The impact of preoperative breast MRI on the re-excision rate in invasive lobular carcinoma of the breast.

Re-excision rates after breast conserving surgery(BCS) of invasive lobular carcinoma (ILC) are high.Preoperative breast MRI has the potential to reduce re-excision rates, but may lead to an increased rate of mastectomies. Hence, we assessed the influence of preoperative breast MRI on the re-excision rate and the rate of mastectomies. We performed a retrospective cohort study of a consecutive series of patients with ILC who presented in one of two dedicated tertiary cancer centers between 1993 and 2005. We assessed the initial type of surgery(BCS or mastectomy), the re-excision rate and the final type of surgery. Patients were stratified into two groups:those who received preoperative MRI (MR? group) and those who did not (MR- group). In the MR- group, 27%of the patients underwent a re-excision after initial BCS. In the MR? group, this rate was significantly lower at 9%.The odds ratio was 3.64 (95% CI: 1.30-10.20, P = 0.010).There was a trend towards a lower final mastectomy rate in the MR? group compared to the MR- group (48 vs. 59%,P = 0.098). In conclusion, preoperative MRI in patients with ILC can reduce re-excision rates without increasing the rate of mastectomies.

Hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa is a chronic, recurrent, suppurative cutaneous disease. Despite its incidence, optimal medical or surgical treatment remains unclear. This review describes the disease, ranging from pathogenesis to treatment and prognosis. METHODS: Articles were sourced from PubMed and Medline, using the MeSH terms 'hidradenitis suppurativa' and 'acne inversa'. Selection of articles was based on peer review, journal, relevance and English language. RESULTS AND CONCLUSION: On the basis of histological findings, the disease is now considered inflammatory and originating from the hair follicle; therefore, the term 'acne inversa' is favoured by some experts. The exact aetiology remains obscure but smoking seems to be a major triggering factor. Treatment should be individualized according to the site and extent of the disease. Absolute cessation of smoking is essential in the treatment of hidradenitis. Management with antibiotics or other medications may relieve early symptoms, but radical surgery may be necessary for control and to prevent recurrence.

[Hepatocellular adenoma, a tumour particularly seen in mostly young women]. / Het leverceladenoom, een tumor bij veelal jonge vrouwen.

A 37-year-old woman was examined because of temporary diarrhoea. On CT scan, there was an abnormality of the liver. MRI showed a tumour that was suspicious for adenoma. Biopsy confirmed the diagnosis of hepatocellular adenoma. The patient then discontinued the use of oral contraceptives. The tumour regressed and was resected after two years. A 22-year-old woman presented with abdominal pain. A tumour was found in the upper right quadrant of the abdomen. In the laboratory, liver function tests were abnormal. Ultrasound and a CT scan of the liver showed an adenoma. After withdrawal of oral contraceptives, abdominal complaints lessened, but no regression of the tumour was detected. Surgical resection was uncomplicated. Hepatocellular adenoma is a rare, benign tumour of the liver, most often seen in young healthy women. Its incidence is rising due to the prolonged use of oral contraceptives. Not rarely, benign liver tumours are incidental findings on echography. If symptomatic, the presentation usually consists of vague abdominal complaints. Spontaneous rupture and malignant degeneration have been reported for adenoma. A reliable diagnosis is mandatory for the decision whether to apply surgery or continue observation. Radiological investigations play a key role in the detection and diagnosis of hepatocellular adenoma. Due to the risk of bleeding and malignant degeneration, elective surgical resection is indicated in symptomatic adenomas, asymptomatic adenomas larger than 5 cm in diameter, and smaller adenomas without regression after discontinuation of oral contraceptives.

Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer.

