Healing of colonic anastomoses after immediate postoperative intraperitoneal administration of oxaliplatin

Aim  The aim of this experimental study was to investigate the effect of intraperitoneal administration of oxaliplatin on the healing of colonic anastomoses when injected immediately after colon resection. Materials and methods  Thirty male Wistar rats were used. During the operation, the rats were randomized to two groups of 15 rats each. Immediately after colonic anastomoses were performed, the rats were injected intraperitoneally with either 3 ml of 0.9% NaCl solution or oxaliplatin (2.4 mg/kg body weight) depending on their group. All rats were killed on the eighth postoperative day. The anastomoses were examined macroscopically. The anastomotic bursting pressures were recorded, the anastomoses graded histologically, and the hydroxyproline tissue contents determined. Results  Anastomotic leakage was noted in four rats (26.7%) of the oxaliplatin group, whereas no anastomotic dehiscence was detected among rats of the control group (p = 0.016). The adhesion formation at the anastomotic sites and the inflammatory cell infiltration were significantly higher in the oxaliplatin group than in the control group (p = 0.001). The bursting pressures (p = 0.001), the hydroxyproline tissue content (p = 0.001), the neoangiogenesis (p = 0.033), the fibroblast activity (p = 0.001), and the collagen deposition (p = 0.001) were significantly lower in the oxaliplatin group in comparison to the control group. Conclusion  The immediate postoperative intraperitoneal administration of oxaliplatin seems to impair healing of colonic anastomoses in rats.     

Histological evaluation of colonic anastomotic healing in the rat following preoperative 5-fluorouracil, fractionated irradiation, and combined treatment

There is a growing interest in neoadjuvant chemo- and radiotherapy as a treatment modality for colorectal cancer which could affect mechanical and biochemical parameters of anastomotic healing. This study investigated the effect of such protocols on colonic anastomotic healing by evaluating the histopathological parameters. One hundred and sixty male Wistar rats were divided into six groups: a control group (I, n=20), a saline group (II, n=30) which received 1 ml NaC1 intraperitoneally, a sham-irradiated group (III, n=20), a 5-fluorouracil (5-FU) group (IV, n=30), which received 5-FU (20 mg/kg) intraperitoneally for 5 consecutive days, an irradiated group (V, n=40) which received fractionated irradiation to the whole pelvis to a totaldose of 22 Gy, 5.5 Gy per fraction on 4 consecutive days, and a concomitant 5-FU + irradiation group (VI, n=20) which received 5-FU as in group IV and irradiated as in group V. All groups underwent left colonic resection with primary anastomosis, and the last fraction of irradiation and the last injection were given 4 and 3 days before the operation, respectively. Within each group one half of the animals were killed on the third postoperative day and the other half on the seventh postoperative. day. After the resection of the anastomotic segments, histopathological examination was evaluated. Apposition of the wound edges of the mucosa and the muscularis were not affected by the therapy. The level of granulocytes was high, inflammatory exudate and necrosis persisted, granulation tissue formation was delayed, and the levels of macrophages and fibroblasts were low. We conclude that colonic anastomotic healing can be affected by the administration of preoperative chemotherapy, irradiation, and chemoirradiation. Accepted: 17 July 1998     

Surgical complications after preoperative irradiation of Ewing's sarcoma

The influence of preoperative irradiation on surgical complications in 42 patients with Ewing's sarcoma was analysed. After preoperative irradiation and chemotherapy, 35 of 40 patients showed a good histological response and 25 of 40 patients had no viable tumour cells in the resected specimen. Local relapse alone did not develop, local relapse and metastasis developed in 2 patients and metastasis alone in 15 patients. Surgical complications appeared in 12 of 42 patients: 9 of 19 central tumours (19 pelvic lesions), 1 of 13 proximal and 2 of 10 distal tumours. Surgical complications after preoperative irradiation are distributed as follows: delayed wound healing 8, hematoma 2, thrombosis 2, skin infection 1, and abscess 1. On the other hand, complications appeared in 2 of 28 patients without preoperative irradiation: none in 9 patients having central tumours including 2 pelvic lesions, 1 in 12 patients with proximal tumours, and 1 in 7 patients with distal tumours. The multivariate regression test showed that the tumour site (central) is an influencing factor in the appearance of surgical complications. In central tumours, the surgical complication rate increases after preoperative irradiation; however, it is affected by the increase of the ratio of patients with pelvic tumours.The first and second authors contributed equally to this work, so the second author is also qualified as the first author     

