A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. National Polyp Study Work Group.

BACKGROUND: After patients have undergone colonoscopic polypectomy, it is uncertain whether colonoscopic examination or a barium enema is the better method of surveillance. METHODS: As part of the National Polyp Study, we offered colonoscopic examination and double-contrast barium enema for surveillance to patients with newly diagnosed adenomatous polyps. Although barium enema was performed first, the endoscopist did not know the results. RESULTS: A total of 973 patients underwent one or more colonoscopic examinations for surveillance. In the case of 580 of these patients, we performed 862 paired colonoscopic examinations and barium-enema examinations that met the requirements of the protocol. The findings on barium enema were positive in 222 (26 percent) of the paired examinations, including 139 of the 392 colonoscopic examinations in which one or more polyps were detected (rate of detection, 35 percent; 95 percent confidence interval, 31 to 40 percent). The proportion of examinations in which adenomatous polyps were detected by barium enema colonoscopy was significantly related to the size of the adenomas (P=0.009); the rate was 32 percent for colonoscopic examinations in which the largest adenomas detected were 0.5 cm or less, 53 percent for those in which the largest adenomas detected were 0.6 to 1.0 cm, and 48 percent for those in which the largest adenomas detected exceeded 1.0 cm. Among the 139 paired examinations with positive results on barium enema and negative results on colonoscopic examination in the same location, 19 additional polyps, 12 of which were adenomas, were detected on colonoscopic reexamination. CONCLUSIONS: In patients who have undergone colonoscopic polypectomy, colonoscopic examination is a more effective method of surveillance than double-contrast barium enema.

Human MDR 1 protein overexpression delays the apoptotic cascade in Chinese hamster ovary fibroblasts.

Several laboratories have reported that overexpression of the multidrug resistance (MDR) protein is associated with intracellular alkalinization, and several investigators have reported that cells induced to undergo programmed cell death (apoptosis) acidify quite significantly. Because it is difficult to fully explain the resistance to apoptosis-inducing chemotherapeutic drugs that is exhibited by MDR tumor cells solely via altered drug transport alone [Hoffman et al. (1996) J. Gen. Physiol. 108, 295-313], we have investigated whether overexpression of the hu MDR 1 protein alters progression of the apoptotic cascade. LR73 fibroblasts induced to undergo apoptosis either via treatment with the chemotherapeutic drug colchicine or by serum withdrawal exhibit cellular volume changes, intracellular acidification, nuclear condensation, and chromosomal digestion ("ladder formation"), characteristic of apoptosis, in a temporally well-defined pattern. However, multidrug resistant LR73/20E or LR73/27 hu MDR 1 transfectants recently created in our laboratory without selection on chemotherapeutic drug are significantly delayed in the onset of apoptosis as defined by the above criteria, regardless of whether apoptosis is induced by colchicine treatment or by serum withdrawal. Thus, the delay cannot simply be due to the well-known ability of MDR protein overexpression to lower chemotherapeutic drug accumulation in MDR cells. LR73/27V500 "selectants", exhibiting similar levels of MDR protein overexpression but higher multidrug resistance due to selection with the chemotherapeutic drug vincristine, exhibit a slightly longer delay in the progression of apoptosis. Normal apoptotic cascade kinetics are partially restored by pre-treatment of the MDR cells with the MDR protein inhibitor verapamil. Untransfected LR73 cells not expressing MDR protein but elevated in pHi via manipulation of CO2/HCO3- as described [Hoffman et al. (1996) J. Gen. Physiol. 108, 295-313] are inhibited in DNA ladder formation, similar to LR73/hu MDR 1 transfectants. These results uncover an additional mechanism whereby MDR protein overexpression may promote the survival of tumor cells and further support the notion that in some systems intracellular acidification may be either causal or permissive for proper progression of the apoptotic cascade.