BACKGROUND: Although breast cancer screening is recommended to start at a younger age for women with a hereditary risk of breast cancer, the sensitivity of mammography for these women is reduced. We compared magnetic resonance imaging (MRI) with mammography to determine which is more sensitive and whether MRI could play a role in the early detection of breast cancer for these women. METHODS: We constructed a retrospective cohort of all breast MRI and mammography surveillance reports made in our department from November 1994 to February 2001. All of the 179 women in the cohort had received biannual palpation in addition to annual imaging by MRI, mammography, or both. The 258 MRI images and the 262 mammograms were classified with the use of the BI-RADS (i.e., Breast Imaging Reporting and Data System) scoring system, which has five categories to indicate the level of suspicion of a lesion. Receiver operator characteristic curves were generated for MRI and mammography, and the area under each curve (AUC) was assessed for the entire cohort of 179 women and for a subset of 75 women who had received both an MRI and a mammographic examination within a 4-month period. All statistical tests were two-sided. RESULTS: In the cohort of 179 women, we detected 13 breast cancers. Seven cancers were not revealed by mammography, but all were detected by MRI. For the entire cohort, the AUC for mammography was 0.74 (95% confidence interval [CI] = 0.68 to 0.79), and the AUC for MRI was 0.99 (95% CI = 0.98 to 1.0). For the subset of women who had both examinations, the AUC for mammography was 0.70 (95% CI = 0.60 to 0.80), and the AUC for MRI was 0.98 (95% CI = 0.95 to 1.0). CONCLUSION: MRI was more accurate than mammography in annual breast cancer surveillance of women with a hereditary risk of breast cancer. Larger prospective studies to examine the role of MRI in screening programs are justified.

[The great important of tumor-free margins in the breast-saving procedure]. / Het grote belang van tumorvrije snijvlakken bij de borstsparende behandeling.

There is increasing evidence that local recurrence after breast-conserving surgery may lead to an increase in distant metastases and disease-specific mortality. The most important factor responsible for recurrence is the margin status after excision. The treatment of patients with breast cancer should be decided upon by a multidisciplinary treatment group so that the candidates for a breast-conserving procedure can be adequately selected with emphasis on achieving maximum local control.

Heterogeneous expression of immunotherapy candidate proteins gp100, MART-1, and tyrosinase in human melanoma cell lines and in human melanocytic lesions.

In recent years, it has become evident that T cells can recognize peptides of melanocytic lineage antigens such as gp100, MART-1, and tyrosinase at the tumor cell surface and can subsequently destroy these cells. It is thus feasible to develop immunotherapeutic approaches based on the melanocytic marker profiles of melanoma cells. One of the predictors of the success rate of such a treatment is the extent of positive (target) tumor cells within the lesions of the patient. First, we investigated the presence of these three proteins in 18 human melanoma cell lines using RT-PCR and immunohistochemistry. In 11 cell lines, mRNA and protein of all three markers could be detected; in one cell line, only two markers were present, and six melanoma cell lines showed no evidence for these markers. Secondly, we stained frozen sections of 105 human melanocytic lesions, 13 common nevocellular nevi, 13 atypical nevi, 13 early primary melanomas (Breslow < 1.5 mm), 25 advanced primary melanomas (aPM; Breslow > or =1.5 mm), and 41 melanoma metastases (MM) with antibodies against glycoprotein 100, melanoma antigen recognized by T cells, and tyrosinase. In addition, we used the 3,4-dihydroxy-L-phenylalanine reaction to detect tyrosinase enzyme activity as a confirmation of the tyrosinase immunohistochemical results in a subset of the lesions. In the benign lesions, glycoprotein 100 was more prominently expressed in epidermal melanocytes, whereas melanoma antigen recognized by T cells was encountered in all or nearly all dermal melanocytes in all nevocellular nevi and atypical nevus lesions. Tyrosinase was found in a lower percentage of melanocytes, both in the epidermis and in the dermis within these lesions. With regard to heterogeneity of staining within the malignant lesions, we found that 54% (early primary melanomas), 48% (aPMs), and 56% (MM) of the lesions stained within the same staining category for all three proteins studied. Approximately 17% of the aPM and MM lesions did not show positive tumor cells for any of the three proteins. We conclude that a subgroup of patients with high expression should be selected for immunotherapeutic treatment approaches based on the presence of these proteins.

Polymorphic expression of the glutathione S-transferase P1 gene and its susceptibility to Barrett's esophagus and esophageal carcinoma.

