Estimation Of Prognosis In Patients Research Articles

Molecular Imaging Kits for Hexosamine Biosynthetic Pathway in Oncology

Noninvasive imaging assessment of tumor cell proliferation could be helpful in the evaluation of tumor growth potential, the degree of malignancy, and could provide an early assessment of treatment response prior to changes in tumor size determined by computed tomography (CT), magnetic resonance imaging (MRI), Positron emission tomography (PET), Single-Photon emission computed tomography (SPECT) or ultrasonography, respectfully. Understanding of tumor proliferative activity, in turn, could aid in the selection of optimal therapy by estimating patient prognosis and selecting the proper management. PET/CT imaging of (18)F-fluoro-2-deoxy-glucose (FDG) is recognized as a technology for diagnosing the presence and extent of several cancer types. Recently, radiolabeled glucosamine analogues were introduced as a promising SPECT agent to complement FDG imaging to increase specificity and improve the accuracy of lesion size in oncology applications. Radiolabeled glucosamine analogues were developed to localize in the nuclear components of cells primarily via the hexosamine biosynthetic pathway whereas glucose localizes in the cytoplasm of cells through the glycolytic/TCA pathway. This paper reviews novel kit-based radiolabeled glucosamine analogues for metabolic imaging of tumor lesions. The novel radiolabeled glucosamine analogues may increase the specificity in oncology applications and can influence patient diagnosis, planning and monitoring of cancer treatment.

Is cardiac magnetic resonance imaging assessment of myocardial viability useful for predicting which patients with impaired ventricles might benefit from revascularization?

A best evidence topic in cardiac magnetic resonance imaging (MRI) was written according to a structured protocol. The question addressed was: what is the role of cardiac magnetic resonance (CMR) imaging in viability assessment of ischaemic cardiomyopathy? Altogether more than 164 papers were found using the reported search; of which, 6 represented the best available evidence to answer the clinical question and an additional 4 were found by crosschecking the reference lists for further 'best available evidence' papers. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Using late-gadolinium enhancement-cardiac magnetic resonance (LGE-CMR) imaging, infarcted myocardium can be identified by the presence of hyperenhanced signal. The extent of myocardial hyperenhancement correlates inversely with improved myocardial contractility following surgical or percutaneous revascularization. Furthermore, CMR is able to assess not only viability, but also make gold-standard assessment of ventricular function and volume as well as identify stress perfusion deficits, each of which is relevant to estimating patient prognosis. National bodies have also begun to formally recommend CMR imaging for cardiac viability assessment. For example, the Canadian Cardiovascular Society (CCS) has stated that 'assessment of myocardial viability in patients with left ventricle dysfunction or akinetic segments for predicting recovery of ventricular function following revascularization is a class I indication for the use of LGE-CMR'. We conclude that cardiac MRI is an excellent tool for predicting myocardial viability, in the context of acute and chronic ischaemic heart disease whether subsequent revascularization is achieved by surgical or percutaneous means. In addition, the versatility of CMR imaging makes it an increasingly attractive tool for the complete assessment of the patient with ischaemic cardiomyopathy.

Speicheldrüsenkarzinome

Due to their infrequency, diagnosis of salivary gland tumors remains a challenge for the practicing pathologist with respect to subtyping, grading and estimating patient prognosis. In a 3 center collaborative study of 288 cases with clinical follow-up information, it could be demonstrated that apart from clinical parameters like high patient's age, male sex and high tumor stage, the application of a 3-tiered grading system incorporating the histological tumor type is of high prognostic relevance. In immunohistochemical and molecular analyses overexpression of epidermal growth factor receptor (EGFR), high expression of human epidermal growth factor receptor 2 (HER2), amplification and gains of EGFR and HER2, absent expression of C-KIT, loss of maspin and of O(6)-methylguanine DNA-methyltransferase (MGMT) as well as MGMT promoter methylation turned out to be negative prognostic factors. In mucoepidermoid carcinomas the presence of a translocation t(11;19) was less relevant than recognizing different subtypes (classical type, eosinophilic, clear-cell and squamoid variants). Acinic cell carcinoma with mixed acinar-ductular differentiation as judged by expression of CK7 was characterized by a higher frequency of early relapse. The presented results underline the pathologist's role in the diagnosis and management of patients with salivary gland carcinomas.

