Combretastatin A-1 phosphate potentiates the antitumor activity of carboplatin and paclitaxel in a severe combined immunodeficiency disease (SCID) mouse model of human ovarian carcinoma.

In search for new therapeutic modalities to target epithelial ovarian carcinomas, we investigated the effect of the antiangiogenic drug combretastatin A-1 phosphate (CA1P) as a single treatment or in combination with established therapy, ie, carboplatin and paclitaxel. Five different human epithelial ovarian carcinoma cell lines were inoculated subcutaneously into FOX CHASE CB-77 severe combined immunodeficiency disease (SCID) mice. When tumors reached a volume of approximately 100 mm(3), the treatment was initiated. All drugs were given intraperitoneally at weekly doses. CA1P was more effective as an antitumor agent than combretastatin A-4 phosphate as a single-drug treatment or in combination with carboplatin and paclitaxel. CA1P had a strong tumor outgrowth inhibiting effect on four out of five tumors included in this study. Comparing animals receiving CA1P with animals receiving a combination of carboplatin and paclitaxel, CA1P was more effective on two out of three tested tumors, whereas carboplatin and paclitaxel were more effective on one out of three of the tumors. We show that treatment of human ovarian carcinomas with CA1P in the SCID mouse model results in a strong antitumor effect both as a single-drug treatment and as an enhancement of the therapeutic effect in a combination treatment protocol with carboplatin and paclitaxel.

Identification of genes differentially expressed in TLS-CHOP carrying myxoid liposarcomas.

Myxoid liposarcomas (MLS) carry a t(12;16) or, more rarely, a t(12;22) resulting in fusion of the transcription factor gene CHOP on chromosome 12 with TLS/FUS on chromosome 16 or EWS on chromosome 22. The chimeric TLS-CHOP or EWS-CHOP proteins most probably function as abnormal transcription factors, causing transcriptional de-regulation of several target genes and relaxation of functions critical for growth and differentiation control. A PCR-based subtractive hybridization technique was used to identify genes that are differentially expressed in TLS-CHOP-carrying MLS but not in normal fat tissue. Six myxoid-liposarcoma-associated transcripts, MLAT, were isolated. The genes identified as MLAT can be divided into 2 groups. MLAT1, 2 and 6 show high similarity to glia-derived nexin, neuronatin and the RET oncogene, respectively, all normally involved in development of tissues of neural origin. MLAT3 to MLAT5 represent new genes.

Bone mineral content in patients with Crohn's disease. A longitudinal study in patients with bowel resections.

BACKGROUND: Low bone mineral content (BMC) has been reported in patients with inflammatory bowel disease. The aim of the present study was to measure BMC in patients with Crohn's disease. METHODS: BMC was monitored for a mean period of 5.5 years in 108 patients. The patients were divided into two groups: group A, patients with the colon preserved; group B, patients with a resected colon. The mean length of the resected small intestine was 90 cm. RESULTS: The BMC of the lumbar spine expressed as Z-score ((actual value-mean)/s) was significantly reduced: mean Z-score for group A, -0.51, P < 0.05; group B, -0.80, P < 0.001. The BMC of the femoral neck was significantly reduced: mean Z-score for group A, -1.24, P < 0.001; group B, -1.23, P < 0.001. A Z-score below -2.0 of spine or femoral neck BMC was found in 10% and 23% of the patients, respectively. The BMC of the femoral neck decreased significantly in both groups during the study period (group A, -2.2%, P < 0.001; group B, -1.21%, P < 0.05). The BMC of the lumbar spine did not change. There was an inverse correlation between the initial Z-score and the rate of change in BMC (P < 0.05). We found no correlation between Z-score or change in BMC and period of prednisolone treatment. Moreover, there was no correlation between the length of the resected small intestine and BMC or annual percentage change in BMC. CONCLUSION: At inclusion the BMC of the spine and femoral neck was low in patients with Crohn's disease. During the study significant bone loss was only demonstrated in the femoral neck. BMC or rate of change in BMC was not related to treatment with steroids or length of the resected small intestine.

The metabolism of [75Se]selenite in patients with short bowel syndrome.