Factors determining individual susceptibility to esophageal cancer or premalignant Barrett's epithelium are still largely unclear. An imbalance between phase I drug metabolism [e.g., cytochrome P450 (CYP)] and phase II detoxification [e.g., glutathione S-transferase (GST)] may contribute to the development of these diseases. Polymorphic variants in the CYP1A1 gene were described leading to increased levels of bioactive compounds, whereas polymorphisms in GST genes often resulted in impaired detoxification. We studied the frequencies of polymorphic variants in CYP1A1, GSTP1, GSTT1, and GSTM1 genes in 98 patients with Barrett's epithelium and 34 patients with esophageal cancer. The results were compared with those obtained from 247 healthy blood donors. DNA was extracted, and PCR-RFLP methods were used to detect genetic polymorphisms. Chi2 analysis, Spearman rank correlation, and Wilcoxon rank sum tests were used for statistical evaluation. Polymorphisms in CYP1A1, GSTM1, and GSTT1 occurred at an equal frequency in patients and controls. Occurrence of the polymorphic GSTP1b variant in the GSTP1 gene resulted in a significantly lower GST enzyme activity (P < 0.05), and GSTP1b was found significantly more often in patients with Barrett's epithelium (70%; P < 0.001) and patients with esophageal adenocarcinoma (76%; P = 0.005), as compared to healthy blood donors (41%). In conclusion, presence of the GSTP1b allele leads to lower GST enzyme activity levels and, consequently, impaired detoxification. This most important esophageal GST isoform may, therefore, contribute to the development of Barrett's epithelium and adenocarcinoma.

Breast-conserving treatment or mastectomy in early breast cancer: a clinical decision analysis with special reference to the risk of local recurrence.

A clinical decision analysis was performed to judge the impact of local recurrences after breast-conserving treatment (BCT) on the (quality-adjusted) life expectancy of breast cancer patients. A life-long follow-up of two patient groups, one of which had undergone mastectomy and one BCT, was simulated by a Markov model of medical prognosis. Data used in the model originated from the literature. Since results in the source papers were not split according to stage, we performed two analyses: one with data from all source studies (T1 and T2) and one with data from source studies, concerning only T1 patients. In both analyses, the conclusion was that BCT yields better quality-adjusted life expectancy than mastectomy. Sensitivity analysis, however, identified subgroups of patients who should preferably undergo mastectomy. These subgroups are: patients preferring mastectomy to BCT, patients with a high risk of local recurrence, young patients and patients at high age, if they also have a high local recurrence risk. For these groups, patient preferences should play a major role in recommending treatment.

Inhibition of fibroblast collagen synthesis and proliferation by levamisole and 5-fluorouracil.

Experimental studies indicate that anastomotic healing in the intestine is compromised by the immediate postoperative administration of 5-fluorouracil and levamisole. Since fibroblast functions are crucial to healing, we investigated the effects of (combinations of) both drugs on proliferation and collagen synthesis of rat skin fibroblasts in vitro. Proliferation was measured in actively dividing cells by cellular [3H]thymidine uptake and collagen synthesis in non-dividing cells by [3H]proline incorporation into collagenase-digestible protein. 5-Fluorouracil strongly and significantly (P < 0.05) reduced DNA synthesis and collagen synthesis at concentrations of 1 microM or more. The latter effect was not specific for collagen since total protein production was affected similarly. Both effects depended on the duration of exposure to the drugs. Levamisole also inhibited fibroblast proliferation dose-dependently, but less effectively than 5-fluorouracil: 50% inhibition was observed at approximately 0.1 mM. Collagen synthesis was unaffected by levamisole. If levamisole was added together with a low (0.1 microM) concentration of 5-fluorouracil, which in itself did not decrease thymidine incorporation, levamisole's antiproliferative effects became apparent at concentrations as low as 1 microM. A similar effect, but at a much higher concentration (1 mM) was noted on fibroblast collagen synthesis. These results indicate that levamisole potentiates 5-fluorouracil effects in fibroblast cultures and that direct effects of these drugs, alone or in combination, on fibroblast proliferation and collagen synthesis may be responsible for their negative influence on wound repair.