Expression and clinical significance of galetin-3 and EGFR proteins in esophageal squamous carcinoma

Objective To explore the correlation of expression of galetin-3 (Gal-3) and epidermal growth factor receptor (EGFR) with the biological behaviors in esophageal squamous carcinoma(ESC). Methods Immunohistochemical method was used to examine the expression of Gal-3 and EGFR in 80 specimens of ESC. Results The positive rates of Gal-3 and EGFR was 73.8％ (59/80)and 56. 3％ (45/80)respectively. The positive rates of Gal-3 and EGFR expression in the patients with poor differentiation, deep infiltration and lymph node metastasis was significantly higher than those with well differentiation, shallow infiltration and without lymph node metastasis ( P ＜ 0. 05 ). The high expression of Gal-3 and EGFR was correlated with higher percentage of death and lower survival rate ( P ＜ 0.05 ). Conclusion The abnormal expression of Gal-3 and EGFR is closely related with the pathological biology behaviors of ESC. Gal-3 and EGFR can be regarded as objective indicators for forecasting metastasic potential of ESC and estimating prognosis of patients with ESC. Key words: Esophageal neoplasms; Carcinoma, squamous cell; Receptor, epidermal growth factor; Galectin-3

Reply to Dr. Wiwanitkit’s letter to the editor

We are grateful to Dr. Wiwanitkit for his positive review of our recent publication. Dr. Wiwanitkit noted that there are many other systems that can be used to classify cholangiocarcinoma and that additional comparative assessments using these systems will provide useful data that can help us identify the best classification system. We believe that a useful classification contains three categories, including local tumor extension, lymph node metastasis, and distant metastasis in patients with extrahepatic cholangiocarcinoma as well as other gastrointestinal malignancies. The Bismuth–Corlette and modified Memorial Sloan–Kettering Cancer Center classifications [1, 2] both consider local tumor extension, but these two classifications are not commonly used to estimate patient prognosis or evaluate treatment results. The TNM staging of the International Union Against Cancer (UICC) and the classification system of the Japanese Society of Biliary Surgery (JSBS) include these three categories. The JSBS classification was revised five times, and the sixth edition has been revised by reacting to and drawing from the UICC-TNM classification. In order to generate the best classification system, we believe that it is eminently important to compare these two classifications and identify important aspects in these systems. In the near future, these two classifications may become similar and be integrated to generate an improved classification system that will greatly help surgeons assess patients with extrahepatic cholangiocarcinoma.

Detecting Minimal Residual Disease in Neuroblastoma: Still a Ways to Go

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 10% of all cancers in children. The development of neuroblastoma involves both embryonic and tumorigenic factors, making the tumor very heterogeneous both biologically and clinically. Neuroblastoma tumors originate from embryonic neural crest cells committed to the development of the sympathetic nervous system, and their malignancy varies from totally benign with spontaneous regression to highly malignant (1). Prognostic factors include age of the patient at diagnosis, INSS (International Neuroblastoma Staging System) stage, tumor histopathology, and ploidy status of DNA content (2). Despite the availability of many clinical and biologic markers proposed as predictive of disease outcome and the use of advanced multimodal therapy, treatment results are still suboptimal for patients with these tumors. Thus, how to best estimate patient prognosis and choose optimal individual therapy remain fundamental challenges. Since the discovery by Moss et al. (3) 20 years ago of neuroblastoma cells in the blood of a majority of patients with known disseminated disease, much work has been devoted to the development and improvement of methods for detection of minimal residual disease (MRD).1 In this issue of Clinical Chemistry Stutterheim et al. (4) address the question of how to best identify the presence of neuroblastoma cells in blood and bone marrow by use of reverse transcription quantitative PCR (RQ-PCR). The authors recently investigated the use of paired-like homeobox 2b ( PHOX2B )2 as a marker for MRD in neuroblastoma and claimed reported that this transcript was the most specific single marker for this purpose (5). In the current study they selected 28 genes from SAGE libraries that showed high expression in neuroblastoma tumors and little or no expression in normal tissues. Preliminary studies of these 28 genes and 5 previously described markers (identified by using RQ-PCR and …

