Clinical significance of serum soluble interleukin 2 receptor-alpha in esophageal squamous cell carcinoma.

Although the serum level of soluble interleukin-2 receptor alpha (sIL-2Ralpha) has been shown to correlate with progression and prognosis of several cancers, data to support its clinical significance to esophageal squamous cell carcinoma (ESCC) are limited. This study was conducted to assess the prognostic value and source of sIL-2Ralpha in patients with ESCC. From January 1986 to June 1997, 125 patients with histopathologically confirmed ESCC were enrolled for study. Ninety-three patients underwent en bloc esophagectomy, and 32 patients with unresectable tumor underwent palliative surgery. Four (4.3%; 4 of 93) patients died of surgical complications. Serum levels of sIL-2Ralpha were measured by ELISA. Expression of IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma in the pathological section was determined, respectively, by immunohistochemistry (IHC) and in situ hybridization (ISH). Compared with the healthy control group (1020 +/-476 pg/ml, n = 103), ESCC patients tended to have significantly higher serum sIL-2Ralpha concentrations (1424 +/- 798 pg/ml, n = 121). The sIL-2Ralpha level was correlated with age, Tumor-Node-Metastasis classification, tumor stage, reading score of the IHC staining, and survival but not with the pathological grade or lymphovascular invasion. Prognosis was worse for patients with high sIL-2Ralpha levels (> or =1500 pg/ml) than for those with low serum sIL-2Ralpha levels (< 1500 pg/ml; P = 0.0209). It can be used as an independent prognostic factor of ESCC. In the pathological sections, expression of IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma was detected in 17 (18.1%), 83 (89.2%), and 83 (89.2%) cases, respectively, by IHC, and the message of IL-2Ralpha was identified in tumor cells by ISH in 30.1% (28 of 93) of the cases. Serum concentrations of sIL-2Ralpha are frequently elevated in ESCC patients and are correlated with disease progression and survival. These data indicate that, in addition to activated T cells, cancer cells could be an important source of sIL-2Ralpha in ESCC patients.     

Prognostic significance of serum soluble interleukin-2 receptor level in non-Hodgkin's lymphoma: a single center study in Japan

Interleukin 2 receptor is expressed not only on the surface of activated T or B lymphocytes, but also on certain lymphoid malignancies. The receptor is released from the cell membrane as soluble form (sIL-2R). Serum sIL-2R level is a sensitive and quantitative marker of circulating peripheral blood mononuclear cell activation or specific tumor cell growth including non-Hodgkin's lymphoma (NHL). However, the relevance of serum sIL-2R levels relating to clinical outcome in adult patients with NHL remains uncertain. Therefore, we investigated the serial serum sIL-2R levels in 28 untreated patients with NHL to evaluate its correlation with clinical characteristics. High serum sIL-2R level (>1000 U/ml) at diagnosis was associated with a high incidence of treatment failure (p=0.03) and poor overall survival (p=0.057). The serum sIL-2R levels decreased significantly after achieving complete remission (p=0.003). Further larger studies are required to evaluate whether serum sIL-2R level is an independent prognostic factor or not. However, adding this parameter to those already employed in the International Prognostic Index would perhaps provide a better prognostic index for adult patients with NHL.     

Prognostic significance of grading in lung adenocarcinoma

BACKGROUND:

Although grading has prognostic significance for many tumor types, a prognostically significant grading system for lung adenocarcinoma has not yet been established. The aim of this study was to evaluate histologic characteristics included in tumor grading systems, establish optimal cutoff values that have the strongest association with overall survival, and develop a grading system incorporating the histopathologic characteristics that the authors found to have prognostic significance in patients with lung adenocarcinoma.

METHODS:

The authors studied lung adenocarcinomas from 85 consecutive patients, and evaluated the percentage of solid pattern (as a reflection of tumor architecture), the degree of cytologic atypia, and the mitotic count.