Prospective randomised study of split-course radiotherapy versus cisplatin plus split-course radiotherapy in inoperable squamous cell carcinoma of the oesophagus.

Between 1983 and 1989, 211 patients with inoperable squamous cell carcinoma of the oesophagus were randomised in a study comparing split-course irradiation (two courses of 20 Gy in five fractions of 4 Gy, separated by a rest of 2 weeks) (arm A) and the same split-course irradiation in combination with cisplatin (CDDP) (3-4 days before each of the two courses of radiotherapy, repeated every 3-4 weeks, for a total of six cycles) (arm B). The Cox's regression model with retrospective stratification was used to compare the two arms to correct for the imbalance at randomisation of the T classification. The median overall survival was 7.9 (95% confidence interval (CI) 7.3-9.4) months in arm A and 9.6 (95% CI 8-13.5) months in arm B. The difference in overall survival was only borderline significant (P=0.048) with a reduction of the instantaneous rate of death of 24%. The 1 and 2 year overall survival rate were respectively 29% (95% CI 21-37%) and 15% (95% CI 8-22%) in arm A and 45% (95% CI 36-54%) and 20% (95% CI 13-27%) in arm B; thereafter, the survival curves became similar. The median progression free survival (PFS) was 5.0 (95% CI 4.6-5.7) versus 6.9 (95% CI 5.3-8.7) months (P=0.028) and the median time to local progression was 6.2 (95% CI 5.1-7.6) months versus 10.9 (95% CI 8.1-15.5) months (P=0.018), respectively, in arms A and B. Haematological toxicities were slightly more commonly observed in the combined group (1% versus 6%). This study shows that split-course irradiation in combination with CDDP is very well tolerated and should be preferred to radiotherapy alone.

CA 125 serum levels in the early post-operative period do not reflect tumour reduction obtained by cytoreductive surgery.

In order to assess whether CA 125 serum levels reflect the outcome of cytoreductive surgery, CA 125 antigen levels were determined prior to and after debulking surgery in 50 ovarian cancer patients and compared to CA 125 serum levels before and after surgery in a control group of 140 patients undergoing laparotomy for various malignant or benign diseases. A significant CA 125 decrease in the first post-operative week was seen in 56% of ovarian cancer patients whereas 26% remained stable and 18% showed a significant increase after surgery. Although removal of tumour had been complete in all 14 stage I-II ovarian carcinomas, only 2 of these patients showed a subsequent significant CA 125 decrease after cytoreductive surgery, while 4 patients showed a significant increase. Such increases of CA 125 following surgery were also seen in uterine carcinomas (30%), in gastrointestinal carcinomas (75%) and in patients after laparotomy for benign gynaecological diseases (23%). CA 125 pre-treatment levels were significantly lower in patients with post-operative increases than in patients with stable or decreasing CA 125 patterns. Patients with stable CA 125 levels also had lower CA 125 pretreatment levels compared to patients with a post-operative CA 125 decrease. Post-operative increases were observed for at least 2 weeks after debulking in the case of ovarian cancer. Pre-operative levels of these patients were either within the normal range or moderately elevated. Serial measurements during surgery in partial debulking showed a rapid CA 125 decline within 24 h followed by increasing CA 125 values thereafter. Our data indicate that CA 125 serum levels in the direct post-operative period do not always reflect the outcome of cytoreductive surgery. There appears to be an effect on CA 125 levels caused by the abdominal surgical procedure itself. Consequently, CA 125 levels after abdominal surgery should be interpreted with caution.

Effect of irradiation on healing of newly made colonic anastomoses in the rat.

