Tumor-ratio-metastasis staging system as an alternative to the 7th edition UICC TNM system in gastric cancer after D2 resection--results of a single-institution study of 1343 Chinese patients.

BACKGROUND: In this study, we assessed the prognostic value of the lymph node ratio (LNR), established a hypothetical tumor-ratio-metastasis (TRM) staging system and compared it with the 7th edition International Union Against Cancer pathological N (pN) and tumor-node-metastasis (TNM) system. PATIENTS AND METHODS: A total of 1343 gastric cancer patients undergoing D2 resection were staged using the TRM staging system and the 7th edition TNM system. Optimal cut points of LNR were calculated using X-tile software and validated by bootstrapping. Homogeneity, discriminatory ability, and monotonicity of gradients of the TRM and TNM systems were compared using linear trend χ(2), likelihood ratio χ(2) statistics, and Akaike information criterion (AIC) calculations. RESULTS: Optimal cut points classified patients into LNR0 (0%), LNR1 (1%-30%), LNR2 (31%-60%), and LNR3 (61%-100%) groups. In univariate, multivariate and stratified analyses, the LNR staging showed superiority to the 7th edition pN staging. The TRM staging system had higher linear trend and likelihood ratio χ(2) scores and smaller AIC values compared with those for the TNM system, which represented the optimum prognostic stratification. CONCLUSIONS: The novel TRM staging system predicts survival of gastric cancer more accurately than the 7th edition TNM system. It may be considered as an alternative to TNM system.

Cell growth suppression by thanatos-associated protein 11(THAP11) is mediated by transcriptional downregulation of c-Myc.

Thanatos-associated proteins (THAPs) are zinc-dependent, sequence-specific DNA-binding factors involved in cell proliferation, apoptosis, cell cycle, chromatin modification and transcriptional regulation. THAP11 is the most recently described member of this human protein family. In this study, we show that THAP11 is ubiquitously expressed in normal tissues and frequently downregulated in several human tumor tissues. Overexpression of THAP11 markedly inhibits growth of a number of different cells, including cancer cells and non-transformed cells. Silencing of THAP11 by RNA interference in HepG2 cells results in loss of cell growth repression. These results suggest that human THAP11 may be an endogenous physiologic regulator of cell proliferation. We also provide evidence that the function of THAP11 is mediated by its ability to repress transcription of c-Myc. Promoter reporter assays indicate a DNA binding-dependent c-Myc transcriptional repression. Chromatin immunoprecipitations and EMSA assay suggest that THAP11 directly binds to the c-Myc promoter. The findings that expression of c-Myc rescues significantly cells from THAP11-mediated cell growth suppression and that THAP11 expression only slightly inhibits c-Myc null fibroblasts cells growth reveal that THAP11 inhibits cell growth through downregulation of c-Myc expression. Taken together, these suggest that THAP11 functions as a cell growth suppressor by negatively regulating the expression of c-Myc.

Overexpression of a hematopoietic transcriptional regulator EDAG induces myelopoiesis and suppresses lymphopoiesis in transgenic mice.

Erythroid differentiation-associated gene (EDAG) is a hematopoietic tissue-specific gene that is highly expressed in the earliest CD34+ lin- bone marrow (BM) cells and involved in the proliferation and differentiation of hematopoietic cells. To investigate the role of EDAG in hematopoiesis, we established an EDAG transgenic mouse model driven by human CD11a promoter. The transgenic mice showed increased mortality with severe organ infiltration by neutrophils, and the homeostasis of hematopoiesis was broken. The myelopoiesis was enhanced with expansion of myeloid cells in BM, increased peripheral granulocytes and extramedullary myelopoiesis in spleen. In contrast to myeloid cells, the lymphoid commitment was severely impaired with the B lymphopoiesis blocked at the transition from pro/pre-B I to pre-B II stage in BM and T thymocytes development blocked at the most immature stage (DN I). Moreover, we showed that EDAG was a transcriptional regulator which had transactivation activity and regulated the expression of several key transcription factors such as PU.1 and Pax5 in transgenic hematopoietic stem cells. These data suggested that EDAG was a key transcriptional regulator in maintaining the homeostasis of hematopoietic lineage commitment.

EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of nuclear factor-kappa B.

Erythroid differentiation-associated gene (EDAG) is considered to be a human hematopoiesis-specific gene. Here, we reported that downregulation of EDAG protein in K562 cells resulted in inhibition of growth and colony formation, and enhancement of sensitivity to erythroid differentiation induced by hemin. Overexpression of EDAG in HL-60 cells significantly blocked the expression of the monocyte/macrophage differentiation marker CD11b after pentahydroxytiglia myristate acetate induction. Moreover, overexpression of EDAG in pro-B Ba/F3 cells prolonged survival and increased the expression of c-Myc, Bcl-2 and Bcl-xL in the absence of interleukin-3 (IL-3). Furthermore, we showed that EDAG enhanced the transcriptional activity of nuclear factor-kappa B (NF-kappa B), and high DNA-binding activity of NF-kappa B was sustained in Ba/F3 EDAG cells after IL-3 was withdrawn. Inhibition of NF-kappa B activity resulted in promoting Ba/F3 EDAG cells death. These results suggest that EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of NF-kappa B.

Isolation and Characterization of EDAG-1, A Novel Gene Related to Regulation in Hematopoietic System.

