001) associated with oestrogen receptor and progesterone receptor negativity and high grade both on TMA and large sections. Cyclin A overexpression was significantly associated with poor metastasis-free survival both on TMA and large sections. The relative risks for metastasis were similar on TMA and large sections. This study suggests that TMA technique could be useful to study histological correlations and prognostic significance of cyclin A on breast cancer on a large scale.

Biopsy↗
PubMed2006

The prevalence of axillary lymph-node metastases in patients with pure tubular carcinoma of the breast and sentinel node biopsy.

AIMS: We aimed to evaluate the prevalence of and the risk factors for axillary lymph-node metastases in pure tubular carcinoma (PTC) of the breast. The role of axillary staging and treatment in PTC was also evaluated. METHODS: Between March 2001 and August 2004, 33 PTC patients underwent sentinel node (SN) biopsy as a part of their surgical treatment. Level I/II axillary clearance was carried out in case of tumour positive SN findings. To confirm the correct histological diagnosis (PTC, >90% tubular component), the breast tumours were reviewed by an expert breast pathologist. RESULTS: The SN were successfully harvested in all patients. The median number of SN harvested in the axilla was 3 (range 1-10). Nine (27%) of the 33 patients had axillary nodal metastases. The median number of metastatic nodes was 1 (range 1-3). The median size of the SN metastases was 0.5 mm (mean 1.7 mm, range 0.4-5 mm). In six patients, micrometastases were the only tumour positive SN findings. The median histological tumour size was similar, 9 vs 10mm, in patients with or without axillary metastases. The median patient age was 54 (range 44-71) and 57 (range 39-80) years, respectively. After the histopathological review, six of the 27 patients with true PTC had axillary metastases. The review did not significantly change the risk factors for axillary metastases. CONCLUSIONS: Every fourth PTC patient has axillary lymph-node metastases, most often micrometastases. SN biopsy appears as a feasible method for axillary staging in PTC patients.

Adenocarcinoma↗
PubMed2006

Effect of treatment of larynx and hypopharynx carcinomas on serum syndecan-1 concentrations.

PURPOSE: Syndecan-1 is a multifunctional transmembrane heparan sulfate proteoglycan present on a variety of cell types that mediates basic fibroblast growth factor (bFGF) and other growth factor binding. High serum syndecan-1 (S-syndecan-1) ectodomain levels have been found to be associated with poor outcome in lung cancer and myeloma, but little is known about the effect of cancer treatment on S-syndecan-1 levels. We studied S-syndecan-1 levels longitudinally in a series of patients diagnosed with locoregional squamous cell larynx or hypopharynx carcinoma (n=44) and who we treated with surgery and/or radiation therapy. METHODS: S-syndecan-1 and S-bFGF levels were measured with ELISA prior to, during, and following primary treatment of patients. Syndecan-1 expression was assessed from formalin-fixed and paraffin-embedded tumour samples using immunohistochemistry. RESULTS: S-syndecan-1 levels tended to correlate positively with S-bFGF levels, and the pretreatment levels decreased from a median value of 75 to 58 ng/ml 3 months following treatment (P<0.0001). Patients treated with radiation therapy had a transient increase in S-syndecan-1 during the course of radiation therapy. Patients whose S-syndecan-1 decreased >or=10% from the pretreatment level had more favourable survival than those whose levels remained stable or increased (P=0.0069). Recurred cancer was associated with elevated S-syndecan-1 as compared to the levels measured 3 months following completion of primary therapy. CONCLUSIONS: These findings suggest that a part of S-syndecan-1 originates from the cancerous tissue, and that S-syndecan-1 levels generally decrease following successful cancer treatment.

Aged↗
PubMed2004

Transcription factors GATA-4 and GATA-6 in human adrenocortical tumors.

Transcription factors GATA-4 and GATA-6 are expressed during normal adrenocortical development in mice and humans, and in vitro studies have linked them to adrenal steroidogenesis. GATA-4 is highly expressed in the adrenocortical tumors of gonadectomized mice, whereas GATA-6 is down-regulated in the tumor area. Based on these findings we studied GATA-4 and GATA-6 expression in 39 human adrenocortical tumors using RT-PCR, Northern analysis and immunohistochemistry. 6/18 adenomas and 4/11 carcinomas were positive for GATA-4 mRNA. GATA-6 mRNA was expressed in 19/19 adenomas and 9/10 carcinomas, and GATA-6 immunoreactivity was remarkably lower in adrenocortical carcinomas than in adenomas (p < 0.05). Some of the steroidogenically active human adrenocortical cells (NCI-H295R) were weakly positive for GATA-4, whereas steroidogenically inactive cells (ACT-1) were totally GATA-4 negative. In contrast, both cell lines expressed GATA-6. GATA expression patterns similar to the animal models can thus be observed in human adrenocortical tumors, but the pathophysiological significance of these findings remains to be elucidated.

