Positron Emission Tomography/Computed Tomography and Biomarkers for Early Treatment Response Evaluation in Metastatic Colon Cancer

Background.

Treatment options for metastatic colon cancer (mCC) are widening. We prospectively evaluated serial 2-deoxy-2-[18F]fluoro-d-glucose positron-emission tomography/computed tomography (PET/CT) and measurements of tissue inhibitor of metalloproteinases-1 (TIMP-1), carcinoembryonic antigen (CEA), and liberated domain I of urokinase plasminogen activator receptor (uPAR(I)) for early assessment of treatment response in mCC patients.

Methods.

Thirty-three mCC patients scheduled for first-line chemotherapy with capecitabine and oxaliplatin (CAPOX) and bevacizumab participated; 27 were evaluated by PET/CT before treatment, after one and four treatment series. Morphological and metabolic response was independently assessed according to Response Evaluation Criteria in Solid Tumors and European Organization for Research and Treatment of Cancer PET criteria. Plasma TIMP-1, plasma uPAR(I), and serum CEA were determined.

Results.

Metabolic response after one treatment course predicted the ability of CAPOX and bevacizumab to induce morphological response after four treatment series with a sensitivity of 80%, specificity of 69%, and odds ratio of 13.9 (95% confidence interval [CI] 1.9; 182). Early metabolically stable or progressive disease was associated with shorter progression-free survival (hazard ratio [HR] = 3.2 [CI 1.3; 7.8]). Biomarker levels at early evaluation were associated with shorter OS (TIMP-1 per unit increase on a log-2-transformed ng/mL scale: HR = 2.6 [CI 1.4; 4.9]; uPAR(I) per 25 fmol/mL increase: HR = 1.5 [CI 1.1; 2.1]).

Conclusion.

This monocentric study demonstrated predictive value of early metabolic PET response and prognostic value of TIMP-1 and uPAR(I) levels in mCC treated with CAPOX and bevacizumab. Results support investigation of PET/CT, TIMP-1, and uPAR(I) guided early treatment adaptation in mCC.     

人脑胶质瘤PET成像中11C-蛋氨酸摄取与LATl和4F2hc表达的关系

背景与目的：以“C-蛋氨酸（11C-MET）为示踪剂的正电子发射体层成像（PET）可为脑肿瘤的氨基酸代谢提供重要信息,大型氨基酸转运载体1（LATl）和细胞表面抗原4F2重链（4F2hc）所形成的LATl／4F2hc复合物是包括蛋氨酸在内的大型、中性氨基酸的主要转运载体．本研究旨在探讨人脑胶质瘤中11C-MET摄取量与LATl和4F2hc表达的关系。方法：对30例新诊断的脑胶质瘤患者行11C-METPET检查．计算11C-MET最大标准化摄取值（SUVmax）;采用免疫组化方法检测LATl和4F2hc在相同脑胶质瘤标本中的表达;分析11C-METSUVmax、LATl和4F2hc表达水平与胶质瘤临床病理学特征的关系以及三者之间的关系。结果：HC．METSUVmax、LATl和4F2hc表达均随胶质瘤病理级别的升高而明显增强（P=0．000。P=0．028。P=0．003）,在高恶性度胶质瘤中11C．METSUVmax、LATl和4F2hc表达也均明显强于低恶性度胶质瘤（P=0．000．P=0．032．P=O．004）：LAT1和4F2hc表达之间存在明显正相关（P=0．036）;uC．METSUVmax与IATl表达也存在明显正相关（P=0．003）,但与4F2hc表达无明显相关性（P=0．366）。结论：11C-MET摄取量以及LATl和4F2hc表达与脑胶质瘤的病理学特征关系密切．LATl高表达可能是脑胶质瘤11C-MET摄取量增高的一个重要因素。     

p185HER-2/neu and p21CIP1/WAF1 Expression in Primary Tumors and Lymph Node Metastases in Non-small Cell Lung Cancer

p185^HER-2/neu, a tyrosine kinase receptor, is one of the target molecules for cancer therapy, and its expression may reduce the sensitivity of tumor cells to anti-cancer drugs. p21^CIP1/WAF1 is a cyclindependent kinase inhibitor, and its expression may also be involved in chemoresistance. Non-small cell lung cancer (NSCLC) is a potentially systemic disease, and systemic therapies play an important role in its treatment. However, there have been no studies comparing the expression of these molecules between primary and metastatic tumors. We investigated the expression of p185^HER-2/neu and p21^CIP1/WAF1 in 57 paired samples of primary NSCLC tumors and corresponding lymph node metastases by immunohistochemistry. Expression of each of p185^HER-2/neu and p21^CIP1/WAF1 was highly correlated between primary tumors and lymph node metastases, and similar correlations were also obtained when adenocarcinoma and squamous cell carcinoma cases were analyzed individually. However we failed to detect any correlation between p185^HER-2/neu and p21^CIP1/WAF1 expression. Our results suggested that expression of both p185^HER-2/neu and p21^CIP1/WAF1 is concordant between primary and metastatic tumors.     