PURPOSE: Short-term effects of radiotherapy on the healing process of newly made colonic anastomoses are investigated by measuring the anastomotic strength in a rat model. METHODS AND MATERIALS: Four groups of Wistar rats were used. In all groups, rats underwent a 1 cm sigmoid resection with end-to-end anastomosis. Group I served as a control group. In group II the anastomosis was irradiated after closure of the abdominal wall with a single dose of 20 Gy of 250 kV x rays. Group III was irradiated with a single dose of 20 Gy while the abdominal wall was not closed, and the surrounding tissues were carefully covered by a lead plate, simulating intra-operative radiotherapy. Group IV was treated as group III, but a larger dose of 25 Gy was applied. Animals were sacrificed 3 or 7 days after the operation. General condition of the rats was determined by observation, weight loss, serum protein and albumin at sacrifice. Anastomotic healing was evaluated by inspection, bursting pressure, hydroxyproline and protein contents of the anastomotic segment. RESULTS: Direct postoperative externally irradiated rats (group II) showed a marked weight loss, hypoproteinaemia and hypo-albuminaemia because of involvement of small bowel in the irradiated volume. With respect to anastomotic healing there were no significant differences between control and irradiated groups. CONCLUSION: These data suggest that the application of a single dose of irradiation (20 and 25 Gy) on colonic anastomoses given in a direct postoperative or intraoperative model has no measurable side effect on the early healing of newly made colonic anastomoses. Direct postoperative external irradiation results in unwanted side effects in the adjacent bowel.

Late effects of intraoperative radiation therapy in anastomotic rat colon.

PURPOSE: to determine whether intraoperative radiotherapy causes long-term negative effects on the healing of colonic anastomoses in the rat. METHODS AND MATERIALS: 175 rats were divided into seven equal groups. One group served as sham-irradiated control group. In the others, following a colonic resection, 1 or 2 cm of the distal bowel limb was irradiated with a single dose of 10, 15, or 20 Gy (groups 10/1, 15/1, 20/1, 10/2, 15/2, and 20/2, respectively). Subsequently, an anastomosis was constructed. The animals were killed after 6 (n = 10 in each group) or 12 (n = 15) months. The abdomen was inspected for abnormalities and the colonic diameter was measured. The anastomotic segment was analyzed biochemically (hydroxyproline) and histologically. RESULTS: During the experimental period, 1 rat (group 15/1) died because of anastomotic leakage and 3 others died from unknown causes. There was no difference in colonic diameter between groups. Altogether 17 rats developed an adenocarcinoma in the irradiated area: 11 of these had received a dose of 20 Gy. Histological observation indicated that fibrosis was present only in a limited number of animals, mostly after irradiation with a dose of 15 or 20 Gy. All anastomoses were functional and showed normal histology. The hydroxyproline content of the anastomotic segment was increased--with respect to the control group--only in the 20/2 group after 6 months. After 12 months, the hydroxyproline concentration in the (irradiated) segment distal to the anastomosis proper was higher in the 10/1 and 15/1 groups than in the control group. Otherwise, there were no differences between groups. CONCLUSION: Intraoperative irradiation with a single dose of 10-20 Gy, delivered to the distal limb used for anastomotic construction, does not appear to constitute a threat to anastomotic integrity. Dose-related changes included formation of adenocarcinomas and fibrosis, but function and histology of the anastomosis proper remained unaffected.

Combined preoperative irradiation and direct postoperative 5-fluorouracil without negative effects on early anastomotic healing in the rat colon.

BACKGROUND AND PURPOSE: Preoperative irradiation with direct postoperative chemotherapy could benefit patients undergoing surgery for colorectal cancer. This study was designed to examine, in an experimental model, if such treatment is feasible without detrimental effects on early anastomotic healing. MATERIAL AND METHODS: A colonic segment was irradiated (25 Gy) in 3 groups (n = 10 each) of male Wistar rats. After 5 days, a colonic resection was performed with anastomotic construction; only the distal limb consisted of irradiated bowel. Postoperatively, animals received daily intraperitoneal 5-fluorouracil (5-FU, group I/CH: 17.5 mg/kg; group I/CL: 12.5 mg/kg) or saline (group I). Three additional groups were treated similarly, but with sham-irradiation: CH, CL and C, respectively. All rats were killed 7 days postoperatively. Parameters measured were: weight, serum albumin and protein, and anastomotic bursting pressure, breaking strength and hydroxyproline content. RESULTS: Body weight was diminished significantly in rats receiving chemotherapy. Serum albumin and protein was significantly lower in irradiated groups. At sacrifice, 40% of I/CH rats had functional rectal stenosis. The average bursting pressure (P = 0.0005) and the average breaking strength (P = 0.012) were only reduced significantly in the CH group. The anastomotic hydroxyproline content was significantly higher in the I/CH and I/CL groups vs. the control group. CONCLUSION: High-dose direct postoperative 5-FU leads to reduced anastomotic strength. Although the combination of preoperative irradiation (25 Gy) and direct postoperative high-dose 5-FU does not reduce early anastomotic strength, some stenosis may occur. The combination of preoperative irradiation and low-dose 5-FU has no such effect.