Adenoma↗
PubMed2004

cAMP-dependent protein kinase activation inhibits proliferation and enhances apoptotic effect of tumor necrosis factor-alpha in NCI-H295R adrenocortical cells.

Adrenocorticotropin is the major regulator of adrenocortical development and function. It acts mainly through the cAMP-dependent protein kinase A (PKA) pathway. Our aim was to study the interaction of tumor necrosis factor-alpha (TNFalpha) and the PKA pathway in adrenocortical cell proliferation and apoptosis. The PKA activator Dibutyryl cAMP ((Bu)2cAMP) strongly induced differentiation and inhibited proliferation in the human adrenocortical cell line NCI-H295R (H295R). TNFalpha induced apoptosis of H295R cells. Interestingly, (Bu)2cAMP treatment clearly enhanced TNFalpha-induced apoptosis in H295R cells, but not in another human adrenocortical cell line SW-13, the mouse adrenocortical Y-1 cell line or the human HeLa cell line. This synergistic effect was not due to the (Bu)2cAMP-induced glucocorticoid secretion since dexamethasone had no significant effect on the TNFalpha-induced apoptosis. (Bu)2cAMP treatment rapidly increased the expression of the proto-oncogene c-myc in H295R cells, but not in SW-13, Y-1 or HeLa cells. In transient c-myc transfection assay, c-myc expression associated with decreased expression of the proliferation marker Ki-67 in H295R cells. In conclusion, cAMP-dependent protein kinase activation reduced proliferation and augmented TNFalpha-induced apoptosis in adrenocortical H295R cells, and these effects were associated with increased c-myc expression.

Adrenal Cortex Neoplasms↗
PubMed2003

Lack of histologically suspicious features, proliferative activity, and p53 expression suggests benign diagnosis in phaeochromocytomas.

AIMS: The malignancy of phaeochromocytomas is difficult to predict. Traditionally, only a metastasized tumour is considered malignant. The aim of this study was to assess the histopathological and clinical features, as well as the proliferative activity, and to analyse p53 and p21 expression in 105 phaeochromocytomas. METHODS AND RESULTS: All malignant phaeochromocytomas (n = 8) showed at least one of the histologically suspicious features, i.e. over five mitoses/10 high-power fields, necrosis, capsular or vascular invasion. Malignant tumours were larger, but the age and gender of the patients were not significantly different. All benign (n = 33) and most of the borderline (18/21) adrenal phaeochromocytomas had less than 6% Ki67+ tumour cells, while most malignant tumours (6/7) expressed Ki67 in >6% of the cells. p53+ immunohistochemistry was found in two malignant tumours, while p21 expression did not correlate with malignancy. CONCLUSIONS: These data suggest that the lack of histologically suspicious features, low proliferative activity, smaller size, and negative p53 immunostaining point to a benign diagnosis in phaeochromocytomas.

Adolescent↗
PubMed2003

Retrospective exposure assessment and quality control in an international multi-centre case-control study.

The paper presents the exposure assessment method and quality control procedure used in an international, multi-centre case-control study within a joint Nordic and Italian cohort. This study was conducted to evaluate whether occupational exposure to carcinogens influenced the predictivity of high frequency of chromosomal aberrations (CA) in peripheral lymphocytes for increased cancer risk. Occupational hygienists assessed exposures in each participating country: Denmark, Finland, Italy, Norway and Sweden. The exposure status to a carcinogen or a clastogen was coded in the cohort according to the original CA studies at the time of CA testing, but not for the whole work life. An independent occupational hygienist coordinated harmonization of the assessment criteria and the quality control procedure. The reliability of the exposure assessments was calculated as deviation from the majority of the assessors, as Cohen's kappa and as overall proportion of the agreements. The reassessment of the exposures changed the exposure statuses significantly, when compared with the original cohort. Harmonization of the exposure criteria increased the conformity of the assessments. The prevalence of exposure was higher among the original assessors (the assessor from the same country as the subject) than the average prevalence assessed by the other four in the quality control round. The original assessors classified more job situations as exposed than the others. Several reasons for this are plausible: real country-specific differences, differences in information available to the home assessor and the others and misunderstandings or difficulties in translation of information. To ensure the consistency of exposure assessments in international retrospective case-control studies it is important to have a well-planned study protocol. Due to country-specific environments a hygienist from each participating country is necessary. A quality control study is recommended, to be performed as described, combined with round-table meetings to minimize information bias between the assessors.