Effect of fibrin glue on irradiated colonic anastomoses

INTRODUCTION: The present study was planned to research the effects of fibrin glue on irradiated colonic anastomoses. METHOD: The effect of fibrin glue on irradiated colonic anastomoses was investigated in four identical groups of rats. In Group I (control group) colonic anastomoses were performed without radiotherapy; in Group II, colonic anastomoses were performed five days after radiotherapy; in Group III, fibrin glue was applied to anastomotic line without radiotherapy; in Group IV, fibrin glue was applied to anastomotic line with radiotherapy. The healing of left colonic anastomoses was evaluated through the bursting pressure of the anastomotic segment and the hydroxyproline contents of the anastomosis. RESULTS: Measurements done on the fourth postoperative day revealed that anastomotic healing was impaired in rats that underwent radiotherapy ( P <0.001); fibrin glue had no effect on anastomotic healing in groups with or without radiotherapy. CONCLUSION: In the early phases of anastomotic healing, fibrin glue cannot help remove unwanted effects of preoperative radiotherapy.     

The effects of preoperative radiation on healing of rat colonic anastomoses

The effect of delaying surgery, after a nominal standard dose of 4500 rad was administered to the abdomen of rats, on the healing of colonic anastomoses was evaluated. Healing, as determined by bursting pressure of colonic segments, was significantly depressed (p<0.05) at five days after surgery in groups irradiated five or 15 days prior to surgery as compared with groups receiving either no radiotherapy or irradiation ten days prior to surgery. Five-day healing was not significantly depressed in the group irradiated ten days prior to operation as compared with the group receiving no irradiation. No significant (p<0.05) differences were noted at ten or 15 days after surgery between groups that were and were not irradiated. At ten days after surgery all groups had higher bursting pressures than the control group at five days after surgery. Thus, there appears to be an optimal time interval between radiation and surgery to ensure maximal colonic healing.     

Effects of amniotic membrane on the healing of normal and high-risk colonic anastomoses in rats

Bacground  This study was aimed at examining whether or not the addition of amniotic membrane to a sutured colonic anastomosis improves its healing. Material and methods  Ninety female Sprague Dawley rats were used in the study. Ten served as controls for bursting pressure measurement, while the other 80 animals were divided into four groups: Anastomosis group (NA), high-risk anastomosis group (HRA), anastomosis plus amniotic membrane group (NA-AM), and high-risk anastomosis plus amniotic membrane group (HRA-AM). The last two groups had amniotic membrane covering their anastomoses. Anastomotic evaluation was carried out on the third (NA3, HRA3, NA-AM3, and HRA-AM3, respectively) and seventh (NA7, HRA7, NA-AM7, and HRA-AM7, respectively) postoperative days. The main outcome measures were gross anastomotic healing, adhesion formation, mechanical strength, hydroxyproine content, and parameters of histopathological healing. Results  Anastomotic dehiscence rate was 66.7%, 40%, 20%, and 10% in group HRA7, HRA3, NA7, and NA3, respectively. However, there was no significant difference between groups regarding the dehiscence rate. The adhesion scores were significantly higher in groups NA3 and HRA3 compared with groups NA-AM3 and HRA-AM3, respectively (p < 0.05, p < 0.001). Bursting pressure was significantly higher in groups with amniotic membrane compared without amniotic membrane (p < 0.05, for all comparison). Inflammatory cell infiltration was significantly lower in groups with amniotic membrane compared with groups without amniotic membrane (p < 0.05, for all both comparisons). Neoangiogenesis was significantly higher in the NA-AM3 and HRA-AM3 groups compared with the NA3 (p < 0.01) and HRA3 (p < 0.05) groups, respectively. Fibroblast activity was significantly higher in groups NA-AM3 and NA-AM7 compared with groups NA3 (p < 0.05) and NA7 (p < 0.05), respectively. Collagen deposition and hydroxyproline concentrations were significantly higher in groups with amniotic membrane compared with groups without amniotic membrane (p < 0.05, for all both comparisons). Conclusion  The covering of both normal and high-risk colonic anastomoses with amniotic membrane provides a beneficial effect over conventional suturing of healing. This study was presented as an oral presentation in the 18th World Congress of the International Association of Surgeons, Gastroenterologists, and Oncologists.     

