p53, cellular proliferation, and apoptosis-related factors in thymic neuroendocrine tumors.
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Thymic neuroendocrine tumors are biologically aggressive neoplasms with extensive local invasion and high mortality. Although various markers of cellular proliferation and apoptosis have correlated with degrees of tumor differentiation in pulmonary neuroendocrine neoplasms, they have not been systematically studied in thymic neuroendocrine tumors. We immunostained 21 cases of thymic neuroendocrine tumors for p53, MIB-1, and the apoptosis-related markers Bcl-2, Bcl-x, and Bax. By histological classification the cases were low-grade (nine cases), intermediate-grade (eight cases), and high-grade (four cases) thymic neuroendocrine tumors. p53 was expressed in five cases: 1/9 low grade, 3/8 intermediate grade, and 2/4 high grade. The mean cellular proliferation (MIB-1) was 7.1% (range 2-12%) in low-grade thymic neuroendocrine tumors, 6.1% (range 2-15%) in intermediate-grade thymic neuroendocrine tumors, and 34.2% (range 2-80%) in high-grade thymic neuroendocrine tumors. Bcl-2 was expressed in 16 cases: 7/9 low grade, 5/8 intermediate grade, and 4/4 high grade. Bcl-x was expressed in 16 cases: 7/9 low grade, 6/8 intermediate grade, and 3/4 high grade. Bax was expressed in 13 cases: 5/9 low grade, 4/8 intermediate grade, and 4/4 high grade. The presence of mutant p53 in the tumor was associated with a statistically significant decreased mean survival (P<0.05). In contrast, either by positive or negative staining or by the score technique (staining intensity x percentage of cells staining), the presence of Bcl-x was associated with an increased mean survival (P<0.05). Finally, a Bcl-x : Bax ratio >or=1 was also associated with an increased mean survival, as compared to a Bcl-x : Bax ratio >or=1 (P<0.05). Our study shows that p53 expression and certain apoptosis markers correlate with survival. The expression of these markers may account for differences in biological behavior. (+info)
Prognostic relevance of activated Akt kinase in node-negative breast cancer: a clinicopathological study of 99 cases.
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Patients with lymphnode-negative breast cancer show a 10-year tumor recurrence rate of approximately 30%. Therefore, it is important to identify high-risk patients who would benefit from further adjuvant therapy. For this purpose, we examined the activation state of two kinases important in the regulation of cell proliferation and apoptosis in a series of 99 node-negative breast cancer cases with a mean follow-up of 10 years: Akt and extracellular regulated kinase (ERK1/2). The activation of Akt and ERK1/2 was investigated by immunohistochemistry using phospho-specific antibodies. The results were correlated with HER-2/neu expression, histological grading, receptor status, overall survival (OS) as well as with cell proliferation (Ki67 immunoreactivity, mitotic count) and tumor apoptosis assessed by TUNEL staining. Activation of Akt (pAkt) but not activation of ERK1/2 (pERK1/2) correlated with HER-2/neu overexpression (P<0.05) and was related to reduced tumor apoptosis (P<0.05). No association was found between pAkt or pERK1/2 with cell proliferation assessed by Ki67 and mitotic count (MC). Survival analysis of receptor status, HER2/neu expression, histological grading, MC and pAkt immunoexpression showed a significant correlation with decreased OS, but only pAkt reached statistical significance in the multivariate Cox regression analysis (P=0.015). Activation of Akt in node-negative breast cancer may indicate aggressive tumor behavior and may constitute an independent prognostic factor of OS. The determination of pAkt status may be of value in identifying high-risk patients, who would benefit from adjuvant therapy, and gives a rationale to investigate new therapy strategies by specific inhibition of the Akt signaling pathway in breast cancer. (+info)
Serum nucleosomes during neoadjuvant chemotherapy in patients with cervical cancer. Predictive and prognostic significance.
