Carcinoma Of Large Bowel Research Articles

Near diploid large bowel carcinomas have better five-year survival than aneuploid ones

One hundred patients who underwent surgery for large bowel carcinoma between 1978 and 1982 were examined by flow cytometric DNA quantitation of fresh tumor specimens and divided into an aneuploid (AN) group of 63 and a near diploid (ND) one of 37. All patients were followed until death (n = 63) or until December 31, 1988. Forty-one patients (65%) with AN tumors died of cancer, as did 12 patients (32%) with ND carcinomas. Thus patients with ND tumors had a better survival rate (P = 0.04) than did those with AN ones. The difference was apparent in Dukes' Stages A, B, and C, but not in Stage D. All patients with tumors in this stage died from their carcinomas irrespective of ploidy group. Multiple regression analyses (Cox) of prognostic factors revealed that the most important prognostic variables were (in descending order) Dukes' Stage D, Dukes' Stage C, and DNA ploidy pattern. Histologic grade was not significant as an independent prognostic variable. These results indicate that the presence of a distinctly aneuploid DNA ploidy pattern in large bowel carcinoma is an important prognostic variable that worsens survival rates significantly.

Investigation of colonic prostaglandins in carcinogenesis in the rat colon

Large bowel carcinoma was induced in rats by injecting MNNG intrarectally, and changes in the large bowel mucosa prostaglandin (PG) with time were determined. The PGE2 levels of the colonic mucosa in a control group were 20.9 +/- 9.7 (pg/mg total protein) at 5 weeks, 25.5 +/- 9.7 at 10 weeks, 26.5 +/- 18.1 at 20 weeks, and 34.8 +/- 12.7 at 40 weeks. The PGE2 levels in the MNNG-treated group were 44.7 +/- 6.2 at 5 weeks, 43.1 +/- 14.9 at 10 weeks, 70.1 +/- 23.4 at 20 weeks, and 79.7 +/- 54.1 at 40 weeks. The intrinsic PGE2 levels of the noncancerous mucosa were thus significantly higher for the MNNG group than for the control group at all weeks. At 40 weeks, the PGE2 levels of cancer lesions were significantly high compared with those of the noncancerous area. In the cancerous lesions, 6-keto-PGF1 alpha and PGF2 alpha decreased and TXB2 increased significantly at 40 weeks. The observations demonstrated that PGE2 was implicated as a promoter in the development and proliferation of carcinoma in MNNG-induced large bowel carcinogenesis in rats.

Nuclear shape as a prognostic discriminant in colorectal carcinoma

In search for a more reliable prognostic discriminant, a retrospective analysis of 100 cases of colorectal carcinoma having undergone curative resection and followed for at least 5 years were assessed by nuclear morphometry. Each case was staged according to the Dukes' classification as well as graded histologically. For all patients in this series, the perimeter, area, and nuclear shape factor of 50 interphase nuclei were determined for each carcinoma. The information was obtained through the use of an image analysis system by tracing the nuclear profiles (magnification 1000x) as digitized on a video screen. The nuclear shape factor was defined as the degree of circularity of the nucleus, a perfect circle recorded as 1.0. A nuclear shape factor greater than 0.84 was associated with poor outcome. Multiple regression models showed that the single nuclear parameter of the shape factor was the most highly significant predictor of survival (P less than 0.0001). This variable remained highly significant even when corrected for sex, age, histologic grade, and Dukes' classification. These findings indicate that a nuclear shape factor greater than or equal to 0.84 as determined by nuclear morphometry is an independent morphometric nuclear variable of great importance in the prognosis of large bowel carcinoma.

Surgical Treatment and Prognosis of Obstructed and Perforated Large Bowel Carcinoma

Surgical Treatment and Prognosis of Obstructed and Perforated Large Bowel Carcinoma

Stomal adenocarcinoma in Crohn's disease.

Malignant change occurring at the site of a stoma in two patients with proved Crohn's disease is described. Patients with ulcerative colitis have an increased risk of colonic malignancy and Crohn's disease is also associated with both small and large bowel carcinoma. Most previous reports of stomal carcinoma have been associated with ulcerative colitis although Crohn's disease seems to carry a greater risk of associated small bowel carcinomas. This is the first report of stomal carcinoma complicating Crohn's disease. Epithelial dysplasia is associated with gastrointestinal carcinomas in both ulcerative colitis and Crohn's disease and a dysplasia-carcinoma sequence has been suggested as the origin of these tumours. In both our patients with stomal adenocarcinoma, dysplasia was identified in adjacent tissues, which suggests a similar mechanism. Malignant change should be suspected if epithelial dysplasia is discovered in a biopsy specimen from the mucosa of an ileostomy in Crohn's disease, and this risk is increased if the dysplasia is of a high grade.