Carcinogens↗
PubMed2002

Absent aortic and dysplastic pulmonary valves associated with ventricular septal defect in fetal hydrops.

We describe worsening cardiac failure in a hydropic male fetus with a large ventricular septal defect associated with severe pulmonary and mild aortic regurgitation detected prenatally by echocardiography. The hemodynamic transition after emergency cesarean section at 31 weeks of gestation resulted in amelioration of the pulmonary incompetence but exacerbation of aortic insufficiency causing coronary steal. Death followed withdrawal of support 4 hours after delivery. Autopsy revealed absent aortic valve cusps, dysplastic pulmonary valve, and a large ventricular septal defect.

Abnormalities, Multiple↗
PubMed2001

Pulmonary vascular endothelial growth factor and Flt-1 in fetuses, in acute and chronic lung disease, and in persistent pulmonary hypertension of the newborn.

Respiratory distress syndrome (RDS) and development of bronchopulmonary dysplasia (BPD) are characterized by endothelial cell damage. Persistent pulmonary hypertension of the newborn (PPHN) is a disorder that alters the pulmonary microvasculature. Immunohistochemistry for VEGFA(165), an endothelial cell mitogen, and its receptor Flt-1, was performed on lung tissues from autopsies from four fetuses, three preterm infants, four term infants without primary lung disease, four infants with BPD, and four infants with PPHN. VEGF was measured in tracheal aspirates from 31 preterm infants, 5 intubated term infants without primary lung injury, and 12 infants with PPHN during the first 10 postnatal days, and from 8 infants with BPD. Immunohistochemistry for VEGF and Flt-1 was similar in fetuses, preterm infants, and term infants: for VEGF mostly in bronchial epithelium and alveolar macrophages, and for Flt-1 mostly in vascular endothelial cells and bronchial epithelial cells. In patients with BPD, and PPHN, staining for VEGF and Flt-1 appeared also in Type II pneumocytes. Preterm infants with more severe RDS had lower VEGF than those who recovered. The persistent expression of VEGF and Flt-1 during the fetal and neonatal period supports a physiological role for VEGF in human lung development. The lower pulmonary VEGF in preterm infants with more severe RDS may contribute to the pathophysiology of the acute lung injury. In BPD, the expression of VEGF in alveolar epithelium may represent a compensatory increase after the acute phase of the lung disease. In PPHN, that more cell types express VEGF and Flt-1, and the tendency toward a higher concentration of pulmonary VEGF may represent enhanced production of VEGF in response to impaired endothelial function.

Acute Disease↗
PubMed2001

Cell-specific expression of manganese superoxide dismutase protein in the lungs of patients with respiratory distress syndrome, chronic lung disease, or persistent pulmonary hypertension.

The developmental profile of manganese superoxide dismutase (MnSOD) and its regulation in hyperoxia vary between species. We hypothesized that MnSOD increases in human lung in response to oxygen treatment, although this response could be restricted to certain cell types and depend on gestational age. Therefore, the cell-specific expression of pulmonary immunoreactive MnSOD protein was investigated during development, and in patients with respiratory distress syndrome (RDS), chronic lung disease (CLD), or persistent pulmonary hypertension (PPHN). Throughout ontogenesis, all cell types expressed MnSOD, but the most intense positivity was found in bronchiolar epithelium and (pre-) type-II pneumocytes. MnSOD protein did not increase during development. The MnSOD staining pattern in arterial endothelium was more intense in RDS patients than in age-matched controls, but this may be related to induction of MnSOD by increased blood flow rather than by oxygen. MnSOD expression in other cell types of RDS, CLD, or PPHN patients did not differ from that in age-matched controls. We conclude that, in terms of mitochondrial enzymatic superoxide scavenging capacity, preterm infants are not more vulnerable than term infants to oxygen-induced lung injury at physiological oxygen concentrations. However, the inability to induce MnSOD in response to oxygen treatment may result in a poor outcome.

Embryonic and Fetal Development↗
PubMed2001

High syndecan-1 expression is associated with favourable outcome in squamous cell lung carcinoma treated with radical surgery.