Comparison of electromagnetic field stimulation on the healing of small and large intestinal anastomoses

PURPOSE: Magnetic fields have been shown to affect biologic processes. Accordingly, an experimental study was designed to investigate the effect of electromagnetic field stimulation on intestinal healing and to compare small and large intestinal anastomoses. METHODS: An ileal or a colonic anastomosis was constructed in rats. Beginning the day after surgery, randomly assigned groups were exposed to sinusoidal electromagnetic field stimulation of 10.76-mT intensity and 50-Hz frequency, with 2-hour-on/10-hour-off cycles. After seven days, intestinal anastomoses were assessed for hydroxyproline content and breaking strength. Statistical comparison between each experimental and control group yielded significance (P<0.05) in all cases. RESULTS: Hydroxyproline content increased significantly in ileum from 1.650±0.11 (mean ± standard error of the mean) to 2.036±0.11µg/mg (P=0.0249) and in colon from 1.526±0.11 to 1.922±0.11µg/mg (P=0.0135). Breaking strength also increased significantly in ileum from 0.213±0.01 to 0.255±0.01 MPa (P=0.001) and in colon from 0.227±0.01 to 0.270±0.01 MPa (P=0.006). CONCLUSIONS: Electromagnetic field stimulation provided a significant gain in anastomotic healing in both small and large intestine. There were no apparent differences detected between the healing of small and large intestinal anastomoses except for slight differences in the time sequences of events and magnitude. The study demonstrated a significant increase in both biochemical and mechanical parameters. Additional investigations are needed to determine optimal conditions and promote selective biologic responses.     

Combined treatment of colonic cancer

One hundred seventy-eight patients with cancer of different segments of the colon were treated with preoperative radiation and surgery. Preoperative radiation with 25 MeV betatron was employed according to the method developed by the authors. Radiation treatment was tolerated by patients in the absence of manifest general and local reactions. No decrease below 3000 in the rate of leukocytes was observed after a total dose of up to 40 Gy. After radiotherapy, improvement in the general state was achieved in 72 percent and positive roentgenologic findings were seen in 70.8 percent of patients. The preoperative irradiation therapy was followed by 153 radical and 28 palliative operations. There was no increase in postoperative morbidity or mortality. The morphologic study of surgical specimens showed that considerable changes in the tumoral tissue, including disappearance of cancer cells, were seen in 75 percent of cases. The five-year survival rate of 112 patients after radical surgery indicates that it is worthwhile to use the combined treatment approach for tumors located in the right colon and in cases of suspected or existing infiltration into adjacent organs and tissues. Editorial Comment Our Journal is pleased to receive this contribution from the Soviet Union. The paper does not fall into the usual format of our Journal, and the subjective format of the authors leaves many unsubstantiated claims in the paper. Nevertheless, it provides unique insight into practices in the Soviet Union and into an exceptionally large experience in the management of colon and rectal cancer. For these reasons, we believe the paper warrants publication although its format is somewhat unusual.     

Effects of high-dose and low-dose preoperative irradiation on low anterior anastomoses in dogs

Twenty mongrel dogs underwent preoperative irradiation to the colon and rectum, receiving 4000 rads according to the Nominal Standard Dose Equation. Each dog then underwent anterior resection of the rectosigmoid, and reconstructive technique was randomized into two groups consisting of either handsewn or EEA-stapled anastomoses. Anastomoses were examined digitally and radiographically at the time of surgery and on the seventh postoperative day. There were four radiographic leaks among the handsewn anastomoses, but only one was clinically significant and associated with peritonitis. There were no leaks among the ten EEA-stapled anastomoses. The data suggest that low anterior resection and anastomosis can be done safely after 4000 rad irradiation and that the EEA-stapled anastomosis may be preferable. Presented as part of symposium at the meeting of the American Society of Colon and Rectal Surgeons, Colorado Springs, Colorado, June 7 to 11, 1981.     

