Open compared with laparoscopic complete mesocolic excision with central lymphadenectomy for colon cancer: a systematic review and meta-analysis.

AIM: Several studies report improved survival in colon cancer with use of extended lymphadenectomy techniques (ELTs), such as D3 lymphadenectomy or complete mesocolic excision. The noninferiority of laparoscopic versus open techniques has already been established in D2 resections. The aim of this study was to compare the safety and efficacy of open and laparoscopic approaches for ELTs in colon cancer. METHOD: Major databases, including PubMed, Scopus and the Cochrane library, were searched using defined inclusion and exclusion criteria, and relevant data were extracted. The Cochrane and Newcastle-Ottawa tools were used for critical appraisal and quality assessment. Meta-analysis with various subgroup analyses were undertaken, and clinical and statistical heterogeneity, along with publication bias, were also assessed. RESULTS: One randomized and seven case-control trials were included. All studies were found to be of low methodological quality with some external validity issues. There was no difference in short-term mortality [OR = 2.16 (95% CI: 0.73-6.41); P = 0.16], anastomotic leakage, ileus or deep-sited infection/abscess. There was a trend for longer operative time [weighted mean difference (WMD) = -30.88 (95% CI: -62.38 to 0.61); P = 0.05] and shorter length of hospital stay [WMD = 2.29 (95% CI: -0.39 to 4.98); P = 0.09] with the laparoscopic approach. Laparoscopic right hemicolectomy had a lower wound-infection rate [OR = 2.87 (95% CI: 1.38-5.98); P = 0.005] compared with the relevant open group. No statistically significant difference was found in overall survival [hazard ratio (HR) = 0.85 (95% CI: 0.69-1.06); P = 0.15], disease-free survival, local recurrence and distant metastases. CONCLUSION: Based on the current evidence, the laparoscopic technique appears to be at least as safe as the open technique when used in performing ELTs for colonic cancer, with similar morbidity and oncological outcomes.

A new technique of extreme lateral positioning for laparoscopic splenic flexure mobilization.

AIM: This aim of this study was to describe a novel positioning technique that assists in the expeditious mobilization of the splenic flexure without the need for redraping or compromise of port placement. METHOD: A prospective case series was studied to evaluate the technique and its ability to facilitate splenic flexure mobilization. RESULTS: The technique was used in 12 patients. There were no adverse intra- or postoperative events. The median time (interquartile range) for laparoscopic splenic flexure mobilisation was 10 (9-11.25). CONCLUSION: This novel positioning technique is safe and feasible. We include a detailed video that describes and demonstrates the requisites for its safe conduct. We also include intra-operative footage demonstrating the benefits of the patient's position.

Fecal lactoferrin: a noninvasive fecal biomarker for the diagnosis and surveillance of pouchitis.

BACKGROUND: Fecal lactoferrin is a marker of intestinal inflammation and can be assessed with a simple qualitative immunochromatographic rapid test. OBJECTIVE: We aimed to assess the sensitivity and specificity of the test in the diagnosis of pouchitis and evaluate its clinical utility in the surveillance of inflammation of the pouch after antibiotic therapy. DESIGN: Between October 2005 and September 2009, we recruited a consecutive series of patients who had their ileal pouch examined under a general anesthetic. Distinctions between healthy and inflamed pouches were made by the use of the Pouch Disease Activity Index. Fecal samples were taken before biopsy of the pouch, and a clinician blinded to the examination findings performed the lactoferrin test. After antimicrobial treatment, a number of patients with pouchitis had a repeat examination and lactoferrin test. RESULTS: There were 85 (41 male) patients. Median age was 42 (interquartile range, 36-49) years. Twenty-four patients had pouchitis. The test was positive in all 24 patients with pouchitis and 5 patients with a healthy pouch. The sensitivity and specificity of the test for pouchitis was 100% and 92%. The positive predictive value was 82%. In 7 patients who received antibiotic treatment for their pouchitis, the test was able to accurately predict the resolution and/or persistence of pouchitis. CONCLUSION: The qualitative fecal lactoferrin rapid test is a sensitive method for the diagnosis and confirmation of resolution of pouchitis. The test provides clinicians with greater confidence in the prescription of antibiotics for suspected pouchitis and its surveillance.

