Carcinoma Of Large Bowel Research Articles

A phase II study of 6-diazo-5-oxo-L-norleucine (DON, NSC-7365) in advanced large bowel carcinoma.

A phase II study of 6-diazo-5-oxo-L-norleucine (DON, NSC-7365) in advanced large bowel carcinoma.

A case-control study of risk factors for large bowel carcinoma.

Two hundred and seven large bowel cancer patients (93% of all cases diagnosed in a defined community between 1965 and 1976) were matched at random with non-cancer subjects of same age, sex, and place of residence. Men with cancer, aged 75 years and younger than, had a more frequent history of work in a local factory handling synthetic fiber than controls (22 versus 10; P less than 0.025). In this factory 45% of cancers occurred before age 60, while this was true in only 24% of cancer cases outside the factory (P less than 0.05). There was a greater tendency for cancers in factory workers to occur in the colon than in the rectum. Heredity was not found to be a risk factor for large bowel cancer. The rate of prior appendectomy was higher in men with colon cancer (P less than 0.05) and the rate of prior cholecystectomy was lower in females with colonic cancer (P less than 0.05). A previous hemorroidectomy was also found more often in males with colonic cancer (P less than 0.05). Long-standing severe constipation was present more often in patients with cancer (P less than 0.01). There was some evidence for a compounding influence of different risk factors, as studied by relative risk ratio. This study confirms the existence of a high risk of large bowel cancer in a group of workers in a synthetic fiber factory and suggests other factors antecedent to large bowel cancer.

Significance of polypectomy in the large bowel--endoscopy.

The precancerous and early stages of colorectal carcinoma are, in the vast majority of cases, known and pathologically unequivocally defined. The precancerous and early stages of colorectal carcinoma can be detected by routine diagnostic measures (colonoscopy) with an adequate degree of reliability. A curative treatment of precursor and early stages of colorectal carcinoma is possible. As a rule, the procedure used is endoscopic polypectomy. A lowering of the incidence rates and mortality figures of large-bowel carcinoma through the routine detection and thoroughgoing endoscopic treatment of precursors of colorectal carcinoma would appear possible. The conclusion follows logically from the established points 1 to 3. The significance of polypectomy in the large bowel, which today is carried out routinely using a standardized technique, is to be seen in the prevention and early detection of colorectal carcinomas.

A phase II study of alanosine in advanced large bowel carcinoma.

Thirty patients with advanced metastatic colorectal adenocarcinoma were treated with alanosine at a dose of 160 mg/m2 daily for 5 days every 4 weeks. Sixteen patients had received no prior chemotherapy and 14 had been previously treated with one or more cytotoxic agents. No patient met the criteria for a complete or partial response. The major toxicity was stomatitis.

Fecal Bile Acids and Neutral Sterols in Japanese with Large Bowel Carcinoma

We compared the level of fecal bile acids and neutral sterols in 15 Japanese with large bowel carcinoma and 10 healthy controls. There was no significant difference in the amount of total fecal bile acids and neutral sterols between the patients and the controls. However, the amount of primary bile acids, especially chenodeoxycholic acid, tended to be higher in the patients. Conversely, lithocholic, beta-lithocholic and 3 alpha-hydroxy-12-ketocholanoic acid levels were higher in the controls. Trace amounts of 3 alpha-hydroxy-6-ketocholanoic acid were detected in some of the patients; none was found in the controls. Although a hasty conclusion should be avoided in the present study, it is of considerable interest that there was a difference in fecal bile acid composition between large bowel carcinoma patients and healthy controls.

Liver scintigraphy in colon carcinoma: correlation with modified Duke pathological classification.

Hepatic scintigraphy was performed prior to surgical exploration in 89 patients with primary carcinoma of the large bowel. Of these patients, 26% had positive liver scans at the time the diagnosis was established. The presence or absence of liver metastasis by scintigraphic criteria was correlated with surgical findings, a modified Duke pathologic classification, and the presence of tumor markers. The sensitivity of hepatic scintigraphy was 96% and the specificity was 98%. A total of 63% of patients with abdominal lymph node involvement had positive liver scans while 4.6% of patients without lymph node involvement had positive scans. A total of 91% of patients with positive liver scans had positive abdominal nodes. Of 60 patients with normal liver scans, one (1.7%) had hepatic metastasis and 27% had tumor in regional lymph nodes. Hepatic scintigraphy is highly sensitive in detecting liver metastasis from large bowel carcinoma. However, a negative liver scan did not exclude abdominal lymph node spread.