BACKGROUND: Patients on home parenteral nutrition (HPN) require significantly higher amounts of selenium compared with controls. The purpose of the present study was to investigate if selenium deficiency of patients with short bowel syndrome is caused by selenium malabsorption or by excessive intestinal or renal loss. METHODS: The metabolism of [75Se]selenite was investigated in eight selenium-depleted short bowel patients on HPN and in six control subjects. The isotope was given orally, and in a subsequent study as bolus injection or as 12-hour IV infusion. RESULTS: The fractional intestinal absorption of selenium was significantly reduced in the patients (2% to 58%, median 20%) when compared with the reference group (79% to 91%, median 82%) (p < .001). Within the group of patients we found a positive significant correlation between fractional selenium absorption and the length of the remaining small intestine (r = 0.95, p < .05). After parenteral [75Se]selenite administration, the patients showed a significantly higher fecal loss and a significantly reduced urinary excretion of 75Se when compared with the controls. Bolus injection vs 12-hour infusion of [75Se]selenite did not affect the cumulative fecal or urinary 75Se excretion in the HPN patients. CONCLUSIONS: Reduced intestinal selenium absorption is probably the most important cause of the selenium deficiency reported in patients with short bowel syndrome, but increased endogenous intestinal selenium loss and low selenium intake may also contribute. Despite the renal counterregulation, which results in a low urinary selenium excretion, HPN patients need a supply of selenium with their parenteral nutrition.

Body composition in patients on home parenteral nutrition.

Dual energy X-ray absorptiometry (DXA) measures and separates three of the principal compartments of the body, fat mass (FM), fat-free mass (FFM), comprising muscle, inner organs and body water, and the total bone mineral content (TBMC). The aim of the present study was to determine body composition by DXA scan in 37 patients who had been on home parenteral nutrition (HPN) for 6-216 months. The height and weight of patients were significantly lower when compared to a group of healthy subjects. The weight, however, was relatively more reduced than the height. This is reflected by a significantly reduced body mass index in young female and male patients (p < 0.05). Fat-free mass and total body mineral content were significantly reduced (p < 0.05) in patients on home parenteral nutrition compared to a group of healthy subjects. However, the percentage of fat-free mass was unchanged. No significant change in fat mass was observed. We conclude that patients, with intestinal failure due to short bowel syndrome, who are on HPN have a smaller body size with a normal relative body composition.

Nutrition in short-bowel syndrome.

Short-bowel syndrome is a state of severe malabsorption secondary to extensive bowel resection. The most common reasons for extensive bowel resection are Crohn's disease and mesenteric infarction. The pathophysiological consequences depend on extent and site of resection, integrity and adaptation of the remaining bowel, and secondary effects on other organs. Most extensively bowel resected patients can be adequately nourished by mouth, especially since they develop compensatory hyperphagia. For patients with colon in function a high-carbohydrate low-fat diet is beneficial compared to a diet with a normal fat content, because it results in decreased diarrhoea, decreased faecal mineral losses, and increased energy assimilation. The relative amount of dietary fat does not influence stool mass or energy assimilation in jejunostomy patients. Patients with jejunostomy have a high faecal output of water, sodium, and divalent cations, and they often need permanent parenteral supply of saline as well as calcium and magnesium if their small intestinal remnant is < 200 cm and parenteral nutritional support if they retain < 100 cm small bowel. In contrast, 50 cm of the jejunum often suffices for adequate oral nutrition if most of the colon is preserved. The majority of patients needing long-term intravenous supply are trained to administer parenteral nutrition at home (HPN). Most patients on HPN obtain a good or fair quality of life with hospital readmissions corresponding to an average of 10% of the HPN duration and an overall HPN related mortality of about 4%.

Bone mineral content in patients on home parenteral nutrition.

Bone mineral content (BMC) was monitored in 15 patients with short bowel syndrome receiving home parenteral nutrition (HPN). Thirteen patients had Crohn's disease and 2 ulcerative colitis (mean age 36 years, range 23-69 years). During the study the patients received HPN for a mean period of 62 months, range 20-106 months. At the time of inclusion the patients had a significantly reduced BMC of lumbar spine and femoral neck compared to normals (Z-scores = -3.35 +/- 3.49, p < 0.05 and Z-score = -2.23 +/- 2.11, p < 0.05). During HPN the Z-score of lumbar spine BMC decreased in 8 patients and increased slightly or was unchanged in 7 patients. The mean Z-score of BMC of lumbar spine declined by 1.46 +/- 2.48 (p < 0.05) and the Z-score of femoral neck BMC declined by 0.831 +/- 1.14 (p < 0.05). This corresponds to a yearly decrease of lumbar spine BMC of 4%. There was no correlation between the decline in BMC during the study and the period of length the patients were on HPN. We conclude that patients on HPN have a low bone mineral density and that the bone loss continues during prolonged HPN.