Metastatic adenocarcinoma involving a mesothelial/monocytic incidental cardiac excrescence (cardiac MICE)

Mesothelial/monocytic incidental cardiac excrescence (MICE) is a recently described, peculiar microscopic finding in the endocardium or pericardium. These lesions are characterized by a mixture of mesothelial cell clusters and histiocytes, aggregated by fibrin. They have been interpreted as reactive or even artifactual, and the importance of distinguishing these aggregations from metastatic carcinoma has been emphasized. We report a unique case of a MICE that was seeded by clusters of metastatic adenocarcinoma cells. The patient was a 38-year-old woman with no history of previous cardiac instrumentation who was found to have an adenocarcinoma of the right lung involving the hilus but apparently not invading the pericardium. At surgery, a small fragment of tissue was found floating in the pericardial cavity, and microscopic examination revealed a cluster of histiocytes, mesothelial cells and fibrin (components of usual, benign MICE) in which rare pleomorphic adenocarcinoma cells were scattered. Unlike the surrounding mesothelial cells and histiocytes, the pleomorphic cells stained for carcinoembryonic antigen, epithelial membrane antigen, and BerEP4 and focally produced intracellular mucin, confirming their malignant glandular nature. It is possible that the surrounding mesothelial cells, histiocytes, and fibrin were formed in response to invasion of the pericardial space by adenocarcinoma. This case indicates that not all lesions with the characteristic architecture of MICE can be dismissed as non-neoplastic without careful evaluation of both the cellular constituents and the clinical circumstances.

Apoptosis induced in advanced CD8F1-murine mammary tumors by the combination of PALA, MMPR and 6AN precedes tumor regression and is preceded by ATP depletion.

The drug combination N-(phosphonacetyl)-L-aspartic acid (PALA), methylmercaptopurine riboside (MMPR) and 6-aminonicotinamide (6AN), referred to as PMA, induces regressions of advanced CD8F1 murine mammary carcinomas in vivo. We demonstrated that CD8F1 tumor regressions were preceded by the appearance of apoptotic bodies, as observed by microscopic examination of morphology and TUNEL endlabeling, and fragmentation of DNA into nucleosomal "ladder" patterns. These indications of apoptosis were present as early as 6 h after simultaneous administration of MMPR and 6AN and further increased by over fivefold during the next 3 to 6 h, then remained at 7 to 12.8% (0.6 to 2.4% in saline-treated controls) of the cell population for at least 24 h after MMPR + 6AN administration. The 5'-phosphate derivative of MMRP, MMPR-5P, which inhibits de novo purine biosynthesis, was present at a "steady-state" level, and significant (40%) depletion of ATP had occurred by 3 h and both of these events preceded the onset of apoptosis. In addition, MMPR-5P was retained in CD8F1 tumors at a high level over a prolonged period (> 96 h) even as tumors were undergoing regression. The prolonged presence of MMPR-5P was important for optimal chemotherapeutic effect, since treatment with iodotubercidin (IodoT), an inhibitor of MMPR/adenosine kinase, 6 h after MMPR+6AN administration prevented the prolonged accumulation of MMPR-5P and reversed the regression of CD8F1 tumors. In addition, compared to the PMA-treated group, there was a significant restoration of ATP levels after treatment with IodoT. In individual PMA-treated CD8F1 tumors the degree of ATP depletion was found to correlate with the degree of tumor shrinkage at 24 h, after tumors had sufficient time to respond to treatment. These results define the time-course of drug-induced apoptosis in CD8F1 tumors, show that ATP depletion occurs prior to apoptosis and demonstrate that prolonged retention of MMPR-5P is associated with optimal chemotherapy. Collectively, these results suggest that the depletion of ATP by PMA treatment may be a component of the biochemical apoptotic cascade in the CD8F1 tumor.

Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup.