B-type natriuretic peptides: prognostic markers in stable coronary artery disease

Circulating concentrations of B-type natriuretic peptide (BNP) and the N-terminal fragment (NT) of its prohormone (proBNP) are related to cardiac function and have emerged as clinically useful tools for the diagnosis of heart failure and for the estimation of prognosis in patients with heart failure and acute coronary syndromes. Recent studies have also convincingly documented that both BNP and NT-proBNP are powerful, independent prognostic indicators in patients with stable coronary artery disease. The associations are strongest for the end-points of death and heart failure, whereas the association with cardiac ischemic events is weaker or nonexistent, after adjustment for confounding factors. Importantly, BNP and NT-proBNP appear to provide incremental prognostic information to conventional risk factors, including markers of ventricular function and ischemia. Data documenting that BNP or NT-proBNP measurements can be used to guide treatment decisions in patients with stable coronary artery disease are still lacking.

P53 expression, Ki-67 status, and cell density have no prognostic significance in glioblastomas treated with radio-chemotherapy

Purpose: To identify subgroups in glioblastoma multiforme (GBM) with different susceptibilities to radio-chemotherapy by p53 protein and Ki-67 expression.Patients and Methods: Thirty-one patients with primary GBM underwent a combined radio-chemotherapy with topotecan. Percentage of cells expressing p53 protein and Ki-67 antigen was determined immunohistochemically. Additionally, the cell density within the tumour tissue was measured.Results: Median percentages of p53 and Ki-67 expressing cells were 4.3% (range = 0–28%) and 12.0% (range = 0–28%), respectively. Dividing the cases into two groups by high or low p53 protein 1-year disease-free survival rates were 13.3% and 23.6%. High or low Ki-67 expression showed one-year disease-free survival rates of 18.8% and 17.1%. Neither p53 nor Ki-67 expression showed a significant correlation with disease-free survival or overall survival. Median cell density was 252 cells/field (range = 42–595). 1-year disease-free survival rates were 14.5% and 21.7% in high and low cell density group, respectively. A significant correlation with progression-free survival was observed, whereas the stratification into two groups revealed no significance. Cell density showed a significant inverse correlation with p53 and Ki-67 immunopositivity.Conclusion:p53 protein and Ki-67 expression seem to be inappropriate for the estimation of prognosis in patients receiving a combined radio-chemotherapy with topotecan.

P27kip1 Deficiency Confers Susceptibility to Gastric Carcinogenesis in Helicobacter pylori–Infected Mice

Determining how Helicobacter pylori promotes gastric cancer and whether H pylori eradication decreases cancer risk would be helped by suitable murine models. Mice lacking the cyclin-dependent kinase inhibitor p27kip1 are susceptible to carcinogen-induced tumors. Furthermore, p27 stimulates gastric epithelial apoptosis and inhibits proliferation, expression is decreased by H pylori, and low levels are associated with a poor prognosis in gastric cancer. We therefore evaluated p27-deficient mice as a model for H pylori-associated gastric cancer. Wild-type and p27-/- C57BL/6 mice were infected with H pylori mouse-adapted Sydney strain at 6-8 weeks of age and 6-10 mice of each type were euthanized 15, 30, 45, 60, and 75 weeks later. Uninfected p27-/- mice developed gastric hyperplasia. H pylori-infected p27-/- mice frequently developed intestinal metaplasia (40% at 30 weeks, 67% at 45 weeks), and after 60 weeks 7 of 12 mice developed significant dysplasia and gastric cancer, recapitulating human intestinal-type gastric carcinogenesis. Wild-type mice developed intestinal metaplasia only after 75 weeks of infection; significant gastric dysplasia was observed in 1 animal (P < .05 for each comparison with p27-/- mice). No disease developed in uninfected mice. H pylori infection in p27-/- mice was associated with significantly decreased apoptosis and increased epithelial proliferation, inflammation, and H pylori density compared with infection in wild-type mice. p27 loss and H pylori colonization cooperate to produce gastric cancer. The p27-deficient mouse affords opportunities to examine the pathogenesis of H pylori in gastric carcinogenesis and to test eradication and chemopreventive strategies.