RESULTS:

In univariate analysis, overall survival was associated significantly with sex (P = .045), age (P = .0008), tumor status (P < .0001), lymph node status (P = .02), solid pattern (P = .046), and cytologic atypia (P = .01), but not with mitotic count (P = .26). On the basis of optimal cutoff values, the authors found that a solid pattern ≥90% and severe cytologic atypia were the best discriminators of worse outcome. A grading score, computed as the sum of the architecture score and cytologic atypia score (2 = well differentiated, 3 = moderately differentiated, 4 = poorly differentiated), was a significant predictor of overall survival in univariate analysis (median overall survival times, 72.4, 39.5, and 8.7 months for well, moderately, and poorly differentiated adenocarcinoma, respectively; P = .0001). Moreover, grading was an independent predictor of survival in multivariate analysis (P = .002).

CONCLUSIONS:

The authors describe a grading system that incorporates the percentage of solid pattern and degree of the cytologic atypia that is an independent predictor of survival in patients with lung adenocarcinoma. Cancer 2010. © 2009 American Cancer Society.     

The biological significance of soluble interleukin-2 receptors in solid tumors

In an attempt to further understand the biological significance of soluble IL-2 receptors (sIL-2R) in solid tumors, we have evaluated 160 cancer patients (breast: 40; lung: 66; colon: 18; stomach: 22; uterine cervix: 14) and 58 healthy subjects, as controls. Serum mean levels of sIL-2R, measured with an enzyme immunoassay, were significantly higher in cancer patients than in controls. Metastatic cancer patients showed significantly higher values than the non-metastatic ones; this difference was significant in all tumor histotypes, except small cell lung carcinoma. Moreover, in 15 patients in whom sIL-2R were evaluated either before or after radical surgery, a significant surgery-induced increase in sIL-R mean values was seen. Finally, the chemotherapy-induced rise in sIL-2R appeared to be associated with a lack of clinical response. These results seem to suggest that sIL-2R may be a marker of host biological response in patients with solid tumors, the significance of which needs further investigation.     

Prognostic significance of laminin in adenocarcinoma of the lung

The distribution of laminin in tumor-associated basement membrane was immunohistochemically investigated in 115 cases of adenocarcinoma of the lung. The distribution of laminin was classified into continuous and discontinuous staining patterns. The incidence of the discontinuous pattern was less in early-stage disease than that in advanced stages (P less than 0.01). In patients with stage I, the incidence of discontinuous patterns was greater in short-term survivors than in long-term survivors (P less than 0.05). By contrast, in patients with stage III, the discontinuous pattern of laminin was frequently seen in both long-term survivors and short-term survivors, with no difference between the two groups. These data suggest that the discontinuous pattern of laminin in tumor-associated basement membrane reflects the spread and dissemination of tumor, hence a close relationship to the prognosis.     

Prognostic significance of neuroendocrine differentiation in prostate adenocarcinoma

Much progress has been made toward an understanding of the development and progression of prostate cancer (PC) and the factors that drive the development of androgen independence. Neuroendocrine (NE) cells may provide an intriguing link between NE cell differentiation (NED) and tumor progression in PC. NED in PC generally confers a more aggressive clinical behavior and less favorable prognosis than conventional PC. In this article, we review the known functions of NE cells in PC and discuss the current knowledge on stimulation of cancer proliferation, invasion, apoptosis resistance, serum and immunohistochemical markers, and the prognostic significance of NED in human PC.     

Prognostic significance of HE4 expression in pulmonary adenocarcinoma

We investigated the possibility of human epididymis 4(HE4) to predict survival for patients with pulmonary adenocarcinoma. One hundred and thirty-seven patients with pulmonary adenocarcinoma underwent surgery in our institute from 2000 to 2008. We used immunohistochemical analysis to determine the expression of HE4 and compared with the clinicopathological factors and survival. Serum levels of HE4 in lung adenocarcinoma were investigated by enzyme immunometric assay. Fifty-seven of 137 cases (41.6%) were HE4 positive. It was found that there was no correlation between HE4 expression by immunohistochemistry and clinicopathological factors, however, adenocarcinoma subtype was significantly associated with HE4 expression. Sera in lung adenocarcinoma were significantly higher than in healthy control. Five-year disease-free survival in the HE4-positive group (44.6%) was significantly different from that in the negative group (82.3%, p?=?0.001) by immunohistochemistry. The five-year overall survival rate was 60.1% in the HE4-positive group, as compared with 90.8% in the HE4-negative group (p?=?0.001). In multivariate Cox regression analysis, positive HE4 protein expression was a worse prognosis factor of disease-free and overall survival (HR?=?3.7, 95%CI?=?[1.7–8.4], p?=?0.001; HR?=?5.5, 95%CI?=?[1.8–17.2], p?=?0.003, respectively), in addition to nodal status as a powerful value. When HE4 expression in adenocarcinoma cases except the BAC were analyzed, nodal status and HE4 expression were independent prognostic factors in disease-free and overall survivals. These data showed that HE4 expression is associated with a worse prognosis and is a possible prognostic factor of lung adenocarcinoma.     