BACKGROUND: The adenoma-adenocarcinoma sequence in colorectal cancer suggests an increased risk of colorectal cancer in the families of patients with adenomatous polyps. METHODS: A random sample of participants in the National Polyp Study who had newly diagnosed adenomatous polyps were interviewed for information on the history of colorectal cancer in their parents and siblings. The risk of colorectal cancer in family members was analyzed according to the characteristics of the patients with adenomas and in comparison with a sample of patients' spouses, who served as controls. RESULTS: Among the patients with adenomas, 1199 provided information on whether they had a family history of colorectal cancer. After the exclusion of families for which information was incomplete and of 48 patients who had been referred for colonoscopy solely because they had a family history of colorectal cancer, there were 1031 patients with adenomas, 1865 parents, 2381 siblings, and 1411 spouse controls. The relative risk of colorectal cancer, adjusted for the year of birth and sex, was 1.78 for the parents and siblings of the patients with adenomas as compared with the spouse controls (95 percent confidence interval, 1.18 to 2.67). The relative risk for siblings of patients in whom adenomas were diagnosed before 60 years of age was 2.59 (95 percent confidence interval, 1.46 to 4.58) as compared with the siblings of patients who were 60 or older at the time of diagnosis and after adjustment for the sibling's year of birth and sex and a parental history of colorectal cancer. The risk increased with decreasing age at the time of the diagnosis of adenoma (P for trend < 0.001). The relative risk for the siblings of patients who had a parent with colorectal cancer, as compared with those who had no parent with cancer, was 3.25 (95 percent confidence interval, 1.92 to 5.52), after adjustment for the sibling's year of birth and sex and the patient's age at diagnosis. CONCLUSIONS: Siblings and parents of patients with adenomatous polyps are at increased risk for colorectal cancer, particularly when the adenoma is diagnosed before the age of 60 or--in the case of siblings--when a parent has had colorectal cancer.

Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup.

BACKGROUND: The current practice of removing adenomatous polyps of the colon and rectum is based on the belief that this will prevent colorectal cancer. To address the hypothesis that colonoscopic polypectomy reduces the incidence of colorectal cancer, we analyzed the results of the National Polyp Study with reference to other published results. METHODS: The study cohort consisted of 1418 patients who had a complete colonoscopy during which one or more adenomas of the colon or rectum were removed. The patients subsequently underwent periodic colonoscopy during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with that in three reference groups, including two cohorts in which colonic polyps were not removed and one general-population registry, after adjustment for sex, age, and polyp size. RESULTS: Ninety-seven percent of the patients were followed clinically for a total of 8401 person-years, and 80 percent returned for one or more of their scheduled colonoscopies. Five asymptomatic early-stage colorectal cancers (malignant polyps) were detected by colonoscopy (three at three years, one at six years, and one at seven years). No symptomatic cancers were detected. The numbers of colorectal cancers expected on the basis of the rates in the three reference groups were 48.3, 43.4, and 20.7, for reductions in the incidence of colorectal cancer of 90, 88, and 76 percent, respectively (P < 0.001). CONCLUSIONS: Colonoscopic polypectomy resulted in a lower-than-expected incidence of colorectal cancer. These results support the view that colorectal adenomas progress to adenocarcinomas, as well as the current practice of searching for and removing adenomatous polyps to prevent colorectal cancer.

Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. The National Polyp Study Workgroup.

BACKGROUND: The identification and removal of adenomatous polyps and post-polypectomy surveillance are considered to be important for the control of colorectal cancer. In current practice, the intervals between colonoscopies after polypectomy are variable, often a year long, and not based on data from randomized clinical trials. We sought to determine whether follow-up colonoscopy at three years would detect important colonic lesions as well as follow-up colonoscopy at both one and three years. METHODS: Patients were eligible if they had one or more adenomas, no previous polypectomy, and a complete colonoscopy and all their polyps had been removed. They were randomly assigned to have follow-up colonoscopy at one and three years or at three years only. The two study end points were the detection of any adenoma, and the detection of adenomas with advanced pathological features (defined as those > 1 cm in diameter and those with high-grade dysplasia or invasive cancer). RESULTS: Of 2632 eligible patients, 1418 were randomly assigned to the two follow-up groups, 699 to the two-examination group and 719 to the one-examination group. The percentage of patients with adenomas in the group examined at one and three years was 41.7 percent, as compared with 32.0 percent in the group examined at three years (P = 0.006). The percentage of patients with adenomas with advanced pathological features was the same in both groups (3.3 percent). CONCLUSIONS: Colonoscopy performed three years after colonoscopic removal of adenomatous polyps detects important colonic lesions as effectively as follow-up colonoscopy after both one and three years. An interval of at least three years is recommended before follow-up colonoscopy after both one and three years. An interval of at least three years is recommended before follow-up examination after colonoscopic removal of newly diagnosed adenomatous polyps. Adoption of this recommendation nationally should reduce the cost of post-polypectomy surveillance and screening.