Composite abdominosacral resection for recurrent rectal cancer.

BACKGROUND: En bloc resection of the tumour and adjacent involved organs offers the only realistic curative option for patients with locally recurrent rectal cancer. This study assessed outcomes of composite resection for recurrent tumours involving the sacrum. METHODS: A consecutive series of patients underwent composite abdominosacral resection (abdominal mobilization and stoma construction followed by sacral division and tumour retrieval) for recurrent rectal cancer between 2001 and 2007. Patients were staged with preoperative computed tomography, magnetic resonance imaging and positron emission tomography. Data were collected prospectively. RESULTS: Forty patients (28 men; median age 59 (range 31-77) years) underwent surgery with sacral division at the S2/3 interface in 13, S3/4 level in 20 and S4/5 level in seven patients. One patient died and 24 had complications. An R0 resection was achieved in 20 patients and conferred benefit in disease-free interval over an R1 resection. The mean disease-free interval was 55.6 (95 per cent confidence interval (c.i.) 40.0 to 71.3) months for R0 and 32.2 (95 per cent c.i. 19.7 to 44.7) months for R1 resection (P = 0.048). CONCLUSION: Composite abdominosacral resection of locally recurrent rectal cancer is an effective treatment for a difficult clinical scenario.

Multimedia article. Laparoscopic abdominosacral composite resection.

Primary rectal cancer with direct invasion into the sacrum requires en bloc resection that encompasses both the rectum and the sacrum. Application of laparoscopic techniques to the abdominal component should potentially provide the patient with the short-term benefits of a minimally invasive approach and permit adequate mobilization to permit completion of the procedure via the transsacral route. The aim of this video was to describe the operative details of such a technique.

Laparoscopic restorative proctocolectomy with and without previous subtotal colectomy.

INTRODUCTION: Laparoscopic techniques have been applied to the procedure of restorative proctocolectomy (RPC). The aim of this study was to compare the outcomes of patients after laparoscopic ileal pouch-anal anastomosis (IPAA) with restorative proctocolectomy (RPC) and without previous colectomy [restorative proctectomy (RP)] and to highlight some technical tips. METHOD: Data were collected prospectively from all patients who underwent laparoscopic IPAA from July 2006 to December 2007. RESULTS: Thirty-six patients underwent IPAA either with total proctocolectomy (n = 25) or after previous emergency colectomy (n = 11). Postoperative morbidity occurred in 22% of patients. The overall median operative time was 210 (range 120-325), 240 (170-325) and 180 (120-240) min for RPC and RP respectively (P < 0.05). The median length of stay for all patients was 6 (3-26), 6 (4-26) and 4 (3-13) days for RPC and RP respectively (P < 0.05). There was no correlation between BMI, age, use of immunosuppressive agents and length of stay. The operative procedure was facilitated by the use of specific devices at particular stages of the operation. CONCLUSION: Laparoscopic IPAA is not only safe and feasible for the virgin abdomen but also for patients with a previous emergency colectomy through a midline laparotomy incision.

Feasibility and functional outcome of laparoscopic sacrocolporectopexy for combined vaginal and rectal prolapse.

PURPOSE: Prolapse of multiple pelvic organs causes a variety of symptoms that impair a patient's quality of life. A laparoscopic procedure is described that uses a mesh fixation of the mid-compartment vagina to the sacrum with additional rectopexy to correct both the anatomical deformities and the dysfunction of the posterior compartment. METHODS: Patients with significant rectal and vaginal prolapse with or without rectocele were recruited. A thorough preoperative physiological assessment of each of the compartments of the pelvic floor was carried out. Patients also completed the Pelvic Floor Distress Inventory before and six months after surgery. RESULTS: Ten patients underwent the procedure of laparoscopic sacrocolporectopexy (median age 47 years, interquartile range 43-53). No mortality or morbidity occurred. Median global distress inventory scores were significantly lower postoperatively (8.3, interquartile range 0-20.8 vs. 37.5, interquartile range 16.6-60.4) P = 0.012. All three median subscales were also significantly lower postoperatively. The procedure corrected associated rectoceles and descent of the perineum on straining. CONCLUSION: The described laparoscopic procedure of mesh sacrocolpopexy with rectopexy was safe and feasible and conferred good symptomatic improvement in pelvic floor dysfunction.