Prognostic significance of Bcl-2 expression and p53 nuclear accumulation in colorectal adenocarcinoma

The products of bcl-2 and p53 genes are involved in the regulation of apoptosis and proliferation and have been associated with prognosis in several malignancies, including colorectal adenocarcinoma. Although 2 European studies have reported a prognostic significance of Bcl-2 expression in colorectal adenocarcinomas, a study from the United States did not observe such an association. Therefore, we used immunohistochemistry to evaluate the prognostic significance of Bcl-2 expression, p53 nuclear accumulation and their concomitant expression in 134 US patients with colorectal adenocarcinoma. Antigen retrieval was required for adequate detection of Bcl-2 expression. Fifty percent of the colorectal tumors were classified as expressing Bcl-2, and Bcl-2 expression was associated with longer patient survival. Antigen retrieval was not necessary for detecting nuclear accumulation of p53 by immunohistochemistry. Nuclear accumulation of p53 was detected in 44% of colorectal adenocarcinomas and was associated with decreased patient survival. Tumors that did not express detectable levels of Bcl-2 but exhibited nuclear accumulation of p53 were associated with the shortest patient survival (log rank, p = 0.001). Multivariate Cox regression analysis demonstrated that Bcl-2 expression (p = 0.018), p53 nuclear accumulation (p = 0.024) and regional lymph-node metastasis (p = 0.005) were independent prognostic factors. Although a trend toward an inverse correlation between Bcl-2 and p53 expression was observed, the prognostic value of Bcl-2 expression was independent of p53 status. Thus, assessment of both Bcl-2 and p53 status may be valuable in predicting the prognosis of patients with colorectal adenocarcinomas. Int. J. Cancer 74:346–358, 1997. © 1997 Wiley-Liss, Inc.     

Prognostic significance of tissue factor in pancreatic ductal adenocarcinoma.

Tissue factor (TF) is a transmembrane glycoprotein that plays roles in the blood coagulation and intracellular signaling pathways, and has also been suggested to modulate the biological behavior of cancer cells. In order to examine the clinicopathologic significance of TF expression in pancreatic ductal adenocarcinoma, TF expression was determined by immunohistochemistry using a newly raised anti-TF monoclonal antibody in 113 patients who had undergone surgical resection of pancreatic ductal adenocarcinoma. According to the incidence of tumor cell immunopositivity, patients were divided into "negative TF" (0%), "weak TF" (<25%), or "high TF" (25% or more) groups, which accounted for 11.6% (n = 13), 44.2% (n = 50), and 44.2% (n = 50) of the total, respectively. Increased TF expression was correlated with the extent of the primary tumor (P = 0.0043), lymph node metastasis (P = 0.0043), lymphatic distant metastasis (P = 0.0039), advanced tumor-node-metastasis stage (P = 0.0002), and high tumor grade (P = 0.0164). Multivariate analysis using the Cox proportional hazards model showed that high TF expression was an independent negative predictor for survival (hazard ratio, 2.014; P = 0.0076). Moreover, patients with TF-negative tumors had a significantly better prognosis even if lymph node metastasis was present (P < 0.0001). We also showed that TF knockdown by RNA interference suppressed the invasiveness of a pancreatic adenocarcinoma cell line in vitro. These results indicate that TF expression may contribute to the aggressiveness of pancreatic ductal adenocarcinoma by stimulating tumor invasiveness, and that evaluation of the primary tumor for TF expression may identify patients with a poor prognosis.     