The National Polyp Study. Design, methods, and characteristics of patients with newly diagnosed polyps. The National Polyp Study Workgroup.

The National Polyp Study (NPS) is a multicenter prospective randomized trial designed to evaluate follow-up surveillance strategies in patients who have undergone polypectomy for the control of large bowel cancer. The study design was developed by a joint research committee from American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the American College of Gastroenterology. Subjects who met the eligibility criteria were randomized into two different treatment arms. Eligibility criteria included: removal of one or more adenomas; complete colonoscopy; no prior polypectomy, inflammatory bowel disease, or familial polyposis; and no history of colon cancer. The treatment arms consisted of a frequent follow-up (1 and 3 years after initial polypectomy) and a less frequent follow-up (3 years). Follow-up examinations included fecal occult blood tests, air-contrast barium enema, and colonoscopy. The latter was done on 9112 referred patients at the seven participating centers from November 1980 until February 1990 who had no history of polypectomy, colon cancer, familial polyposis, or inflammatory bowel disease. Of these patients, 4763 (52.3%) had no polyps; 549 (6.0%) had an invasive cancer; 776 (8.5%) had nonadenomatous polyps; 208 (2.3%) had incomplete examinations; 184 (2.0%) had other findings; and 2632 (28.9%) had one or more adenomas, of which 1418 (53.9%) were randomized to one of the two treatment arms. This article reports the background, rationale, objectives, methods, and organization of this study and includes patient characteristics on initial presentation. Future data provided by the NPS may help in the development of recommendations for surveillance guidelines for such patients. This study also provides a framework to address questions regarding the natural history of adenomas and their relationship with colorectal cancer.

Serosal cytologic study to determine free mesothelial penetration of intraperitoneal colon cancer.

BACKGROUND: The presence of complete transmural penetration with tumor cells at the free mesothelial surface in patients with intraperitoneal colon cancer is an important prognostic feature and may alter the decision regarding adjuvant chemotherapy. METHODS: In this prospective study of 65 patients, specimens obtained by scraping the serosa overlying the primary tumor mass were analyzed by routine Papanicolaou cytologic study. RESULTS: Malignant cells were present in 23.1% of patients. In 46 patients with histologic pT3 tumors (through the muscularis propria but not through serosa), serosal cytologic study results were positive in 26.1% of patients. Serosal cytologic results were positive from an area of normal colon at least 10 cm proximal or distal to the primary tumor in one patient. CONCLUSIONS: Serosal cytologic study appeared to be a simple and reliable method to detect serosal penetration and the presence of tumor cells at the mesothelial surface.

Fatal thrombocytopenia and liver failure associated with carboplatin therapy.

A patient with fatal severe thrombocytopenia and acute hepatic necrosis complicating carboplatin (JM8, CBDCA, NSC 241240) therapy is described. The patient, an 18-year-old man with acute lymphocytic leukemia, was given high-dose carboplatin as a part of a phase I trial of this agent for the treatment of leukemia. Carboplatin (270 mg/m2/day) was administered as an intravenous infusion on five consecutive days, and the patient died 10 days after his last dose of carboplatin from complications of thrombocytopenia and acute liver necrosis. Autopsy revealed hemorrhage into the substance of the myocardium and hemorrhagic centrilobular liver necrosis. The temporal relationship between the initial rise in this patient's liver function tests and treatment with carboplatin suggests that this patient's liver failure was in part due to carboplatin. The autopsy findings of hemorrhage into the substance of the myocardium and centrolobular liver necrosis suggest that, in addition to its direct effects, carboplatin may have also contributed indirectly to this patient's liver failure through the complications of thrombocytopenia.