Tissue carcinoembryonic antigen and dna aneuploidy in precancerous and cancerous colorectal lesions

Chronic inflammatory bowel disease (CIBD) and colorectal adenoma are considered as precancerous conditions and lesions of large bowel carcinoma, respectively. They, therefore, may be used to study the behavior of such different factors as tumor-associated antigens and nuclear DNA content abnormalities in colorectal carcinogenesis. Tissue concentrations of carcinoembryonic antigen (CEA) were significantly higher in those precancerous lesions (CIBD: 61 +/- 11.2 ng/mg, adenoma: 70 +/- 6 ng/mg; mean +/- standard error of the mean) than in normal colonic mucosa (36 +/- 4.7 ng/mg). Colorectal carcinoma had still higher tissue levels (437 +/- 108.2 ng/mg). No correlation between tissue CEA and tumor differentiation could be found, but there was a significant difference between aneuploid (747 +/- 354 ng/mg) and diploid (139 +/- 43 ng/mg) tumors. Using flow cytometry DNA aneuploidy was present in 31.6%, 10.5%, and 51.6% of CIBD, colorectal adenoma, and carcinoma, respectively. These data suggest that the occurrence of aneuploidy is not strongly dependent on a malignant transformation, but it may also be present in premalignant colorectal lesions without cellular dysplasia.

A prospective cohort study on the development of colorectal cancer after gastrectomy

A prospective cohort study was conducted to examine whether an association exists between gastric surgery and the subsequent development of colorectal carcinoma. One thousand nine hundred twenty-seven patients (1316 men and 611 women) who had undergone curative gastrectomy for gastroduodenal diseases in the First Department of Surgery, Tottori University Hospital, during the 18-year period from 1964 to 1981, were followed to determine the incidence of the development of large-bowel carcinoma after gastric surgery. The age-, sex-, and calendar-specific population at risk was calculated by the person-years method. The observed number of colorectal cancers after gastrectomy was 19 (15 men, 4 women) compared with 9.69 expected carcinomas. The difference between the observed and expected numbers was statistically significant. The authors believe that patients with previous gastrectomy are at high risk for colorectal carcinoma.

大腸癌によるイレウス症例の検討 臨床病理学的特徴と治療法を中心に

過去12年間に経験した原発性大腸癌944例のうちイレウス症状を呈した87例 (9.2%) を非イレウス症例と臨床的および病理学的に対比検討した.イレウス症例はDukes C, Dの進行例が多く, 治癒切除率は59%にとどまった.治癒切除例の5年生存率は結腸64%, 直腸38%で, いずれも非イレウス症例より不良であった, 右側大腸癌イレウス症例の68%は待期手術が施行され, 緊急手術例のほとんどで一期的切除吻合が行われた.一方左側大腸癌イレウス症例の85%には緊急手術が施行され, その69%で一時的人工肛門造設に続く段階的切除が行われた.緊急に一期的切除を施行した症例ではリンパ節郭清の程度が低かったのに対して, 段階的切除例ではリンパ節郭清が不十分であったために非治癒切除となった症例はなく, 治癒切除率も段階的切除例で一期的切除例よりも高かったことより, 左側大腸癌イレウスに対する治療として段階的切除は妥当であると考えられた.

大腸癌の発生母地と発育進展について

当科で経験した早期大腸癌と実験大腸腫瘍を病理組織学的に検討し, 大腸癌の発生母地, 発育進展について考察を加えた.早期大腸癌32病変, 実験大腸腫瘍34病変を対象とした.腺腫を有する早期大腸癌は21病変を占め肉眼形態はすべて隆起型であった.2.0cm未満のものはすべてm癌であった.径が大きくなるにつれ sm癌が多くなった.腺腫を伴わない早期大腸癌は11病変を占めた.陥凹型が3病変にみられ, 肉眼形態と壁深達度との間には特別な関係はみられなかった.腺腫を有する早期大腸癌とは逆に2.0cm未満のものがすべてsm 癌であった.実験大腸腫瘍では18病変が癌であった.肉眼形態はすべて隆起型で径の小さなものは腺腫, 大きなものは癌であった.腺腫と癌を合併したものはみられなかった.以上より腺腫を伴わない早期大腸癌や実験大腸癌の大部分が de novo 発生と考えられた.

