Ian G. Finlay

Large volume hepatic freezing: Association with significant release of the cytokines interleukin-6 and tumor necrosis factor a in a rat model

Although cryotherapy of liver tumors is generally considered a safe procedure, a syndrome of coagulopathy and fatal multiorgan failure has been observed in some patients and is called the cryoshock phenomenon. Our aim was to establish an animal model of this phenomenon and examine the effects of the basic parameters of freezing or cryotherapy on it. A group of 75 female Sprague-Dawley rats were allocated randomly to five groups: (1) sham laparotomy (n=15); (2) small (25% liver volume) single freeze (n=15); (3) small (25% liver volume) double freeze (n=15); (4) large (50% liver volume) single freeze (n=15); (5) large (50% liver volume) double freeze (n=15). Blood samples were collected at different postoperative times, and organs were harvested for histopathology. There was a significant release of tumor necrosis factor-α (TNFα:) and interleukin 6 (IL-6) following hepatic freezing, which was greatest in group 5. Postoperative serum cytokine levels were significantly associated with hepatocellular injury, as measured by postoperative serum aspartate transaminase (AST) concentrations. Severe hemoglobinuria and renal injury, as demonstrated by the serum creatinine level and the glomerular neutrophil count, were observed and were greatest in group 5. Hepatic cryosurgery is associated with release of IL-6 and TNFα and renal injury in a rat model. It is likely that the cryoshock phenomenon is another form of the systemic inflammatory response syndrome. Based on the results of this study, it is possibly mediated by cytokines released from the frozen liver tissue. We therefore caution against cryothérapy of large tumor volumes.RésuméAlors que la cryothérapie des tumerus du foie est généralement considérée comme un procédé sur, on peut observer quelque fois un syndrome de coagulopathie et de défaillance multiviscérale fatale, appelé le phénomène du «cryochoc». Notre but a été et d’étudier les effets de la cryothérapie sur les paramètres de base chez un modèle animal. 75 rates femelles Sprague-Dawley ont été randomisées en cinq groupes: (1) laparotomie factice «sham» (n=15); (2) un seul «gel» de petit volume (25% volume du foie) (n=15): (3) deux «gels» de petit volume (25% du volume du foie) (n=15); (4) un seul «gel» de volume important (50% du volume du foie) (n=15); (5) deux «gels» de volume important (50% du volume du foie) (n=15). Les échantillons sanguins ont été collectés à des moments postopératoires différents et les organes ont été prélevés pour examen histopathologique. On a constaté un largage significatif de TNFα: et d’IL-6 après cryothérapie du foie, plus important dans le groupe 5. Les taux de cytokines du sérum ont été significativement córreles avec les lésions hépatocellulaires, mesurées par les taux postopératoires des AST. Une hémoglobinurie et des lésions rénales sévères, mises en évidence par un taux élevé de créatinine et par la numération des neutrophils, ont été observées surtout dans le groupe 5. La cryothérapie hépatique est associée à un largage d’lL-6 et de TNFα ainsi que de lésions rénales dans le modèle du rat. 11 est probable que le phénomène du cryochoc est une manifestation du syndrome de réponse systémique inflammatoire. Basé sur les résultats de cette étude, on pense que les cytokines largués par le tissu hépatique refroidi sont les médiateurs de ce phénomène. Nous ne recommandons donc pas la cryothérapie pour les tumeurs volumineuses.ResumenAunque la crioterapia de los tumores hepáticos es una técnica bastante segura, se han descrito algunos casos en los que se produjo un sÍndrome coagulopático y fracaso multiorgánico mortal. Este sÍndrome se ha considerado como un fenómeno del crioshock (shock por congelación). El objetivo del trabajo fue conseguir un modelo animal del llamado fenómeno del crioshock y evaluar en el mismo, los efectos de la congelación o de la crioterapia sobre parámetros básicos. 75 ratas hembras Sprague-Dawley se distribuyeron de forma aleatoria en 5 grupos: (1) Laparatomía simulada ( n=15); (2) Pequeña (25% del volumen hepático) congelación única (n=15); (3) Pequeña (25% volumen hepático) congelación doble (n=15); (4) Gran (50% volumen hepático) congelación única (n=15); (5) Gran (50% volumen hepático) congelación doble (n=15). Muestras de sangre se obtuvieron en diversos momentos del periodo postoperatorio y los órganos fueron recogidos para su ulterior estudio histopatológico. Tras la congelación hepática se constato una significativa liberación de TNFα y IL-6, que fue más marcada en el grupo 5. Los niveles séricos de citocinas en el postoperatorio guardan estrecha relación con el trauma hepatocelular, como se constató midiendo las concentraciones séricas postoperatorias de la AST. Se observó grave hemoglobinuria y lesión renal, demostrada por los valores séricos de creatinina y el recuento de neutrófilos en los glomerulos, siendo estas alteraciones mucho más graves en el grupo 5. En un modelo de rata la criocirugía hepática produce una liberación de IL-6 y TNFα así como lesiones renales. Posiblemente el denominado fenómeno del crioshock no es más que una forma diferente del sÍndrome de respuesta sistémica inflamatoria. Según nuestros hallazgos los mediadores de dicho fenómeno son citocinas liberadas del tejido hepático congelado. De ahí, que se aconseje prudencia en la crioterapia de grandes tumores hepáticos.

