Recurrent deep vein thrombosis, ovarian carcinoma and antibodies to mitochondria M5 in a patient with asymptomatic primary "plus" antiphospholipid syndrome: an unusual combination.

An asymptomatic thirty-eight-year-old female developed recurrent DVT at the latter end of her first pregnancy and in the puerperium. Blood tests revealed a moderately elevated ANF (1:640) with a speckled pattern, hyperglobulinemia, and antibodies to thyroid tissues. Two months postpartum, following neurological disturbances she was found to have a patent foramen ovale and had developed paradoxical emboli to the brain causing multiple arterial occlusions. However, she also had cerebral venous occlusions as well as deep venous thromboses and pulmonary emboli, indicating a generalised prothrombotic state. Abdominal ultrasound examination revealed the presence of tumour which, on surgical removal, proved to be an ovarian carcinoma. The only antiphospholipid antibodies detectable were antibodies to mitochondria Type M5 in moderately elevated titres.

Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors.

Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity. We compared the anti-inflammatory effects of roflumilast with those of PDE4 inhibitors rolipram, piclamilast, and cilomilast in ovalbumin (OVA)-sensitized and challenged Brown-Norway rats. Animals were treated orally 1h before OVA challenge with roflumilast (0.3, 1.0, and 3.0mg/kg), rolipram (0.8, 2.8, and 8.3mg/kg), piclamilast (10.0, 20.0, and 30.0mg/kg), or cilomilast (10.3, 34.3, and 103.0mg/kg). Airway hyperresponsiveness (AHR) against adenosine was investigated by measuring airway resistance 200min after OVA challenge. Subsequently, neutrophil influx and tumor necrosis factor-alpha (TNF-alpha) release in the lungs were determined by bronchoalveolar lavage. Direct bronchodilation at the time point of AHR assessment by PDE4 inhibitors was examined in serotonin-challenged animals. Evaluation of neutropenic animals or treatment with anti-TNF-alpha antibody revealed that AHR was independent of neutrophil accumulation or TNF-alpha release. Roflumilast (50% inhibitory dose [ID(50)]=1.5mg/kg) inhibited AHR 3-, 16-, and 27-fold more potently than rolipram, piclamilast, and cilomilast, respectively. Likewise, roflumilast was a more potent inhibitor of neutrophil influx (ID(50)=0.9mg/kg) than rolipram (ID(50)=6.9mg/kg), piclamilast (ID(50)=28.1mg/kg), or cilomilast (ID(50)=37.7mg/kg). Roflumilast, rolipram, and piclamilast-but not cilomilast-suppressed OVA-induced TNF-alpha release in a dose-dependent manner. Roflumilast (ID(50)=0.9mg/kg) exhibited 9- and 23-fold more potent inhibition of TNF-alpha release than rolipram and piclamilast, respectively. Roflumilast did not inhibit serotonin-induced bronchoconstriction 4.5h after administration, suggesting that inhibition of AHR by roflumilast results from anti-inflammatory, not bronchodilatory, effects. This study suggests that roflumilast has anti-inflammatory action and provides rationale for the investigation of roflumilast in asthmatic patients.

Assessing patient safety risk before the injury occurs: an introduction to sociotechnical probabilistic risk modelling in health care.

Since 1 July 2001 the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has required each accredited hospital to conduct at least one proactive risk assessment annually. Failure modes and effects analysis (FMEA) was recommended as one tool for conducting this task. This paper examines the limitations of FMEA and introduces a second tool used by the aviation and nuclear industries to examine low frequency, high impact events in complex systems. The adapted tool, known as sociotechnical probabilistic risk assessment (ST-PRA), provides an alternative for proactively identifying, prioritizing, and mitigating patient safety risk. The uniqueness of ST-PRA is its ability to model combinations of equipment failures, human error, at risk behavioral norms, and recovery opportunities through the use of fault trees. While ST-PRA is a complex, high end risk modelling tool, it provides an opportunity to visualize system risk in a manner that is not possible through FMEA.

Bone turnover markers in serum and periodontal microenvironments.

