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High expression levels of x-linked inhibitor of apoptosis protein and survivin correlate with poor overall survival in childhood de novo acute myeloid leukemia.

PURPOSE: Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. EXPERIMENTAL DESIGN: Using flow cytometry and Western blot analysis, we, therefore, investigated 45 leukemic cell samples from children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins [CD95, Bcl-2, Bax, Bcl-xL, procaspase-3, X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein-1 (cIAP-1), survivin]. RESULTS: XIAP (P < 0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by French-American-British (FAB) morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (P < 0.01) and Bcl-xL (P < 0.01) expression was lower in patients with favorable rather than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP [30 (n = 10) versus 41 months (n = 34); P < 0.05] and survivin [27 (n = 10) versus 41 months (n = 34); P < 0.05]. CONCLUSIONS: We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups, and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics, and poor overall survival should be confirmed within prospective pediatric AML trials.

Adolescent↗

Cyclooxygenase-2 expression in human colorectal cancer is unrelated to overall patient survival.

PURPOSE: Cyclooxygenase-2 (COX-2) expression in human colorectal cancer and adenoma tissue seems to be higher than in normal mucosa. However, data about the relation between COX-2 expression and patient survival are inconclusive as yet. Therefore, we studied COX-2 expression in surgery tissue and survival time in a cohort of 747 colorectal cancer patients. EXPERIMENTAL DESIGN: Surgical specimens of primary colorectal cancer from 747 individuals were immunostained for COX-2 and evaluated under a transmission light microscope. COX-2 expression was scored according to intensity and extent of staining, resulting in the COX-2 immunoreactivity score (IRS-COX2). All possible cutoff points for IRS-COX2 were analyzed for a relation between COX-2 expression and patient survival. RESULTS: Both univariable and multivariable analysis have shown that the COX-2 expression in human tumor epithelial cells was unrelated to overall patient survival and to disease-free survival, irrespectively of the cutoff point for IRS-COX2. The survival rates for 1, 3, 5, and 10 years were 81.0%, 66.8%, 60.2%, and 49.8% (median: 117.3 months; 95% confidence interval, 102.3-132.0), respectively. In the multivariable analysis, only node and metastasis were significantly related to overall patient survival. Similar results were obtained when stage IV and rectal cancer patients were excluded from the analysis. CONCLUSIONS: COX-2 expression in tumor epithelial cells does not seem to be related to survival of colorectal cancer patients. Besides COX-2, there are several targets, such as the peroxisome proliferator-activated receptors, that are involved in carcinogenesis and may be modulated by nonsteroidal anti-inflammatory drugs. Further studies are needed to determine their prognostic relevance.

Aged↗

Recombinant human erythropoietin is associated with increased overall survival in patients with multiple myeloma.

BACKGROUND: Recombinant human erythropoietin (rhEPO) is effective for the treatment of anemia associated with multiple myeloma. Data from animal studies and case reports suggest that rhEPO has antineoplastic properties. METHODS: Two hundred and ninety-two patients enrolled on different chemotherapy clinical trials at the Cleveland Clinic Myeloma Program between 1997 and 2003 were the subjects of this study. Information on erythropoietin use as well as baseline prognostic variables were collected retrospectively. RESULTS: The population consisted of 257 patients with multiple myeloma treated at the Cleveland Clinic Foundation from 1997 to 2003 and followed for at least 1 month. Thirty-five patients were excluded from this analysis because information on erythropoietin use was not available. One hundred and twenty-seven patients received rhEPO for at least 1 month and the rest did not received rhEPO. On average, patients who received rhEPO were older, had a higher Southwest Oncology Group (SWOG) stage, higher serum creatinine, lower serum hemoglobin, higher beta2-microglobulin, lower platelet counts, and a longer time from diagnosis to enrollment at the myeloma program (p < 0.001 for all). After adjusting for age, months from diagnosis to enrollment, serum creatinine, hemoglobin, platelet count, and beta2-microglobulin, the use of rhEPO was associated with improved overall survival (hazard ratio = 0.6; 95% CI = 0.38-0.94) in patients with SWOG stages II, III and IV but not in patients with SWOG stage I. CONCLUSION: rhEPO was associated with improved overall survival in this population of anemic multiple myeloma patients with SWOG stages of II, III and IV. A prospective randomized trial is warranted to corroborate this finding.