Nm23 as a prognostic marker in primary cutaneous melanoma: evaluation using tissue microarray in a patient group with long-term follow-up

The accurate estimation of prognosis in patients with melanoma is of increasing importance with novel adjuvant therapies on the horizon. The current prediction of prognosis employs techniques involving sentinel lymph node biopsy, which carries an associated morbidity and is of little use in patients who develop direct distant metastases or direct in-transit metastases. New strategies or factors are therefore needed to improve the accuracy of determination of prognosis. nm23 is a putative metastasis suppressor; however, conflicting data exist as to its role in melanoma progression and its use as a potential prognostic marker. The purpose of this study was to use the technique of tissue microarray to study a cohort of melanoma patients with long-term follow-up data in order to ascertain its potential use as a prognostic marker. One hundred and twenty patients with primary cutaneous melanoma were included in the tissue microarray and a commercially available immunohistochemical marker for nm23 was used for protein detection. nm23 expression was strongly correlated with Clark's level (P<0.001), Breslow depth (P=0.002) and patient age (P=0.014). nm23 expression was significantly associated with a poor patient outcome (chi2=7.2219, P=0.0072). Further analysis revealed that the intensity of nm23 expression also correlated with patient outcome (chi2=11.3281, P=0.0035). However, on multivariate analysis, nm23 was shown not to be an independent marker of prognosis. The results of this study, when taken with the existing literature, suggest a role for nm23 in melanoma disease progression. However, its use as a prognostic marker in routine practice does not appear to be justified.

Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features

The array-based comparative genomic hybridization using microarrayed bacterial artificial chromosome clones allows high-resolution analysis of genome-wide copy number changes in tumors. To analyze the genetic alterations of primary lung adenocarcinoma in a high-throughput way, we used laser-capture microdissection of cancer cells and array comparative genomic hybridization focusing on 800 chromosomal loci containing cancer-related genes. We identified a large number of chromosomal numerical alterations, including frequent amplifications on 7p12, 11q13, 12q14-15, and 17q21, and two homozygous deletions on 9p21 and one on 8p23. Unsupervised hierarchical clustering analysis of multiple alterations revealed three subgroups of lung adenocarcinoma that were characterized by the accumulation of distinct genetic alterations and associated with smoking history and gender. The mutation status of the epidermal growth factor receptor (EGFR) gene was significantly associated with specific genetic alterations and supervised clustering analysis based on EGFR gene mutations elucidated a subgroup including all EGFR gene mutated tumors, which showed significantly shorter disease-free survival. Our results suggest that there exist multiple molecular carcinogenesis pathways in lung adenocarcinoma that may associate with smoking habits and gender, and that genetic cancer profiling will reveal previously uncharacterized genetic heterogeneity of cancer and be beneficial in estimating patient prognosis and discovering novel cancer-related genes including therapeutic targets.

Left ventricular function studied with MDCT

Accurate determination of left ventricular (LV) myocardial function is fundamental for clinical diagnosis, risk stratification, and estimation of prognosis in patients with ischemic and nonischemic cardiomyopathy. Primarily, multi-detector-row spiral CT (MDCT) of the heart aimed at detecting coronary artery obstruction and cardiac morphology. Multiple studies have demonstrated that retrospectively, ECG-gated MDCT determination of LV volumes and consequently global LV function parameters is feasible in good agreement with established imaging modalities such as cineventriculography, echocardiography, and cine magnetic resonance imaging (CMR). Post-processing tools allow fast and semi-automatic determination of LV function parameters from MDCT data in analogy to known CMR evaluation approaches. Although MDCT is not considered to be first-line modality for LV function assessment, this technique provides accessory dynamic information in patients undergoing MDCT coronary angiography, contributing to combined assessment of cardiac morphology and function without need of additional radiation exposure. MDCT regional LV wall motion analysis at rest is feasible, but further improvement in temporal resolution seems mandatory to match results obtained from competing modalities. This paper will discuss the diagnostic potential of MDCT for assessment of LV function with regards to accuracy and clinical applications, as well as limitations, particularly in comparison with CMR as modality of reference.