Chemosensitivity of medullary neurons in explant tissue cultures.

To determine whether cultured medulla contains chemosensitive neurons which are excited by CO2 and fixed acid and whether this function is specific to the ventral medulla, tissue explants of ventral and dorsal medulla were prepared from neonatal rats and incubated for two to three weeks. Cultures were superfused with artificial cerebrospinal fluid, maintained at 37 degrees C, and pH of the superfusate was varied either with PCO2 (14-71 Torr) at constant HCO3- (22 mM) or HCO3- (10-30 mM) at constant PCO2 (35 Torr). Spontaneous action potentials were recorded extracellularly in 51 ventral and 23 dorsal medullary neurons. Ventral medullary neurons exhibited a steady baseline firing frequency of 4 +/- 0.8 Hz. In contrast, dorsal medullary neurons exhibited two different patterns of spontaneous activity: 11 fired continuously (7.2 +/- 1.4 Hz) while 12 fired with a bursting pattern. Burst duration was 0.80 +/- 0.14 min and cycle time was 1.74 +/- 0.43 min. Decreasing pH with CO2 caused an increase in the activity of 10 of 27 ventral medullary neurons and two of six dorsal medullary neurons with a mean response of 7.5 Hz/pH unit. Varying pH by changing HCO3- had no effect on firing frequency. These results demonstrate that: (i) chemosensitive neurons are present in both ventral and dorsal medullary explant cultures; (ii) these cells only respond to changes in pH induced with CO2; and (iii) about half of the dorsal medullary neurons fire spontaneously with a regular bursting pattern of activity.

Central respiratory and circulatory depression caused by intravascular saxitoxin.

1 In cats anaesthetized with pentobarbitone and vagotomized, observations were made on the phrenic nerve action potential and the diaphragm electromyogram (EMG) at constant end-tidal Pco(2). Arterial blood pressure was stabilized by intravenous infusions of noradrenaline.2 Intravenous administration of saxitoxin (STX) initially abolished respiratory activity in the EMG and caused a slowing of oscillation in the central phrenic neurogram. Additional STX produced apneustic phrenic discharges followed by a progressive loss of nerve action potentials.3 The inspiratory centre in the medulla oblongata was stimulated electrically to evoke a sustained phrenic nerve discharge. STX, given intravenously, resulted in the elimination of spontaneous nerve activity without interfering with the evoked response.4 The cephalic intravascular infusion of STX into a carotid or vertebral artery depressed spontaneous respiratory activity while sparing EMG activity evoked by electrical stimulation of the intact phrenic nerve.5 Spontaneous respiratory discharge in the phrenic nerve was eliminated by smaller doses of STX administered intra-arterially than were required intravenously. In addition, onset of and recovery from neural silence occurred faster following intra-arterial injection of STX.6 Depressant effects on arterial blood pressure coincided with those on respiration when STX was given intra-arterially.7 An electrophysiological assay on frog sartorius muscle was used to measure STX in the cerebrospinal fluid. Levels of STX detected were proportional to amounts of the toxin infused intra-arterially.8 It is concluded that STX exchanges rapidly between blood and brain to bring about central depression and this adds to its peripheral paralytic actions.

The anti-emetic effects of CP-99,994 in the ferret and the dog: role of the NK1 receptor.