BACKGROUND: Periodontitis is characterized by altered bone turnover, but local measurements are difficult. OBJECTIVES: The objective of this study was to develop a method to measure multiple markers of bone turnover from single samples collected at various bone surfaces of the periodontium, and to test the ratios of these markers against more traditional serum and gingival crevicular fluid (GCF) samples. MATERIALS AND METHODS: Fourteen subjects with untreated periodontitis were recruited for sampling serum, GCF (from sites > or = 5 mm probing depth that bled on probing) and washes of periodontal bone surfaces (adjacent interproximal, vestibular cortical and trabecular bone) with a novel irrigating device. All samples were analyzed for osteocalcin (OC, bone turnover marker; RIA), cross-linked N-telopeptide of type I collagen (NTx, bone resorption marker; ELISA) and albumin (Alb, serum protein; ELISA). Results were reported as ratios: OC/NTx to determine relative bone turnover, and OC/Alb or NTx/Alb to determine local OC or NTx production. RESULTS: The OC/NTx ratio was significantly higher (p < or = 0.05) in serum vs. GCF (OC undetectable), interproximal bone and cortical vestibular bone, but significantly lower than in trabecular vestibular bone. The OC/Alb ratio for serum was also statistically lower than for vestibular trabecular bone. The NTx/Alb ratio for serum was statistically lower than for GCF and all the bone wash test sites. The results indicated considerable local production of both OC and NTx. CONCLUSIONS: This system demonstrated that multiple markers of bone turnover can be harvested by irrigation from periodontal bone microenvironments. Bone turnover profiles from periodontal bone surfaces and GCF differed from systemic bone turnover profiles (serum) and may be valuable in tracking site-specific responses to disease or treatment.

Effects of locally-delivered human macrophage products and estrogen on murine inflammatory bone resorption.

The objective of this study was to use an in vivo model of periodontitis (mouse calvaria) to quantify the effects of local release of secreted human macrophage products, 17beta-estradiol (E2), and proinflammatory lipopolysaccharide (LPS) on histologic bone resorption. Human THP-1 monocytes (106) were converted to macrophage phenotype by 500 ng/ml phorbol 12-myristate- 13-acetate (PMA) and treated as follows: no stimulation or Escherichia coli LPS (10 microg/ml) alone or in combination with a physiologic dose of E2 (100 pg/ml) for 24 h in RPMI/10% FBS, washed extensively, then incubated for 24 h in serum-free media. Supernatant products were concentrated and incorporated into a 4% (w/v) methylcellulose gel. Separate gels were incorporated with the following: LPS (500 microg/animal) alone, high dose of E2 (10 ng/animal) alone, a combination of LPS + E2, or gel only (controls). Loaded or control gels were placed into a polylactic acid occlusive dome, inserted subcutaneously over the calvaria of mature ovariectomized ICR Swiss mice (8 mice x 7 groups x 2 times [5/14 days] = 112 animals), then calvaria were evaluated histologically. Macrophage stimulation with LPS alone, but not LPS in combination with E2, produced supernatants which upregulated osteoclast numbers in the suture area compared to gel controls at 5 days (p = 0.009). The addition of LPS directly to the local delivery gels significantly upregulated osteoclasts in endosteal surfaces compared to gel controls at 5 days (p = 0.024) and at 14 days (p = 0.025). The addition of E2 to LPS down-regulated resorption to a level not different from gel controls at 14 days. This in vivo model appears effective in studying inflammatory bone resorption, which may be inhibited by E2 directly or through its influence on secreted macrophage products.

Systemic delivery of cetrorelix to rats by a new aerosol delivery system.