Changes in tumor proliferation of rectal cancer induced by preoperative 5-fluorouracil and irradiation

PURPOSE: This study examines the effect of 5-fluorouracil administration during preoperative irradiation on rectal cancer tumor proliferation. PATIENTS AND METHODS: One hundred and fifty-three patients with locally advanced rectal cancer received 45 to 50 Gy of preoperative irradiation with (103 patients) and without (50 patients) concurrent 5-fluorouracil, followed by surgery. Pretreatment tumor biopsies and postirradiation surgical specimens were scored for proliferative activity by assaying the extent of Ki-67 and proliferating cell nuclear antigen immunostaining and the number of mitoses per ten high-powered fields. Postirradiation specimens were also assessed for downstaging. RESULTS: Although 5-fluorouracil did not improve downstaging rates, marked decreases in the activity of all three markers of proliferation (mitotic counts, Ki-67, and proliferating cell nuclear antigen immunostaining) were seen in rectal cancers of patients receiving the drug. No significant decreases were noted in patients undergoing irradiation only. CONCLUSION: The addition of 5-fluorouracil to preoperative irradiation resulted in a more complete inactivation of the proliferating population. Frequency of downstaging, however, was unaffected. Thus, the quiescent cell population appears to represent a substantial barrier to further downstaging. New treatment strategies should be aimed at controlled recruitment of quiescent tumor cells at the time of irradiation.     

Tempol prevents harmful effects of remote ischemia reperfusion injury on healing of experimental colonic anastomoses

Background and aims Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is a water-soluble analogue of the spin label TEMPO. As an antioxidative agent, it is a member of nitroxides, which detoxifies superoxide and possibly other toxic radicals in vivo. In this study, we aimed to investigate whether tempol prevents harmful systemic effects of superior mesenteric ischemia-reperfusion on left colonic anastomosis in rats. Materials and methods Anastomosis of the left colon was performed in 30 rats that were divided into three groups each having ten animals: sham-operated control (group I), 60 min of intestinal ischemia-reperfusion by superior mesenteric artery occlusion (group II), and tempol-treated group (30 mg/kg before and after the ischemia-reperfusion (group III). On postoperative day 5, all animals were killed and anastomotic bursting pressures were measured in vivo. Tissue samples were obtained for further investigation of anastomotic hydroxyproline content, perianastomotic malondialdehyde, and glutathione levels. Results There was a statistically significant increase in the quantity of myeloperoxidase activity and malondialdehyde levels in group II, along with a decrease in glutathione levels, anastomotic hydroxyproline content, and bursting pressure values when compared to controls. However, all of the investigated parameters were normalized in tempol-treated animals (group III). Conclusion We conclude that tempol significantly prevents harmful systemic effects of reperfusion injury on colonic anastomoses in a rat model of superior mesenteric artery occlusion.     

Healing of colonic ischemic anastomoses in the rat

PURPOSE: The aim of this study was to evaluate the role of superoxide radicals in the healing of ischemic colonic anastomoses in the rat. METHODS: Adult male Wistar rats were used in a factorial design with two factors (normal or ischemic colonic anastomoses) each having two levels (treatment with saline or allopurinol). Colonic anastomoses were performed either in normal or previously devascularized colons (ischemic anastomoses) at identical locations, using the same technique. On the fourth postoperative day, animals were killed, and specimens were taken for determinations. RESULTS: Ischemic anastomoses displayed significant increases in superoxide radical (assayed as superoxide anion), superoxide dismutase, and glutathione peroxidase concentrations. Bursting strength and hydroxyproline levels were also significantly lower in these anastomoses. Allopurinol administration elicited a significant decrease in superoxide anions and raised both bursting strength and hydroxyproline levels only in ischemic anastomoses. CONCLUSIONS: Superoxide radicals are involved in the delay in healing of ischemic anastomoses. Allopurinol lowers superoxide anion production and has beneficial effects on the cicatrization of ischemic anastomoses.     

Effects of the use of fibrin glue around the colonic anastomosis of the rat

Abstract. Background: This study was aimed at examining whether the addition of fibrin glue to a sutured colonic anastomosis improves its healing or not. Methods: We studied the effect of adding fibrin glue on a sutured colonic anastomosis. Thirty-six Wistar rats were randomized into two groups of 18 rats each. A sutured anastomosis was performed in all rats. Fibrin glue was applied around the anastomosis of the rats of group B. Rats were sacrificed on the eighth postoperative day. Results: The rate of anastomotic leakage was found not to be significantly different between the two groups. The mean bursting pressure of the colonic anastomoses was significantly higher in group B (fibrin-treated) than in group A. Conclusion: Fibrin glue application around a sutured anastomosis provides a safer anastomosis which is stronger than the sutured one.     