Loss of Heterozygosity in (Lewis×F344)F1 Rat Urinary Bladder Tumors Induced with N-Butyl-N-(4-hydroxybutyl)nitrosamine Followed by Dimethylarsinic Acid or Sodium L-Ascorbate

Dimethylarsinic acid (DMA), a main metabolite of arsenicals which are carcinogenic in man, exerts tumor-promoting activity on rat urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Sodium L-ascorbate (Na-AsA) is also a strong tumor promoter in this animal model. In this study, we used (Lewis×F344)F₁ rats to compare molecular alterations in urinary bladder tumors caused by BBN followed by DMA or Na-AsA. Male, 6-week-old rats were given 0.05% BBN in their drinking water for 4 weeks, and then the rats in group 1 were maintained with no further treatment for 40 weeks. The animals of groups 2 and 3 were administered 0.01% DMA in their drinking water (group 2) or 5% Na-AsA in the powder diet (group 3) after the BBN treatment. Group 4 rats were given 0.05% BBN continuously for 36 weeks. At weeks 12, 20, 36 and 44, subgroups of rats were killed. Histopathological examination revealed promoting activity for DMA and, to a greater extent, Na-AsA on urinary bladder carcinogenesis. Loss of heterozygosity (LOH), detected with the polymerase chain reaction using 36 microsatellite markers, was found to be present in 2 of 9 (22%) urinary bladder tumors after treatment with DMA and 3 of 22 (14%) induced by continuous administration with BBN. No LOH was, however, detected in urinary bladder tumors after treatment with Na-AsA. The results thus suggest that the mechanisms of action of these two promoters, DMA and Na-AsA, may differ in rat urinary bladder carcinogenesis.     

Aberrant α1→2Fucosyltransferases Found in Human Colorectal Carcinoma Involved in the Accumulation of Leb and Y Antigens in Colorectal Tumors

Evidence indicates that the presence of aberrant α 1→2fucosylation pathways is responsible for the accumulation of large quantities of Le^b and Y antigens in human colorectal carcinoma. Significantly higher activities of α 1→2 as well as α 1→3 and α 1→4fucosyltransferases were found in most of the tissues from carcinoma than in the adjacent normal tissues and in healthy subjects. α 1→2Fucosyl-transferases associated with the synthesis of Le^b (Fucal→2Gal β 1→3[Fucc1→4]GlcNAc β ) and Y (Fuc α 1→2Ga1 β→ 4[Fuc α 1→3]GlcNAc β ) structures from Le^→ (GaI β 1→3[Fucal→4]GlcNAcβ) and X (Galβ1→4[Fuc α 1→3]GlcNAc β ) ones, respectively, were demonstrated in colorectal carcinomas and in colorectal carcinoma cell lines (COLO201, LS174T and SW1116). The activation of α 1→2fucosyltransferase with such new substrate specificities in colorectal carcinoma might result in the preferential synthesis of Le^b and Y structures from Le^→ and X rather than from H type 1 and H type 2 structures.     

Enhancement of Ca2+-dependent Endonuclease Activity in L1210 Cells during Apoptosis Induced by 1-β-D-Arabinofuranosylcytosine: Possible Involvement of Activating Factor(s)

Internucleosomal DNA fragmentation and morphological changes in nuclei typical of apoptosis were observed in L1210 cells incubated with 1.0 μg/ml of 1-β-D-arabinofuranosylcytosine (ara-C). To investigate the mechanisms involved, we examined the activities of endogenous endonucleases in nuclei and cytoplasm. Both fractions of control cells contained Ca²⁺ -dependent endonuclease which was capable of mediating internucleosomal DNA fragmentation. The assay system using two kinds of target substrates, i.e., nuclear chromatin of CCRF-CEM cells and naked DNA purified from the same cells, revealed that the activity of Ca²⁺-dependent endonuclease was enhanced in the crude nuclear extracts of cells treated with 1.0 μg/ml of ara-C for 24 h or 48 h. The activity was extracted more easily from ara-C-treated cells than control cells without sonication of the nuclear fraction. On the other hand, in the cytoplasmic fraction of the cells, the activity towards naked DNA was unchanged, whereas that towards nuclear chromatin was clearly enhanced. These results suggest that internucleosomal DNA fragmentation induced by ara-C treatment is associated with enhancement and activation of constitutively expressed Ca²⁺ -dependent endonuclease in L1210 cells.     

Aberrations of the MRE11–RAD50–NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene

The MRE11, RAD50, and NBS1 genes encode proteins of the MRE11–RAD50–NBS1 (MRN) complex critical for proper maintenance of genomic integrity and tumour suppression; however, the extent and impact of their cancer-predisposing defects, and potential clinical value remain to be determined. Here, we report that among a large series of approximately 1000 breast carcinomas, around 3%, 7% and 10% tumours showed aberrantly reduced protein expression for RAD50, MRE11 and NBS1, respectively. Such defects were more frequent among the ER/PR/ERBB2 triple-negative and higher-grade tumours, among familial (especially BRCA1/BRCA2-associated) rather than sporadic cases, and the NBS1 defects correlated with shorter patients’ survival. The BRCA1-associated and ER/PR/ERBB2 triple-negative tumours also showed high incidence of constitutively active DNA damage signalling (γH2AX) and p53 aberrations. Sequencing the RAD50, MRE11 and NBS1 genes of 8 patients from non-BRCA1/2 breast cancer families whose tumours showed concomitant reduction/loss of all three MRN-complex proteins revealed two germline mutations in MRE11: a missense mutation R202G and a truncating mutation R633STOP (R633X). Gene transfer and protein analysis of cell culture models with mutant MRE11 implicated various destabilization patterns among the MRN complex proteins including NBS1, the abundance of which was restored by re-expression of wild-type MRE11. We propose that germline mutations qualify MRE11 as a novel candidate breast cancer susceptibility gene in a subset of non-BRCA1/2 families. Our data have implications for the concept of the DNA damage response as an intrinsic anti-cancer barrier, various components of which become inactivated during cancer progression and also represent the bulk of breast cancer susceptibility genes discovered to date.