PURPOSE: To study the pulmonary absorption and tolerability of various formulations of the decapeptide cetrorelix acetate in rats by a new aerosol delivery system (ASTA-ADS) for intratracheal application. METHODS: Using the ASTA-ADS, cetrorelix liquid formulations (aqueous solutions for ultrasonic nebulization) were firstly selected and subsequently delivered as nebulized aerosol to orotracheally cannulated rats. The pharmacologic effect (decrease of testosterone serum level) of four cetrorelix formulations was determined in rats by enzyme linked immunosorbant assay, and pharmacokinetic data were determined after measurement of cetrorelix serum level by radioimmunoassay. Histological examination of the lung was performed at the end of the experiments, and in a supplementary experiment the respiratory parameters (resistance and compliance) of rats were monitored by a validated pulmonary monitoring system during the aerosol application of the same formulations. RESULTS: After an exposure time of 5 min, the applied formulations reduced the testosterone concentration in serum to subnormal levels (< or =1 ng/ml) over a period of 24 h. Comparing the plasma concentration after intratracheal aerosolization with data of intravenous administration, the mean calculated bioavailabilities for the four formulations using the corrected dose (delivered--exhaled amount) were between 48.4 +/- 27.0% and 77.4 +/- 44.0%. The histologic examination of the lungs revealed different tolerability of the various tested formulations ranging from locally intolerable to well tolerated. The measurement of the lung function parameters did not reveal any compound or formulation related changes. CONCLUSIONS: Our studies show that cetrorelix can be effectively administered as aerosol and that intratracheal aerosolization via the ASTA-ADS provides results that are well comparable to other application routes, as demonstrated by statistical comparison of the newly obtained data with previous results from intratracheal instillation of cetrorelix solutions in rats.

Detection of serum autoantibodies to tumor suppressor gene p53 with a new enzyme-linked immunosorbent assay in patients with ovarian cancer.

Sera from 99 ovarian cancer patients were assayed for serum autoantibodies to p53 using a newly developed enzyme-linked immunosorbent assay (ELISA). Results were compared to the investigation using the former ELISA. The incidence of autoantibodies (25%) was lower using the newly developed ELISA as compared to the previous results (41%). The results were consistent in 79% of patients (P < .001). The incidence of autoantibodies was lower in patients with complete remission (19%) as compared to that of patients with recurrence (30%) and before primary surgery (26%). No statistically significant correlation was found among p53 serum autoantibody status and tumor stage, degree of malignancy, histologic subtype, and residual tumor after primary surgery. Use of the newly developed ELISA resulted in a higher consensus between immunohistochemically negative and autoantibody negative cases. Owing to further purifying of the prepared human recombinant p53. the newly developed ELISA seems to be of higher specificity as compared to the former ELISA.

Outcomes associated with supportive periodontal therapy in smokers and nonsmokers.

PURPOSE: This study evaluated the effects of smoking status on retrospective clinical and radiographic measures of periodontal disease and compared these to prospective changes in digital radiographic bone height. METHODS: Clinical data on moderate (4 to 6 mm) and severe (> 6 mm) periodontal pocket depths, and bleeding on probing, were obtained from 95 subjects on suggested three-month supportive periodontal therapy (SPT) for AAP Class III/IV periodontitis. Standardized radiographic data were obtained concerning posterior interproximal alveolar bone height from 36 of the 95 subjects using computer-assisted digital technology at baseline and one year later. The subjects were divided into groups by smoking status: current, former, and never. Data were evaluated using a general linear statistical model. RESULTS: Evaluation of clinical data showed that current smokers exhibited a significantly higher percentage of moderate (18%) and severe (1%) periodontal pockets than nonsmokers (10% and 0%, respectively; p < 0.002). Baseline radiographic interproximal bone height loss also was greater in current smokers (5.75 +/- 1.07 v. 4.64 +/- 1.16 mm). Bone loss over one year occurred in 5% of the sites, but was not significantly different among groups. CONCLUSION: Clinical periodontal pockets and bone loss accumulated more rapidly in smokers, even though they submitted to regular supportive periodontal therapy. Although this population was clinically compliant over a one year period, digital radiography showed a high incidence of detectable bone loss. The impact of smoking, however, may require longer than one year to show longitudinal changes. It is recommended that a periodic radiographic analysis on bone height be considered during SPT, and longer term studies be conducted in order to accurately identify the outcome of smoking status on this variable.