A phase II study of aziridinylbenzoquinone (AZQ) in advanced large bowel carcinoma

Aziridinylbenzoquinone (AZQ: NSC-182986), is a quinone derivative which has been shown to have activity in implanted murine tumor systems.1 Toxicity in small and large animals included hypothermia, diarrhea, anorexia, emesis, weight loss, and gastrointestinal bleeding. In addition, there was myelosuppression and elevated liver function tests.2 In a phase I study at the Mayo Clinic, dose-limiting toxicity was myelosuppression. Patients with prior radiation therapy or prior chemotherapy were more sensitive to this toxicity. A dose schedule of 27.5 mg/m2 q4 weeks was recommended for patients who had had no previous chemotherapy and 22.5 mg/m2 for previously treated patients or for patients who had had extensive prior radiation therapy. The objective of this study was to determine therapeutic activity for AZQ in patients with advanced colorectal adenocarcinoma.

A phase II study of aziridinylbenzoquinone (AZQ) in advanced large bowel carcinoma

Aziridinylbenzoquinone (AZQ: NSC-182986), is a quinone derivative which has been shown to have activity in implanted murine tumor systems. Toxicity in small and large animals included hypothermia, diarrhea, anorexia, emesis, weight loss, and gastrointestinal bleeding. In addition, there was myelosuppression and elevated liver function tests. In a phase I study at the Mayo Clinic, dose-limiting toxicity was myelosuppression. Patients with prior radiation therapy or prior chemotherapy were more sensitive to this toxicity. A dose schedule of 27.5 mg/m2 q4 weeks was recommended for patients who had had no previous chemotherapy and 22.5 mg/m2 for previously treated patients or for patients who had had extensive prior radiation therapy. The objective of this study was to determine therapeutic activity for AZQ in patients with advanced colorectal adenocarcinoma.

Plasma carcinoembryonic antigen concentrations and immunohistochemical patterns of epithelial marker antigens in patients with large bowel carcinoma.

Carcinoembryonic antigen (CEA), secretory component (SC), and epithelial IgA were traced by paired immunofluorescence staining in 102 large bowel carcinomas from 99 patients. The immunohistochemical results were evaluated semiquantitatively in relation to histological tumour grade, clinicopathological stage, and preoperative plasma CEA concentration. CEA expression was significantly increased (p less than 0.05) in the following order: histologically normal colon mucosa, transitional mucosa adjacent to tumours, neoplastic epithelium; the reverse was true for the expression of SC and epithelial IgA (p less than 0.01). CEA was significantly more abundant in the moderately and poorly differentiated tumors than in the well differentiated ones (p less than 0.05), whereas the latter showed better expression of SC (p less than 0.05) and epithelial IgA (p approximately 0.06). In the transitional mucosa, CEA staining tended to be inversely related to histological tumour grade, whereas SC and epithelial IgA were significantly better seen in this zone when the adjacent tumour was well differentiated than when it was moderately or poorly differentiated (p less than 0.01). Furthermore, the expression of SC and epithelial IgA in the transitional mucosa decreased with increasing invasiveness of the tumours, whereas the opposite relation was indicated for CEA expression. Plasma CEA concentrations were not clearly correlated with histological levels than the localised well differentiated tumours tended to be associated with lower levels than the localised moderately differentiated ones (p approximately 0.06). Moreover, the latter variety was associated with lower plasma CEA concentrations than disseminated tumours of comparable differentiation (p less than 0.01).

The 'transitional' mucosa adjacent to large bowel carcinoma--electron microscopic features and myofibroblast reaction.

An electron microscopic study of the 'transitional' mucosa adjacent to 10 carcinomas of the colon showed impaired maturation of epithelial cells. The pericryptal fibroblast layer was absent, accounting for an increase in the length and distension of crypts. In the tunica propria a massive accumulation of myofibroblasts was noted and was indicative of an intensive fibre-producing activity. Review of the literature identifies various theories concerning the functions of myofibroblasts in respect of contraction, embryonal collagen-fibre formation and non-specific stromal reaction. Of these, the latter two are considered likely in relationship to transitional colonic mucosa.