Effect of polarity and differentiation on antibody localization in multicellular tumour spheroid and xenograft models and its potential importance for in vivo immunotargeting.

Two monoclonal antibodies (MAbs) AUAI and HMFGI recognize antigens located on different membrane domains of polarized epithelial cells. We have assessed the accessibility of these antigens in multicellular tumour spheroids produced in culture using a well-polarized (HRA-19) and a non-polarized cell line (LoVo) of human large-bowel carcinoma origin. Multicellular spheroids of HRA-19 cells develop polarity, so that the membrane which is in contact with the culture medium (apical) becomes antigenically distinct from the membrane facing the centre of the spheroids (basolateral). This was confirmed by immunostaining sections of spheroids with 2 MAbs, AUAI and HMFGI. AUAI recognizes an antigen located exclusively on the basolateral membranes of polarized epithelial cells, and stained only internal membranes in spheroid sections. Conversely HMFGI, which recognizes an antigen located on the apical membranes, stained only the periphery of the spheroids. These 2MAbs were then radiolabelled with 125I and incubated with live spheroids for 4 hr at 37 degrees C. Autoradiographs of spheroid sections showed a marked difference between the 2 MAbs. 125I-HMFGI-radioantibody localized exclusively on the spheroid surface in a pattern identical to the in vitro immunostaining pattern, while 125I-AUAI radioantibody showed no binding in spite of the uniform presence of antigen on all tumour cells basolaterally. This appeared to be the result of the inaccessibility of basolateral antigenic sites in well-polarized epithelial cells because of the tight junctions connecting these cells at their apical surfaces. In contrast to the HRA-19 cell line LoVo, spheroids do not develop polarity; as a result, when stained with AUAI, variable antigenic expression all over the cell surface was seen. Autoradiographs of these spheroids showed 125I-AUAI binding with a penetration to a depth of about 1-3 cells, while HMFGI which shows no reactivity with this cell line in vitro, did not bind. This phenomenon was further investigated in xenografts of the HRA-19 cell line. It was shown that in a well-differentiated adenocarcinoma where the tumour cells forming acini are arranged in a polarized fashion, the luminal antigenic sites may be inaccessible to the injected MAb. The striking differences in binding of MAbs on polarized and unpolarized tumours indicate the importance of cell polarization and exact location of antigenic sites for in vivo immunotargeting.

Effect of OK-432 on large-bowel carcinogenesis in rats

To examine the carcinogenetic and growth inhibitory effects of OK-432, large-bowel carcinoma was induced experimentally in rats by intrarectal injection of N-methyl-N-nitrosourea (MNU), and OK-432 was administered intradermally. Rats were sacrificed after six months and the large intestine was cut into serial sections. Histopathologic examination and analysis of the infiltrating mononuclear cells, using monoclonal antibodies, were performed. The average rate of carcinogenesis per rat was 15.7 +/- 8.5 in the MNU alone group (n = 10) and 8.3 +/- 3.5 in the MNU and OK-432 group (n = 6). The invasion was deeper than the muscularis propria in 16 out of 157 lesions (10.2 percent) in the MNU alone group and in one out of 50 lesions in the MNU + OK-432 group (2.0 percent) (P less than 0.05). When time of appearance of atypical glands or carcinomas were compared in the MNU alone and MNU + OK-432 group, carcinogenesis was found to be delayed in the MNU + OK-432 group. In the investigation of infiltrating mononuclear cells using monoclonal antibodies, there were increases in helper T cells in both the MNU alone and MNU + OK-432 groups, but there was little difference between the two groups. The results of this study suggest that the suppression of experimental carcinogenesis in the large bowel by the concomitant administration of OK-432 with MNU, may be due to the enhanced activation or prolonged activated state of immunocompetent cells, which appear via antigen recognition, by OK-432.

Prognostic significance of DNA content in large bowel carcinoma: a retrospective flow cytometric study.

Flow cytometric (FCM) determination of DNA content was performed on surgical specimens from 44 patients with previously untreated colonic carcinoma. For each tumor, cell suspensions were prepared from 2-4 40-microns thick sections obtained from formalin-fixed and paraffin embedded tissue samples. Aneuploidy was found in 47.2% of all the tumors and the aneuploid clone had a median DNA index of 1.49 (range: 1.24-1.93). Aneuploidy was found in 26.7% of highly differentiated tumors (WHO histologic classification), in 53.8% of moderately differentiated tumors and in 100% of poorly differentiated tumors (P = 0.04). The 33.3% of stages 1 + 2 (TNM) and the 70.6% of stages 3 + 4 tumors were aneuploid (P = 0.002). Median survival from surgery was 46.4 months for all patients. It was 18.8 months for patients with aneuploid tumors and 85.7 months for those with diploid tumors (P = 0.0002). FCM determination of DNA in colon carcinomas can easily be performed on archival histological material and provides prognostic information.