ELISA-Based Quantification of p105 (c-erbB-2, HER2/neu) in Serum of Ovarian Carcinoma.

The most important prognostic parameters for gynecologic malignancies are tumor stage, residual tumor after surgical treatment, histological subtype, and degree of malignancy (1-2). However, these factors present an incomplete picture of the tumor biology. Therefore, investigation of other prognostic factors is of special clinical relevance, particularly in view of the unexpectedly progressive course of the disease and frequent relapses in some cases.

Differential Expression of Apoptosis-Associated Genes bax and bcl-2 in Ovarian Cancer.

The deregulation of the balance between proliferation and programmed cell death is considered one of the most important features of malignant tumors. The search for new markers, which may reflect the tumor progress and response to various therapy regimens, has recently focused on alterations of genes involved in regulation of programmed cell death and apoptosis. The bcl-2-family is a still growing family of genes, which play a major role in regulation of cell suicide, acting either as inhibitors (e.g., bcl-2, bcl-xl, mcl-1) or promoters (e.g., bcl-xs, bax, bak, bad) of apoptosis (1-3). The chromosomal translocation t(14;18), leading to overexpression of the Bcl-2 protein was first described in human B-cell lymphoma (4). Later on, Bcl-2-overexpression without chromosomal translocations was also detected in various epithelial tumors (5-12). It has been suggested that Bcl-2 as the major inhibitor of apoptosis plays a role in tumor development and progress by prolonging the survival of malignant cells. Unexpectedly, expression of Bcl-2 has been shown to be connected with parameters of favorable prognosis and prolonged survival in nonsmall-cell lung cancer (6), breast (7-9), and, recently, in ovarian cancer (10-12). Bax-expression, in contrast, was associated with an unfavorable outcome, as well as negative histopathological features in breast (13) and ovarian cancer (12). Moreover, the association of Bax-expression with predictors of poor clinical outcome was strongly connected with concomitant downregulation of Bcl-2-expression (12,13). The unexpected effect of Bcl-2- and Bax-expression on prognosis of ovarian cancer patients is underlined by the survival curves of patients. Especially, patients with exclusively Bax-positive tumors had a statistically significantly reduced survival as compared to patients with exclusively Bcl-2-positive tumors (12). This difference could be observed for patients with tumors of different stage and grade, as well as for patients with no evidence of disease or residual tumor after primary surgery (12). One explanation for these observations is that the apoptosis inhibiting or promoting effect of these homologous proteins depends partly on protein-protein interactions. Bax, for example, the main antagonist of Bcl-2, heterodimerizes with Bcl-2 or Bcl-Xl and homodimerizes with itself (1-3). The ratio of Bax-heterodimers to Bax-homodimers seems to be the critical determinant for regulating cell death (2,3). In cells in which 80% of Bax is found in homodimers, an apoptotic signal results in cell death (2,3), suggesting a crucial role of the Bax/Bcl-2 balance for the regulation of proliferation or cell suicide.

Animal models of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), which encompasses both chronic bronchitis and emphysema, is one of the most common respiratory conditions of adults in the developed world. Despite the high prevalence and enormous cost to healthcare and society, COPD has received scant attention in comparison to other respiratory conditions such as asthma and lung cancer. It is often thought of as a self-inflicted disease. But not all people who smoke develop COPD and not all patients with COPD are smokers. The causes of COPD are different. Its pathogenesis is complex. There are very few effective treatments. Therefore, there is an urgent need to improve present therapy by drugs with new modes of actions. In contrast to many human diseases, chronic bronchitis and emphysema occur seldom in the animal world. Therefore, we have to mimic some characteristic features of these diseases in animals. For this reason, a wide variety of animal models have been developed and are employed in the search for new chemical entities for the treatment of COPD. In the present paper, the experimental models of COPD are critically reviewed.

[Acute hemorrhage in Crohn's disease]. / Akutní krvácení u Crohnovy choroby.