The changing distribution of large intestinal cancer

In recent years, several accounts have reported a proximal migration of colorectal cancer. To determine the experience at the Jewish General Hospital in Montreal, 1044 cases of large-bowel cancer that presented between the years 1955 and 1978 were analyzed. The colon was arbitrarily divided into five anatomic regions, and the distribution of cancer in each region for each of eight three-year periods was calculated. An increase in right-sided lesions occurred from 15.6 per cent in the first three-year period to 37.6 per cent in the final three-year period (P less than 0.01). No significant change occurred in transverse and left-colon lesions. An increase in sigmoid carcinomas occurred from 14 per cent to 35 per cent (P less than 0.01). A dramatic decrease in rectal carcinoma from 53 per cent to 2.1 per cent occurred (p less than 0.001). These findings imply that methods for the early detection and screening of large-bowel carcinoma should be directed at the entire colon rather than the distal 25 cm.

Weekly large fraction radiotherapy and 5 fluorouracil as a palliative treatment for large bowel carcinoma: a pilot study

Palliative radiotherapy for large bowel cancer is generally given in fraction sizes of 2–3 Gy. Theoretical considerations led us to believe that a larger fraction size would not lead to a decreased response rate and practical considerations led us to treat patients once a week. The results of a pilot study of 32 patients with large bowel cancer are presented. Patients were treated with a fraction size of 6 Gy given weekly and combined with 5 FU. The response rate of 58% and the median survival of 9 months seems comparable with other regimens, as does the rate of acute side effects. The late high dose effect of subcutaneous fibrosis was seen in 30 % of the long term survivors; the implications of this are discussed. We draw the conclusion that this treatment is convenient and effective in terms of tumor response, but that the late high dose effects were more severe than expected and that these effects may be potentiated by 5 FU.

Large-bowel carcinomas with different ploidy, related to secretory component, IgA, and CEA in epithelium and plasma.

Immunofluorescence staining for carcinoembryonic antigen (CEA), secretory component (SC), and epithelial IgA was evaluated semiquantitatively in 85 large-bowel carcinomas in relation to degree of tumour differentiation, Dukes' stage, and plasma CEA level. The tumours were divided into a near-diploid (ND, 28) and an aneuploid group (AN, 57) by means of flow-cytometric DNA measurements. Expression of SC and IgA in neoplastic epithelium was positively related to differentiation in both groups. The AN tumours scored significantly higher for CEA than the ND ones, but the staining was apparently unrelated to differentiation or Dukes' stage. CEA expression in the transitional mucosa adjacent to ND tumours was negatively correlated with tumour differentiation, whereas epithelial IgA and SC in this zone showed a substantially higher positive correlation with tumour differentiation, and a somewhat stronger negative correlation with Dukes' stage in the ND than in the AN group. Plasma CEA levels were significantly related to Dukes' stage, only in patients with AN tumours, and only in this group were positively correlated with estimates of total tumour CEA for Dukes' stages A and B. For Dukes' stages C and D (disseminated tumours), moreover, the plasma CEA levels were found to be significantly higher in the AN group. These findings indicate that the DNA profile of large-bowel carcinomas is related both to the way neoplastic cells influence the activity of the transitional mucosa and their capacity for expression and release of epithelial products. AN tumours thus seem to be more active as "secretors" of CEA than ND ones.

The occurrence of severe epithelial dysplasia and its bearing on treatment of longstanding ulcerative colitis.