A novel gene, named embryonic develop associated gene 1 ( EDAG -1) and abundantly expressed in human fetal liver tissues, was isolated by screening a human fetal liver cDNA library and the 5' RACE. The full length of EDAG-1 mRNA is 2 166 bp, with an open reading frame of 1 452 bp neucleotides, encoding a 484 amino acid protein. No domain or motif was found similar with other genes by Blast program. Two copies of AUUUA motif in 3' non-translated region show instability of its mRNA. The molecular weight of the protein is 55.3 kD identified by the translation in vitro. EDAG-1 is specifically expressed in hematopoietic tissues, and is quickly down-regulated during the differentiation of K562 cells induced by hemin and EPO. These results show that EDAG-1 is related to the regulation in hematopoietic system and the development of leukemia.

[Primary retroperitoneal tumor--an analysis of 303 cases].

Primary retroperitoneal tumor (PRT) is of a heterogeneous group of neoplasms of mesenchymal origin. From April 1964 through April 1992, 303 PRT cases were treated. Of the 288 cases with histological confirmation, 197 suffered from malignant tumors and 91 were benign. Since the PRT patients were usually symptomless, diagnosis was made late in the majority of patients. It resulted in low radical resection rate in both the malignant (36.9%) and the benign (84.6%) PRT owing to invasion to adjacent organs. The tumor recurrence rate was also high, being 74.2% for the malignant and 11.7% for the benign tumors. The overall 2-, 5-, and 10-year survival rates in the patients with malignant tumors were 55.3%, 19.5%, and 9.8%, respectively. The results of treatment were dependent primarily on completeness of tumor resection. Adjuvant radiotherapy could improve the survival rates but adjuvant chemotherapy did not help. In patients with tumor recurrence, operation remained to be the treatment of choice. If complete resection was impossible, the alternative was debulking operation followed by radiotherapy.

Evaluation of partial hepatectomy for primary liver carcinoma.

From 1964 to 1985, 120 cases of primary liver carcinoma had undergone hepatectomy in our hospital. Seven of these cases underwent hepatic lobectomy, 28 cases had palliative hepatic resection, and 85 cases had partial hepatectomy. We introduced different surgical modes and compared the mortality, survival rates, and complications between the hepatic lobectomy and partial hepatectomy groups. The mortality rates of these two groups were 14.3 and 3.5%, respectively, and the 1, 3, and 5 year survival rates were 83.3, 33.3, and 16.7 and 68.8, 48.1, and 20%, respectively. In the palliative hepatectomy group (28 cases), ten cases received combined radiotherapy postoperation. Most of these cases died during the first year postoperation. Primary liver cancer in Asia is commonly associated with hepatic cirrhosis. We suggest that partial hepatectomy is suitable for such patients. The results of the present series showed that the outcomes of the hepatic lobectomy and partial hepatectomy groups did not differ, but in partial hepatectomy, the operative mortality and complications were reduced, bleeding minimized, and operation time also shortened.

[Surgical treatment of breast cancer in elderly women--analysis of 244 patients].

From April 1964 to December 1981, 244 patients, women over 60 years old, with unilateral breast cancer were treated by surgery in our hospital. In this series, 15 patients (6.1%) had Stage I, 131 (53.6%) Stage II, 82 (33.6%) Stage III and 16 (6.6%) unstaged lesions. Of these patients, 3 were treated by extended radical mastectomy (ERM), 140 by standard radical mastectomy (SRM), 49 by modified radical mastectomy (MRM) and 52 by total mastectomy (TM). Except 52 cases by TM, axillary lymph node metastasis rate in 192 patients of this series was 49.3%. The 5- and 10-year survival rates were 33.3% in ERM group, 53.4% and 39.5% in SRM group, 70.8% and 48.5% in MRM group, and 73.4% and 55.3% in TM group, respectively. The overall 5-and 10-year survival rates were 62.1% and 45.6%. In Stage I, II patients, the 5-and 10-year survival rates of TM group were much higher than those of SRM and MRM groups (P less than 0.01), but in Stage III, the 5- and 10-year survival rates of MRM group were higher than those of other groups (P less than 0.05). Noticeably, the 5- and 10-year survival rates of SRM group in Stage I approximately III were not satisfactory. Our data show that the postoperative radiotherapy or chemotherapy was ineffective in elderly patients with breast cancer.

[Evaluation of irregular hepatectomy for primary liver carcinoma].

From 1964 to 1985, 120 patients with primary liver carcinoma were treated by operation in our hospital. Regular hepatectomy was done in 7 patients, palliative irregular hepatectomy in 28 and radical irregular in 85. The operation mortality was 4.2% in irregular hepatectomy group (113 cases) but 14.3% in regular hepatectomy group (7 cases) (P greater than 0.05). The 1, 3 and 5 year survival rates were 68.8%, 48.1% and 20.0% in radical irregular hepatectomy group but 83.3%, 33.3% and 16.7% in regular hepatectomy group. 10 of 28 patients treated by palliative hepatectomy were added with radiation. Majority of these patients died in 1 year after operation but 2 patients survived for more than 2 years and 1 for more than 7 years. The data show that in Asia, the incidence of primary liver carcinoma concurrent with liver cirrhosis is high and irregular hepatectomy is a suitable treatment. There is no difference between irregular and regular hepatectomy groups in the prognosis. But the former could reduce the operative time, mortality and the possibility of bleeding and complications.