The authors present a case of profuse haemorrhage into the lower part of the digestive tract in a 17-year-old patient where Crohn's disease of the terminal ileum and right colon up to the hepatal flexure was diagnosed by sonographic examination. The haemorrhage occurred after preparation for coloscopic examination with Fortrans only 2 months after the onset of the first symptoms of the disease. Because of developing signs of haemorrhagic shock emergency surgery was necessary. Resection of the terminal ileum and dextrolateral hemicolectomy was performed and during operation coloscopy to eliminate further sources of haemorrhage. The patient recovered p.p.i. and was discharged on the 10th day after surgery. The authors discuss diagnostic and therapeutic pitfalls of this rare complication of Crohn's disease and compare their findings with data from the literature.

Therapy of bronchial asthma with adenosine receptor agonists or antagonists.

Adenosine is an endogenous nucleoside that is released under pathological conditions and interacts with four G-protein-coupled receptor subtypes. These receptors are widely distributed throughout the body. They are involved in many central and peripheral processes, including immunological and inflammatory responses. In inflammatory and asthmatic conditions, the extracellular concentration of adenosine increases in the airway tissue. It enhances mast cell degranulation and bronchoconstriction, but may also inhibit eosinophil or lymphocyte function or modulate reactive oxygen species generation in neutrophils. Despite a large number of studies clearly indicating the effects of adenosine in vitro, many aspects of the mechanisms involved in the adenosine-mediated responses are still unclear, and our knowledge is limited in understanding the complex multifactorial interactions occurring in the whole body. The discovery of adenosine receptor compounds acting with increasing selectivity will bring new approaches to the use of adenosine receptor agonists and antagonists and may clarify some of the current uncertainties. On the basis of our present knowledge, the development of adenosine A(2A)- or (A3)-receptor agonists as antiinflammatory agents or A(2B)-receptor antagonists as inhibitors of mast cell degranulation for the treatment of asthma holds promise.

Comparison of methods for measuring root and mucogingival sensitivity.

OBJECTIVE: The aim of this study was to compare the variability of measurements of root and mucogingival sensitivity over a 24-hour period. STUDY DESIGN: Sixteen individuals (46.8 +/- 3.2 years old) were randomly tested for pain thresholds with calibrated electrical stimulation of the root and adjacent mucosa (electric pulp tester), pressure on mucosa (pressure-sensitive probe), and cold on the root (experimental thermocoupler probe) at baseline and after 4, 8, and 24 hours. Variability between and within subjects was estimated by using analysis of variance for random effects. RESULTS: Intrasubject variability was highest for electric testing of the root and lowest for cold testing of the root across time. Of all subjects, 93% fell within 5 degrees C at all periods for the cold stimulation/moderate pain threshold. CONCLUSIONS: Calibrated cold stimulation of root areas appears to provide the most sensitive measure to assess therapeutic interventions to control cervical dental pain because of low intrasubject variability in untreated patients.

nm23-H1 expression defines a high-risk subpopulation of patients with early-stage epithelial ovarian carcinoma.

The role of the nm23 gene in human ovarian cancer is still controversial. We studied the expression of the nm23-H1 gene in 247 human epithelial ovarian carcinomas. The patients were followed-up until their death, or for a minimum of 5 years if they survived. The expression of the gene was studied by means of immunohistochemistry and a semiquantitative scoring system considering the staining intensity and the number of reactive tumour cells. Patients carrying tumours with higher expression scores (4-6 on a scale from 0 to 6) had a significantly lower survival (P = 0.01) than the rest. Further stratified statistical analysis revealed that this effect was mainly attributable to the subgroup of patients with early-stage (I and II), well- and moderately differentiated tumours. In fact, a multivariate analysis carried out for this subset of patients showed nm23-overexpression to be the only significant independent predictor of an ominous prognosis. The association of nm23-overexpression with a worse prognosis was most probably not due to mutation of the nm23 gene, since mutational analysis in 60 tumours by means of single-strand conformational polymorphism and direct sequencing disclosed only one mutation, which was located outside the open reading frame. Our results seem to indicate that nm23 expression is associated with a significantly worse prognosis in early-stage, well-differentiated epithelial ovarian carcinoma, a finding with important clinical implications, considering that many patients with ovarian cancers showing these features do not undergo any further treatment beyond surgical staging. If confirmed, they could help in tailoring the treatment of these patients in the future.