1. The selective NK1 receptor antagonist, CP-99,994, produced dose-related (0.1-1.0 mg kg-1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2. Parallel studies with the enantiomer, CP-100,263 (1 mg kg-1, s.c.), which is > 1,000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuSO4, loperamide, cisplatin and apomorphine-induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately 1/10th the potency of CP-99,994. 3. The 5-HT3 receptor antagonist, tropisetron (1 mg kg-1, s.c.) inhibited retching and vomiting to cisplatin and ipecac, but not CuSO4 or loperamide. 4. CP-99,994 (1 mg kg-1, i.v.) blocked retching induced by electrical stimulation of the ventral abdominal vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves. CP-99,994 (1 mg kg-1, i.v.) did not alter baseline cardiovascular and respiratory parameters and it failed to block the characteristic heart rate, blood pressure and respiratory rate/depth changes in response to i.v. 2-methyl-5-HT challenge (von Bezold-Jarisch reflex). 5. Using in vitro autoradiography, [3H]-substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus solitarius being much greater than in the area postrema. This binding was displaced by CP-99,994 in a concentration-related manner. 6. In dogs, CP-99,994 (40 micrograms kg-1 bolus and 300 micrograms kg-1 h-1, i.v.) produced statistically significant reductions in vomiting to CuSO4 and apomorphine as well as retching to CuSO4. 7. Together, these studies support the hypothesis that the NK1 receptor antagonist properties of CP-99,994 are responsible for its broad spectrum anti-emetic effects. They also suggest that CP-99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.

Time course for development of anticonvulsant tolerance and GABAergic subsensitivity after chronic diazepam.

The time courses for development of neuronal and behavioral tolerance to diazepam (DZ) were estimated in rats continuously exposed to low levels of DZ for 3, 7, 14 or 21 days. Microiontophoretic sensitivity of dorsal raphe neurons to gamma-aminobutyric acid (GABA) was initially facilitated after short-term exposure to DZ released from implanted capsules for up to 3 days but returned to control levels by 7 days postimplantation and continued to decrease thereafter. GABAergic sensitivity remained depressed for a minimum of 5 days following removal of DZ capsules. To obtain a behavioral measure of tolerance, the anticonvulsant activity of DZ against bicuculline-induced seizures was also assessed. Rats studied 3 days after capsule implantation showed a significant elevation in seizure threshold. Seizure liability returned to control levels ca. 7 days after chronic treatment was initiated. These results indicate that tolerance to anticonvulsant efficacy against bicuculline seizures are temporally related to the onset of reduced GABA sensitivity on dorsal raphe neurons during prolonged exposure to DZ.

Continuous release of diazepam: electrophysiological, biochemical and behavioral consequences.

Neuronal GABAergic sensitivity was assessed using electrophysiological, biochemical and behavioral techniques following the continuous release and maintenance of relatively constant brain levels of diazepam for greater than or equal to 21 days. Our studies indicate that long-term exposure to diazepam results in: (1) a decrease in iontophoretic sensitivity to GABA in the dorsal raphe nucleus, (2) an increase in the affinity of the GABA recognition site in brain tissue and (3) an increase in susceptibility to bicuculline-induced seizures in the intact animal. Since the decrease in GABAergic responsiveness was observed in the presence of measurable levels of diazepam, it was concluded that this subsensitivity phenomenon is associated with tolerance and not with withdrawal effects of the benzodiazepines.

beta-Adrenoceptor blockade spares chemoreceptor responsiveness to hypoxia.

The effect of beta-adrenoceptor blockade on the carotid body chemoreceptor response to hypoxia was assessed in anesthetized and paralyzed cats. Propranolol, atenolol and ICI 118,551 each abolished the enhancement of chemoreceptor activity produced by i.v. infusion of exogenous isoproterenol; however, the blocking drugs did not significantly diminish the increase in chemoreceptor neural discharge induced by hypoxia. These results do not support the hypothesis that beta-adrenergic receptors play an essential role in the chemoreceptor response to oxygen deprivation.

Excitability of 'silent' respiratory neurons during sleep-waking states: an iontophoretic study in undrugged chronic cats.

An iontophoretic study of respiratory-related neurons (RN) was conducted in the medullary ventral respiratory area of chronically implanted, undrugged cats during states of sleep and wakefulness. Most RN recorded were unaffected by sleep-wake states but a few RN decreased their firing rate during sleep (sleep sensitive cells). The excitability of RN was assessed in the different states by local application of L-glutamate. Glutamate iontophoresis revealed the presence of 5 cells which were silent during sleep and completely or mostly silent during undisturbed wakefulness but always discharged with a respiratory-modulated pattern of the expiratory type in response to glutamate application. Arousing stimuli induced spontaneous firing of these cells and REM sleep reduced glutamate effectiveness. It was concluded that silent RN and RN which become inactive during sleep permanently receive subthreshold respiratory-modulated inputs which are amplified or depressed by state-dependent tonic inputs.