Aged↗

Cordocentesis: overall pregnancy loss rate as important as procedure loss rate.

A 4-year retrospective review of cordocentesis at a single center with four operators identified 182 patients undergoing 214 cordocenteses. The major indications were chromosomal, fetal platelet and rhesus evaluation. The procedure was successful in 95%. A positive genetic diagnosis was present in 18% with 64% having trisomy 18, 21 or 13. The procedural pregnancy loss rate was 3.25, 1.25 and 2.75% for chromosomal and nonchromosomal indications and total population, respectively. The overall fetal loss rate (procedural, nonprocedural) in chromosomal risk population was 47%. This overall pregnancy loss risk should be included in patient counselling.

Chromosome Aberrations↗

Automated rescreening in cervical cytology. Mathematical models for evaluating overall process sensitivity, specificity and cost.

OBJECTIVE: To develop mathematical models to assist decision makers with the difficult task of evaluating the use of automated rescreening in the process of screening cervical smears. STUDY DESIGN: Using assumptions about incidence, per smear screening costs, and the sensitivity and specificity of cytotechnologists, pathologists and the rescreening device, basic probability models were developed to describe the overall sensitivity, specificity and cost of the screening process. RESULTS: The optimal screening policy is highly dependent on assumptions, and an automated system can significantly affect the overall system cost and accuracy. CONCLUSION: Mathematical planning models are valuable tools to assist decision makers in the design of a screening process for cervical smears.

Automation↗

Decline in out-of-hospital coronary heart disease deaths has contributed the main part to the overall decline in coronary heart disease mortality rates among persons 35 to 64 years of age in Finland: the FINAMI study.

BACKGROUND: Out-of-hospital deaths constitute the majority of all coronary heart disease (CHD) deaths and are therefore of considerable public health significance. METHODS AND RESULTS: We used population-based myocardial infarction register data to examine trends in out-of-hospital CHD deaths in Finland during 1983 to 1997. We included in out-of-hospital deaths also deaths in the emergency room and all deaths within 1 hour after the onset of symptoms. Altogether, 3494 such events were included in the analyses. The proportion of out-of-hospital deaths of all CHD deaths depended on age and gender. In the age group 35 to 64 years, it was 73% among men and 60% among women. These proportions did not change during the study. The annual average decline in the age-standardized out-of-hospital CHD death rate was 6.1% (95% CI, -7.3, -5.0%) among men and 7.0% (-10.0, -4.0%) among women. These declines contributed among men 70% and among women 58% to the overall decline in CHD mortality rate. In all, 58% of the male and 52% of the female victims of out-of-hospital CHD death had a history of symptomatic CHD. Among men with a prior history of myocardial infarction, the annual average decline in out-of-hospital CHD deaths was 5.3% (-7.2, -3.2%), and among men without such history the decline was 2.9% (-4.4, -1.5%). Among women, the corresponding changes were -7.8% (-14.2, -1.5%) and -4.5% (-8.0, -1.0%). CONCLUSIONS: The decline in out-of-hospital CHD deaths has contributed the main part to the overall decline in CHD mortality rates among persons 35 to 64 years of age in Finland.

Adult↗

Influence of timing of admission after aneurysmal subarachnoid hemorrhage on overall outcome. Report of the cooperative aneurysm study.

The overall management results after aneurysmal rupture were studied in 158 patients admitted to the hospital on day 0--3 and 175 patients admitted on day 4--7 following subarachnoid hemorrhage. In this series surgery was planned no sooner than 12 days following the ictus. Despite effective medical and surgical therapy overall results were disappointing: 3 months following the initial hemorrhage only 43% of patients in the 0--3 day group and 53% of patients in the 4--7 day group were capable of independent functional living. Patients admitted on days 4--7 also had a lower mortality rate, re-bled less frequently, and had lower postoperative mortality and morbidity than those admitted on days 0--3. For reasons not well defined, time of admission following aneurysmal SAH has an important influence on outcome. Accordingly, in evaluating outcome for patients with ruptured aneurysms treated with different therapeutic modalities, time of admission must be carefully controlled.