Management of obstructed and perforated large bowel carcinoma

Obstructed large bowel carcinoma is a disease of the aged, often with concomitant disease and also advanced malignancy. The immediate mortality rate of operation is high and long-term prognosis is poor in comparison with elective surgery. It is important before operation that the diagnosis be established by sigmoidoscopy and emergency contrast studies. Staged procedures based on considerations of safety have given way to immediate resection. For right-sided colonic obstruction immediate resection and anastomosis is now almost universal and for left-sided tumours primary resection has overtaken staged resection in the UK. An anticipated survival advantage for primary resection has not, however, been confirmed. Obstruction complicated by perforation is an absolute indication for resection. After left-sided resection, making an anastomosis is associated with higher risk of leakage than after an elective operation. In the most adverse circumstances of associated sepsis, Hartmann's operation retains its place but immediate anastomosis is the most frequent option for many. Additional manoeuvres to make this safe include peroperative antegrade colonic irrigation and subtotal colectomy, although segmental resection with anastomosis and without bowel preparation is also practised and may be safe in selected patients. When major resectional surgery is undertaken in aged patients at high risk of mortality, the rule that the operator should be fully trained in elective large bowel surgery is incontrovertible. It is at least equally important that the anaesthetist is experienced and capable of instituting, interpreting and acting upon sophisticated cardiopulmonary monitoring.

Phase I study of recombinant human tumor necrosis factor alpha in advanced malignant disease.

A phase I study with recombinant human tumor necrosis factor alpha (rhuTNF-alpha; Knoll AG, Ludwigshafen, FRG) in patients with advanced malignant disease was undertaken to evaluate drug toxicity (organ specificity, time course, predictability, reversibility, maximal tolerated dose), effectiveness, antigenicity and pharmacokinetics. TNF was administered as a test dose followed by daily i.v. infusions for 5 days, every 3 weeks (single i.v. infusion lasting 10 min, TNF dissolved in 50 ml 5% human albumin). Dosage was increased in groups of 3 or 4 patients from 0.04 mg/m2 to 0.28 mg/m2. A total of 19 patients with different cancers, including seven large-bowel carcinomas, three chronic myelogenous leukemias, three hypernephromas, two small-cell lung cancers, one malignant melanoma, one malignant lymphoma, one rhabdomyosarcoma and one fibrosarcoma were treated. Major side-effects were chills and fever (maximum 40.4 degrees C, median 38.7 degrees C, 19/19), headache (12/19), nausea and vomiting (12/19) and pronounced (greater than 20%) hypotension (4/19). Acute side-effects could be diminished by paracetamol or indomethacin pretreatment, and with one possible exception no tachyphylaxis to TNF was noted. Mild renal toxicity was seen during TNF treatment. Pharmacokinetic studies showed a serum half-life (t1/2) ranging from 11 min to 17 min for doses from 0.04 mg/m2 to 0.16 mg/m2 and prolonged clearance with t1/2 ranging from 54 min to 70 min in the 0.20-0.28 mg/m2 dose range. No objective antitumor effects were observed in this phase I study.

Crohnʼs Disease-Associated Carcinoma

We have reviewed eight cases of Crohn's disease associated carcinoma (CDAC) of the bowel treated at Saint Barnabas Medical Center since 1977. Five patients had colorectal carcinoma in areas of dysplasia within histologically recognizable Crohn's disease. One of the large bowel carcinomas was a diffusely infiltrating signet ring adenocarcinoma (linitis plastica), three were mucinous carcinomas, and one contained both cell types. Survival ranged from 4 to 55 months. Three patients developed ileal carcinomas in areas of dysplasia within histologically recognizable Crohn's disease. One of the ileal cancers was a moderately differentiated adenocarcinoma; two were poorly differentiated adenocarcinomas. Survival ranged from 8 to 44 months. The dysplastic changes seen in the bowel adjacent to the tumors in these patients were identical to the characteristic pre-cancerous (dysplastic) changes well described in ulcerative colitis. The histopathologic changes seen in this high-risk group of patients are also similar to those of previously reported CDAC. Those patients with the more diffuse dysplastic changes might have been detected before the development of invasive cancer had they undergone periodic colonoscopic surveillance. One patient in the series with an asymptomatic lesion was, in fact, identified at surveillance colonoscopy. It would appear that Crohn's disease patients have a similar risk for carcinoma previously recognized in ulcerative colitis patients and that surveillance protocols should be developed for this group of patients.

