Influence of HER2 expression on prognosis in metastatic triple-negative breast cancer-results from an international, multicenter analysis coordinated by the AGMT Study Group.

BACKGROUND: Triple-negative breast cancer (TNBC) is associated with poor prognosis, and new treatment options are urgently needed. About 34%-39% of primary TNBCs show a low expression of human epidermal growth factor receptor 2 (HER2-low), which is a target for new anti-HER2 drugs. However, little is known about the frequency and the prognostic value of HER2-low in metastatic TNBC. PATIENTS AND METHODS: We retrospectively included patients with TNBC from five European countries for this international, multicenter analysis. Triple-negativity had to be shown in a metastatic site or in the primary breast tumor diagnosed simultaneously or within 3 years before metastatic disease. HER2-low was defined as immunohistochemically (IHC) 1+ or 2+ without ERBB2 gene amplification. Survival probabilities were calculated by the Kaplan-Meier method, and multivariable hazard ratios (HRs) were estimated by Cox regression models. RESULTS: In total, 691 patients, diagnosed between January 2006 and February 2021, were assessable. The incidence of HER2-low was 32.0% [95% confidence interval (CI) 28.5% to 35.5%], with similar proportions in metastases (n = 265; 29.8%) and primary tumors (n = 425; 33.4%; P = 0.324). The median overall survival (OS) in HER2-low and HER2-0 TNBC was 18.6 and 16.1 months, respectively (HR 1.00; 95% CI 0.83-1.19; P = 0.969). Similarly, in multivariable analysis, HER2-low had no significant impact on OS (HR 0.95; 95% CI 0.79-1.13; P = 0.545). No difference in prognosis was observed between HER2 IHC 0/1+ and IHC 2+ tumors (HR 0.89; 95% CI 0.69-1.17; P = 0.414). CONCLUSIONS: In this large international dataset of metastatic TNBC, the frequency of HER2-low was 32.0%. Neither in univariable nor in multivariable analysis HER2-low showed any influence on OS.

Mismatch repair status predicts survival after adjuvant treatment in stage II colon cancer patients.

BACKGROUND AND OBJECTIVES: Stage II colon cancer is primarily a surgical disease. Only a still not well-defined subset of patients may benefit from postoperative adjuvant chemotherapy. The relationship between adjuvant chemotherapy and survival after relapse is furthermore still not definitely explored in this group of patients. A number of reports suggest some association between defective mismatch repair (dMMR) and colorectal cancer stage II prognosis, but due to contradictory results from existing studies, the exact predictive role is still not fully understood. METHODS: Retrospective multicenter study including 451 stage II colon cancer patients. The proficiency or deficiency of mismatch repair was tested using immunohistochemistry and analyzed in relationship to two survival outcomes: overall survival (OS) and postrelapse survival. RESULTS: Patients with dMMR (20.4%) derived no OS benefit from adjuvant chemotherapy (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.47-2.38; P = .897). Patients with proficient mismatch repair (pMMR) tumors receiving adjuvant chemotherapy had the significantly better OS in comparison to those not receiving chemotherapy (HR, 0.54; 95% CI, 0.35-0.82; P = .004). This relationship remained significant in multivariable analysis (HR, 0.42; 95% CI, 0.22-0.78; P = .007). Patients with pMMR relapsing after adjuvant treatment lived significantly longer than those relapsing without previous adjuvant treatment (HR, 0.55; 95% CI, 0.32-0.96; P = .033) and this result remained significant in the multivariable model (HR, 0.49; 95% CI, 0.26-0.93; P = .030). CONCLUSION: In stage II CC patients, adjuvant chemotherapy improves therapeutic outcomes only in patients with pMMR tumors. Survival after relapse in patients having received adjuvant chemotherapy is significantly longer for patients with pMMR. No survival benefit from adjuvant chemotherapy was seen among patients with dMMR tumors.

Hypothalamo-pituitary dysfunction in patients with chronic subdural hematoma.