One hundred twenty-four patients with extensive ulcerative proctocolitis were operated upon with proctocolectomy. The mean observation time was 10.3 years. Before surgery rectal biopsies were taken in all patients. The relationship between precancerous lesion in rectal biopsies and the presence of precancer and/or cancer in the rectum or colon in the removed specimen was evaluated. Thirteen out of 14 patients showed evidence of severe rectal dysplasia as well as severe dysplasia in the large bowel specimen, and five of these patients had a carcinoma as well. The 14th patient showed severe dysplasia only in the rectum as well as a rectal carcinoma. Of 110 patients without severe rectal dysplasia, 36 showed evidence of severe colon dysplasia, and three of these patients had a large bowel carcinoma as well. Only one patient had a large bowel carcinoma without evidence of severe dysplasia in the rectum or colon. Thus, nine patients out of ten with large bowel carcinoma showed severe dysplasia in rectum and/or colon. Four of these carcinomas were unknown before surgery. Although severe dysplasia in the rectal biopsy is a strong indication of a large bowel carcinoma (6/14), a negative rectal biopsy does not exclude a large bowel carcinoma (4/110). Proctocolectomy cannot be looked upon only as a prophylactic procedure in patients with severe dysplasia in the rectal biopsy, but also as an attempt to curative surgery, as large bowel carcinoma may have already developed in a considerable number of patients where precancer is diagnosed in biopsies.

THE PRESENCE OF ONCOFOETAL ANTIGENS IN LARGE BOWEL CARCINOMA

This paper is an immunohistological study of the occurrence of the oncofoetal antigens, (carcinoembryonic antigen (CEA), small intestine mucin antigen (SIMA), and normal large bowel mucin antigen (LIMA) in 60 surgically resected colons: 10 non-malignant specimens and 50 colorectal carcinomas. SIMA is a new oncofoetal antigen found in mucinous carcinoma of the large bowel. In the adult it is normally present only in the duodenum and jejunum. Of the 50 carcinoma specimens, 13 were mucinous, 17 non-mucinous and 20 mixed mucinous and non-mucinous. LIMA was the only antigen detected in the mucosa of non-malignant specimens. In mucinous carcinomas only SIMA was present, whilst in the non-mucinous specimens CEA was always found and to a lesser extent LIMA. The same relationship was observed in mixed tumours: SIMA in mucinous and CEA-LIMA in the non-mucinous parts. In the mucosa adjacent to the cancer in all 50 cases there was evidence of an increase or decrease in LIMA. In 42 cases (84%) both oncofoetal antigens (CEA and SIMA) could also be detected in this transitional or perineoplastic epithelium at varying distances from the tumour. These results provide evidence to suggest that the majority of large bowel carcinomas occur in areas of metaplastic change.

Positive skin tests with autologous tumor cells of increased membrane viscosity

Skin tests were carried out with irradiated autologous tumor cells in patients with solid tumors (large-bowel carcinoma, gastric carcinoma, malignant melanoma, and breast cancer). With untreated cells, the skin reaction was negative or very weakly positive. A strong skin reaction, however, was elicited with cells of elevated membrane lipid microviscosity. This was induced by incorporation of cholesterol or, more effectively, by cholesterly hemisuccinate (CHS). A fair correlation was observed between the level of skin reaction with CHS-treated cells and the clinical stage of the tumor. It is suggested that rigidification of the cell membrane lipid layer exposes latent tumor-associated antigens, which enhances the cell-specific tumor immunogenicity. CHS-treated cells could therefore be of clinical value in active immunotherapy of human cancer.

Tumor-associated antigens in polyps and carcinoma of the human large bowel.

The presence of a number of tumor-associated antigens was studied in eight metaplastic polyps, 22 tubulovillous adenomas, and 20 carcinomas. Specific tumor antigens were identified using the immunohistochemical (P.A.P.) technique to detect carcinoembryonic antigen (CEA), human placental lactogen (HPL), alphafetoprotein (AFP), colon-specific antigen (CSA), pregnancy-specific beta lipoprotein 1 (SP1), human beta chorionic gonadotropin (beta hCG), and placental alkaline phosphatase (P Alk P), isoferritins (FE), and transferrin (TF). There is no difference in either the number of antigens present or the number of cases positive for each antigen in cancers and tubulovillous adenomas, but the majority of metaplastic polyps show only CEA and HPL positivity. The two metaplastic polyps showing a full range of positivity were atypical and over 5 mm in diameter. The findings have shown a remarkable similarity between polyps and cancer, which strengthens the concept of the relationship between adenomatous polyps and carcinoma of the colon.

