Human colorectal cancers with an intact p16/cyclin D1/pRb pathway have up-regulated p16 expression and decreased proliferation in small invasive tumor clusters.

A systematic spatial heterogeneity with high proliferative activity at the luminal border and low activity at the invasive margin is an unexpected behavior that has been observed in colorectal cancer (CRC). To clarify this phenomenon and possible underlying regulatory mechanisms, we have by immunohistochemistry elucidated the proliferative activity and the expression of G1/S regulatory proteins in small and large tumor cell clusters at the invasive margin in 97 CRCs. By identifying small tumor clusters at the tumor front, actually invading cancer cells could be characterized and analyzed separately. These cells could then be compared with the main tumor mass represented by the larger tumor clusters. The proliferation was significantly lower in small tumor clusters compared with larger clusters (P < 0.001) and the decrease in proliferation was correlated with a p16 up-regulation (r(s) = -0.41, P < 0.001). Interestingly, CRCs lacking p16 expression (18%) or tumors with other aberrations in the p16/cyclin D1/pRb pathway had a less pronounced decrease in proliferation between large and small clusters (P < 0.001), further strengthening the association between p16 and ceased proliferation at the invasive margin. This contrasts to tumors with low p27 or abnormal p53 levels showing sustained proliferation in small tumor clusters. Our findings imply that invading CRC cells generally have low proliferative activity, and this phenomenon seems to be mediated through p16 and the p16/cyclin D1/pRb pathway.

Eighteen-year surveillance of dysplasia-associated lesion in ulcerative colitis.

The case of a 65 year old patient with ulcerative colitis is reported, who had a dysplasia-associated lesion or mass (DALM) in her rectum. Refusing surgery after detection of the lesion and on follow-up, she underwent surgery only 18 years later when frank carcinoma (Dukes C) was detected. Even if DALM may take a variable course, surgical excision is still highly recommended.

DNA aneuploidy as a marker of premalignancy in surveillance of patients with ulcerative colitis.

BACKGROUND: Patients with ulcerative colitis have an increased risk of developing colorectal cancer. Specific and sensitive markers for premalignancy are needed. The present study evaluates the status of DNA aneuploidy (abnormal stemlines) as such a marker. METHODS: A prospective surveillance programme was conducted for all patients with ulcerative colitis from a defined area. Regular colonoscopy with mucosal sampling for histological evaluation and flow cytometric DNA analysis was performed. Some 147 patients were studied from 1984 to 1997. RESULTS: DNA aneuploidy was found in 20 patients. All but one had total colitis. The time from onset of disease to aneuploidy ranged from 5 to 31 years. Fourteen of the patients developed morphological alterations. In the same interval 127 patients, of whom 75 had total colitis, did not develop aneuploidy. Among patients with morphological alterations and aneuploidy, aneuploidy preceded these alterations in four patients and was present at the same examination in three; in seven patients the morphological alterations preceded the aneuploidy. Aneuploidy was diagnosed before the appearance of a dysplasia- associated lesion or mass in four of five cases. CONCLUSION: Flow cytometric DNA analysis has definite value as a complement to histological examinations in cancer surveillance of patients with ulcerative colitis. Aneuploidy indicates a high risk for developing severe premalignant changes. However, there is no evidence to support the use of DNA aneuploidy as a sole indication for prophylactic surgery against cancer.

Low tumour cell proliferation at the invasive margin is associated with a poor prognosis in Dukes' stage B colorectal cancers.

The conflicting results about the prognostic impact of tumour cell proliferation in colorectal cancer might be explained by the heterogeneity observed within these tumours. We have investigated whether a systematic spatial heterogeneity exists between different compartments, and whether the presence of such a systematic heterogeneity has any impact on survival. Fifty-six Dukes' stage B colorectal cancers were carefully morphometrically quantified with respect to the immunohistochemical expression of the proliferative marker Ki-67 at both the luminal border and the invasive margin. The proliferative activity was significantly higher at the luminal border compared with the invasive margin (P<0.001), although the two compartments were also significantly correlated with each other. Tumours with low proliferation at the invasive margin had a significantly poorer prognosis both in univariate (P = 0.014) and in multivariate survival analyses (P = 0.042). We conclude that Dukes' B colorectal cancers exhibit a systematic spatial heterogeneity with respect to proliferation, and tumours with low proliferation at the invasive margin had a poor prognosis. The present data independently confirm recent results from the authors, and provide new insights into the understanding of tumour cell proliferation in colorectal cancer.