Relatively frequent pituitary hormone deficiencies are observed after traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and according to the published studies the neuroendocrine consequenses of traumatic brain injury are underdiagnosed. In a cohort of 59 patients (49 males, mean age 68.3 years, 36-88 years) after evacuation of subdural hematoma (SDH) were evaluated hypothalamo-pituitary functions one week after surgery, after three months and after one year. Hypogonadism was present in 26 % of patients in an acute phase, but in the majority had a transient character. Less than half of patients was GH deficient (GHD) according to the GHRH+arginine test. We did not find any serious case of hypocortisolism, hypothyroidism, diabetes insipidus centralis nor syndrome of inappropriate secretion of ADH (SIADH). Transient partial hypocortisolism was present in two cases, but resolved. We did not find relation between extension of SDH or clinical severity and development of hypopituitarism. In conclusion, in some patients with SDH growth hormone deficiency or hypogonadism was present. No serious hypocortisolism, hypothyroidism, diabetes insipidus nor SIADH was observed. The possibility of neuroendocrine dysfunction should be considered in patients with SDH, although the deficits are less frequent than in patients after TBI or SAH.

The importance of prognostic factors in premenopausal women with breast cancer.

BACKGROUND: Basic conventional prognostic factors for breast cancer include the age of the patient, tumor grade, regional lymph nodes status, and estrogen (ER) and progesterone (PR) receptor status. Positivity of the HER2 receptor (c-erbB-2) seems to be a new prognostic and predictive factor. Prognostic factors seem to be more important in the high-risk group of the premenopausal females. We evaluated individual prognostic factors (age, histology, TNM classification, ER, PR, CA 15-3, CEA, HER2) and their impact on disease-free survival (DFS) and overall survival (OS) during the 5-year follow-up period. PATIENTS AND METHODS: Forty-two patients were monitored after standard oncology treatment for a period of at least 5 years. The statistical significance of the individual prognostic parameters was evaluated in relationship to the time to progression (DFS and OS). RESULTS: The following were evaluated as statistically significant prognostic parameters for DFS: PR positivity (p = 0.0036), proliferative marker MIB1 (p = 0.0108), pre-operative level of CA 15-3 (p = 0.0425), ER negativity (p = 0.0507). The following were evaluated as statistically significant prognostic parameters for OS: PR positivity (p = 0.0003), MIB1 (p = 0.0005), ER (p = 0.0440), pre-operative level of CEA (p = 0.0495). Positivity of immunohistochemically performed test of c-erbB-2 was not statistically significant for DFS os OS (p = 0.6361 and 0.9323, respectively). CONCLUSION: The statistically significant prognostic importance of the levels of tumor markers CA 15-3 and CEA for prognosis in breast cancer of premenopausal females was proven. So far, these factors have been underestimated. The prognostic parameters of ER, PR and MIB1 were statistically significant. While no prognostic importance was confirmed for c-erbB-2 positivity; this factor cannot be evaluated in premenopausal females separately from the other prognostic factors due to the predictive value in relation to the adjuvant therapy (patients with HER+, ER+, PR-).

Association of PAX5 expression with clinical outcome in patients with TaT1 transitional cell carcinoma of the bladder.

OBJECTIVES: To assess the frequency and intensity of PAX5 gene messenger ribonucleic acid (mRNA) expression in TaT1 bladder cancer tissue, as well as its correlation with clinicopathologic variables and patient outcome. METHODS: The RNA expression of PAX5 was evaluated with reverse transcriptase polymerase chain reaction in the tumor tissue of 75 patients with stage TaT1 bladder cancer treated with transurethral resection. Patients were observed with cystoscopy and urinary cytologic evaluation. The association between PAX5 expression and clinicopathologic variables and patient outcome was evaluated. Benign urothelium from 8 patients with benign prostatic hyperplasia was obtained. These patients were used as a control group. RESULTS: PAX5 expression was found in 62 patients with bladder cancer (82.7%) but in no patient from the control group. High PAX5 expression (greater than 0.2) was confirmed in 19 patients (25.3%). No significant relationship was observed between quantity of PAX5 expression and clinicopathologic variables. The 3-year recurrence-free and progression-free survival rates in highly positive patients were 13.2% and 71.6%, compared with 40.6% and 92.8%, respectively, in patients with weak or negative expression (log-rank test, P = 0.0075, P = 0.022). Multivariate Cox proportional hazard model analysis identified PAX5 expression as an independent predictor of tumor recurrence. CONCLUSIONS: PAX5 gene expression is a frequent finding in superficial transitional cell carcinoma of the bladder. High levels of PAX5 are associated with poorer recurrence-free and progression-free survival rates. Moreover, PAX5 expression was found to be an independent prognostic factor for recurrence-free survival by a multivariate analysis.