Female↗

Definition of initial grading, specific events, and overall outcome in patients with aneurysmal subarachnoid hemorrhage. A survey.

BACKGROUND AND PURPOSE: Scientific communication in medicine can be effective only if reports are based on unequivocal criteria for clinical conditions or specific diagnoses. METHODS: We reviewed all articles about subarachnoid hemorrhage published in nine neurosurgical or neurological journals from 1985 through 1992 and assessed the presence and the precision of definitions used for reporting the initial grade, the specific complications of rebleeding, delayed cerebral ischemia, and hydrocephalus, and the overall outcome. We identified 184 articles reporting direct observations in at least 10 patients on one or more of these conditions. RESULTS: Of 161 articles reporting the initial condition, only 19% used an unequivocal grading system (World Federation of Neurological Surgeons Scale or Glasgow Coma Scale); this proportion did not increase after 1988, when the World Federation of Neurological Surgeons Scale was introduced. The specific outcome events of rebleeding, ischemia, and hydrocephalus (283 instances) were sufficiently defined in only 31% of instances, incompletely in 22%, and not at all in 47%. The proportions were similar when the results were analyzed according to the type of complication, the year of publication, or per study. The four exclusively neurosurgical journals featured suitable definitions for any of the three outcome events in 20% of 209 instances, whereas the five mainly neurological journals published fewer articles about subarachnoid hemorrhage (74 instances of outcome events) but more often with precise criteria (65%). Overall outcome was adequately reported in 63% of all articles, with an increase over the years (54% in 1985 through 1988, 71% in 1989 through 1992). CONCLUSIONS: Reports about subarachnoid hemorrhage require closer scrutiny before publication to ascertain whether the conclusions about specific outcome events are based on unequivocal criteria.

Bias↗

Peak flow as predictor of overall mortality in asthma and chronic obstructive pulmonary disease.

Lung function is a strong predictor of overall mortality in asthma and chronic obstructive pulmonary disease (COPD). FEV1 is considered to be the "gold standard," whereas peak expiratory flow (PEF) is mostly used in absence of FEV1 measurements. We compared the predictive power of PEF and FEV1, measured after maximal bronchodilation, which included a short course of oral corticosteroids. The study population comprised 491 asthmatics and 1,095 subjects with COPD. Pulmonary function tests were performed between 1983 and 1988, and survival data were obtained by September 1997, when 127 asthmatics and 723 subjects with COPD had died. Predictors of survival were examined by Cox proportional hazards analyses. After controlling for age, smoking, sex, and body mass index, we found best PEF to be at least equal to best FEV1 as predictor of overall mortality in subjects with COPD. The predictive power of best PEF was in part maintained after controlling for best FEV1. In asthma, best FEV1 seemed to be a better predictor of mortality than best PEF. Despite close correlation to FEV1, PEF apparently provides independent prognostic information in patients with COPD. This may be due to PEF and FEV1 reflecting different components of COPD, i.e., chronic bronchitis, small airways disease, and emphysema. Furthermore, extrapulmonary components such as muscle mass and general "vigour" probably affect PEF to a greater extent than they affect FEV1.

Asthma↗

How do patients with Alzheimer disease rate their overall quality of life?

OBJECTIVE: The authors asked how Alzheimer disease (AD) patients assess their overall quality of life (QOL) and sought to determine the characteristics associated with this assessment. METHODS: The authors performed a cross-sectional survey of 193 persons with mild-to-severe-stage AD in a University Memory Disorders Clinic using a single-item self-assessment of overall QOL. RESULTS: The 181 of 193 patients (94%) able to complete a single-item QOL self-rating had less severe dementia than patients not able to complete, but some had Mini-Mental State Exam scores as low as 0. Most patients rated their QOL as "good" (35%) or "very good" (36%). Latino patients, patients with less education, and depressed patients were more likely to rate their QOL lower. Among patients able to estimate how they thought their family caregiver would rate their QOL (N=173; 90%), there was moderate agreement between this estimate and their self-ratings. CONCLUSION: A single-item global rating of patient QOL could prove useful in assessing QOL of most mild-to-severe-stage AD patients. Affective impairment, more than cognitive or functional impairment, drives this assessment. Screening for and addressing depressive symptoms could improve AD patients' QOL. Despite impairments in insight, patients see a difference in how their caregivers would rate their QOL.