Glutathione, glutathione-s-transferase and p-170 glycoprotein in metastases of malignant melanomas.

P-170 glycoprotein, glutathione and glutathione S-transferases are important in in vitro drug resistance, but their clinical relevance is unclear. Therefore glutathione content, glutathione S-transferase enzyme activity, isoenzyme composition as well as P-170 glycoprotein level were studied in metastases of malignant melanomas of thirteen patients. P-170 glycoprotein and glutathione S-transferases were quantified by immunoblotting with monoclonal antibodies, glutathione S-transferase enzyme activity was measured with 1-chloro-2,4-dinitrobenzene as substrate, and glutathione was assayed by HPLC. Glutathione and glutathione S-transferase enzyme activity were measurable in all samples and mean values were 40+/-7 nmol/mg protein (mean+/-SEM; range: 13-98) and 310+/-72 nmol/min mg protein (range: 15-819), respectively. Glutathione S-transferases present were mainly of class pi (2817+/-402 ng/mg protein); class alpha enzymes were detectable only in one case in low amounts (71 ng/mg protein), and class mu transferases were present in 5 out of the 13 samples (38%; 391+/-206 ng/mg protein). The P-170 glycoprotein plasma membrane located drug efflux pump was found in 8 out of 12 samples (67%). In three samples values were much higher as compared to the other specimens. In the metastatic melanoma of one patient, both high levels of glutathione S-transferase and P-170 glycoprotein were found. Further studies are necessary to reveal whether melanoma tissues containing high levels of P-170 glycoprotein, glutathione S-transferases or a combination of both systems do respond differently towards anti-cancer drug treatment.

The effect of zymosan-induced generalized inflammation on tumor-growth in a rat renal-cell carcinoma model.

We investigated the inhibition of tumour growth by induction of a generalized inflammatory response. 45 Lewis rats were randomly divided in three groups. A rat renal cell carcinoma was transplanted subcutaneously on day one in group I and group II. When the tumour became measurable on day 16, a generalized inflammation was induced by intraperitoneal injection with a suspension of zymosan and paraffin in group I and in group III, consisting of non-tumour bearing animals. Group II was inoculated with paraffin only. Seven and 14 days following intraperitoneal injection two rats out both group I and group II were sacrificed in order to obtain tumour biopsies at different stages of a generalized inflammatory response. Spontaneous mortality occurred twice in group III, consisting of non-tumour bearing animals. On day 37 all surviving rats were killed. Microscopical examination was carried out on all tumours and on lungs, liver, spleen and kidneys. A generalized inflammation response was confirmed in group I and III through biologic and microscopic parameters. After a zymosan induced generalized inflammation response in the rat, tumour growth rate was significantly lower compared with paraffin treated animals.

Towards a more standardized assessment of diagnostic tumor-markers.

The estimation of sensitivity and specificity are mainly used as summary measures of diagnostic power of new diagnostic tests. Unfortunately, the positive assessment outcome is often recanted, frequently because only a preliminary assessment is done in a highly selected population of already diagnosed patients and healthy individuals. Furthermore, diagnostic marker outcomes are dichotomised for the calculation of sensitivity and specificity, with loss of information as a consequence. We plead for the presentation of all relevant diagnostic information, which includes extensive description of the composition of the study group, distributions of test results for different patient groups and the use of the ROC curve and the area under it as the statistical summary measure.

High-dose preoperative irradiation without detrimental effect on early repair of anastomoses in the colon of the rat.

