Preservation of cytometric DNA distribution and epithelial marker expression after tumor progression of human large bowel carcinomas

Tumor specimens were obtained from seven patients with large bowel carcinomas at operation of the primary neoplasm and by resection of local recurrences or metastases 2 1/2 to 36 months later. All specimens were evaluated with regard to nuclear DNA distribution as measured by flow cytometry and expression of carcinoembryonic antigen (CEA), secretory component, epithelial IgA, and HLA-DR antigens, as determined by immunofluorescence staining of tissue sections. Both the DNA distributions and the immunohistochemical staining patterns were similar in the primary and secondary tumors. These findings are in keeping with a monoclonal or oligoclonal tumor progression in advanced large bowel carcinoma.     

Expression of P-cadherin in gastric carcinomas and its reduction in tumor progression

The expression of P-cadherin, one of the Ca²⁺-dependent cell-cell adhesion molecules, in human gastric carcinomas was examined by Northern blotting, Western blotting and immuno-histochemistry. P-cadherin mRNA was expressed in all the gastric carcinoma tissues examined, whereas no message was detected in non-neoplastic mucosa. By Western-blot analysis, P-cadherin protein was expressed in 83% and 29% of the well-differentiated and poorly differentiated gastric adenocarcinomas, respectively, the incidence being significantly different. Immunohistochemically, P-cadherin immunoreactivity was localized on the cell surface or the cell-to-cell borders of well-differentiated adenocarcinomas. P-cadherin was not detected in Borrmann's type-4 or scirrhous carcinomas where the tumor cells proliferate diffusely with productive fibrosis. The level of P-cadherin expression in stage-2 carcinomas was significantly higher than in stage-1 carcinomas. In the case of patients in stages 2 to 4, however, the level of P-cadherin expression decreased as the stage progressed, the difference between stages 2 and 3 and between stages 3 and 4 being significant. Our findings suggest that P-cadherin might play an important role in the development of well-differentiated gastric adenocarcinomas and the decreased expression of P-cadherin might be responsible for the infiltrative growth and progression of gastric carcinomas.     

Relationship between CaMBr1 expression and tumor progression in small cell lung carcinomas

In order to study the possible relationship between antigenic phenotype and tumor progression, 63 small cell lung carcinomas (SCLC) biopsies derived from primary or metastatic tumors were tested by immunofluorescence and immunoperoxidase techniques with an anti-carcinoma monoclonal antibody designated MBr1. Primary tumors were found to be less reactive with MBr1 than the local and distant metastatic lesions (57% versus 75% and 89% positivity respectively). A life table analysis on the tested cases indicated an inverse association between the expression of the marker recognized by the MBr1 MAb (CaMBr1) and overall survival (p less than 0.01): patients with MBr1-positive tumors showed a shorter survival time in comparison to patients whose tumors did not express the marker. The same correlation between survival and CaMBr1 expression was found even when only the 31 cases of early stage disease patients were considered (p less than 0.05). Different tumor aggressiveness or resistance to therapy of MBr1-positive tumors could be responsible for the shorter survival time of the patients.     

Socioeconomic and demographic disparities in treatment for carcinomas of the colon and rectum

BACKGROUND: The current study examined the relationship between socioeconomic and demographic factors and type of treatment for carcinomas of the colon and rectum. The National Institutes of Health and the National Cancer Institute recommend surgery followed by adjuvant chemo- and/or radiotherapy for Stage III colon and Stages II and III rectal carcinomas. METHODS: The authors linked Washington State's cancer registry and hospital discharge records and U.S. census data to assess socioeconomic and demographic factors related to treatment, controlling for clinical factors. RESULTS: Compared to colon carcinoma patients under age 65 years, patients aged 75-84 years and 85 years or older were at higher risk for a treatment plan of surgery without adjuvant therapy (adjusted odds ratio [OR] = 2.5, 95% confidence interval [CI] = 1.3-4.7; OR = 14.1, CI = 6.3-31.4, respectively). Risk of no adjuvant therapy was more than doubled for patients in zip codes in the lowest quartile of per capita income compared to the top three quartiles (OR = 2.3, CI = 1.5-3.4) and for those with Medicare compared to private insurance (OR = 2.2, CI = 1.3-3.8). Older patients with rectal carcinoma were also at higher risk of a treatment plan that did not include adjuvant therapy. CONCLUSIONS: The current findings suggest disparities in the provision of recommended medical procedures related to socioeconomic and demographic factors.     