Aged↗

Determining the appropriate level of care. An analysis of factors affecting the staff's overall needs assessments, using data collected through the ASIM monitoring system.

For the purpose of evaluating the validity of the staff's overall needs assessment in terms of the 'appropriate level of care' as a measurement of resource needs--with particular emphasis on the need for institutional resources--an analysis was made concerning the relation of the assessment to various other factors. In the analysis, we used data collected in a survey undertaken in Solna municipality on November 1, 1991 according to the ASIM monitoring system. It was found by multiple regression analysis, that the 'appropriate level of care' was closely related to the client's degree of disability, age, and actual level of care. On the other hand, variables describing the client's social situation--marital status, single-living, informal social support, standard and accessibility of housing--bore no relation to the assessment of need for institutional care. Chiefly because of the close relation to the actual level of care it was concluded that the staff's overall assessment of 'appropriate level of care' should be used with a degree of caution as measure of the need for institutional resources, since it would tend to overrate that need. A more systematic needs assessment procedure is required in order to provide the municipal authorities with unbiased estimates of institutional resource needs.

Aged↗

Brain metastases from gynecological cancers: factors that affect overall survival.

We retrospectively reviewed factors that affected overall survival for patients with gynecological cancers that had metastasized to the brain. Between January 1985 to November 1999, we treated 25 patients with brain metastases from gynecological malignancies (cervix n=6, endometrium n=10, and ovary n=9). Various patient and tumor characteristics were identified and analyzed for their significance. Median age was 46 years old (range, 37-78 years) with the majority of tumors being adenocarcinoma (20/25 patients). The treatment consisted of whole brain radiation therapy (WBRT) in 11 patients, focal therapy (surgery and/or stereotactic radiosurgery [SRS]) in 6 patients, and combination therapy (WBRT and surgery and/or SRS) in 8 patients and resulted in median survivals of 6 months, 7 months and 11 months, respectively. Overall median survival was 7.3 months (range, 1 to 88 months). Cause of death was systemic in 9, neurologic in 8 and progression of primary in 2. Those with single lesions had better median survivals compared to those with multiple lesions (17 months vs. 3 months, p=0.017). Our results suggest that patients with a single lesion had improved outcomes. We encourage enrollment of patients with brain metastases onto prospective clinical trials.

Adult↗

Overall activity of all masticatory muscles during lateral excursion.

Quantification of the overall activity of every masticatory muscle is requisite for the analysis of stomatognathic function, which has not been accomplished by conventional electromyography. We used positron emission tomography and 18F-fluoro-deoxy-glucose to quantify the overall activity of every masticatory muscle during lateral excursion, and to evaluate the relative contribution of each masticatory muscle to lateral excursion. The present study suggested that lateral and medial pterygoid muscles are more responsible for lateral excursion than are masseter and temporal muscles. In particular, the contralateral lateral pterygoid muscle plays a major role, followed by the contralateral medial pterygoid muscle.

Adult↗

Overall survival in advanced breast cancer: relevance of progesterone receptor expression and DNA ploidy in fine-needle aspirates of 392 patients.