Cell proliferation, apoptosis and the related regulators p27, p53 expression in hepatocellular carcinoma

To investigate the expression of cell apoptosis, proliferation and the related regulators p27, p53 in hepatocellular carcinoma (HCC). The expression of p27, p53, proliferating cell nuclear antigen (PCNA) and apoptosis in 47 HCC specimens and 42 surrounding non-cancerous tissues were detected by the immunohistochemistry and terminal deoxy-nucleotidyl transferase-mediated nick end labeling (TUNEL) technique. Meanwhile, the clinical significance of them was analyzed combining with the clinicopathological factors and follow-up data. (1) The average proliferating index and apoptotic index in HCC were significantly higher than that in adjacent liver tissues. The proliferating index was associated with extrahepatic metastasis. The apoptotic index was significantly lower in TNM stage I-II than in stage III-IV. The proliferating index of groups with p53-/p27+ was significantly lower than that in group with p53+/p27- (P = 0.030); (2) The level of p27 in the cytoplasmic fraction was higher in non-tumoral liver tissues and was associated with clinical stage; (3) Survival analysis showed advanced stage (P = 0.031) and with extrahepatic metastasis (P = 0.045) was significantly associated with shorter survival. In addition, the prognosis of patients with p53-/p27+ was longer than that of patients with p53+/p27- (P = 0.0356). The p53 mutation and decreased p27 expression might be involved in the imbalance of proliferation and apoptosis in HCC. Cytoplasmic displacement might lead to the inactivation of p27 protein in HCC cells and acts early during carcinogenesis of HCC. The combined examination of p27, and p53 expression allows reliable estimation of prognosis for patients with primary hepatic carcinoma.

Survival analysis with p27 expression and apoptosis appears to estimate the prognosis of patients with synovial sarcoma more accurately.

Although recent experimental studies have implicated p27 as a regulator of apoptosis in a number of neoplasms, to the authors' knowledge the relation between p27 expression and apoptosis has not yet been established in synovial sarcoma. The relation between p27, apoptosis, and clinicopathologic features were examined in 62 synovial sarcoma cases. p27 expression was found to be correlated inversely with the extent of apoptosis in synovial sarcomas. On survival analysis, p27 expression was found to be a significant and independent prognostic factor. Although the extent of apoptosis was determined to be prognostically significant, it failed to retain an independent and significant value on multivariate analysis. The combination of p27 expression and apoptosis allowed for the more accurate estimation of prognosis in patients with synovial sarcoma than either parameter alone. A combination of p27 expression and extent of apoptosis permitted the more accurate estimation ofy the prognosis of patients with synovial sarcoma.

Combined examination of p27Kip1, p21Waf1/Cip1 and p53 expression allows precise estimation of prognosis in patients with gastric carcinoma

In order to estimate the prognostic values of p27(Kip1), p21(Waf1/Cip1), and p53, alone and in combination, we investigated immunohistochemically the expression of p27(Kip1), p21(Waf1/Cip1), and p53 proteins in gastric carcinomas. The expression of p27(Kip1), p21(Waf1/Cip1), and p53 was immunohistochemically examined in 140 gastric carcinomas. Positive expression of p27(Kip1) and p21(Waf1/Cip1) correlated significantly with a favourable prognosis (P < 0.05), whereas, positive expression of p53 tended to correlate with poor prognosis. Multivariate survival analysis revealed that TNM stage of tumour (P < 0.001), lymph node state (P=0.005), and p27(Kip1) expression (P=0.006) were independent prognostic factors. A striking stratification of mortality rate was found when patients were divided into four groups according to the expression of p21(Waf1/Cip1) and p27(Kip1). The mortality rate was higher in patients with both p21(Waf1/Cip1)- and p27(Kip1)-negative gastric carcinoma than in patients with one or both positive carcinomas (P < 0.01). In addition, if the four p21(Waf1/Cip1)/p27(Kip1) groups were compared based on p53 status, p53+ cases tended to have a higher mortality rate than p53- cases. Our results suggest that low expression of both p27(Kip1) and p21(Waf1/Cip1), could be useful as markers of poorer prognosis, and the combined examination of p27(Kip1), p21(Waf1/Cip1) and p53 expression allows reliable estimation of prognosis for patients with gastric carcinoma.