Prognostic significance of histologic subtype in pStage I lung adenocarcinoma

The International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society (IASLC/ATS/ERS) proposed a new histologic classification of lung adenocarcinoma in 2011. While several studies have already validated the prognostic value of this new classification of lung adenocarcinoma, we conducted own investigation in the present study. This study included 197 patients with invasive lung adenocarcinoma who underwent complete resection. Pathologic diagnoses were made in accordance with the new IASLC/ATS/ERS classification for lung adenocarcinoma. The lepidic/acinar/papillary group had a significantly better prognosis than the micropapillary/solid/invasive mucinous adenocarcinoma group (5-year recurrence-free survival [RFS] 73 vs. 21%: p < 0.01, 5-year overall survival 85 vs. 52%: p < 0.01). Age (hazard ratio [HR], 1.898; p = 0.03), CEA (HR, 1.873; p = 0.03), pStage (HR, 6.149; p < 0.01), and histologic subtype (HR, 2.342; p = 0.01) were independent prognostic factors for the RFS. Furthermore, age (HR, 3.242; p = 0.04), CEA (HR, 3.405; p = 0.03) and histologic subtype (HR, 11.108; p < 0.01) were independent prognostic factors for the progression-free survival in pStage I. The histologic subtype correlated with the prognosis of pStage I of lung adenocarcinoma. Patients in the high-grade group of lung adenocarcinoma, which included solid, micropapillary and invasive mucinous adenocarcinoma with pStage I, should be considered candidates for postoperative adjuvant therapy.     

Possible role of granulocyte colony-stimulating factor in increased serum soluble interleukin-2 receptor-alpha levels after allogeneic bone marrow transplantation.

Serum soluble interleukin-2 receptor - alpha (sIL-2R) levels markedly increased at the engraftment period in patients who underwent allogeneic bone marrow transplantation (BMT). Since serum G-CSF levels increased during G-CSF administration and decreased after the cessation, increased sIL-2R levels appeared to be induced by G-CSF administration. There was no increase in sIL-2R levels in a patient given macrophage colony-stimulating factor (M-CSF). The sIL-2R levels at the engraftment period and the onset of acute graft-versus-host disease (GVHD) were higher in patients who developed acute GVHD during G-CSF administration than in those who developed acute GVHD after G-CSF cessation. This finding suggests that G-CSF administration may possibly augment acute GVHD. However, it appears to be unlikely, because in the entire population, 18 of 35 patients had acute GVHD while only 6 of 17 patients had acute GVHD during G-CSF administration. Further analysis is still needed in order to draw definite conclusions. Preconditioning regimens did not appear to affect the sIL-2R levels, when the variable frequencies of methotrexate (MTX) administration were compared.     

