Secondary hemochromatosis as a long-term complication of the treatment of hematologic malignancies.

The increased cure rate of hematologic malignancies including the use of bone marrow transplantation has focused attention on the chronic toxicity and quality of life of the survivors. We have observed five patients who have been diagnosed with clinically significant iron overload, presumably due to packed red blood cell transfusions, >/=12 months after transplant for a hematologic malignancy. In these patients, there is no history of veno-occlusive disease or family history of hemochromatosis. The allotransplant patient has been free of chronic graft versus host disease. Family screening has been negative. No patient developed clinically significant endocrinopathy, arthropathy, or cardiac disease. The patients have been treated with phlebotomy to bring the transferrin saturation and ferritin levels to normal. The long-term follow-up of patients treated for a hematologic malignancy should include analysis of hepatitis C virus and iron status. This may prevent the development of clinically significant chronic liver disease and possibly malignancy.

Prospective analysis of colorectal carcinoma. Determination of an age-site and stage relationship and the correlation of DNA index with clinicopathologic parameters.

PURPOSE: A prospective study of colorectal cancer (1987-1991) using flow cytometry was performed to determine the relationship of age with DNA index (DNA-I), sites of disease, Dukes stage, grade, and survival. METHODS: The flow cytometry was performed on 138 fresh, unfixed, surgical specimens using 4',6'-diamidino-2-phenylindole, a DNA fluorochrome. RESULTS: The mean age was 66.9 (42.8 percent > or = 70; range, 22-92; median, 68) years, and 48.6 percent were female. The patients' stages were (in percent): A, 4.4; B, 53.0; C, 38.2; D, 4.4. Tumor grades of differentiation (in percent) were well, 14.4; moderate, 68.9; poor, 16.7; and sites (in percent) were: rectum, 19.6; sigmoid/left, 50.7; transverse/right, 29.0. Aneuploidy (DNA-I not equal to 1.0; CV, 3.5 percent) was found in 58.8 percent. Age (by decade of presentation) was compared with site and Dukes stage. Older patients had more transverse/right-sided lesions (P = 0.003). Patients with Dukes C and D tumors had a lower age (by decade of presentation) than patients with B2 lesions (P = 0.03). Age was not related to DNA-I or grade or DNA-I with sex, grade, site, stage, or survival (P > 0.05). CONCLUSIONS: This prospective study suggests that colorectal cancer tends to present at an earlier stage and in the more proximal colon in the older population. Because right-sided lesions are beyond the reach of sigmoidoscopy, these findings have prognostic and screening implications.

Altered eicosanoid levels in human colon cancer.

Eicosanoids may participate in colon carcinogenesis, as evidenced from work in animal tumor models showing prevention of colon cancer by inhibitors of their synthesis and epidemiologic studies demonstrating reduced risk of colon cancer in long-term users of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). The levels of prostaglandin E2 (PGE2), PGF2 alpha, PGI2, thromboxane A2 (TXA2), and leukotriene B4 (LTB4), which represent the cyclooxygenase and 5-lipoxygenase pathways, were determined in 21 pairs of surgically excised human colon cancer and histologically normal mucosa samples 5 to 10 cm away from the tumor. The levels of PGE2 were elevated in colon cancer samples as compared with histologically normal mucosa samples distant from the cancer (p < 0.01), whereas levels of prostacyclin (PGI2) were decreased (p < 0.05). The differences in the levels of PGF2 alpha, TXA2, and LTB4 between normal and malignant tissue were not statistically significant. No statistically significant association was found between the level of each of the eicosanoids assayed and Dukes' stage of colon cancer. These findings, confirming and extending earlier work from tumors and cell culture, suggest that the protective effect of aspirin and other NSAIDs in the development of human colon cancer may be mediated, at least in part, through their inhibition of arachidonic acid metabolism by cyclooxygenase.

Crohn's disease and pancreatitis.

Pancreatitis has rarely been reported as a complication of Crohn's disease. We report our experience with two cases of pancreatitis associated with Crohn's disease. In one, the pancreatitis occurred secondary to duodenal Crohn's disease involving the ampulla of Vater. Endoscopic retrograde pancreatography demonstrated involvement of the ampulla, with marked dilation and delayed drainage of the pancreatic duct, suggesting mechanical obstruction. In the second patient, Crohn's disease was localized to the ileum and colon. We conclude that duodenal Crohn's can cause pancreatitis, and this may, in some cases, be on an obstructive basis. In addition, non-duodenal Crohn's disease can be associated with pancreatitis as well. In a patient with a history of Crohn's disease presenting with an atypical exacerbation, pancreatitis should be considered.

Reduced expression of HLA class I and II antigens in colon cancer.

The expression of HLA class I and II antigens was studied by immunohistochemistry in (a) specimens of colon cancer from 25 patients, (b) normal colonic mucosa obtained 5-10 cm away from each tumor, and (c) colonic mucosa from 13 normal individuals. Thirteen of the tumor specimens had normal epithelium adjacent to the cancer, which thus served as an internal control. The expression of HLA class I antigens in colon cancer was dramatically reduced compared to control (P less than 0.0001): undetectable in 28%, diminished in 68%, normal in 4%. The expression of class II antigens was also reduced in cancer (P less than 0.0001 for all when compared to normal), being undetectable in most (HLA-DP 64%, HLA-DQ 72%, HLA-DR 68%). In 44% of the cancers all three HLA class II antigens were undetectable; in 92% at least one class II antigen was undetectable; and in 20% both class I and class II antigens were undetectable. No cancer specimen had a completely normal HLA phenotype. The expression of other surface antigens was preserved in cancer tissues and, therefore, loss of HLA antigens was not due to a nonspecific decline in surface molecules. When glands of normal mucosa immediately adjacent to cancer were compared to those of normal controls, significantly reduced expression of only HLA class I antigens (P = 0.0149) and HLA-DP (P = 0.034) was found. The expression of the HLA antigens in colonic mucosa remote from the cancer was no different from that of normal controls. Our data show extensive and significant reduction in the expression of HLA antigens in colon cancer; its potential relationship to immunosurveillance in cancer is discussed.