Mucinous carcinomas of the colon and rectum and their relation to polyps

A study of 44 mucinous carcinomas (MC) from a series of 324 colorectal cancers was made (221 surgical resections and 103 endoscopic biopsies). This study showed that MC were associated, in a significantly higher proportion when compared to non MC, with polypoid adenomas of different kinds (hyperplastic polyps not included), in other segments of the surgical specimen (P less than 0.001). MC originated from adenomas, particularly villous, but also mixed and tubular, in a significantly higher proportion than non-MC (P less than 0.001). Carcinomas arising from adenomas were mucinous in 11/14 cases. The type of adenomas from which MC arose were characterized by usually having areas with a particular arborizing mucus hyperplasia. At the time of resection, MC had metastases (Stages C and D) more frequently then non MC (P less than 0.02).     

Obstructing carcinomas of the colon and rectum: clinicopathologic analysis of 40 cases

A review of 40 cases of obstructing colorectal carcinoma selected from 1,786 cases of surgically resected colorectal carcinomas was undertaken. The average age of the patients was 63 years, and there were 22 women and 18 men. Twenty-three lesions (58%) arose in the sigmoid colon and nine (23%) in the transverse colon, and obstructing rectal carcinomas were significantly rare. All of the obstructing tumors displayed a circumferential growth, 32 being examples of the annular constricting type. Obstructive colitis was caused by a combined lesion in only three cases. Microscopic characteristics of the obstructing carcinomas were as follows: 1) invasion of the whole thickness of the colorectal wall by the malignant tissue, 2) complete discontinuance of the muscularis propria in the affected area, 3) striking fibrous stromal reaction in the tumor, 4) upward rising, not descending, of both stumps of the discontinuous muscularis propria, 5) infiltrative growth of the tumor into the subserosa with scar-like fibrosis. It is indicated from the present study that obstructing carcinomas have features promising construction of the bowel lumen, but patients with such a tumor are not appreciably different in prognostic, histologic nor immunohistochemical aspects from those with a non-obstructing carcinoma.     

The significance of synchronous carcinoma and polyps in the colon and rectum

The relationship of colorectal carcinoma with polyps was studied retrospectively in 1202 patients. The incidence of synchronous carcinoma (SC) and metachronous carcinoma (MC), prognosis, and recurrence patterns were studied. Synchronous polyps (SP) were found in 36% of the patients. SC was found in 4.4% of the patients, and MC developed in 3.5% of patients. The incidence of SC and of MC increased with SP, and varied according to number, size, and histologic features of the polyps. The adjusted 5-year survival rate was improved in patients with SP compared with those without SP, both overall (79% versus 64%, respectively) and by Dukes' Stage B (87% versus 73%, respectively) and Dukes' Stage C (56% versus 39%, respectively). The pattern of relapse was the same for the SP and non-SP groups. Subtotal colectomy is recommended for colorectal carcinoma and SP in good-risk patients.     