[Fluorescence cystoscopy in the diagnostics and treatment of superficial urinary bladder tumors]. / Fluorescencní cystoskopie a její místo v diagnostice a lécbe povrchových nádoru mocového mechýre.

BACKGROUND: 5-aminolevulinic acid induced fluorescence cystoscopy can detect more tumour lesions comparing to standard cystoscopy. The goal of our study was to assess the influence of fluorescence cystoscopy used during transurethral resection on the recurrence rate and the length of tumor-free interval in stage Ta, Tl transitional cell carcinoma of the urinary bladder. METHODS AND RESULTS: In prospective randomized study 109 patients with primary or recurrent stage Ta Tl bladder transitional cell carcinoma treated with transurethral resection were enrolled. 17 patients with high grade tumors were evaluated separately. In group A the transurethral resection was performed with standard white light endoscopy, in group B with fluorescence cystoscopy. The patients were followed using standard cystoscopy and urinary cytology. Recurrence free interval was evaluated in whole groups and also for single and multiple and for primary and recurrent tumors separately. The median time to recurrence was 8.05 months in group A and was significantly shorter than 13.54 months in group B (p = 0.04, log-rank test). In separate analyses the median time to recurrence was significantly shorter using fluorescence cystoscopy in multiple (p = 0.004) and in recurrent (p = 0.02) tumors, but not in solitary and primary tumors. CONCLUSIONS: 5-aminolevulinic acid induced fluorescence cystoscopy used during transurethral resection reduces the early recurrence rate in stage Ta Tl bladder transitional cell carcinoma.

TPS, thymidine kinase, VEGF and endostatin in cytosol of thyroid tissue samples.

The aim of the study was to determine whether VEGF, TPS, TK or Endostatin determination in tissue cytosol may have some additional value in distinguishing among different types of thyroid lesions. These markers were chosen as representatives of the 2 main pathways (angiogenesis and proliferation) involved in thyroid diseases. VEGF is the most potent angiogenic promoter and Endostatin plays an opposing role. Thymidine kinase (TK) is a marker of DNA synthesis and TPS, cytokeratin 18 fragments, is a marker of the rate of proliferation. We determined qualitatively all four markers in tissue extracts: cytosol from 157 tissue specimens (93 goitre, 12 Hashimoto's thyroiditis, 39 adenomas and 13 carcinomas). In 6 cases we were able to compare both normal and pathological tissue samples from a single patient. Statistically significant differences were found in the measured markers, but outliers were present in all groups. This fact does not permit their use in differential diagnosis. The highest levels of all markers were reached in adenomas, being higher than in carcinomas, probably explained by the higher overall metabolic rate in adenomas.

Comparative analysis of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in colorectal cancer and surrounding normal tissue.

Thymidylate synthase [TS], thymidine phosphorylase [TP] and dihydropyrimidine dehydrogenase [DPD] play the essential role in the activation and catabolism of the fluoropyrimidines used in cancer therapy. Its expression may influence the antitumor activity or toxicity of these drugs. We studied the expression levels of selected enzymes in colorectal tumors and adjacent normal mucosa. The analysis of TS, TP and DPD gene expression was performed using quantitative Real time PCR technique (Roche) in 15 (TS), 64 (TP) and 12 (DPD) of 64 colorectal cancer patients. The mean gene expression of TS, TP and DPD was found to be 3.29; 3.79 and 8.24 in tumors and 1.88; 3.80 and 19.69 in normal mucosa. The corresponding median gene expression was 1.87; 2.32 and 4.50 for tumors and 2.14; 2.63 and 11.64 for normal tissue. We did not find any significant differences in TS, TP and DPD gene expression between colorectal tumor and surrounding mucosa.

Diurnal blood pressure variation in pheochromocytoma, primary aldosteronism and Cushing's syndrome.