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BACKGROUND: It has been shown that free DNA circulates in serum plasma of patients with cancer and that at least part is present in the form of oligo- and monucleosomes, a marker of cell death. Preliminary data has shown a good correlation between decrease of nucleosomes with response and prognosis. Here, we performed pre- and post-chemotherapy determinations of serum nucleosomes with an enzyme-linked immunosorbent assay (ELISA) method in a group of patients with cervical cancer receiving neoadjuvant chemotherapy. METHODS: From December 2000 to June 2001, 41 patients with cervical cancer staged as FIGO stages IB2-IIIB received three 21-day courses of carboplatin and paclitaxel, both administered at day 1; then, patients underwent radical hysterectomy. Nucleosomes were measured the day before (baseline), at day seven of the first course and day seven of the third course of chemotherapy. Values of nucleosomes were analyzed with regard to pathologic response and to time to progression-free and overall survival. RESULTS: All patients completed chemotherapy, were evaluable for pathologic response, and had nucleosome levels determined. At a mean follow-up of 23 months (range, 7-26 months), projected progression time and overall survival were 80.3 and 80.4%, respectively. Mean differential values of nucleosomes were lower in the third course as compared with the first course (p >0.001). The decrease in the third course correlated with pathologic response (p = 0.041). Survival analysis showed a statistically significant, better progression-free and survival time in patients who showed lower levels at the third course (p = 0.0243 and p = 0.0260, respectively). Cox regression analysis demonstrated that nucleosome increase in the third course increased risk of death to 6.86 (95% confidence interval [CI 95%], 0.84-56.0). CONCLUSION: Serum nucleosomes may have a predictive role for response and prognostic significance in patients with cervical cancer patients treated with neoadjuvant chemotherapy. (+info)
Prognostic risk factors in patients with interstitial lung disease referred for lung transplantation.
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The aim of the study was to identify prognostic factors that would differentiate patients with interstitial lung disease between those with and without a chance to survive until lung transplantation. A retrospective study was performed in patients with interstitial lung disease referred for lung transplantation between September 1999 and April 2005. The analysis included the demographic data, the time from referral to transplantation, the functional tests (FVC, FEV1, FEV1%VC, the PaO(2) at rest and after oxygen supplementation via a nasal catheter), the count of NYHA functional classes, the left ventricular ejection fraction (EF), the distance covered during a 6-min walk test, and the pathogens in the respiratory tract. The patients were divided into two groups: Group 1 - lung transplant candidates who survived until the successful procedure and Group 2 - lung transplant candidates who died while on the waiting list. There were statistical differences between the two groups in PaO2 after supplementation (P=0.005), EF (P=0.002), and the 6-min walk distance (P=0.001). It appears that simple functional tests of the cardiorespiratory system may define survival of patients with interstitial lung disease waiting for lung transplantation. (+info)
Quantitative flow cytometry of ZAP-70 levels in chronic lymphocytic leukemia using molecules of equivalent soluble fluorochrome.
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BACKGROUND: ZAP-70 has emerged as a potential pivotal prognostic marker for patients with chronic lymphocytic leukemia (CLL), which could replace immunoglobulin heavy chain mutation status. Although several flow cytometry assays have been described for assessing ZAP-70 in CLL, certain technical and scientific issues remain unsolved, which have prevented results of this crucial test from being reported, even in the best routine flow cytometry laboratories. In this report, we aimed to solve some of these issues by providing a computerized quantitative flow cytometric assay for ZAP-70 within the entire CLL population, which would be easy to perform and enable standardization between laboratories. METHODS: Intracellular ZAP-70 levels in CLL and normal B cells were assessed by molecules of equivalent soluble fluorochrome (MESF), employing Quantum FITC MESF calibration beads to establish a standard curve relating channel value to fluorescence intensity in MESF units and the QuickCal v. 2.2 program (www.bangslabs.com) and clinical relevance of the data was determined. RESULTS: The average ZAP-70 expression value in the CD19(+)/CD5(+) cells from 35 CLL patients was 103,701 MESF when compared with 12,621 MESF in B cells from 20 normal blood samples. "Low" and "high" ZAP-70 CLL subgroups were defined. Patients with "high ZAP-70 MESF" CLL had a shorter time to disease progression (P = 0.0005) and a more advanced clinical stage (P = 0.0018) when compared with patients in the "low ZAP-70 MESF" CLL subgroup. CONCLUSIONS: This quantitative analysis method can be employed to obtain a more specific and highly accurate assessment of ZAP-70 levels in CLL cells. The method can easily be standardized, in any routine flow laboratory, thereby improving reproducibility and reliability of ZAP-70 analysis. (+info)
Long-term outcome after Talent endograft implantation for aneurysms of the abdominal aorta: a multicenter retrospective study.