Obstructing carcinomas of the colon and rectum have a smaller size compared with those of non-obstructing carcinomas

The aim of the current study was to elucidate the histopathological characteristics of obstructing carcinoma of the colon and rectum. We studied 72 patients with colorectal carcinoma, including 13 with obstructing carcinoma. The obstruction carcinomas occurred in sigmoid colon significantly more frequently than did non-obstructing carcinomas (p=0.007). The mean size of the obstructing carcinomas was 3.7+/-0.9 cm, which was significantly smaller than that of non-obstructing carcinomas (5.4+/-1.9 cm, p=0.003). The proportion of lymph node metastasis in obstructing carcinomas was 66.9%, which was significantly higher than that in non-obstructing carcinomas (42.4%, p=0.021). The proportion of carcinomas classified into Dukes' C or D in obstructing carcinomas was 84.6% and was significantly higher than that in non-obstructing carcinomas (52.5%, p=0.026). The pathogenesis of obstruction in colorectal carcinoma can be also derived from the contraction of the intestinal lumen caused by the condensation of cancer cells.     

Adrenal adenomas and adrenal carcinomas in association with hereditary adenomatosis of the colon and rectum

Hereditary adenomatosis of the colon and rectum (HACR) is associated with a wide variety of extracolonic manifestations. Two cases of neoplasia involving the adrenal gland are reported, one adenoma and one carcinoma. The literature relating these lesions to HACR and other syndromes of malignant and nonmalignant growth disturbance is reviewed. The increasing list of the extracolonic manifestations associated with HACR emphasizes the generalized nature of the growth disorder of this disease. An increased awareness of these lesions is important, as many patients with HACR now live longer by avoiding death from colorectal carcinomas due to the increasing usage of prophylactic colectomy.     

A case of multiple carcinomas of the colon and rectum associated with ulcerative colitis

The present paper describes a patient with four independent carcinomas associated with ulcerative colitis. Subtotal colectomy with lymph node dissection was done on June 28, 1978. The operative specimen revealed a carcinoma at the descending colon, two independent cancerous lesions and papillary polyps at the sigmoid colon and a scirrhous, flat elevated neoplasm at the rectum. These carcinomas were surrounded by lesions of various degrees of epithelial dysplasia, suggesting precancerous change. Carcinomas and precancerous lesions were stained for carcinoembryonic antigen (CEA) by the CEA peroxidase antiperoxidase method, which is considered to be useful to discriminate precancerous change from an inflamed mucous membrane.     

The prognostic significance of growth pattern and its relation to tumor cell nuclear DNA content in endometrial carcinoma

Hysterectomy specimens from 21 endometrial carcinoma patients, who died from their disease, and 23 patients selected at random from 307 survivors, were analysed for tumor growth pattern and tumor cell nuclear DNA content. The results indicate that tumor growth pattern, reflected by the mode of infiltration, is significantly correlated to the clinical course of the disease. Patients with carcinomas exhibiting contiguous growth pattern had a better outcome than patients with discontiguously growing carcinomas. It was also found that tumor growth pattern correlated well with tumor nuclear DNA content. It is suggested that the pattern of infiltration of the tumors is a sensitive predictor of prognosis and that this prognostic information, which only can be obtained postoperatively, to a large extent is reflected by tumor cell nuclear DNA content in curetted diagnostic material, obtained prior to treatment.     

TCGA database analysis of the tumor mutation burden and its clinical significance in colon cancer