We examined circadian blood pressure (BP) variation (expressed as a relative night-time BP decline) in subjects with primary aldosteronism (78 patients), pheochromocytoma (n=45) and Cushing's syndrome (n=18). Subjects with aldosterone-producing adenoma (n=21) and pheochromocytoma (n=27) were also investigated after the tumour removal. In all, 65 patients with essential hypertension served as a control group. The night-time BP decline was significantly attenuated in all three forms of endocrine hypertension compared to the control group (primary aldosteronism P<0.0001, pheochromocytoma P<0.0001 for systolic and diastolic BP and Cushing's syndrome P<0.0001/<0.001 vs essential hypertension). In the case of pheochromocytoma, the absence of the night-time BP decrease was more prominent compared to the primary aldosteronism group (P=0.003/0.001) and for the diastolic BP also in comparison with the Cushing's syndrome group (P=0.03). Tumour removal led in both groups to the restoration of the previously altered circadian rhythm (aldosterone-producing adenoma: P=0.0005/0.0009; pheochromocytoma: P=0.001/0.0007). Our study demonstrates a blunted circadian BP variation in all forms of adrenal hypertension in comparison with essential hypertension. This reduction of the night-time BP decrease was more prominent in pheochromocytoma than in primary aldosteronism or Cushing's syndrome.

Immunohistochemical detection of dipeptidyl peptidase IV (CD 26) in thyroid neoplasia using biotinylated tyramine amplification.

Differential diagnosis between malignant and benign thyroid tumors derived from follicular cells can pose certain difficulties in routine surgical pathology. The aim of the study was to evaluate dipeptidyl peptidase IV (DPP IV/CD 26) in differential diagnostics of thyroid lesions. DPP IV/CD 26 was evaluated in thyroid glands of 309 patients (261 females and 48 males, age range of patients 15-80 years). DPP IV/CD 26 was assessed in paraffin-embedded thyroid specimens immunohistochemically using commercially available antibody (Serotec) and biotinylated tyramine amplification kit (DAKO). Well-differentiated carcinoma revealed DPP IV/CD 26 positivity in 33 out of 42 cases (79%). Neither medullary nor insular carcinoma was DPPIV/CD 26 positive (only one case of each tested). DPPIV/CD 26 expression in isolated cells was seen in 18/261 (7%) benign disorders. The sensitivity of the method was 68%, the specificity was 94%, and the diagnostic accuracy was 91%, respectively, using 5% threshold of positive follicular cells. DPP IV/CD 26 can be assessed immunohistochemically using biotinylated tyramine amplification kit. DPP IV/CD 26 could be an adjunct in the thyroid gland differential diagnosis. However, DPP IV/CD 26 positivity is limited to the group of well-differentiated carcinomas, particularly papillary carcinoma. Furthermore, it is of limited value for follicular and oncocytic tumors.

Diagnostic role of markers dipeptidyl peptidase IV and thyroid peroxidase in thyroid tumors.

BACKGROUND: In seeking to improve the differential diagnosis between malignant and benign thyroid tumors of follicular cell origin, we assessed the expression of dipeptidyl peptidase IV (DPP IV) and thyroid peroxidase (TPO). DPP IV is a membrane peptidase expressed in many human tissues, excluding the normal thyroid gland. However, aberrant expression has been described in thyroid carcinomas. TPO is an essential enzyme in the biosynthesis of thyroid hormones with various types of expression in pathological thyroid lesions. MATERIALS AND METHODS: A total of 151 thyroid glands were examined: 24 malignant tumors, 29 benign tumors, 98 benign lesions and 5 normal glands. DPP IV expression was analyzed by a histochemical technique in both frozen sections and imprint/aspirate smears. TPO was assessed immunohistochemically in paraffin-embedded specimens. RESULTS: DPP IV sensitivity in frozen section was 56% and its specificity was 99%, in both cases with a 50% threshold. In cytology, the sensitivity was 68% and the specificity was 98% using the 50% threshold. TPO sensitivity and specificity was 64% and 99%, respectively. The sensitivity and specificity of both markers was 92% and 94%, respectively. CONCLUSION: We recommend adding DPP IV and TPO to the list of diagnostic tumor markers for malignant thyroid tumors of follicular cell origin.

Criteria for the selection of referential groups in tumor marker statistical evaluation on the basis of a retrospective study.

The authors of this study are concerned with the analysis of optimal criteria for the selection of referential groups in the statistical evaluation of tumor markers for early detection of recurrent disease. Although criteria for the selection of optimal referential groups have already been published on a number of occasions (EGTM recommendation), these criteria are not followed in daily routine, which leads to a false interpretation of results and the impossibility of comparing individual studies. The commonest problem is an incorrect determination of cut-off, caused by not following the recommended specificities at 95%, which results in an incorrect assessment of tumor marker sensitivities. Other faulty interpretations happen in consequence of inaccurate and not clearly defined referential groups, which differ from each other by, for example, stage of the disease, length of the follow-up and so on. Comparing tumor marker results still remains a problem, since they are assessed with diagnostic kits from different manufacturers which may misrepresent the final value of the results, and thus imitate remission or progression of the tumor disease. Similarly, mutual comparison of results from prospective and retrospective studies without standardization of clinical conditions leads to an unreliable interpretation. The authors show, through concrete examples, the possibility of a completely different interpretation of the results in identical referential groups in consequence of their inaccurate characteristics.

