Predictive factors for long-term survival in patients with intrahepatic cholangiocarcinoma

BACKGROUND: In order to elucidate the predictive factors for long-term survival in patients with intrahepatic cholangiocarcinoma (ICC), we evaluated 7 patients who survived for more than 5 years (5-year survivors). METHODS: We examined the clinicopathologic and biologic factors of the 5-year survivors, and these findings were then compared with those in 20 patients who died within 5 years after surgery (control group). RESULTS: In the 5-year survivors, the gross appearance of the tumors included a mass-forming (MF) type in 5 cases, an intraductal growth (IG) type in 1, and another type (microcarcinoma with hepatolithiasis) in 1. No case demonstrated a periductal infiltrating (PI) type. Except for 1 case with an IG type tumor, no lymph node metastasis was seen in any patients. All of the 5-year survivors were classified from stage I to III, and all also underwent a curative resection. The clinicopathologic factors demonstrating significant differences between the 5-year survivors and the control group included the gross type of the tumor, lymph node involvement, the surgical margin, curability, and pTNM stage. CONCLUSION: The predictive factors for long-term survival in patients with ICC are thus suggested to include not only tumor staging and curability, but also lymph node metastasis and the gross type of the tumors.     

A modified MethyLight assay predicts the clinical outcomes of anti‐epidermal growth factor receptor treatment in metastatic colorectal cancer

DNA methylation status correlates with clinical outcomes of anti‐epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti‐EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low‐methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor‐derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P = .004), progression‐free survival (median: 2.5 vs 6.6 mo, P < .001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P < .001, HR = 0.23) than did LMCC in patients with RAS wild‐type mCRC who were refractory or intolerable to oxaliplatin‐ and irinotecan‐based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti‐EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.     

Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer

Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a BRAF V600E mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with BRAF V600E mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression.     

Heme oxygenase‐1: a new drug target in oxidative tissue injuries in critically ill conditions

Oxidative stresses associated with ischemia/reperfusion, neutrophil activation, and anesthesia with certain volatile agents, etc., are thought to play an important role in the development of acute organ failure in critical illnesses, such as acute lung injury, acute coronary artery insufficiency, acute liver failure, acute renal failure, and multiple organ dysfunction syndrome. Such oxidative stressors provoke a set of cellular responses, particularly those that participate in the defense against tissue injuries. Free heme, which can be rapidly released from hemeproteins, may constitute a major threat in the oxidant stress because it catalyzes the formation of reactive oxygen species. To counteract such insults, cells respond by inducing the 33‐kDa heat shock protein, heme oxygenase (HO)‐1, the rate‐limiting enzyme in heme degradation. Induced HO‐1 as such removes free heme by an enzymatic process. In addition, HO‐1 induction itself confers protection to tissues from further oxidative injuries. In contrast, the abrogation of HO‐1 induction, or chemical ablation of HO activity abolishes the beneficial effect of HO‐1, and results in the aggravation of tissue injuries. In this article, we review recent advances in the essential role of HO‐1 in tissue protection in various models of experimental oxidative tissue injuries as well as in human disorders, which is related to critically ill conditions, with special emphasis on the role of its induction in tissue defense and its potential therapeutic implications. Drug Dev. Res. 67:130–153, 2006. © 2006 Wiley‐Liss, Inc.     

The BPV-1 E5 oncoprotein expressed in Schizosaccharomyces pombe exhibits normal biochemical properties and binds to the endogenous 16-kDa component of the vacuolar proton-ATPase

The 44-amino-acid E5 oncoprotein of bovine papillomavirus type 1 transforms immortalized murine fibroblast cell lines. This highly hydrophobic protein forms homodimers, localizes to intracellular membrane compartments (including the Golgi apparatus), and forms a complex with the 16-kDa membrane-embedded constituent (16k) of the vacuolar proton-ATPase. To develop a system for the genetic and biochemical analysis of the E5/16k interaction, the E5 gene was cloned into a new vector which was designed for expression in the fission yeast Schizosaccharomyces pombe. The E5 protein synthesized in this system dimerized normally and bound to endogenous and overexpressed S. pombe 16k protein. Comparison of the S. pombe and mammalian 16k proteins showed strong conservation in carboxyl-terminal amino acids but greater variation in the amino-terminal sequences, suggesting that E5 was interacting with the 16k carboxyl domains. Finally, a new protein epitope tag is described which permitted for the first time the coprecipitation of E5 with antibodies directed against the 16k protein.     

Enzymatic determination of a molar ratio of free branched-chain amino acids to tyrosine (BTR) and its clinical significance in plasma of patients with various liver diseases

A molar ratio of free branched-chain amino acids to tyrosine (BTR) was determined in the plasma of patients with liver diseases using a new enzymatic method. In addition, clinical significance of BTR was studied by comparing particularly with that of Fischer's ratio (a molar ratio of branched-chain amino acids to aromatic amino acids (tyrosine+phenylalanine], which was obtained by conventional HPLC (Amino acid autoanalyzer, Hitachi 835). Following results were obtained: 1) Enzymatically determined branched-chain amino acids and tyrosine showed significant correlations with respective results obtained by HPLC (r = 0.937, 0.972). 2) Significant correlation was also found between enzymatically determined BTR and Fischer's ratio obtained by HPLC. Changes of BTR in clinical courses were found to be in parallel with those of Fischer's ratio. 3) BTR as well as Fischer's ratio correlated significantly with ICG R15, KICG, prothrombin time (%) and serum albumin level. 4) BTRs in patients with decompensated liver cirrhosis or with fulminant hepatitis were significantly lower than those in patients with acute or chronic hepatitis. In conclusion, new enzymatic assay of branched-chain amino acids and tyrosine as described here is quite simple method, and is also considered to be very useful parameter of the clinical conditions of patients with liver diseases, particularly representing the severity of liver diseases and the protein nutritional status.     

Oxidized proteins in astrocytes generated in a hyperbaric atmosphere induce neuronal apoptosis

In the present study, we investigated the influence of the oxidative damage to astrocytes on neuronal cell survival using cultures of rat cerebral astrocytes and neurons. The exposure of astrocytes to hyperbaric oxygen induced a time-dependent apoptotic cell death, as observed by DNA ladder assessment. When astrocytes damaged by oxidative stress were cocultured with normal neurons from the cerebrum of a newborn rat, neuronal cell death was markedly induced, although normal astrocytes not subjected to hyperoxia cocultured with normal neurons showed no neuronal cell apoptosis. It was found that either the supernatant from the homogenate of astrocytes cultured in hyperbaric oxygen atmosphere or a protein mixture extracted from the supernatant induced neuronal cell death. The level of protein carbonyls, an index of protein oxidation analysis, in cultured astrocytes increased significantly with oxidative stress, and vitamin E inhibited the increase in the level of such oxidized proteins in astrocytes. Furthermore, a two-dimensional (2D) electrophoresis of a protein mixture extracted from the supernatant showed several changes in proteins. These results imply that reactive oxygen species (ROS) induced by oxidative stress attack astrocytes to induce oxidatively denatured proteins in the cells that act as a neurotoxic factor, and that vitamin E protects neurons by inhibiting astrocyte apoptosis caused by oxidative stress.     

Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases

Eomesodermin-expressing (Eomes⁺) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes⁺ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes⁺ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes⁺ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes⁺ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093–1098