Results of a Television-Advertised Public Screening Program for Colorectal Cancer

We report the results of a free, television-advertised mass screening program for colorectal cancer using stool guaiac kits. A total of 57,000 test kits were picked up and 29,619 (53%) were returned; 3.9% (1165) of the tests were positive. Ninety-three percent of persons with a positive screen sought medical evaluation after screening. Detailed follow-up was available on 744 persons. Fifty-eight persons had large-bowel carcinomas diagnosed, 80% of which were localized. One hundred sixty persons had adenomatous polyps removed. Forty percent of cancers and 58% of polyps were detected in persons with only one or two positive test slides out of a total of six. In 33% of persons with a positive screen, the diagnostic workup consisted of a repeated stool guaiac test and/or sigmoidoscopy only. A major drawback to improving the results of mass screening programs for colorectal cancer is the limited gastrointestinal workup conducted by physicians in many persons with a positive fecal occult blood test.

CEA, tumour differentiation and DNA ploidy pattern.

The histological growth pattern of large bowel carcinomas is probably of importance for CEA secretion, since it is demonstrated that moderately differentiated carcinomas have the highest plasma CEA levels. Moderately differentiated carcinomas might thus, because of their glandular architecture, secrete a larger proportion of CEA into the gut lumen than poorly differentiated ones. Nevertheless, of the biological variables investigated in relation to plasma CEA, determination of tumour DNA ploidy has turned out to be of the greatest significance in our laboratory. We suggest therefore, that combined evaluation of the preoperative plasma CEA level and tumour DNA ploidy may aid in the selection of patients who should be followed up with repeated plasma CEA measurements after potentially curative large bowel resection.

Colorectal cancer in patients with family history.

The relationship between first degree family history of colorectal cancer and some pathological and clinical features was investigated in 302 patients affected by large bowel carcinoma. Patients with inherited forms of polyposis of the large bowel were excluded. Thirty-six (11.9%) had at least one close relative affected by intestinal cancer. No relationship between family history and pathological features (anatomic distribution, stage and grading) was found. Moreover no difference in prognosis between patients with a family history and those without was shown. These results suggest no relationship between a first degree family history and the natural history of the disease.

Survival of large bowel carcinoma patients with different DNA ploidy.

One hundred patients operated for large bowel carcinoma were divided into a distinct aneuploid group of 63, and a near diploid one of 37. Flow cytometry was used for determination of the DNA ploidy pattern. All tumours in the aneuploid group contained one or more aneuploid cell populations. All patients were followed clinically from 3.5 to 7.8 years. The corrected 5 year survival was 64% and 49% for patients with near diploid and aneuploid tumours, respectively (not significant). Significant differences in corrected survival time were not observed for Dukes' stages A, B, and C patients pooled, nor for Dukes' stage D patients. However, for Dukes' stage C patients alone, there was a tendency (P = 0.10) for patients with near diploid tumours to show a better survival. A highly significant predominance of aneuploid tumours was seen in males, in contrast to an equal distribution of aneuploid and near diploid tumours in females. A slight predominance of aneuploid tumours in the left colon and rectum was seen. Both these findings indicate the influence of environmental factors (hormonal, anatomical, phenotypical) on the development of tumours with a particular DNA ploidy pattern.

Human chorionic gonadotropin in colorectal carcinoma. An immunohistochemical study.

To assess the biological significance of human chorionic gonadotropin (HCG) detection in large bowel carcinomas, we have studied immunohistochemically 50 colorectal carcinomas, 20 adenomas, 8 ulcerative colitis, and 10 normal colonic mucosae. The HCG-immunoreactive cells were found in 26 carcinomas (52%). Positivity was not detected in any normal mucosa or benign lesions. Cells containing HCG predominated in mucinous (80%) and poorly differentiated carcinomas (92%). No trophoblastic differentiation could be demonstrated in any tumor. Human chorionic gonadotropin was detected more frequently in carcinomas invading the entire bowel wall (67%) than in those confined to the submucosa or muscularis propria (30%). Fifteen of 19 cases (79%) with lymph node and/or hepatic metastases had HCG in the primary tumor, whereas only 9 of 23 cases (32%) without metastases showed HCG immunoreactivity. The eight patients with hepatic metastases had HCG in the primary tumor. Thus, the immunohistochemical detection of HCG in colorectal carcinomas may be a biological marker of prognostic significance.