[Dipeptidyl peptidase IV (DPP IV, CD 26): a tumor marker in cytologic and histopathologic diagnosis of lesions of the thyroid gland]. / Dipeptidyl peptidáza IV (DPP IV, CD 26): nádorový marker v cytologické a histopatologické diagnostice lézí stítné zlázy.

BACKGROUND: Morphological diagnostics of thyroid gland tumours faces certain differential diagnostic problems. Extensive histological examination of the entire tumour is required for the final diagnosis of follicular and oncocytic tumours. Thus, assessment of reliable definitive cytological and/or intraoperative histological diagnosis is not possible. No marker of malignancy has been so far generally accepted in the thyroid tumour diagnosis. The aim of the study was to evaluate membrane protease dipeptidyl peptidase IV (DPP IV) in the differential diagnosis of thyroid tumours. METHODS AND RESULTS: DPP IV was assessed cytochemically in 254 smears, histochemically in 314 cryostat sections, and immunohistochemically in 309 paraffin-embedded sections obtained from the group of 336 patients. There were 283 females and 53 males with the mean age of 48 years (range 15-80 years) in this series. Sensitivity of cytochemical detection was 71%, specificity was 96%, and diagnostic accuracy was 93% using the 50% threshold. Histochemically, sensitivity was 71%, specificity was 93%, and diagnostic accuracy was 90% using the 5% threshold. Using the immunohistochemical assessment, sensitivity was 68%, specificity was 94%, and diagnostic accuracy was 91% using the 5% threshold. CONCLUSIONS: According to our results, DPP IV can be used as a marker of malignancy in well-differentiated carcinomas of follicular cell origin, namely in papillary carcinoma. However, it is less reliable in follicular and oncocytic carcinomas.

Dipeptidyl peptidase IV expression in thyroid cytology: retrospective histologically confirmed study.

Fine needle aspiration cytology (FNAC) of the thyroid gland is a well-established method. However, it has inherent limitations, especially in the diagnosis of follicular and oncocytic tumours and in distinguishing between nuclear atypia in colloid goitre with regressive changes and cystic papillary carcinoma. The aim of our study was to evaluate dipeptidyl peptidase IV (DPP IV) as a marker of malignancy in FNAC. We tested 254 thyroid specimens (intraoperative imprint smears) for DPP IV. The sensitivity was 71%, the specificity was 96%, and the diagnostic accuracy was 93%, respectively, with a threshold of 50% of positive cells. To the best of our knowledge it is the largest histologically confirmed study reported in the literature. We suggest the assessment of DPP IV as an adjunct diagnostic marker of malignancy in thyroid specimens suspicious of papillary carcinoma. However, the value of the marker in follicular lesions is very limited.

Qualitative and quantitative detection of urinary human complement factor H-related protein (BTA stat and BTA TRAK) and fragments of cytokeratins 8, 18 (UBC rapid and UBC IRMA) as markers for transitional cell carcinoma of the bladder.

OBJECTIVE: To evaluate the role of BTA stat, BTA TRAK, UBC Rapid, UBC IRMA and voided urinary cytology in the detection of bladder transitional cell carcinoma (TCC). METHODS: The study included 78 patients with TCC of the bladder (group A), 62 patients with a history of bladder TCC without tumor recurrence at the time of examination (B, control group), 20 patients with other malignancy of the urinary tract (C), 38 patients with non-malignant urinary tract diseases (D), 10 patients with urinary tract infection (E) and 10 healthy volunteers (F). Except in group F, voided urine was collected before cystoscopy or cystectomy. RESULTS: The specificity and sensitivity in bladder cancer detection were 87.1 and 74.4%, respectively with BTA stat, 79.3 and 48.7%, respectively with UBC Rapid, 100 and 33.3%, respectively with cytology, 72.6 and 75.6%, respectively with BTA TRAK, 64.5 and 70.5%, respectively with UBC IRMA. CONCLUSIONS: The BTA stat and BTATRAK tests are superior to UBC Rapid, UBC IRMA and urinary cytology in detection of bladder TCC. In daily practice however cytology remains the best adjunct to cystoscopy because of its high sensitivity in Tis and 100% specificity. Cystoscopy cannot be replaced by any of evaluated methods.