Expression of syndecan-1 is down-regulated in many cellular transformation models. We studied the clinical significance of syndecan-1 expression in 116 squamous cell lung carcinomas treated with radical surgery. Paraffin-embedded tissue samples were immunostained with two antibodies against human syndecan-1 (B-B4 and 104-9). Syndecan-1 expression was higher in well differentiated cancers than in moderately or poorly differentiated cancers with either antibody (P=0.001 for B-B4, and P<0.0001 for 104-9), but no significant association was found with the primary tumour size (T-stage) or the clinical stage. When the median expression (10% of cancer cells positive in B-B4 staining) was used as the cut-off value, cancers with high expression were associated with more favourable survival than those with low expression (the 2-year survival rate corrected for intercurrent deaths 84% vs 61%, P=0.026). However, syndecan-1 expression was not an independent prognostic factor in a multivariate survival analysis. We conclude that syndecan-1 expression decreases in parallel with histological dedifferentiation in squamous cell carcinoma of the lung, and that low syndecan-1 expression is associated with unfavourable outcome.

Adult↗
PubMed2001

Adenovirus-mediated transfer of type IV collagen alpha5 chain cDNA into swine kidney in vivo: deposition of the protein into the glomerular basement membrane.

Gene therapy of Alport syndrome (hereditary nephritis) aims at the transfer of a corrected type IV collagen alpha chain gene into renal glomerular cells responsible for production of the glomerular basement membrane (GBM). A GBM network composed of type IV collagen molecules is abnormal in Alport syndrome which leads progressively to kidney failure. The most common X-linked form of the disease is caused by mutations in the gene for the alpha5(IV) chain, the alpha5 chain of type IV collagen. Full-length human alpha5(IV) cDNA was expressed in HT1080 cells with an adenovirus vector, and the recombinant alpha5(IV) chain was shown to assemble into heterotrimers consisting of alpha3(IV) and alpha4(IV) chains, utilizing a FLAG epitope in the recombinant alpha5(IV) chain. The results indicate that correction of the molecular defect in Alport syndrome is possible. Previously, we had developed an organ perfusion method for effective in vivo gene transfer into glomerular cells. In vivo perfusion of pig kidneys with the recombinant adenovirus resulted in expression of the alpha5(IV) chain in kidney glomeruli as shown by in situ hybridization and its deposition into the GBM was shown by immunohistochemistry. The results strongly suggest future possibilities for gene therapy of Alport syndrome.

Adenoviridae↗
PubMed2001

Increased expression of tenascin in pheochromocytomas correlates with malignancy.

Tenascin is a significant extracellular matrix glycoprotein, which is upregulated in various neoplasias and pathologic processes. Pheochromocytomas are rare tumors of the sympathoadrenal system, whose malignancy is almost impossible to predict. There are no histologic or chemical markers available that would define the malignant behavior of these tumors, except the discovery of metastases. In our search for new markers, we investigated the immunohistochemical expression of tenascin in a large number of pheochromocytomas and paragangliomas. Seven tumors were metastasized and were thus considered malignant. Normal adrenal medulla was tenascin negative. A striking difference was seen between malignant and benign pheochromocytomas. All malignant pheochromocytomas expressed stromal tenascin strongly or moderately, whereas most benign pheochromocytomas (28 of 37, 70%) showed no or only weak immunopositivity. The staining was strong or moderate also in 13 of 28 (46%) of the tumors that showed histologically suspicious features, here called borderline tumors. Paragangliomas showed a more heterogeneous staining pattern, and no significant difference was found between benign and malignant paragangliomas. To our knowledge, this is the first study to demonstrate the expression of tenascin in pheochromocytomas and particularly the enhanced expression in malignant pheochromocytomas. We therefore suggest that tenascin may be associated with the malignant transformation and metastasis of pheochromocytomas. It is also a potential marker predicting more aggressive behavior in pheochromocytomas.

Adolescent↗
PubMed2001

Increased expression of cyclooxygenase-2 in malignant pheochromocytomas.