Postoperative electrolyte and mineral balance after restorative proctocolectomy with ileoanal reservoir.

Postoperative electrolyte and mineral balance was studied in nine patients with ulcerative colitis who underwent restorative proctocolectomy with ileoanal reservoir (J-pouch). The study was carried out during the first seven days of bowel function after construction of the reservoir and temporary ileostomy, and again after the ileostomy was closed and bowel continuity re-established. Stool volume and intestinal sodium excretion were reduced by respectively 40 and 45% after ileostomy was closed (p < 0.05), but potassium excretion was unchanged. The concentration of sodium was higher in ileostomy effluents, whereas the concentration of potassium was higher in stools after the ileostomy was closed (p < 0.05). Significant changes in blood and urinary electrolytes or minerals were not recorded. It is concluded that a major reduction in stool volume and intestinal excretion of sodium is already present in the early postoperative period after bowel continuity has been re-established.

[Chronic radiation enteropathy. A retrospective study]. / Kronisk stråleenteropati. En retrospektiv undersøgelse.

In the period 1968-1989 50 patients, 38 women and 12 men, aged 30-76 years, median 58 years, were referred to the Department of Gastroenterology, Rigshospitalet for severe chronic radiation enteropathy. Most women had received radiation for gynaecological cancer, and most men for urogenital cancer. The initial symptoms of the enteropathy were diarrhoea in 74%, abdominal pain in 62% and weight loss in 52%. Twelve per cent had visible blood in the stools. Ten per cent had fistulas. The symptoms occurred 0-37 years, median ten months after the radiation. The radiation enteropathy had necessitated one or more laparotomies in 35 patients, most often because of subileus/ileus, including resection of the small bowel or the colon in 25 patients, and establishment of an ileostomy or a colostomy in 11. Seven patients developed new fistulas postoperatively. In 32 patients one or more tests for malabsorption were performed as a guidance for therapy: stool mass (26 patients), faecal fat excretion (26 patients), Schilling test (22 patients), lactose absorption (11 patients) and bile acid breath test (seven patients). Half of the patients had diarrhoea, including one third of the patients without intestinal resection. Two thirds had steatorrhoea, including half of the patients without small bowel resection. Three fourths showed decreased absorption of vitamin B12, including half of the patients without ileal resection. All patients studied had abnormal deconjugation of bile acids and more than half of them had bile acid malabsorption. Malabsorption of lactose was found in only one patient. There was no correlation between the radiological and functional abnormalities of the small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)

Selenium depletion in patients on home parenteral nutrition. The effect of selenium supplementation.

Severe selenium (Se) depletion was found in nine patients receiving long-term home parenteral nutrition because of short bowel syndrome. Plasma Se ranged from 0-0.51 (median 0.21 mumol/L), and erythrocyte Se ranged from 0.7-2.6 (median 1.8 mumol/gHgb), which was significantly lower than in the controls. Glutathione peroxidase (GSHPx) in plasma and erythrocytes was also decreased. After bolus injections with 200 micrograms Se/d in the form of sodium selenite for 4 mo, followed by 100 micrograms/d for 8 mo, plasma Se increased to values slightly but significantly higher than in the controls. Erythrocyte Se reached normal levels in most of the patients after 4 mo substitution, but it remained lower than in the controls. Following Se supplementation, plasma and erythrocyte GSHPx did not differ between patients and controls. These data suggest that all patients receiving long-term parenteral nutrition because of short bowel syndrome should receive at least 100 micrograms sodium selenite/d when given as bolus injections to avoid Se depletion.

Selenium status in patients with Crohn's disease.

Twenty-seven of 66 patients with Crohn's disease had reduced concentrations of selenium and glutathione peroxidase in plasma and erythrocytes. When the patients were subgrouped according to the length of resected small bowel, a significant reduction of selenium and glutathione peroxidase in both plasma and erythrocytes was only found in patients with a resection > 200 cm. A highly significant correlation between selenium and glutathione peroxidase was found in plasma (r = 0.81) as well as in erythrocytes (r = 0.62), but no correlation was observed in the control group. A statistically significant correlation was also found between plasma selenium and the Harvey-Bradshaw score (r = -0.44), body mass index (wt/ht2) (r = 0.47), and plasma albumin (r = 0.29). Patients with a small-bowel resection > 200 cm appear to be at risk of developing severe selenium deficiency. These patients should have their selenium status monitored and probably receive selenium supplementation.