Immunohistochemical Study of Secretory Component, Secretory IgA and Carcinoembryonic Antigen in Large Bowel Carcinomas

The epithelium of 41 large bowel carcinomas was scored immunohistochemically on a semiquantitative basis for the presence of secretory component (SC), secretory IgA, and carcinoembryonic antigen (CEA). Both the tumour and the adjacent "transitional mucosa" were evaluated. The various immunofluorescence scores obtained, the histological grades of the tumours, their Dukes' stages, and the plasma CEA levels were subjected to non-parametric correlation analyses. Tumour SC was positively correlated with histological tumour grade and inversely related to Dukes' stage. Tumour secretory IgA generally showed a pattern similar to that of SC. Tumour CEA showed no correlation with any of the other parameters. The contents of SC and secretory IgA in the transitional mucosa were negatively correlated with Dukes' stage and plasma CEA. Whether the variations observed in the epithelial cell markers reflected primary events in the malignant development or secondary alterations is unknown. Nevertheless, especially the amount of tumour SC may turn out to be of prognostic value.

Double minutes in human large bowel cancer

Two patients with large bowel carcinoma are described in whose tumors the presence of double minutes was observed. In one of these, the first such patient to be reported, double minutes were present in 300% of metaphases examined in both the primary tumor and its liver metastasis. The number of double minutes varied from 6 to 93 per metaphase. In the second patient, double minutes were seen only in two metaphases. The literature on double minutes is summarized, and it is concluded that double minutes are found in a wide spectrum of tumors, including human large bowel cancer and are not confined to tumors of neurogenic origin as suggested by earlier workers. In addition, evidence is suggestive of an association between the lack of differentiation and the presence of double minutes, but further data are required to substantiate this.

Tumour associated antigens in polyps and carcinoma of the human large bowel

Eight metaplastic polyps, 16 tubulo-villous adenomas and 20 adenocarcinomas, all from the colon, were examined for the presence of a number of tumour associated antigens. Specific antibodies, raised in rabbits, were used to detect the antigens in formalin fixed (pH 7.0) paraffin embedded material. Antisera were directed against carcino-embryonic antigen (CEA), colon specific antigen (M. Wt) (CSA), α-fetoprotein, pregnancy specific β-lipoprotein 1 (SP 1), human β-chorionic gonadotrophin (HCG), human placental lactogen (HPL), and placental alkaline phosphatase (P Alk P). Antisera against isoferritins, reported in some non-gastrointestinal tumours and transferrin, normally found in small intestinal epithelium were also used. Specificity of antibodies was checked in other systems (RIA and immunodiffusion plates) and using appropriate fixed substrate tissues in the P.A.P. technique. Detection and localization of antigens in tissues was made using the P.A.P. (peroxidase-antiperoxidase) enzyme bridge immunohistochemical method. Results are shown in Tables 1 and 2. Placental alkaline phosphatase was found in only 2 specimens and is not included in the tables. Table 1 Antigen No. cases Condition 0 1 2 3 4 5 6 7 16 TVA 1 3 1 3 1 1 1 6 20 Cancers 0 2 2 0 1 3 3 9 8 Metaplastic polyps 0 1 5 0 0 0 0 2 Table 2 Antigen No. cases Condition SPI HPL βHGG CEA CSA AFP Transfer Ferrit 16 TVA 6 11 10 16 14 9 9 9 20 Cancers 12 9 10 20 20 12 13 10 8 Metaplastic polyps 2 7 2 8 7 2 2 2 There appears to be no difference in either number of antigens present, or in the number of cases positive for each antigen, between cancers and tubulo-villous adenomas, but the majority of metaplastic polyps show only CEA and HPL positivity. The 2 metaplastic polyps showing a full range of positivity were atypical in that they were greater than 5 mm in diameter and had some features of adenomatous polyps, although they appeared as typical metaplastic polyps to an experienced gastrointestinal surgeon. The findings have shown a remarkable similarity between polyps and cancer which strengthens the concept of the relationship between adenomatous polyps and carcinoma of the colon, but have revealed no definite antigenic marker of malignant transformation. It would appear that the difference in behaviour is not related to antigenic profile. Despite the literature stressing the benign nature of metaplastic polyps, a more cautious appraisal of those above 5 mm diameter may be indicated.