BackgroundColon cancer is one of the most common malignant tumors, with high rates of incidence and death. The tumor mutational burden (TMB), which is characterized by microsatellite instability, has been becoming a powerful predictor which can show tumor behavior and response to immunotherapy.MethodsIn this study, we analyzed 437 mutation data of colon cancer samples obtained from The Cancer Genome Atlas (TCGA) and divided patients into low- and high-TMB groups according to the TMB value. Then we identified differentially-expressed genes (DEGs), conducted immune cell infiltration and survival analyses between groups.ResultsThe higher TMB of the patients with colon cancer predicts a poorer prognosis. Functional analysis was performed to assess the prognostic value of the top 30 core genes. The CIBER-SORT algorithm was used to investigate the correlation between the immune cells and TMB subtypes. An immune prognosis model was constructed to screen out immune genes related to prognosis, and the tumor immunity assessment resource (TIMER) was then used to determine the correlation between gene expression and the abundance of tumor-infiltrating immune cell subsets in colon cancer. We observed that APC, TP53, TTN, KRAS, MUC16, SYNE1, PIK3CA have higher somatic mutations. DEGs enrichment analysis showed that they are involved in the regulation of neuroactive ligand-receptor interaction, the Cyclic adenosine monophosphate (cAMP) signaling pathway, the calcium signaling pathway, and pantothenate and Coenzyme A (CoA) biosynthesis. The difference in the abundance of various white blood cell subtypes showed that Cluster of Differentiation 8 (CD8) T cells (P=0.008), activated CD4 memory T cells (P=0.019), M1 macrophages (P=0.002), follicular helper T cells (P=0.034), activated Natural killer (NK cell) cells (P=0.017) increased remarkably, while M0 macrophages significantly reduced (P=0.025). The two immune model genes showed that secretin (SCT) was negatively correlated with survival, while Guanylate cyclase activator 2A (GUCA2A) was positively correlated.ConclusionsThis study conducted a systematically comprehensive analysis of the prediction and clinical significance of TMB in colon cancer in identification, monitoring, and prognosis of colon cancer, and providing reference information for immunotherapy.     

结肠癌淋巴结转移相关基因的表达谱研究

 目的 利用基因芯片技术分析伴与不伴淋巴结转移结肠癌组织中的差异表达基因。方法 将含有16 084 条人类全长基因的PCR 产物点样于特殊处理后的玻片上制备基因芯片。用反转录的方法，分别将两种荧光Cy3-dUTP 和Cy5-dUTP 标记结肠癌组织和淋巴结转移组织mRNA，以制备cDNA 探针，并与芯片杂交。以Agilent 荧光扫描仪扫描芯片上两种荧光信号，获得的荧光信号图像用计算机分析。结果 在16 084条基因中，结肠癌原发灶与转移淋巴结组织间存在差异表达的基因共999条，有537 条基因出现显著性表达上调，462条基因出现显著性表达下调。在4 例患者中出现共同表达上调基因44条，共同表达下调基因30条。包括癌基因、抑癌基因、黏附分子、基质金属蛋白酶、信号转导因子、细胞代谢和免疫相关基因等。结论 结肠癌转移是多基因作用的综合结果，转移相关基因表达谱的分析为预防和控制结肠癌的转移提供了新的思路与线索。     

DNA sequence copy number changes in gastrointestinal stromal tumors: tumor progression and prognostic significance

To identify genetic changes related to tumor progression and find out diagnostic and prognostic genetic markers in gastrointestinal stromal tumors (GISTs), 95 tumor samples (24 benign GISTs, 36 malignant primary GISTs, and 35 GIST-metastases) from 60 patients were studied using comparative genomic hybridization. DNA copy number changes were detected in all samples. Benign GISTs had a mean of 2.6 aberrations/ sample (losses:gains, 5:1) and significantly fewer DNA copy number changes and fewer gains than malignant primary and metastatic GISTs (P < 0.01). High-level amplifications were not seen in benign GISTs. Malignant primary GISTs had a mean of 7.5 aberrations/tumor (losses: gains, 1.6:1), whereas the mean number of aberrations/metastatic GIST was 9 (losses:gains, 1.8:1). Frequent changes observed in all GIST groups included losses in chromosome arms 1p (51%), 14q (74%), and 22q (53%). Gains and high-level amplifications at 8q and 17q were significantly more frequent in metastatic GISTs (57 and 43%) than in benign GISTs (8 and 0%; P < 0.001) and malignant primary GISTs (33 and 25%; P < 0.05). Gains and high-level amplifications at 20q were only seen in malignant primary and metastatic GISTs (P < 0.01), and gains at 5p were not detected in benign GISTs (P < 0.01). Losses in chromosome arm 9p were never seen in benign tumors (P < 0.001), and they were more frequent in metastatic GISTs than in malignant primary GISTs (63 and 36%; P < 0.05). Losses in 13q were less frequent in benign GISTs than in malignant primary (P < 0.05) and metastatic (P < 0.01) GISTs. Our results show that several DNA copy number changes are related to the behavior of GISTs and can be used as prognostic markers for tumor progression.     