Cutting seton without preliminary internal sphincterotomy in management of complex high fistula-in-ano

PURPOSE: The traditional treatment of a complex high fistula-in-ano by internal sphincterotomy and insertion of a cutting seton carries a risk of fecal incontinence. We have assessed the functional impact of treating patients with a complex fistula-in-ano by a cutting seton fistulotomy technique that preserves the internal sphincter. METHODS: The operative steps consisted of initial eradication of sepsis, identification of the internal and external openings of the fistula tract, excision of the fistula tract with anal canal mucosa, and insertion of a cutting silk seton around both the internal and external sphincters. In this way open drainage of the intersphincteric space was avoided, and integrity of the internal sphincter was maintained. Functional outcome following treatment with this technique, with regard to fistula eradication and effect on fecal continence was assessed in 27 patients (15 males) who were treated during a six-year period. Twenty-three patients (85 percent) had a history of previous fistula surgery. RESULTS: The fistula was cured in 26 patients (96 percent) with no reports of altered continence at the time of discharge from outpatient review. Recurrence developed in one patient (4 percent) in whom hidradenitis suppurativa was subsequently diagnosed. All four patients with Crohns disease had their fistulas eradicated; three (75 percent) have subsequently undergone proctectomy for severe perianal and rectal Crohns involvement. Long-term follow-up revealed three patients (19 percent, all rectovaginal fistulas) who experienced a deterioration in continence after discharge. CONCLUSIONS: Although this procedure may not be appropriate for rectovaginal fistulas, the data suggest that cutting setons are effective in treating complex fistula-in-ano, including those that have failed to respond to other forms of surgery. Avoidance of preliminary internal sphincterotomy may prevent deterioration in continence.

Factors that Predict Complications After Construction of a Stoma: A Retrospective Study

OBJECTIVE To find out our incidence of complications of stoma surgery and identify variables that predict outcome. DESIGN Retrospective study. SETTING Teaching hospital, Scotland. SUBJECTS All 121 patients who had 126 stomas constructed during 1996. INTERVENTIONS Follow up until the end of 1999. MAIN OUTCOME MEASURES Morbidity and mortality. RESULTS There were 64 men and 57 women, median age 58 years, range 16-83. Forty-three stomas were constructed for malignancy (34%). Forty-two stomas were raised during emergency operations (33%). Colorectal surgeons created 96 stomas (76%). Sixty-one of 92 potentially reversible stomas were closed (66%). Two patients died (2%) perioperatively. Overall stoma-related morbidity was 68% (n = 85). The rate of major stoma-related complications was 26% (n = 33). Nine major complications resulted in a reoperation rate of 7%. On univariate analysis, age, American Society of Anesthesiologists (ASA) grade, and surgeons speciality were significant predictive variables of major stomal complications (p < or = 0.002, 0.02, and 0.05 respectively). Multivariate analysis showed that the age of the patient was the only factor that independently influenced the outcome of stoma surgery (p < or = 0.001). CONCLUSIONS Optimising the perioperative health status of the patients, particularly the elderly, may reduce morbidity. The results also support specialist surgical care of patients undergoing stomal surgery.