Pheochromocytomas are rare tumors of the adrenal medulla or the paraganglion system. There are no histological or chemical markers available that define the malignant behavior of these tumors; so far only the discovery of metastases reveals malignancy. Cyclooxygenase (Cox) is the key enzyme in conversion of arachidonic acid to PGs, and two isoforms, Cox-1 and Cox-2, have been identified. Cox-2 has been associated with carcinogenesis, and it is overexpressed in many human malignancies. We have now investigated the expression of Cox-2 in normal adrenal gland, in 92 primary pheochromocytomas and in six metastases using immunohistochemistry and Northern blot and Western blot analyses. Cox-2 protein was expressed in the adrenal cortex, whereas the medulla was negative as detected by immunohistochemistry. Interestingly, all malignant pheochromocytomas (n = 8), regardless of the primary location of the tumor, showed moderate or strong Cox-2 immunoreactivity, whereas 75% of the benign adrenal tumors (n = 36) showed no or only weak immunopositivity. The staining was negative or weak in 79% of the adrenal tumors that showed histologically suspicious features (n = 24), but had not metastasized. Most of the pheochromocytoma samples studied also expressed low levels of Cox-2 mRNA. Our data show that normal adrenal medulla does not express Cox-2 immunohistochemically. However, strong Cox-2 protein expression was found in malignant pheochromocytomas, whereas most benign tumors expressed Cox-2 only weakly. To our knowledge, this is the first report on Cox-2 expression in pheochromocytomas and enhanced expression in malignant pheochromocytomas. These findings suggest that negative or weak Cox-2 expression in pheochromocytomas favors benign diagnosis.

Adolescent↗
PubMed2001

Inhibin/activin betaB-subunit expression in pheochromocytomas favors benign diagnosis.

Malignancy of pheochromocytomas is difficult to estimate on the basis of histopathological features. Good prognostic markers are not available. In our search for new markers to differentiate malignant pheochromocytomas from benign ones we tested the value of inhibin/activin subunit expression. Inhibins are heterodimeric glycoproteins consisting of an alpha-subunit and either a betaA- or a betaB-subunit. Activins are composed of beta-subunits only. Immunohistochemically inhibin/activin betaB-subunit was strongly positive in the normal adrenal medulla, but the cortex was negative. A striking difference was found in inhibin/activin betaB expression between benign and malignant pheochromocytomas. The majority of benign adrenal tumors (27 of 30) showed strong or moderate immunoreactivity, whereas all seven malignant tumors were negative or only weakly positive for inhibin/activin betaB-subunit. The percentage of positively staining cells varied greatly in extraadrenal pheochromocytomas and in those benign tumors that showed over 5 mitoses/10 high power fields, necrosis, or capsular or vascular invasion, here called borderline tumors. Inhibin/activin betaB messenger ribonucleic acid was also found in pheochromocytomas. However, no significant differences in messenger ribonucleic acid levels were found in various types of tumors. Weak immunohistochemical positivity for inhibin/activin betaA-subunit was detected in the adrenal cortex, but the medulla and most of the pheochromocytomas were negative. Our data show that inhibin/activin betaB-subunit is expressed in normal adrenal medullary cells. Strong staining is found in most benign adrenal pheochromocytomas, whereas malignant tumors are almost negative. This suggests that loss of inhibin/activin betaB-subunit expression in pheochromocytomas may be used as an indicator of malignant potential.

Activins↗
PubMed2001

A combination of a chemically modified doxycycline and a bisphosphonate synergistically inhibits endotoxin-induced periodontal breakdown in rats.

BACKGROUND: Chemically modified non-antimicrobial tetracyclines (CMTs) have been shown to inhibit pathologically elevated collagenase (and other matrix metalloproteinase, MMP) activity and bone resorption in vivo and in vitro. METHODS: In the current study, suboptimal doses of CMT-8 (a non-antimicrobial chemically modified doxycycline) and a bisphosphonate (clodronate, an anti-bone resorption compound) were administered daily, either as a single agent or as a combination therapy, to rats with experimental periodontitis induced by repeated injection of bacterial endotoxin (LPS) into the gingiva. At the end of the 1-week protocol, the gingival tissues were dissected, extracted, and the extracts analyzed for MMPs (collagenases and gelatinases) and for elastase, and the defleshed jaws were morphometrically analyzed for alveolar bone loss. RESULTS: LPS injection significantly (P<0.001) increased alveolar bone loss and increased collagenase (MMP-8), gelatinase (MMP-9), and elastase activities. Treatment of the LPS-injected rats with suboptimal CMT-8 alone or suboptimal clodronate alone produced slight reductions in the tissue-destructive proteinases and no significant reductions in alveolar bone loss. However, a combination of suboptimal CMT-8 and clodronate "normalized" the pathologically elevated levels of MMPs, elastase, and alveolar bone loss, indicating synergistic inhibition of tissue breakdown in this animal model of periodontitis. CONCLUSIONS: Combination of a CMT and a bisphosphonate may be a useful treatment to optimally suppress periodontal destruction and tooth loss and in other tissue-destructive inflammatory diseases such as arthritis.

Alveolar Bone Loss↗