Prognostic significance of DNA content in stage I adenocarcinoma of the lung

Purpose: Up to 30% of lung cancers (Stage I) with the most favorable outcome recur within 5 years after surgery. This study reviews the pattern of failure after surgical resection in early lung cancers and determines whether flow cytometric DNA variables were prognostic indicators for survival, disease-free survival (DFS), or distant metastasis-free survival (DMFS).Methods and Materials: Pathologic specimens from 45 patients at The University of Texas M. D. Anderson Cancer Center who underwent surgical resection and mediastinal nodal dissection for stage I (AJCC) adenocarcinomas of the lung were analyzed by flow cytometry for DNA content. Survival was calculated by the method of Desu and Lee. Chi-square and cross tabulation were used in the analysis.Results: The mean age of the patients was 62 years, and 52.3% were male. All patients were clinical Stage I (T1-2 N0), Karnofsky performance status ≥70, and had a weight loss <10 lbs. Median overall survival (OS) and DFS were 50 months and 33 months, respectively. OS, DFS, and DMFS at 1, 3 and 5 years were 73%, 57%, and 35%; 63%, 53%, and 45%; and 67%, 56%, and 48%, respectively. Analysis of all 45 patients revealed 86% of patients developing brain metastasis had an abnormal DNA content ≥ 30%, whereas 4% of patients with brain metastasis had abnormal DNA content < 30% (p = 0.01). This correlation maintained significance when only pT1/2 lesions were analyzed. There was a significant statistical correlation between abnormal DNA and 5-year OS, with 74% OS for those with abnormal DNA < 30% vs. 42% for ≥ 30% (p = 0.036). The 5-year DFS for pT1/2 patients was significantly correlated with abnormal DNA content: 53% for patients with abnormal DNA < 30% vs. 17% for patients with abnormal DNA ≥ 30%, respectively (p = 0.03). Of those with %S fraction (%S) < 2, 13% failed locally compared to 41% of those with %S ≥ 2. There was a highly significant correlation between DNA index (DNAI) and aneuploid %S: 68% of patients with a DNAI ≥ 1.7 had ≥ 2.6 aneuploid %S, whereas only 13% of patients with DNAI ≥ 1.7 had aneuploid %S < 2.6. (p < 0.001). Grouping the percent of abnormal DNA and overall %S according to low vs. mixed vs. high values correlated with DFS (p = 0.02).Conclusions: This study confirms significant correlation between a high DNA index and a higher frequency of brain metastasis, as well as worse OS. Although DNA content variables were not predictive of recurrence at other sites, brain metastasis represents the worst outcome from distant metastasis. Further studies are needed, as well as prospective trials, for evaluating adjuvant therapy in patients with adverse DNA variables following complete surgical resection for early disease. If high-risk patients could be identified after resection, adjuvant therapy (chemotherapy or elective brain irradiation) could be administered.     

Clinicopathological significance of galectin-3 expression in ductal adenocarcinoma of the pancreas.

PURPOSE: Galectin-3, a member of the beta-galactoside-binding lectin family, has multiple biological functions including cell-cell interactions and cell-extracellular matrix adhesion, cellular proliferation, cellular differentiation, and apoptosis. The aim of this study was to determine the relationship of galectin-3 expression to clinicopathological findings and patient prognosis in ductal adenocarcinoma of the pancreas. EXPERIMENTAL DESIGN: We examined galectin-3 expression in 104 surgically resected pancreatic ductal adenocarcinoma cases with stages I through IV using immunohistochemistry and investigated the relationship of it to overall survival. RESULTS: Patients were divided into two groups: a low expression group, where <60% of tumor cells were positive; and a high expression group, where > or =60% of tumor cells were positive. Cases in the low expression group had a significant tendency to be at later stages, to have distant metastasis, and to have less differentiated tumors, compared with cases in the high expression group (P = 0.001 for stage, P = 0.001 for metastasis, and P = 0.006 for differentiation). Postoperative overall survival was worse in the low galectin-3 expression group than in the high galectin-3 expression group (P = 0.004). Multivariate analysis showed that the risk ratio of prognosis was 2.06 among patients in the low galectin-3 expression group compared with the high galectin-3 expression group (P = 0.006). CONCLUSIONS: Decreased expression of galectin-3 was associated with advanced stage, tumor de-differentiation, and metastasis in ductal adenocarcinoma of the pancreas. Galectin-3 expression might be a useful prognostic marker for survival in ductal adenocarcinoma of the pancreas.     

Prognostic significance of cyclooxygenase-2 (COX-2) expression in patients with surgically resectable adenocarcinoma of the oesophagus

Background  

COX-2 expression in tumour cells has been associated with poor prognosis in gastrointestinal and non-gastrointestinal cancers. The aim of our study was to test the hypothesis that higher levels of COX-2 expression are prognostically related to poor clinico-pathologic features in adenocarcinoma of the oesophagus.     

口腔癌患者血清sIL－2R表达及其临床意义

采用双抗体夹心ＥＬＩＳＡ法对４０例口腔癌患者的血清可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）水平进行测定。结果发现口腔癌患者血清ｓＩＬ－２Ｒ水平显著高于正常对照组（Ｐ＜０．０１），并与临床分期有关；手术后血清ｓＩＬ－２水平较术前明显下降（Ｐ＜０．０１）；４例复发者血清ｓＩＬ－２Ｒ水平又见增高。因此，血清ｓＩＬ－２Ｒ水平的动态观察有助于口腔癌患者预后判断，并可监测复发与转移。     

Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma.