Expression of the mismatch repair protein hMSH2 in carcinoma in situ and invasive cancer of the breast.

BACKGROUND: Dysregulations in the mechanism of DNA-repair are contributed to tumorgenesis and tumorprogression in human cancer. The mismatch repair gene hMSH2 encodes a protein, which recognizes and binds to mismatch-sequences of the DNA. METHODS: Using immunohistochemical techniques hMSH2 expression was analyzed in invasive cancer (n = 85) and in situ carcinoma (n = 34) of the breast. RESULTS: The percentage of hMSH2 positive cases was significantly (p = 0.0001) decreased in invasive cancer as compared to in situ carcinomas. There was an association of hMSH2 expression with parameters of unfavorable prognosis, such as lymph node involvement (p = 0.03), higher degree of malignancy (p = 0.05) and higher proliferative activity (p = 0.05). CONCLUSIONS: During development from in situ to invasive cancer of the breast, hMSH2 expression seems to be downregulated. However, in invasive cancer, hMSH2 expression seems to be associated with tumor progression. This could be explained by the fact that enhanced proliferation of tumor cells results in increased mistakes within DNA replication procedures.

Effect of regional hyperemia on myocardial uptake of 2-deoxy-2-[(18)F]fluoro-D-glucose.

2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) may be used to predict glucose kinetics when the factor relating differences in transport and phosphorylation between compounds remains constant ("lumped constant"). It is not clear whether hyperemia alters that factor. In anesthetized swine, myocardial FDG uptake was estimated by positron emission tomography, during an intracoronary infusion of either adenosine, ATP, or bradykinin (40 microg x kg(-1) x min(-1), 40 microg x kg(-1) x min(-1), and 2 nmol x kg(-1) x min(-1), respectively; n = 6 for all groups). In controls during normal perfusion (n = 6), FDG uptake was 0.78 +/- 0.32 micromol x g(-1) x min(-1), whereas glucose uptake by Fick was 0.71 +/- 0.25 micromol x g(-1) x min(-1) (r = 0.73; P < 0.05). Adenosine increased blood flow from 1.29 +/- 0.43 to 4.80 +/- 2.19 ml x g(-1) x min(-1) (P < 0.05) and glucose uptake from 1.16 +/- 1.10 to 3.35 +/- 2.12 micromol x g(-1) x min(-1) (P < 0.05), whereas FDG uptake in the hyperemic region was lower than remote regions (0.46 +/- 0.29 and 0.95 +/- 0.55 micromol x g(-1) x min(-1), respectively; P < 0.05). In the ATP and bradykinin groups, blood flow increased four- and twofold, respectively, with no net change in glucose uptake. FDG uptake in the hyperemic region was also significantly lower than remote regions. For all animals, the ratio of blood flow in the hyperemic region relative to remote region was inversely proportional to the ratio of FDG uptake in the same regions (r(2)=0.73; P < 0.001). Because nitric oxide elaboration during hyperemia could potentially alter substrate preference and FDG kinetics, six additional swine were studied during maximal adenosine before and after intracoronary N(G)-monomethyl-L-arginine (1.5 mg/kg). Inhibition of nitric oxide had no effect on either regional myocardial substrate uptake or FDG accumulation. In conclusion, hyperemia decreased regional myocardial FDG uptake relative to normally perfused regions and this effect on the lumped constant was independent of nitric oxide.

Immunohistochemical detection of HSP60-expression in human ovarian cancer. Correlation with survival in a series of 247 patients.