Effect of early preoperative 5-fluorouracil on the integrity of colonic anastomoses in rats

AIM： To determine the effect of chemotherapy on wound healing by giving early preoperative 5-fluorouracil （5-FU） to rats with colonic anastomoses.METHODS： Sixty Albino-Wistar male rats （median weight, 235 g） were used in this study. The rots were fed with standard laboratory food and given tap water ad libitum. The animals were divided into three groups： Group 1： Control group （chemotherapy was not administered）, Group 2： Intraperitoneally （IP） administered 5-FU group （chemotherapy was administered IP to animals at a dose of 20 mg/kg daily during the 5 d preceeding surgery）, Group 3： Intravenously （IV） administered 5-FU group. Chemotherapy was administered v/a the penil vein, using the same dosing scheme and duration as the second group. After a 3-d rest to minimize the side effects of chemotherapy, both groups underwent surgery. One centimeter of colon was resected 2 cm proximally from the peritoneal reflection, then sutured intermittently and subsequently end-to-end anastomosed. In each group, half the animals were given anaesthesia on the 3rd postoperative （PO） day and the other half on the 7th PO day, for in vivo analytic procedures. The abdominal incisions in the rats were dissected, all the new and old anastomotic segments were clearly seen and bursting pressures of each anastomotic segment, tissue hydroxyproline levels and DNA content were determined to assess the histologic tissue repair process. RESULTS： When the IV group was compared with the IP group, bursting pressures of the anastomotic segments on the 3rd and 7th PO days, were found to be significantly decreased, hydroxyproline levels at the anastomotic segment on the 7th PO day were significantly decreased （P 〈 0.01）. CONCLUSION： In this study, we conclude that early preoperative 5-FU, administered IV, negatively affects wound healing. However, IP administered 5-FU does not negatively affect wound healing.     

Early infective complications and late recurrent cancer in stapled colonic anastomoses

Between 1978 and 1981, 73 patients with colonic or rectal cancer were randomized to have their anastomoses made by either a single interrupted layer of braided polyester sutures, or by a circular stapling instrument. Of these operations, 20 were considered to have been palliative, the remaining 53 being potentially curative. The incidence of local recurrence in the latter group was analyzed in relation to initial septic and anastomotic complications. The 53 patients were followed for a median of 36 months (range, 1 to 87); 24 were alive and well and 22 had died of disseminated cancer or unrelated causes. Seven patients died with local recurrent disease proved at laparotomy or autopsy after a median of 33 months (range, 3 to 72). Thirty anastomoses were stapled and 23 sutured; of the seven patients who died with local recurrent disease, six had stapled anastomoses (Fisher's exact probability F₂=0.12; log rank chi-square=3.53, 0.05<P<0.10). Two patients who died with locally recurrent disease had had clinically apparent anastomotic leads and one other patient had had a radiologically demonstrated leak. This compares with a total of seven leaks (clinical or radiologic) in the remaining group of 46 patients with no recurrence (Fisher's exact probability F₂=0.11). These results tend to support the hypothesis that anastomotic leaks may lead to locally recurrent disease, particularly after stapled anastomoses Supported by the Scarborough Research Fund.     

Clinically resectable adenocarcinoma of the rectum treated with preoperative irradiation and surgery

Seventy-four patients with clinically resectable adenocarcinoma of the rectum were treated with preoperative irradiation and surgery at the University of Florida between August 1975 and February 1982. All patients have been folloved for at least five years. Between 1975 and 1978, 29 patients received 3500 cGy; thereafter the dose was increased to 4000 to 5000 cGy for the remaining 45 patients. All patients were treated at 180 cGy per fraction. Following preoperative irradiation, 65 of 74 patients (88 percent) underwent complete resection of their lesions. Compared with a series of historical controls treated with surgery alone, the local recurrence rate at five years was 5 of 65 (7.7 percent)vs. 39 of 135 (29 percent) (P=.001), and the five-year absolute survival was 43 of 65 (66 percent)vs. 51 or 135 (38 percent) (P<.001). The local recurrence rate was 13 percent for patients receiving 3500 cGy and 5 percent for doses of 4000 to 5000 cGy. There was no apparent increased incidence in postoperative complications in the preoperatively irradiated patients. Presented at a panel discussion at the 28th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Los Angeles, California, November 2 to 7, 1987.     