Fine-needle aspiration cytology (FNAC) is essential for making a diagnosis in advanced breast cancer. The determination of hormone receptors in the material obtained is useful for predicting patient response to endocrine therapy, but the prognostic value of hormone receptor expression as well as the clinical utility of DNA flow cytometry are controversial. The aim of this prospective study with long-term follow-up (median: 81 months) was to evaluate these biomarkers in relation to overall survival in a series of 392 patients with advanced breast cancer (stage IIB, n=106; IIIA, n=66; IIIB, n=174; and IV, n=46) using FNAC. Estrogen and progesterone receptor expression was found in 65.1% and 46.1% of the tumors, respectively. Hormone receptors were not found to be associated with clinical staging. DNA aneuploidy was present in 70.9% of the cases and the median S-phase fraction (SPF) was 9.4%. There was a significant correlation of aneuploidy and high SPF with lack of hormone receptors. In univariate analysis, advanced disease stage, absence of hormone receptors, DNA aneuploidy and high SPF showed a statistically significant correlation with poor clinical outcome. In multivariate analysis, disease stage, progesterone receptors and DNA ploidy retained independent prognostic significance in relation to overall survival. These data indicate that progesterone receptor expression and DNA ploidy are independent prognostic factors in advanced breast cancer.

Adult↗

High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma.

The tumor microenvironment plays an important role in the biologic behavior of follicular lymphoma (FL), but the specific cell subsets involved in this regulation are unknown. To determine the impact of FOXP3-positive regulatory T cells (Tregs) in the progression and outcome of FL patients, we examined samples from 97 patients at diagnosis and 37 at first relapse with an anti-FOXP3 monoclonal antibody. Tregs were quantified using computerized image analysis. The median overall survival (OS) of the series was 9.9 years, and the FL International Prognostic Index (FLIPI) was prognostically significant. The median Treg percentage at diagnosis was 10.5%. Overall, 49 patients had more than 10% Tregs, 30 between 5% to 10%, and 19 less than 5%, with a 5-year OS of 80%, 74%, and 50%, respectively (P = .001). Patients with very low numbers of Tregs (< 5%) presented more frequently with refractory disease (P = .007). The prognostic significance of Treg numbers was independent of the FLIPI. Seven transformed diffuse large B-cell lymphomas (DLBCLs) had lower Treg percentages (mean: 3.3%) than FL grades 1,2 (mean: 12.1%) or 3 (mean: 9%) (P < .02). In conclusion, high Treg numbers predict improved survival of FL patients, while a marked reduction in Tregs is observed on transformation to DLBCL.

Aged↗

Split course hyperfractionated accelerated radio-chemotherapy (SCHARC) for patients with advanced head and neck cancer: influence of protocol deviations and hemoglobin on overall survival, a retrospective analysis.

BACKGROUND: The advantage of hyperfractionated accelerated radiation therapy for advanced head and neck cancer has been reported. Furthermore, randomized trials and meta-analyses have confirmed the survival benefit of additional chemotherapy to radiotherapy. We retrospectively analyzed the efficiency and toxicity of the Regensburg standard therapy protocol "SCHARC" and the overall survival of our patients. METHODS: From 1997 to 2004, 64 patients suffering from advanced head and neck cancer (88 % stage IV, 12 % stage III) were assigned to receive the SCHARC protocol. Around half of the patients were diagnosed with oro-hypopharynx carcinoma (52 %), one third with tongue and floor of mouth tumors (29 %) and one fifth (19 %) suffered from H & N cancer at other sites. The schedule consisted of one therapy block with 30 Gy in 20 fractions over a two week period with concomitant chemotherapy (d 1-5: 20 mg/m2/d DDP + 750-1000 mg/m2/d 5FU (cont. infusion). This therapy block was repeated after a fortnight break up to a cumulative dose of 60 Gy and followed by a boost up to 70 Gy (69-70.5 Gy). All patients assigned to this scheme were included in the survival evaluation. RESULTS: Forty patients (63 %) received both radiation and chemotherapy according to the protocol. The mean follow up was 2.3 years (829 d) and the median follow up was 1.9 years (678 d), respectively. The analysis of survival revealed an estimated 3 year overall survival rate of 57 %. No patient died of complications, 52 patients (80 %) had acute grade 2-3 mucositis, and 33 patients (58 %) suffered from acute grade 3 skin toxicity. Leucopenia was no major problem (mean nadir 3.4 g/nl, no patient < 1.0 g/nl) and the mean hemoglobin value decreased from 13.2 to 10.5 g/dl. Univariate analysis of survival showed a better outcome for patients with a hemoglobin nadir >10.5 g/dl and for patients who completed the protocol. CONCLUSION: The SCHARC protocol was effective in patients diagnosed with advanced head and neck cancer. It led to long-term disease control and survival in about 50 % of the patients with significant but acceptable toxicity. Most patients were not anemic at beginning of therapy. Therefore, we could assess the influence of pre-treatment hemoglobin on survival. However, a low hemoglobin nadir was associated with poor outcome. This result suggests an influence of anemia during therapy on prognosis.