Allelotype of Colorectal Carcinomas

To examine the extent and variation of allelic loss in a common adult tumor, polymorphic DNA markers were studied from every nonacrocentric autosomal arm in 56 paired colorectal carcinoma and adjacent normal colonic mucosa specimens. This analysis was termed an allelotype, in analogy with a karyotype. Three major conclusions were drawn from this analysis: (i) Allelic deletions were remarkably common; one of the alleles of each polymorphic marker tested was lost in at least some tumors, and some tumors lost more than half of their parental alleles. (ii) In addition to allelic deletions, new DNA fragments not present in normal tissue were identified in five carcinomas; these new fragments contained repeated sequences of the variable number of tandem repeat type. (iii) Patients with more than the median percentage of allelic deletions had a considerably worse prognosis than did the other patients, although the size and stage of the primary tumors were very similar in the two groups. In addition to its implications concerning the genetic events underlying tumorigenesis, tumor allelotype may provide a molecular tool for improved estimation of prognosis in patients with colorectal cancer.

The prognostic significance of the monoclonal antibody III D 5 to human milk fat globule antigen in breast cancer.

The monoclonal antibody III D 5 identifies an antigen in human milk fat globule membrane, found also on breast epithelial cells. Immunohistochemistry with the antibody was used in the staining of formalin-fixed, paraffin-embedded sections of 80 breast carcinomas. The duration of follow-up of patients was from seven to twelve years. The presence or absence of metastases in regional lymph nodes at the time of primary operation, histological grade and necrosis of tumours correlated highly significantly to the survival of patients. The patients whose tumours exhibited positive staining with the antibody III D 5 had an improved survival-rate compared with those with III D 5 negative tumours. In the patients without metastases at the time of primary operation, the histological grade of primary tumour had only a weak correlation with survival, while the same patients with III D 5 positive tumours had significantly better prognosis compared to the III D 5 negative cases. Inclusion of the III D 5 immunoreactivity with other factors in a prognostic index could permit a more accurate estimation of prognosis in patients with mammary carcinoma.

Immunocytochemical staining of breast carcinoma with the monoclonal antibody NCRC 11: a new prognostic indicator.

The staining of breast cancer with a new monoclonal antibody, NCRC 11, was studied in a series of 126 women with primary breast carcinoma. Tumour samples embedded in paraffin were tested, and the minimum duration of follow up was five years or to death. Altogether 119 tumours stained positively. There was a strong relation between the intensity of staining, divided on a four point scale, and patient survival. Patients whose tumours exhibited intense staining had an improved survival compared with those with less intensely staining tumours (p less than 0.0001). Staining related weakly to histological grade but not significantly to oestrogen receptor state or the pathological stage of lymph node disease. Mathematical analysis showed the relation to survival to be independent of the other known prognostic factors. Inclusion of intensity of staining with other factors in a prognostic index might permit a more accurate estimation of prognosis in patients with breast cancer.

Multivariate analysis of angiographic, histologic, and electrocardiographic data in patients with coronary heart disease.

In 61 consecutive patients undergoing aortocoronary bypass grafting, angiographic and electrocardiographic (ECG) changes were studied. Histologic delineation of myocardium was obtained by analysis of transmural biopsy specimens acquired at the time of surgery. The use of principal-component analysis revealed three definite groups of patients. Group I comprised patients with histologic findings associated with severe left anterior descending coronary artery (LAD) stenosis, without abnormal wall motion or ejection fraction. ECG abnormalities were limited to ST changes. Group II comprised patients with severe myocardial cell degeneration with only modest fibrosis associated with severe LAD stenosis and severely impaired wall motion. The incidence of infarction on the ECG was low. Group III patients had important myocardial cell degeneration with severe fibrosis associated with severe LAD stenosis, severely depressed wall motion, and significantly impaired ejection fraction. In this group there was a high incidence of infarction apparent on the ECG. Postoperative follow-up (24 months) showed a total survival of 94.4% in group I, 92.8% in group II, and only 72.7% in group III. This identification of subtypes of coronary artery disease seems to be helpful in estimating patient prognosis after coronary surgery.