PURPOSE: Akt is a serine/threonine kinase that plays a central role in tumorigenesis. Among the members of Akt family, Akt2 is associated with the development of human cancers. The present study was designed to clarify the prognostic significance of Akt2 and activated Akt expression in pancreatic ductal adenocarcinoma (PDAC). In addition, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the proliferation activity of tumor cells detected by Ki-67 immunohistochemistry were examined. EXPERIMENTAL DESIGN: Immunohistochemical analysis was performed on paraffin-embedded specimens from 65 patients with PDAC; 36 males and 29 females with ages ranging from 48 to 79 years (median, 66 years) of age. Expression levels of Akt2, phosphorylated Akt (p-Akt), and phosphorylated ERK 1/2 (p-ERK 1/2) were categorized as either weaker (low intensity) or equal to stronger (high intensity) compared with those in the endothelial cells of the same specimens. For Ki-67 immunohistochemistry, cases were divided into two groups: level 1, Ki-67 labeling index (LI), <20%; level 2, Ki-67 LI, > or = 20%. RESULTS: Twenty-six (42.6%), 28 (45.9%), 39 (63.9%), and 46 (75.4%) of the tumors showed high intensity of Akt2, p-Akt, and p-ERK 1/2 expression, and Ki-67 LI level 2, respectively. A significant positive correlation was observed between Akt2 and p-Akt expression (P < 0.01). Multivariate analysis revealed that p-Akt expression, Ki-67 LI, and histological differentiation are independent prognosticators for PDAC. CONCLUSIONS: p-Akt expression is a significant prognostic indicator for PDAC. Inhibition of Akt is a possible molecular approach for treatment of PDAC.     

Prognostic significance of the number of examined lymph nodes in node-negative gastric adenocarcinoma

Aim

In this study, we investigated the prognostic significance of the number of examined lymph nodes in node-negative gastric adenocarcinoma (GC).

Patients and methods

A total of 1194 node-positive and 1030 node-negative GC patients undergoing potentially curative gastrectomy was enrolled in this study. Patients were stratified into 3 groups according to the number of examined lymph nodes: group 1, ≤15; group 2, 16–25; group 3, >25.

Results

Patients with node-negative GC had significantly favorable survival compared with those with node-positive. Among patients with node-negative T2–T4 disease, the percentage of locoregional relapse was higher in those with <25 examined lymph nodes than in those with ≥25 examined lymph nodes. The number of examined lymph nodes affected the overall survival rates for patients with node-negative T2–T4 GC but not for patients with T1 lesions. Tumor size, tumor location, the number of examined lymph nodes, T status, and the presence of perineural invasion were significant prognostic factors as determined by multivariate analysis in node-negative GC.

Conclusions

No survival benefit of examining ≥15 lymph nodes was noted for patients with node-negative T1 GC. Extensive lymphadenectomy in patients with node-negative T2–T4 lesions in whom the number of examined lymph nodes was >25 had favorable survival.     

Prognostic significance of microsatellite instability in curatively resected adenocarcinoma of the small intestine

Adenocarcinoma of the small intestine (ACSI) is a rare condition with few studies addressing follow-up and prognosis. Tumors of 35 patients with curative resection of an ACSI were retrospectively analyzed by immunohistochemistry: p53, hMLH1, hMSH2 and hMSH6 and microsatellite instability (MSI): BAT-26, BAX, TGF-beta RII. With a median follow up of 6.1 years, the median cancer-specific survival (CSS) was 36.2 months. Patients who were highly instable (MSI-H) (n=10) had a CSS of 49.6 months in contrast to patients with stable tumors (23.2 months) (P=0.010). Additionally, a low tumor stage according to UICC and MSI-H were shown to be independent factors (P=0.005 and P<0.001) for an increased survival in multivariate analysis. Therefore, it is suggested that analysis of the MSI status might prove useful in discerning prognosis within cancers of the same stage.