Adult↗

Improved overall survival in dendritic cell vaccination-induced immunoreactive subgroup of advanced melanoma patients.

BACKGROUND: We present our experience of therapeutic vaccination using dendritic cells (DC) pulsed with autologous tumor antigens in patients with advanced melanoma. METHODS: Twenty-one pretreated advanced melanoma patients were vaccinated with autologous DC pulsed with 100 microg/ml of autologous-tumor-lysate (ATL) or -homogenate (ATH) and 50 microg/ml of keyhole limpet hemocyanin (KLH). The first 8 patients were treated subcutaneously or intradermally with immature-DC (iDC) (range 4.5-82 x 10(6)) and the remaining 13 intradermally with in vitro matured DC (mDC) (range 1.2-26 x 10(6)). Subcutaneous interleukin-2 (3 x 10(6) IU) was administered from days 3 to 7 of each treatment cycle. RESULTS: Three of the 8 iDC patients obtained stabilizations (SD), each of 6 months' duration. The 13 mDC patients showed 1 complete response (8 months), 1 partial response (3 months), 2 mixed responses (6 and 12 months) and 3 SD (9, 7+, and 3+ months). Overall responses (OR) were observed in 4/21 (19%) patients, or 4/13 (30.7%) considering mDC treatment only. 10/21 (47.6%) patients showed non progressive disease (NPD), with 7/13 (53.8%) cases of NPD for mDC-treated patients. No major toxicities were observed. The positive delayed-type hypersensitivity (DTH) test to ATL/ATH and/or KLH correlated with increased overall survival (OS). Median OS was 24 months (range 3-45) for the 10 DTH-positive (1 iDC and 9 mDC) and 5 months (range 3-14) for the 11 DTH-negative patients (P < 0.001). The in vitro evaluation of gamma IFN-secreting T-cells in 10 patients showed good correlation with both DTH (75%) and clinical outcome (70%). CONCLUSION: Vaccination using DC pulsed with ATL/ATH and KLH in advanced melanoma patients is well tolerated and can induce a clinical response, especially when mDC are used. Successful immunization, verified by positive DTH, leads to longer survival.

Journal Article↗

Are axillary recurrence and overall survival affected by axillary extranodal tumor extension in breast cancer? Implications for radiation therapy.

PURPOSE: To determine the overall survival and local recurrence significance of axillary lymph node extranodal tumor extension (ETE) and whether axillary/chest-wall irradiation influenced any of these outcomes. MATERIALS AND METHODS: The records of 81 breast cancer patients treated with radical or modified radical mastectomy at a single surgical practice were eligible for study. Thirty-four patients had ETE: 17 with focal ETE (< 10 x high-power field) and 17 with extensive ETE (> 10 x high-power field). RESULTS: With a median follow-up duration of 92 months, only two patients had an axillary recurrence (2%): one had focal ETE and one had no ETE. Neither of these patients received axillary radiation therapy. Overall survival and recurrence-free survival were significantly decreased with ETE in patients whether axillary radiation therapy had been administered or not. Analysis showed that the age of the patient correlated significantly with extensive ETE (P = .04) and that the number of positive lymph nodes (< or = three v > three) correlated significantly with ETE (whether focal or extensive) (P = .0001). A multivariate analysis of extranodal tumor extension and number of positive lymph nodes showed that ETE was associated with decreased survival (P = .05), although to a lesser degree than number of positive lymph nodes (P = .003). CONCLUSION: These results show that ETE is associated with decreased survival and increased recurrence rates regardless of the extent of the radiation therapy field. Also, ETE does not necessarily indicate a significantly increased incidence of axillary recurrence. Therefore, axillary irradiation based on this pathologic finding may not be indicated.

Age Factors↗