Lloyd-davies position with trendelenburg—A disaster waiting to happen?

PURPOSE: Lower limb compartment syndrome has been reported to occur after colorectal, urological, and gynecological procedures during which the patients lower limbs are elevated for prolonged periods of time. METHOD: We investigated lower limb perfusion in a group of patients undergoing prolonged pelvic surgery both during and immediately after surgery, using intra-arterial blood pressure monitoring, laser doppler flowmetry, and pulse oximetry. RESULTS: Use of the modified lithotomy position was not associated with any demonstrable decrease in lower limb perfusion. The addition of 15° head-down tilt, however, during pelvic dissection, led to an immediate and significant drop in lower limb perfusion (P<0.05; Mann-WhitneyU test). The subgroup of patients analyzed postoperatively showed a ten-fold increase (P<0.01) in perfusion that was confined to the muscle compartment with no demonstrable increase in skin perfusion or intra-arterial pedal blood pressure. CONCLUSION: The use of the modified lithotomy position during pelvic surgery is not associated with lower limb ischemia. Addition of Trendelenburg position, however, causes profound ischemia of the lower limbs, and this is followed during the recovery period by hyperperfusion that is confined to the muscle compartments, which may put patients at risk of developing lower limb compartment syndrome.

Randomized Trial of Preoperative Cimetidine in Patients with Colorectal Carcinoma with Quantitative Assessment of Tumor-Associated Lymphocytes

Previous studies have suggested that cimetidine, a histamine‐2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo‐controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes.

1α,25-Dihydroxyvitamin D3 and its analogues, EB1089 and CB1093, profoundly inhibit the in vitro proliferation of the human hepatoblastoma cell line HepG2

Background: 1α,25‐dihydroxyvitamin D3 (1,25[OH]2D3) has been shown to inhibit the proliferation of various cancer cells including colon, prostate, melanoma, osteosarcoma and breast cancer.

A phase one study of the hepatic arterial administration of 1,25‐dihydroxyvitamin D3 for liver cancers

Background and Aims: It is well established that exposure to 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3) inhibits the proliferation of human colorectal cancer and hepatoma cell lines, both in vitro and in vivo. However, clinical trials of the administration of 1,25(OH)2D3 and analogs for the treatment of malignancy have been limited by the development of hypercalcemia. 1,25‐dihydroxyvitamin D3 is principally excreted in bile following hepatic catabolism. This suggested the hypothesis that hepatic regional administration may allow high doses of 1,25(OH)2D3 to be administered for the treatment of liver cancers without producing hypercalcemia, caused by a clinically significant first pass effect. This phase one study investigates the effect of hepatic regional administration of 1,25(OH)2D3 on serum calcium levels, together with other markers of renal and liver function.

Hepatic arterial and intravenous administration of 1,25-dihydroxyvitamin D3--evidence of a clinically significant hepatic first-pass effect.