Circulating tumor cells and circulating tumor DNA in colon cancer

It is known that tumor cells have the ability to penetrate into the bloodstream. The identification of such circulating tumor cells (CTC) determines the prognosis in several tumors, including colon cancer. Tumor DNA (ctDNA), which is only a part of the total circulating DNA obtained from the blood of cancer patients, is also further separated from plasma. This separation of the neoplastic derivatives of the primary tumor and metastases (CTC, ctDNA, RNA, proteome) in plasma is called “liquid biopsy.” CTC increasingly represents the pool of tumor cells that can initiate the growth of metastatic lesions, while the ctDNA provides the information about the whole tumor mass. Traditional tissue biopsy gives information based only on one small section of the primary tumor or metastasis, often retrieved before the start of treatment; however, liquid biopsy provides real-time information about the molecular disorders for the whole tumor mass and allows us to estimate the dynamics of the evolutionary tumor changes, the heterogeneity of the disease, and the effect of chemotherapy. With the possibility of obtaining multiple blood samples for analysis during the therapy, in contrast to traditional biopsy, it also allows us to evaluate the mechanisms of resistance to treatment, which in the future will perhaps lead to modification of the treatment in accordance with the detected molecular defects in tumors. Thus, this would facilitate implementing the principles of personalized therapy. In this literature review, we concentrate on liquid biopsy in patients with colon cancer.     

Epigenetic inactivation of IkappaB Kinase-alpha in oral carcinomas and tumor progression.

PURPOSE: The loss of epithelial phenotypes in the process of carcinoma progression correlates with clinical outcome, and genetic/epigenetic changes accumulate aggressive clones toward uncurable disease. IkappaB kinase-alpha (IKKalpha) has a decisive role in the development of the skin and establishes keratinocyte phenotypes. We assessed clinical implications of IKKalpha expression in oral carcinomas and epigenetic aberrations for the loss of expression. EXPERIMENTAL DESIGN: We examined IKKalpha expression in oral carcinomas by immunostaining (n = 64) and genetic instability by microsatellite PCR (n = 46). Promoter methylation status was analyzed by bisulfite-modified sequence (n = 11). RESULTS: IKKalpha was expressed in the nucleus of basal cells of normal oral epithelium, but not or marginally detected in 32.8% of carcinomas. The immunoreactivity was significantly decreased in less differentiated carcinomas (P < 0.05) and correlated to long-term survival of patients (P < 0.01) with an independent prognostic value (P < 0.05). Although allelic/biallelic loss of the gene was limited to four cases, we detected microsatellite instability in 63.0% cases in which the immunoreactivities were decreased and the promoter was hypermethylated. CONCLUSION: These results showed that oral carcinomas exhibiting genetic instability and promoter hypermethylation down-regulate expression of IKK and suggest that the epigenetic loss of the expression closely associates with disease progression toward unfavorable prognosis.     

CD146 expression and its close relationship to tumor progression in systemic malignancies besides gall bladder carcinomas

Recent data suggest that CD146 may be involved in tumor development and may influence tumor prognosis in a number of systemic tumors besides gall bladder carcinomas. For instance, CD146 augments the development and progression of gastric carcinomas. It performs this function by accentuating epithelial mesenchymal transition (Liu et al., Int J Mol Sci 13:6399–6406, 2012). CD146 thus points towards a poor clinical outcome in gastric malignancies. An increase in gastric tissue vimentin is seen with an increase in CD146 levels. Similarly, around 8.7 % of lung adenocarcinomas express CD146. A decreased 5-year overall survival rate is seen following lung resection of pulmonary adenocarcinomas in male patients who express CD146 (Zeng et al., Proc Natl Acad Sci USA 109:1127–1132; 2012).