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BACKGROUND: The development of newer-generation endografts for the endovascular treatment of abdominal aortic aneurysms has resulted in considerable improvements in clinical performance. However, long-term outcome data are still scarce. To assess long-term clinical and radiographic outcomes after use of the Talent stent graft, a retrospective analysis was performed that was based on 165 patients treated with this endograft in Germany between October 1996 and December 1998. METHODS: Data were collected according to the recommendation of the ad hoc committee for standardized reporting practices in vascular surgery and were evaluated statistically by using univariate and multivariate analyses. RESULTS: A total of 165 patients were treated with a Talent endograft in 9 German centers before December 31, 1998. Most were asymptomatic (94.5%), male (97.6%), and treated with a bifurcated graft (86.7%). Two patients (1.2%) died within 30 days, and 28 (17%) died during the follow-up period. The cause of death was aneurysm rupture in one case. Survival was 95.4% +/- 1.7% at 1 year, 89% +/- 2.6% at 2 years, 78.1% +/- 3.6% at 5 years, and 76.2% +/- 4.1% at 7 years. Patients classified as American Society of Anesthesiologists grade IV had a significantly lower survival rate (24.9%) than those classified as American Society of Anesthesiologists grade II and III (91.9% and 77.3%). During a mean follow-up period of 53.2 +/- 20.1 months (range, 1-84 months), 47 secondary procedures were performed in 31 patients (18.8%). Kaplan-Meier estimates showed a freedom from secondary intervention of 94.7% +/- 1.8%, 81.7% +/- 3.3%, and 77.4% +/- 3.6% at 1, 3, and 7 years, respectively. The reason for secondary treatment was endograft thrombosis in 10 patients (6.1%), persisting primary endoleak in 9 (5.5%), late secondary endoleak in 6 (3.6%), graft migration in 3 (1.8%), aneurysm rupture in 2 (1.2%), and graft infection in 1 (0.6%). Device migration (> or =10 mm) occurred in seven patients (4.2%). Other graft changes, such as graft kinking (n = 4; 2.4%), fracture of metallic stents (n = 2; 1.2%), erosion of the longitudinal bar (n = 2; 1.2%), or modular component separation (n = 1; 0.6%), were rare. Follow-up computed tomographic imaging revealed a decrease of the maximum aneurysm sac diameter (>5 mm) in 106 (64.2%) patients and an increase in 14 (8.5%) patients. The mean aneurysm diameter significantly decreased (P < .001). Of the factors recorded at baseline, only endoleaks showed a significant correlation with the risk of aneurysm increase during follow-up (P < .001). Adverse anatomy (neck diameter >28 mm, neck length <15 mm, and '5 patent aortic branches) did not adversely influence the aneurysm shrinkage rate, the risk for a secondary procedure, or the clinical success rate. A significantly higher rate of clinical success (P < .05) was observed in patients older than 65 years of age. CONCLUSIONS: Implantation of the Talent endograft device is a safe and effective alternative to open surgery for exclusion of abdominal aortic aneurysm. In comparison with first-generation grafts, the device showed superior durability for as long as 5 to 7 years after implantation. Even if prototypes of the Talent device were implanted in this study, the graft was also successfully used in most patients, even in those with adverse anatomy. Because improvements of the endograft have been made to address connecting bar breaks, a lower incidence of graft limb occlusion can be expected in the future. (+info)
Carotid artery stenting in octogenarians is associated with increased adverse outcomes.