Gliadin uptake in human enterocytes. Differences between coeliac patients in remission and control individuals.

The pepsin trypsin digest of the wheat prolamin gliadin (PT-gliadin) is deleterious to the small intestinal mucosa of coeliac patients. The handling of PT-gliadin by the intestinal epithelium in coeliac patients in remission and control individuals was investigated by in vivo instillation of PT-gliadin. The uptake of PT-gliadin was monitored by immunofluorescence microscopy of intestinal biopsy specimens, using affinity purified PT-gliadin antibodies. Control individuals show weak staining in the apical region of the enterocytes thereby showing an uptake of PT-gliadin. Coeliac patients have a conspicuous fluorescence in relation to the lateral membrane/intercellular space of enterocytes and intense staining intracellularly in the apical region. There is only weak staining in the enterocytes after the instillation was terminated, indicating an intracellular clearance. The study shows that normal enterocytes are able to take up PT-gliadin. The increased uptake in coeliac patients might be of importance for the pathogenesis either by direct toxicity or by presentation to immunocompetent cells. Furthermore, the results are in agreement with the suggestion of a functional alteration in the zonula occludens in the intestinal epithelium of coeliac patients.

Fate of the rectum after colectomy and ileostomy for Crohn's colitis.

Eighty-four patients had colectomy with ileostomy and oversewing of the rectum for Crohn's colitis. Seventy-two patients were operated on because of intractable disease, colitis in combination with rectal fistulas, and toxic megacolon. The operative mortality was 6 percent, and neither emergency surgery nor treatment with steroids correlated with operative morbidity. After a median 7.7 years of follow-up, 25 ileorectal anastomoses had been undertaken, 16 of which were successful. Twenty-nine protectomies were performed; the resulting 10-year cumulative risk of proctectomy was 50 percent. While the risk of proctectomy was significantly less among patients with a normal rectum at colectomy compared with patients with proctitis, the initial macroscopic degree of proctitis did not correlate with the risk of subsequent proctectomy. The 5-year cumulative ileal resection rate in 29 patients with a rectum in situ but out of circuit was 29 percent. The possibility of a future ileorectal anastomosis should still be considered in patients with proctocolitis.

Absorption studies after ileal J-pouch anastomosis for ulcerative colitis. A prospective study.

Absorption studies were performed in 17 patients with ulcerative colitis operated on with colectomy and an ileal two-limbed J-pouch anastomosis. The patients were studied 3 and greater than or equal to 18 months after closure of the temporary ileostomy. Increased stool mass (median, 609 g/24 h) was found in all patients and was unchanged with time. Moderate steatorrhoea was present in 29% of the patients 3 months postoperatively, but faecal fat excretion normalized with time. Calcium absorption was normal in all but one patient regardless of time after operation. An abnormal bacterial deconjugation, evaluated by a 14C-glycocholic acid breath test was present in 27% of the patients and increased significantly with time. Forty per cent of the patients had increased faecal bile acid excretion. B12 malabsorption was present in 29-35% of the patients. In conclusion, ileal J-pouch anastomosis for ulcerative colitis causes increased stool mass in all patients and produces moderate bile acid deconjugation and malabsorption in about one-third to half. Substitution therapy with vitamin B12 is necessary in about one-third of the patients. Intestinal adaptation as far as absorption is concerned is minimal after the first 3 postoperative months.

Calcium absorption and bone mineral content in patients subjected to ileal bypass because of familial hypercholesterolaemia.

Calcium absorption and bone mineral content were studied prospectively in 30 patients with familial hypercholesterolaemia subjected to partial ileal bypass surgery. One-third of the patients were followed up for 10 years after the operation. Six months postoperatively calcium absorption decreased significantly, from a median of 16% to 13%. The effect persisted up to 5 years of follow-up study. Ten years after the operation the absorption of calcium (median, 14.5%) was not significantly different from the preoperative calcium absorption (median, 16%). Bone mineral content, measured in 76% of the patients, was retained in all patients studied. A significant correlation was present between calcium absorption and urinary calcium. The reduction in calcium absorption did not correlate with increases in faecal fat. Other long-term side effects were persistent diarrhoea and moderate steatorrhoea. A significant weight loss was slowly regained in most patients. An increase of renal oxalate excretion was only small and transient in most patients. The study shows that bypass of the terminal 200 cm of ileum for familial hypercholesterolaemia causes moderate diarrhoea and steatorrhoea in most patients but only a slight reduction of intestinal calcium absorption and apparently no risk of bone demineralization. A benefit of a postoperative calcium and vitamin D supply cannot be excluded.