Human colorectal cancers display abnormal Fourier-transform infrared spectra.

Fourier-transform infrared spectroscopy (FT-IR) was applied to the study of tissue sections of human colorectal cancer. Pairs of tissue samples from colorectal cancer and histologically normal mucosa 5-10 cm away from the tumor were obtained from 11 patients who underwent partial colectomy. All cancer specimens displayed abnormal spectra compared with the corresponding normal tissues. These changes involved the phosphate and C-O stretching bands, the CH stretch region, and the pressure dependence of the CH2 bending and C = O stretching modes. Our findings indicate that in colonic malignant tissue, there are changes in the degree of hydrogen-bonding of (i) oxygen atoms of the backbone of nucleic acids (increased); (ii) OH groups of serine, tyrosine, and threonine residues (any or all of them) of cell proteins (decreased); and (iii) the C = O groups of the acyl chains of membrane lipids (increased). In addition, they indicate changes in the structure of proteins and membrane lipids (as judged by the changes in their ratio of methyl to methylene groups) and in the packing and the conformational structure of the methylene chains of membrane lipids. The cell(s) of the malignant colon tissues responsible for these spectral abnormalities is unknown. Cultured colon adenocarcinoma cell lines displayed similarly abnormal FT-IR spectra. The diagnostic potential of the observed changes is discussed.

Increased hepatic density and phospholipidosis due to amiodarone.

Amiodarone is an amphiphilic iodinated compound that is used as a treatment for refractory ventricular arrhythmias. During evaluation for possible pulmonary toxicity, a patient receiving amiodarone was noted to have an increase in the density of his liver as seen on computed tomographic (CT) scanning of the abdomen. Six additional patients who were receiving amiodarone were subsequently evaluated to ascertain the frequency of this finding. The CT density of the liver was increased in all patients. Values obtained varied from 95 to 145 H, with a mean of 117 +/- 8.9 (normal, 30-70). The alkaline phosphatase was elevated in four patients, but only one had an elevation of either the alanine or aspartate aminotransferase. Two patients underwent liver biopsies, and both revealed membranous lamellar phospholipid-containing structures within hepatocytes. Animal studies done to recreate these findings revealed that amiodarone accumulated in the liver at concentrations 175-500 times greater than those found in serum. Quantitative measurements of iodine in samples from the same liver showed that the iodine levels were correspondingly elevated. In the treated animals, there was a small but statistically significant increase in the CT density of the liver, whereas the values for untreated animals were unchanged. Treatment with amiodarone leads to an accumulation in the liver of this iodinated compound and hence an increase in the CT density of the liver. This accumulation of the drug in hepatic lysosomes apparently causes a secondary phospholipidosis.

Transport of epidermal growth factor by rat liver: evidence for a nonlysosomal pathway.

Epidermal growth factor (EGF), circulating in the blood, is taken up by rat liver hepatocytes by means of specific and saturable receptor-mediated endocytosis. These experiments were undertaken to determine (a) the transport pathway(s) of EGF taken up by rat liver and (b) the effects of lysosomal inhibition on its transport. 125I-EGF was injected into rat portal veins, and bile samples were collected and analyzed for both total and immunoprecipitable radioactivity. In addition, the livers were examined by electron microscopic autoradiography. Some animals received injections of chloroquine before surgery, to disrupt lysosomal function. The results indicate that most of the EGF taken up by the hepatocytes is transported to lysosomes and degraded. However, a small but significant percentage of endocytosed EGF is transported by a pathway independent of the lysosomal system, resulting in secretion of intact EGF: (a) Both degraded and immunoprecipitable EGF are secreted into bile. (b) Immunoprecipitable radioactivity peaks at 20 min after EGF injection, whereas degradation-associated radioactivity does not peak until 40 min postinjection. (c) EGF isolated from bile is specifically taken up by isolated hepatocytes in monolayer culture, indicating that it is still recognizable by the EGF receptor. (d) When the lysosomal system is inhibited with chloroquine, secretion of degraded EGF is significantly inhibited, whereas the amount of intact EGF secreted into bile is unchanged. The utilization by liver of a dual transport process for EGF represents an unusual system of intracellular ligand processing, whose physiological significance has yet to be determined.

The perfused human liver wedge biopsy: a new in vitro model for morphological and functional studies.

We developed a simple and inexpensive method of perfusing small specimens of human liver in vitro that maintains short-term tissue viability as judged by protein transport function and morphological features. The technique allows investigation of liver function at the cellular level in normal specimens and those with hepatobiliary disease. Electron microscopy of specimens perfused with this system demonstrates the presence of an incomplete basement membrane within the space of Disse and shows that human microbodies contain crystalline-like cores morphologically similar to those found in rat liver.