Abstract.Purpose: We have previously shown that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits the proliferation of a number of human cancers, including colorectal and hepatocellular carcinoma, both of which affect the liver and are major causes of cancer death. However, the clinical use of 1,25(OH)2D3 and analogues has been restricted by the development of hypercalcaemia upon systemic administration. We hypothesized that a clinically significant hepatic first-pass effect may exist upon the administration of 1,25(OH)2D3 as a hepatic arterial infusion, and that such an effect may allow high levels of 1,25(OH)2D3 to be delivered to the liver whilst avoiding high systemic levels. Methods: To examine this hypothesis, two groups of Landrace pigs were given identical doses of 1,25(OH)2D3 as continuous infusions, one group systemically, the other as a hepatic arterial infusion. Serum levels of 1,25(OH)2D3, calcium, phosphate and a number of liver and kidney function tests were performed regularly. Results: Concentrations of 1,25(OH)2D3 and calcium remained normal in the hepatic arterial infusion animals, in contrast to the intravenous infusion animals which developed elevated levels of 1,25(OH)2D3 and hypercalcaemia. Hepatic arterial infusion of 1,25(OH)2D3 did not produce any adverse effects upon renal or hepatic function. Conclusion: The present findings support the existence of a clinically significant hepatic first-pass effect when 1,25(OH)2D3 is administered as a continuous hepatic arterial infusion. Hepatic arterial infusion of 1,25(OH)2D3 has great potential in the treatment of hepatic cancers.

Abnormal Colonic Motility: A Possible Association With Urge Fecal Incontinence

PURPOSE: Fecal incontinence is a distressing condition affecting up to 7% of the population. Severe urgency is a symptom associated with hypersensitivity of the rectum, a common finding in both fecal incontinence and irritable bowel syndrome. The purpose of this study was to investigate whether patients with fecal incontinence, urgency, and rectal hypersensitivity have abnormal hindgut motility, suggestive of a more generalized motility problem. METHODS: Eleven females with urgency-associated incontinence and without anal sphincter injury were compared with 5 controls. After full clinical, ultrasonographic, and physiological assessment, patients underwent prolonged colonic manometry studies. Motility patterns were recorded and, in particular, the response to a standard gastrocolic reflex was noted. RESULTS: Rectal sensation values in patients were as follows: first sensation, 22 (range, 5–58) mls; desire to defecate, 31 (range, 13–166) mls; and maximum tolerated volume, 64 (range, 21–254) mls. Compared with controls, patients had significantly higher numbers of 1) low amplitude waves (>5 mmHg) in both the sigmoid colon (101 vs 46.5; P = .028) and the descending colon (101.5 vs 41; P = .036) in the hour before the meal stimulus, and 2) high amplitude waves (>50 mmHg) in the sigmoid colon (2 vs 0; P = .006) in the fasting state. CONCLUSION: Patients with fecal incontinence associated with severe urgency may have rectal hypersensitivity and a more global colonic motility problem similar to irritable bowel syndrome.

Vitamin B12 intake after restorative proctocolectomy

Restorative proctocolectomy (RP) is the surgical treatment of choice for patients with ulcerative colitis and for patients with familial polyposis. Vitamin B12 deficiency has been reported in these patients after RP,1,2 and we carried out a dietary assessment in these patients to determine their intake of vitamin B12. Sixty-six patients, (42 men) median age 44 years (range 19–69 years), who had undergone uncomplicated RP were included in this study. The median duration of follow up after surgery was 10 years (range 2–15 years). Patients with pouchitis or any active systemic illnesses that may interfere with eating habit were excluded from the study. Forty-nine healthy volunteers (23 men: median age 43 years, range 20–62years) were recruited to serve as controls. A dietary assessment was carried out in both patients and controls using a computerized semi-quantitative food frequency questionnaire (Diet Q; Tinuviel Software, Warrington, Cheshire, UK). This comprised a validated seven-page questionnaire that seeks to gain information about the frequency and quantity of consumption of a wide range of food and drink products. Data analysis was undertaken using the software provided. A Mann–Whitney U-test was used to compare the levels of vitamin B12. None of the patients or controls was vegetarian. The median daily intake of vitamin B12 was 5.7mg (range 0.6–13mg) in patients and 5.3mg (1.4–41mg) in controls (P= 0.6). 828 LETTERS TO THE EDITOR