黄连素对大鼠结肠上皮隐窝细胞基底膜钾通道的影响

目的研究黄连素对结肠上皮隐窝细胞基底膜钙依赖钾通道[IK（Ca）]和环磷酸腺苷（cAMP）依赖钾通道[IK（cAMP）]的影响，探讨其治疗分泌性腹泻的机制。方法用乙二胺四乙酸（EDTA）溶液分离结肠上皮隐窝细胞，运用EPC10膜片钳放大器测量全细胞模式下50、100、500μmol／L黄连素对结肠上皮细胞基底膜IK（Ca）和IK（cAMP）的影响，并设PSS对照组。结果50、100、500μmol／L黄连素可抑制大鼠结肠上皮隐窝细胞基底膜IK（Ca）和IK（cAMP）（P值均〈0．05），当阶跃刺激为＋80mV时，其IK（Ca）分别为对照组的（71．43±3．61）％、（54．56±5．13）％、（38．66±3．85）％（P〈0．05）；其IK（cAMP）分别为对照组的（78．55±5．72）％、（60．42±6．33）％、（43．78±6．47）％（P〈0．05）。结论黄连素能抑制大鼠结肠上皮细胞基底膜IK（Ca）和IK（cAMP）的开放，这可能是其治疗分泌性腹泻的机制之一。     

Intravenous butyrate and healing of colonic anastomoses in the rat

PURPOSE: Intracolonic infusions of short chain fatty acids promote healing of colonic anastomoses. Because the intravenous route may have wider clinical application, we studied the effect of intravenous n-butyrate on the mechanical strength of colonic anastomoses in the rat. METHODS: After placement of an indwelling intravenous catheter, the descending colon was transected and an anastomosis was performed. Rats were then randomized to receive total parenteral nutrition (TPN group; n=15) or total parenteral nutrition plus 130 mM/1 of n-butyrate (TPN+BUT group; n=13). On the fifth postoperative day, bursting pressure and bowel wall tension of the anastomoses were measured in situ.Anastomotic tissues were analyzed for hydroxyproline. RESULTS: The TPN+BUT group had a significantly higher bursting pressure (107.5±30.3 vs. 83±41.0 mmHg;P =0.04) and bowel wall tension (20.7±7.6 vs. 14.1±99 Newton;P =0.03). Tissue hydroxyproline was not different between the two groups (TPN, 45.8±9.2, and TPN+BUT, 47.9±2.9 μg/mg tissue nitrogen). CONCLUSIONS: We conclude that intravenous butyrate improves mechanical strength of a colonic anastomosis without a detectable change in total collagen content.     

Comparison of oral lavage methods for preoperative colonic cleansing

Polyethylene glycol electrolyte lavage solution was compared with a 10 percent mannitol solution for preoperative colonic cleansing. Eighty patients were prepared randomly with one of these solutions on the afternoon prior to surgery. Colonic cleansing was better with polyethylene glycol electrolyte lavage (90 percent optimal cleansingvs. 75 percent). Analysis of hematologic, biochemical, and weight changes before and after the bowel preparation, demonstrated a mild subclinical dehydration with the use of mannitol. Evaluation of patient tolerance demonstrated more nausea, cramps, and abdominal pain with mannitol. Other symptoms were similar with both preparations. Colonic hydrogen gas was sampled during surgery, and two patients in the mannitol group had combustible levels. This study confirms that both 10 percent mannitol and polyethylene glycol electrolyte lavage are safe, effective methods of preoperative bowel cleansing. Better cleansing, patient tolerance, and lower hydrogen gas level make polyethylene glycol electrolyte lavage the preferred method. Poster presentation at the metting of the American Society of Colon and Rectal Surgeons, Houston, Texas, May 11 to 14, 1986. The opinions expressed are those of the authors and do not reflect the opinions of the United States Air Force, the Department of Defense or the Cleveland Clinic Foundation.