Preoperative radiotherapy as an adjunct to surgery for rectal carcinoma is generally thought to impair the healing of colorectal anastomoses. To delineate the presumed hazards of preoperative irradiation, we investigated this effect in a new model where, in contrast to experiments reported so far, anastomoses were constructed using normal tissue for the proximal limb and irradiated tissue for the distal limb. A group of 120 male Wistar rats, divided randomly into 12 groups of 10 each, were used. In 60 animals, a colonic segment of 2.2 cm was irradiated with a single dose of 25 Gy X rays administered 28 or 5 days or 3 or 1 day(s) before colonic resection. For each experimental group, a control group was included which was sham-irradiated on the same preoperative day. The animals were sacrificed on the third or the seventh postoperative day, and healing of the anastomosis was evaluated by measurement of bursting pressure, breaking strength and hydroxyproline concentration and content. Comparison between each experimental group and its control group showed that preoperative irradiation did not reduce the strength of the anastomoses. Also, the concentration and content of hydroxyproline in the tissue of the anastomoses were unchanged. These data indicate that construction of a colonic anastomosis consisting of one irradiated bowel end in rats is not by definition detrimental to the development of early wound strength.

Intra-operative irradiation prolongs the presence of matrix metalloproteinase activity in large bowel anastomoses of the rat.

There exists a growing interest in intra-operative radiation therapy as a treatment modality for large bowel cancer. In a previous experimental study we showed that high-dose intra-operative irradiation delays the healing of colonic anastomoses. However, the contribution of proteases is unknown. In the present study, the gelatinolytic and collagenolytic activity in the healing anastomoses is investigated. After a resection of a 1-cm length of colon (uninjured colon), the rats were irradiated with a single dose of 25 Gy, either to the proximal limb, referred to as the proximal group, or to both proximal and distal limbs of the bowel, referred to as the combined group, before anastomotic construction. Both groups were compared to a control group with anastomoses which were sham-irradiated. The animals were killed 1, 3 or 7 days after operation. The gelatinolytic activity in uninjured and anastomotic tissue was quantified by gelatin zymography and the collagenolytic activity by an assay using a fibrillar rat collagen substrate. Compared with resected uninjured colon, most of the gelatinolytic activities were markedly increased in anastomotic tissue of all groups during the first postoperative week, and new additional activities were detected. The additional metalloproteinases (the 95-kDa family) of both irradiated groups were significantly elevated compared to the anastomoses of the sham-irradiated control group at 7 days after operation. In anastomotic tissue of all groups, the collagenolytic activity of the tissue was also significantly increased at 1 and 3 days after construction with respect to the resected, uninjured colon. After 7 days this effect had disappeared for the sham-irradiated anastomoses, but the activity in the anastomoses in both the proximal and combined groups remained significantly elevated. The findings provide evidence that intra-operative irradiation prolongs the presence of elevated gelatinolytic and collagenolytic activities in colon anastomoses. It may contribute to a reduced or delayed accumulation of collagen and other matrix proteins that supply anastomotic strength.

Moderate doses of intraoperative radiation severely suppress early strength of anastomoses in the rat colon.

Intraoperative irradiation appears to be a valuable addition to the modalities available to treat patients with large bowel cancer. However, its potential effect on healing of anastomoses has not been investigated extensively. For this purpose, male Wistar rats underwent colonic resection. Subsequently, 1 cm of each bowel end was irradiated with doses of 10, 15, 20 or 25 Gy and intestinal continuity was restored. After 3 or 7 days, animals were killed and the anastomoses were analyzed for bursting pressure (intraluminal force), breaking strength (longitudinal force) and hydroxyproline content. Intraoperative irradiation led to a massive (40-70%) and significant (P < 0.025) reduction in bursting pressure 3 days after operation compared to the control group for every dose used. After 7 days, the bursting site was outside the area of the anastomosis in all groups. The breaking strength at day 3 was also reduced, even after 10 Gy. At day 7, when tearing still occurred in the wound area, the breaking strength was still significantly lower in the 15- and 25-Gy groups than in the control group. The hydroxyproline content of the anastomoses was significantly reduced only after irradiation with the higher doses. Thus intraoperative irradiation constitutes a threat to early strength of anastomoses in the rat colon, and even at moderate doses it may threaten the integrity of the anastomosis.