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BACKGROUND: Carotid artery stenting is an increasingly common endovascular treatment of carotid artery stenosis advocated in high-risk patients despite reports of increased adverse periprocedural outcomes in patients aged >80 years. We sought to evaluate our single institution experience with octogenarians and whether they have an increased incidence of major complications with carotid artery stenting. METHODS: Three hundred eighty-six patients, including 260 patients from 10 regulatory trials, who underwent carotid artery stenting between June 1996 and March 2004 for symptomatic or asymptomatic carotid stenosis were reviewed from a prospectively maintained database. Periprocedural (< or =30 days after carotid artery stenting) cerebrovascular accident, transient ischemic attack, myocardial infarction, and death outcomes were compared between 87 octogenarians and 295 nonoctogenarians. Univariate and multivariate analysis was performed for confounding factors. Kaplan-Meier analysis of stroke and death outcomes was performed for a 1-year follow-up. RESULTS: All adverse outcomes were significantly higher in octogenarians compared with younger patients: 30-day stroke rate, 8.0% vs 2.7% (P = .02); 30-day stroke, myocardial infarction, or death, 9.2% vs 3.4% (P = .02). Cohorts were similar in terms of gender, comorbidities, antiplatelet medications, symptomatic status, and use of cerebral protection. Octogenarians had a greater incidence of contralateral internal carotid artery occlusion (26% vs 12%, P = .001), atrial fibrillation (21% vs 8%, P = .001), and congestive heart failure (28% vs 15%, P = .007), but a lower incidence of hypercholesterolemia (53% vs 72%, P = .001) and active smoking (8% vs 24%, P = .001). Multivariate analysis of 30-day major adverse outcomes demonstrated an association between age > or =80 and adverse outcome (odds ratio, 2.85; P = .043) as well as a protective effect of the preprocedural use of aspirin (odds ratio, 0.30, P = .027). At 1-year follow-up, only 75% of octogenarians and 87% of nonoctogenarians were free from stroke, myocardial infarction, or death (P = 005, Kaplan-Meier analysis). CONCLUSIONS: Octogenarians undergoing carotid artery stenting are at higher risk than nonoctogenarians for periprocedural complications, including neurologic events and death. Major event-free survival at 1 year is also significantly better in nonoctogenarians. These risks should be weighed when considering carotid stenting in elderly patients. (+info)
Management of in-sent restenosis after carotid artery stenting in high-risk patients.
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BACKGROUND: Carotid artery stenting (CAS) has emerged as an acceptable treatment alternative in patients with carotid bifurcation disease. Although early results of CAS have been promising, long-term clinical outcomes remain less certain. We report herein the frequency, management, and clinical outcome of in-stent restenosis (ISR) after CAS at a single academic institution. METHODS: Clinical records of 208 CAS procedures in 188 patients with carotid stenosis of 80% or greater, including 48 (26.5%) asymptomatic patients, during a 42-month period were analyzed. Follow-up serial carotid duplex ultrasound scans were performed. Selective angiography and repeat intervention were performed when duplex ultrasound scans showed 80% or greater ISR. Treatment outcomes of ISR interventions were analyzed. RESULTS: Over a median 17-month follow-up, 33 (15.9%) ISRs of 60% or greater were found, according to the Doppler criteria. Among them, seven patients (3.4%) with a mean age of 68 years (range, 65-87 years) developed high-grade ISR (> or =80%), and they all underwent further endovascular interventions. Six patients with high-grade ISR were asymptomatic, whereas one remaining patient presented with a transient ischemic attack. Five of seven ISRs occurred within 12 months of CAS, and two occurred at 18 months' follow-up. Treatment indications for initial CAS in these seven patients included recurrent stenosis after CEA (n = 4), radiation-induced stenosis (n = 1), and high-cardiac-risk criteria (n = 2). Treatment modalities for ISR included balloon angioplasty alone (n = 1), cutting balloon angioplasty alone (n = 4), cutting balloon angioplasty with stent placement (n = 1), and balloon angioplasty with stent placement (n = 1). Technical success was achieved in all patients, and no periprocedural complications occurred. Two patients with post-CEA restenosis developed restenosis after ISR interventions, both of whom were successfully treated with cutting balloon angioplasty at 6 and 8 months. The remaining five patients showed an absence of recurrent stenosis or symptoms during a mean follow-up of 12 months (range, 3-37 months). By using the Kaplan-Meier analysis, the freedom from 80% or greater ISR after CAS procedures at 12, 24, 36, and 42 months was 97%, 97%, 96%, and 94%, respectively. CONCLUSIONS: Our study showed that ISR after CAS remains uncommon. Successful treatment of ISR can be achieved by endovascular interventions, which incurred no instance of periprocedural complications in our series. Patients who developed ISR after CEA were likely to develop restenosis after IRS intervention. Diligent ultrasound follow-up scans are important after CAS, particularly in patients with post-CEA restenosis. (+info)