Systematic heterogeneity and prognostic significance of cell proliferation in colorectal cancer.

The prognosis of colorectal cancer has not significantly changed during the last 30 years. While evaluation of tumour cell proliferation may provide prognostic information, results obtained so far have been contradictory Heterogeneity in tumour cell proliferation may explain these contradictions. With in vivo injection of iododeoxyuridine (IdUrd), estimation of labelling index (LI), S-phase transit time (Ts) and potential doubling time (Tpot) may be performed from a single sample. A total of 109 colorectal cancers were studied after in vivo injection of IdUrd before surgical removal. From each cancer, four to eight samples were processed for both flow cytometrical (FCM) and immunohistochemical (IHC) visualization of IdUrd incorporation. LI/IHC was morphometrically quantified at both the luminal border and the invasive margin of these tumours. LI was significantly higher at the luminal border compared with the invasive margin, although they were correlated with each other. Using combined IHC and FCM methods, rapidly growing colorectal cancers (high LI and/or low Tpot) showed an increased survival (significant for LI at the invasive margin and for Tpot at both the invasive margin and the luminal border) in the entire unselected material and for radically removed Dukes' B tumours. FCM data alone did not discriminate for survival, with the exception of Ts in diploid and radically removed Dukes' B tumours.

Tendon arthroplasty for treatment of trapeziometacarpal arthrosis.

Trapeziometacarpal arthrosis is common among middle-aged women, and the surgical treatment options include arthrodesis, excision of the trapezium, prosthetic replacement of the trapezium, reconstruction of the ligaments, and various tendoplasties. We have prospectively studied a simple tendoplasty in which a strip of abductor pollicis longus tendon was anchored to the flexor carpi radialis tendon, the intact part of the abductor pollicis tendon, and the joint capsule, after excision of the trapezium, and carried out 27 operations in 25 patients. The thumb was immobilised for only eight days. Systematic exercises were started on the day of operation. Complete pain relief was obtained in 17 patients and partial relief in eight. Grip strength improved. The mobility was unaltered and functionally satisfactory. Three patients were reoperated on for cutaneous nerve entrapment and one for carpal tunnel syndrome. The procedure is simple, and the patients' symptoms improved without failures. The intensive supervised postoperative physiotherapy was essential to achieve the final results.

Assessment profiles of disease severity in ulcerative colitis.

There is no general agreement as to which activity profile or activity is preferable for the clinical assessment of ulcerative colitis. Examples of qualitative and quantitative indices are given. Most of the latter include clinical data, macroscopic evaluation at endoscopy and histological grading of inflammation. It is proposed that the activity of the disease, reflected by the patient's symptoms, might be the determinant of the treatment, and the severity of the disease, defined by objective means, could be assessed in scientific evaluation.

Normal plasminogen activator inhibitor levels at long-term follow-up after jejuno-ileal bypass surgery in morbidly obese individuals.

Forty-five patients who had been subjected to jejuno-ileal bypass (JIB) surgery for morbid obesity and 10 obese nonsurgery subjects were studied. The former group was examined 14 to 20 years after surgery, and was found to have lower mean plasminogen activator inhibitor type 1 (PAI-1) activity (8.4 v 32 U/mL, P < .001), tissue plasminogen activator (tPA) antigen concentrations (7.2 v 12 micrograms/L, P < .01), body mass index (BMI), and fasting plasma insulin, triglyceride, and cholesterol levels. The PAI-1 levels were correlated with BMI, waist to hip ratio, and insulin, triglyceride, and cholesterol levels. Thus, previously obese subjects have normal PAI levels 14 to 20 years after treatment with JIB surgery, in contrast to the high PAI-1 levels in nonsurgery obese subjects.

Ulcerative colitis. Colorectal cancer risk in an unselected population.

One hundred twenty-seven patients were studied, representing the unselected population of patients with ulcerative colitis from a defined catchment area of about 70,000 inhabitants during 1961-1983. Seventy-seven patients had total colitis, and 50 patients had left-sided colitis. No prophylactic colectomy was performed. Despite this and a comprehensive follow-up of patients with long-standing, extensive colitis, primary colorectal carcinomas were diagnosed in only three patients, all of whom had total colitis. This was significantly (p less than 0.001) more than the expected number of patients with colorectal cancer in this subgroup, namely, 0.13. There were no deaths in colorectal carcinoma. Factors determining completeness of inclusion are discussed, and it is concluded that, in an unselected series of patients with ulcerative colitis, close cancer surveillance is indicated, although prophylactic surgery does not seem to be generally warranted.