The expression of PAX5, p53 immunohistochemistry and p53 mutation analysis in superficial bladder carcinoma tissue. Correlation with pathological findings and clinical outcome.

OBJECTIVES: The expression pattern of PAX5 in the tissue of superficial bladder transitional cell carcinoma (TCC), its prognostic value and its correlation with p53 immunohistochemistry and p53 mutation analysis were evaluated. METHODS: Study comprised 61 patients with histologically confirmed superficial bladder TCC. Expression level of PAX5 mRNA was investigated using reverse transcriptase-polymerase chain reaction (RT-PCR) and determined semiquantitatively. The presence of p53 mutations was determined by SSCP and confirmed by direct sequencing. The p53 immunohistochemistry was performed with DO1 antibody and semiquantitatively evaluated using HSCORE (HS) method. As the control group for the evaluation of the PAX5 expression served 8 men with benign prostatic hyperplasia. RESULTS: PAX5 expression was found in 50 patients with bladder TCC but in no patient from the control group. Its quantity however correlated neither with the stage nor with the grade of the tumor. P53 mutation was confirmed only in 1 patient with pTaG2 tumor in exon 5 (deletion of proline 128). On the contrary, positive immunohistochemical staining of p53 was detected in most patients. Using the cutoff value of HS 200, 56.9% of patients showed p53 overexpression. Quantity of p53 immunochistochemical positivity did not correlate with the quantity of PAX5 expression. Using the cutoff values of HS 200 for p53 and of 0.2 for PAX5, 7 of 8 patients with future progression had p53 and 4 had PAX5 overexpression respectively. CONCLUSION: The expression of gene PAX5 is a frequent event in superficial TCC of the bladder.

Quantitative determination of telomerase activity in breast cancer and benign breast diseases.

Telomerase plays an important role in maintaining the stability of chromosomes. This ribonucleoprotein prevents chromosome ends (telomeres) from gradual loss with each cell division. It enables tumor cells to maintain telomere length, allowing indefinite replicative capacity. Telomerase activity has been detected in the majority of tumor and germ cells and in immortalized cell lines. Quantitative telomerase PCR-ELISA (TeloTAGGG Telomerase PCR ELISA(PLUS)) was evaluated for distinguishing benign and malignant breast tissue. Activity of telomerase was determined in 27 samples of fibrocystic and dysplastic tissues, 28 fibroadenomas and phylloid tumors, and 154 breast cancer tissues; 59 specimens were analyzed retrospectively. Analytical precision and linearity of the assay was tested using breast carcinoma cell line ZR-75-1 and breast tumor tissue extracts. About 4% of tumor samples were excluded from analysis due to interferences in the PCR reaction. Relative telomerase activity differed significantly in the groups of dysplastic tissues, fibroadenomas and carcinomas. The highest activity was found in breast cancer tissue. This method can identify breast cancer tissue with 73% clinical sensitivity and 93% specificity as compared to benign breast tumors. We did not find a correlation between telomerase activity and the tissue levels of estrogen and progesterone receptors, HER-2/neu oncoprotein concentration, tumor size, and lymph node positivity. Probability of disease-free survival was significantly lower for patients with telomerase activity higher than median value. As the assay for telomerase activity has very high analytical sensitivity and high specificity for cancer cells, this routinely used method may prove useful for distinguishing malignant phenotype of breast tissues.

Bone marrow and peripheral blood leptin levels in lymphoproliferative diseases--relation to the bone marrow fat and infiltration.