PURPOSE: In a previous pilot study, HSP60 expression at the transcriptional (mRNA) level was shown to be a negative prognostic factor in ovarian cancer. The aim of this study was to determine HSP60-expression by means of immunohistochemistry and to correlate the results with survival in a large series of ovarian carcinoma patients with a closed follow-up. MATERIALS AND METHODS: Slides from routinely processed, paraffin-embedded tumor blocks belonging to 247 patients with epithelial ovarian carcinoma were studied for the overexpression of HSP60 using the Lk2 monoclonal antibody and the strepatvidin-biotin-peroxidase technique. HSP60-expression was correlated with overall survival by means of life-table analysis and the Kaplan-Meier method. RESULTS: 47 tumors (19%) expressed HSP60. Of them, 12/29 (41.4% positivity) were stage I tumors, whereas only 35 out of the remaining 218 tumors in more advanced surgical stage (16.1%) showed HSP60 staining. This difference was statistically significant (Fisher s exact test; p = 0.004). Even when stratifying stage for stage, the difference between groups still remained statistically significant (Chi square test; p = 0.0095). The survival curve analysis showed a significant difference in favor of those tumors expressing HSP60 (median survival 28 vs. 37 months; log-rank test, p = 0.02). CONCLUSION: Immunohistochemical detection of HSP60-expression in human epithelial ovarian carcinoma is significantly more frequent in tumors from patients with initial stages of the disease. Therefore, HSP60-expression determined by this method is associated with a significantly better prognosis.

Spontaneous apoptosis in laryngeal squamous cell carcinoma is independent of bcl-2 and bax protein expression.

BACKGROUND: bcl-2 and bax genes are known to be involved in the control of apoptotic cell death, an important mechanism of growth regulation that influences the biologic behavior of tumors. The aim of the current study was to investigate the relationship of bcl-2 and bax expression to the rate of spontaneous apoptosis in laryngeal carcinomas, and to assess its relations to clinicopathologic features of tumors. METHODS: Immunohistochemical analyses for bcl-2 and bax were performed on paraffin embedded tissue sections from 134 primary laryngeal squamous cell carcinomas. To visualize apoptotic cells, the nick end labeling method was used. The proliferative activity of tumors was analyzed by determination of mitotic indices. RESULTS: bcl-2 immunoreactivity was positively correlated with tumor grade (P < 0.00001), high T category (P < 0.02), metastatic involvement of cervical lymph nodes (P < 0.003), and supraglottic or subglottic location of primary tumors (P < 0.00005). An inverse relation was found between bcl-2 and bax expression (P < 0.004). The frequency of spontaneous apoptosis was closely associated with mitotic activity (P < 0.0004) but appeared to be unrelated to protein levels of bcl-2 or bax as well as to bcl-2:bax ratios. CONCLUSIONS: The results of this study point to the significance of cell proliferation as a major determinant of the rate of spontaneous apoptosis in laryngeal carcinomas. The bcl-2:bax expression ratio obviously does not affect the incidence of apoptosis, but it may be considered as a marker of disease progression and poor prognosis.

Expression of the p53 tumour suppressor gene as a prognostic marker in platinum-treated patients with ovarian cancer.

Drug resistance is one of the most important clinical problems in the treatment of ovarian cancer. This study was designed to determine whether expression of p53 could be used as a marker for predicting the response to chemotherapy of ovarian cancer. Tissue blocks were obtained from 187 patients with diagnosed untreated ovarian cancer. Paraffin sections from the primaries were immunohistochemically analysed for p53 expression. All patients underwent platinum-based chemotherapy after surgery. We analysed whether the number of chemotherapy cycles was related to survival in women with p53 positive and p53 negative ovarian cancer. 27/187 cases were p53 positive. Expression of p53 was associated with other factors of unfavourable prognosis. Patients with p53 positive tumours had a significantly worse prognosis compared with patients with p53 negative tumours (P = 0.037). There was a statistically significant dose-response effect of platinum-based chemotherapy in patients with p53 negative tumours, which could not be seen in patients with p53 positive tumours (P = 0.01 versus P = 0.553). This could also be observed in patients with residual tumour after surgery (P = 0.0001 versus P = 0.8866). Expression of p53 may be an additional useful marker in predicting response to chemotherapy. Thus, it is possible to identify a subgroup of patients who may benefit from alternative therapy regimens.