Calcium absorption after intestinal resection. The importance of a preserved colon.

Calcium absorption was studied in 62 patients with Crohn's disease during a 1-week admission on a standardized diet supplying 70 g fat, 800 mg calcium, and 200 mg oxalate. All patients had been subjected to a distal small-bowel resection of at least 50 cm. Twenty-two had an ileostomy, and 40 had at least half of the colon in function. In all patients the disease was inactive. Calcium absorption was determined by the fractional accumulation in the skeleton of the antebrachium of an intravenous and oral dose of 47Ca. Calcium absorption was significantly lower in patients with ileostomy (median, 10%; range, 5-18%) than in patients with part of or the whole colon in function (median, 14%; range, 6-22%). The present study shows that in patients with extensive small-bowel resection preservation of at least half of the colon improves calcium absorption.

Catheter-related sepsis in long-term parenteral nutrition with Broviac catheters. An evaluation of different disinfectants.

From April 1976 to January 1988, 58 patients received home parenteral nutrition for 2-138 months, median 36 months, corresponding to a total treatment period of 233 patient years. Before 1980 and after 1985, 0.5-2% iodine tincture or 0.5% chlorhexidine in 70% ethyl alcohol were used to disinfect the exit site of the catheter and the connections of the infusion line. In these periods the sepsis incidence was 0.25-0.28 per catheter year, corresponding to one episode of sepsis per 3.6-4.0 catheter years. In the period 1980 to 1985, 10% povidone-iodine (Isobetadine) was used, and the incidence in this period was 0.58, corresponding to one episode of sepsis per 1.7 catheter year. This suggests that 10% povidone-iodine may be inferior to iodine-tincture and chlorhexidine alcohol in this type of catheter care. The incidence of catheter sepsis was 0.32 per catheter year when the catheter was placed on the chest and 0.86 per catheter year with the catheter on the thigh. Klebsiella pneumoniae was the most common microorganism grown when the catheter was placed on the thigh, while coagulase-negative staphylococci were most common when the catheter was placed on the chest.

Feasibility and effectiveness of a defined-formula diet regimen in treating active Crohn's disease. European Cooperative Crohn's Disease Study III.

In a randomized multicenter trial the efficacy of treatment of active Crohn's disease by means of a liquid defined formula diet (DFD) was tested and compared with a combination of 6-methyl-prednisolone and sulfasalazine. A total of 95 patients participated in the study. By the end of 6 weeks, among 44 patients randomized to drug treatment, 32 showed improvement of the Crohn's disease activity index (CDAI) as compared with 21 of 51 patients receiving oral DFD (p less than 0.05). The proportion of withdrawals in the DFD group (29 of 51) was sevenfold higher than in the drug group (4 of 44). However, most patients (20 of 29) receiving DFD withdrew because of the unpalatability of the liquid diet. Analysis of patients in each group who finished the study showed equal effectiveness of DFD and the drug regimen. In these subsets of patients the CDAI decreased from 280.8 +/- 90.6 to 151.7 +/- 86.5 (DFD) and from 263.7 +/- 86.3 to 129.3 +/- 63.7 (drug), respectively. Improvement of inflammation factors was similar in both groups at the end of the study, although improvement was delayed in the DFD group. In conclusion, our data show a superiority of the drug combination over DFD in the treatment of Crohn's disease under the conditions of this trial. The results do suggest, however, that DFD offers a therapeutic alternative to prednisolone and sulfasalazine in a subgroup of patients, which has to be closer characterized in further studies.

Ulcerative colitis and Crohn's disease of the colon. Is there a macroscopic difference?

The diagnostic reliability of currently accepted gross pathologic signs in patients with ulcerative colitis and Crohn's disease of the large intestine was evaluated. Of 198 patients who had colectomy or proctocolectomy because of inflammatory bowel disease, 52% had ulcerative colitis and 37% had Crohn's disease, 11% were indeterminable according to histologic evaluation of the surgical specimens. Cobblestone mucosa was most common in Crohn's disease (P less than 0.001) and pseudopolyposis in ulcerative colitis (P less than 0.01), but there was considerable overlap. Strictures and skip lesions occurred in both diseases with a similar incidence. It is concluded that the differential diagnosis between ulcerative colitis and Crohn's disease of the large intestine should not be made from macroscopic examination of the resected specimens.