Leptin is a nonglycosylated protein produced mostly by adipocytes. The role ofleptin in body weight regulation through its anorectic effect in hypothalamus is very well known. Less known are other leptin effects such as the stimulation of hematopoesis and some parts of immunity system. The role of leptin in the pathogenesis of some malignant tumors is discussed. Only a little is known about bone marrow adipocyte leptin production. We examined leptin concentrations in the sera from peripheral blood and bone marrow, the percentage of bone marrow fat, the degree of bone marrow infiltration, the body mass index (BMI) in 42 patients with lymphoproliferative diseases. We found that bone marrow has significantly lower leptin levels (6,6+/-10,9 ng/ml) than peripheral blood (9,1+/-11,5 ng/ml) (p < 0.0001). Bone marrow and peripheral blood leptin levels have also a significant thin correlation (r = +0.91, p < 0.0001). Bone marrow (r = +0.55, p < 0.0005) and peripheral blood (r = +0.52, p < 0.0005) leptin concentrations are significantly correlated to BMI. Blood serum leptin (r = +0.46, p < 0.003) and bone marrow leptin (r = +0.40, p < 0.01) are related to the bone marrow fat percentage. In addition we found a negative correlation of blood serum leptin (r = -0.59, p < 0.0001) and bone marrow leptin (r = -0.42, p < 0.005) to bone marrow malignant infiltration. When we divided the patients into groups with bone marrow infiltration more than 10% and without or less than 10% infiltration, the first group had significantly lower peripheral blood (p < 0.001) and bone marrow (p < 0.02) leptin. We also confirmed a relation of bone marrow fat and infiltration (r = +0.49, p < 0.001). Our results suggest a relationship among leptin levels in blood or bone marrow and bone marrow infiltration in lymphoproliferative diseases. This fact needs further investigation and an evaluation of its application in clinical practice.

Endogenous fibrinolysis in patients with lower extremity ischemia.

To explore the relationship between disorders of endogenous fibrinolysis and thrombosis in patients with lower extremity ischemia, we measured the activity of tissue plasminogen activator (tPAac) and plasminogen activator inhibitor (PAlac) and the antigens of tissue plasminogen activator (tPAa) and inhibitor (PAla) in plasma from 420 patients treated for lower extremity ischemia. Values and ratios observed were compared with those in healthy volunteers. Additionally, values and ratios in the patients were examined with respect to the severity of ischemia and site of atherosclerotic occlusion or stenosis (pelvic compared with femoropopliteal or crural). Patients with lower extremity ischemia had higher plasma concentrations of PAla (p<0.01) and PAlac (p<0.0001) than healthy volunteers. In patients with rest pain or gangrene, the ratio of tPAac to PAlac was higher than in patients with claudication (p<0.05). The elevation of tPAac in patients with the more severe form of lower extremity ischemia is probably the feedback protective reaction on prothrombotic mechanisms of the organism suffered from severe atherosclerosis. Results did not vary according to the site of occlusion or stenosis. Our study found defects in endogenous fibrinolysis in patients with lower extremity ischemia. A defect in fibrinolysis may contribute to the development of thrombosis in native arteries and bypasses.

[Leptin levels in peripheral blood and bone marrow in orthopedic patients]. / Hladiny leptinu v sérech z periferní krve a kostní drene u ortopedických pacientu.

Leptin is a protein with hormonal activity and is produced mainly by adipocytes. Its primary function in the human organism is regulation of the calorie intake via the anorectic action in the hypothalamus. Leptin participates also in the regulation of haematopoiesis and immunity processes. There are many data on leptin production by peripheral adipose tissue and it is also known that leptin is produced by adipocytes of bone marrow. It was assumed for a long time that adipocytes of bone marrow are not only a passive source of energy but have, similarly as stromal cells, a regulatory function. However, it is not clear in what way the adipose tissue of bone marrow participates in the regulation of haematopoiesis and what role is played in this relationship by leptin production. The authors attempted to assemble in their small study data on leptin production in bone marrow and at the same time parameters of lipids of bone marrow which can be assessed by cytological examination. The authors examined 16 patients (9 men and 7 women) subjected to orthopaedic surgery. They assessed leptin concentrations in sera obtained from peripheral blood and bone marrow, and at the same time they assessed by morphological examination in smears of bone marrow some parameters associated with lipids. The authors found that serum leptin levels from bone marrow are significantly lower than in peripheral blood (p < 0.0005). These values correlate closely (r = +0.77, p < 0.0005). The authors found also a positive correlation between serum leptin (r = +0.56, p < 0.02) and bone marrow leptin (r = +0.72, p < 0.002) and the body mass index (BMI). A positive correlation was found also between serum (r = +0.65, p < 0.006) and bone marrow leptin (r = +0.80, p < 0.0002) and age. The authors did not detect any significant correlations between parameters of the lipids of bone marrow and leptin levels in serum and bone marrow. The assembled results can in combination with data from the literature indicate that the actual amount of leptin in bone marrow is influenced rather by its consumption by haematopoietic tissue than by its production.