Spontaneous and RO 15-1788-induced reversal of subsensitivity to GABA following chronic benzodiazepines.

Chronic daily injections of diazepam (5 mg/kg i.p.) for 21-30 days have previously been shown to cause a selective subsensitivity to microiontophoretically applied GABA in serotonergic dorsal raphe neurons in the rat. Following termination of chronic benzodiazepine treatment, GABAergic sensitivity remained depressed for up to 96 h even though pharmacologically active concentrations of diazepam and its active metabolites could no longer be detected in brain tissue. In contrast, a single injection of the specific benzodiazepine antagonist, RO 15-1788, given 22 h prior to electrophysiological recording, restored GABAergic sensitivity to the control range. Sensitivity of dorsal raphe neurons to serotonin was not altered by either chronic treatment with or withdrawal from diazepam. These results indicate that (1) RO 15-1788 can accelerate the time course of withdrawal and (2) administration of this benzodiazepine antagonist can induce a persistent change in GABAergic responsiveness.

Tolerance to anti-pentylenetetrazol effects following chronic diazepam.

Continuous release of diazepam from subcutaneously implanted silastic capsules provided significant protection against pentylenetetrazol seizures in rats for up to 3 weeks. However, the degree of protection seen after 3 weeks of exposure to diazepam was significantly less than after 1 h. These data suggest that continuous exposure to constant low levels of diazepam results in the development of partial tolerance which is not sufficient to eliminate significant anticonvulsant effects.

Broad spectrum antiemetic effects of CP-122,721, a tachykinin NK1 receptor antagonist, in ferrets.

The potent, selective, tachykinin NK1 receptor antagonist, CP-122,721 ([(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2- phenylpiperidine]), at 0.01-1 mg/kg, s.c. reduced retching and vomiting elicited by loperamide, copper sulfate, ipecac syrup and cisplatin in a dose-dependent manner. ID50 values after subcutaneous administration ranged from 0.02 mg/kg (loperamide) to 0.08 mg/kg (ipecac). Oral CP-122,721 reduced cisplatin-induced emesis with an ID50 of approximately 0.08 mg/kg. The less active (2R, 3R)-enantiomer, CP-132.687, did not significantly suppress retching or vomiting induced by any of the emetogens. These data support the hypothesis that CP-122,721 blocks emesis by a specific action at tachykinin NK1 receptors. Its broad spectrum of antiemetic activity suggests a central site of action.

Anticonvulsant activity of the glial GABA uptake inhibitor, THAO, in chemical seizures.

The antiseizure activity of the glia-selective GABA uptake inhibitor, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-3-ol (THAO), was evaluated in rats in models of acute chemoconvulsion. In these experiments, intracerebroventricular administration of the drug 30 min prior to testing in doses between 100-750 micrograms provided protection against maximal pentylenetetrazol seizures and increased the latency to isonicotinic acid hydrazide seizures. Pentylenetetrazol seizure thresholds, in contrast, were not significantly elevated. The ability of THAO to suppress tonic but not generalized minor seizures suggests that it may block seizure spread.

CP-96,345 antagonism of NK1 receptors and smoke-induced protein extravasation in relation to its cardiovascular effects.

The effects of the non-peptide NK1 receptor antagonist, CP-96,345, on cardiovascular homeostasis were investigated in conscious and anaesthetized rats in vivo and on heart function and muscle tonicity of vessels in vitro. CP-96,345 and its enantiomer, CP-96,344, which does not exhibit NK1 receptor-blocking activity when tested at a concentration of 1 microM, significantly decreased blood pressure in conscious rats at a dose of 0.32 mg/kg i.v. CP-96,345 and CP-96,344 additionally reduced heart rate at doses of 1 and 3.2 mg/kg, respectively. Studies in anaesthetized rats showed that ganglionic blockade did not modify the decreases in blood pressure and heart rate elicited by CP-96,345. In the isolated guinea-pig heart, CP-96,345 and CP-96,344 exerted negative chronotropic effects at 10(-7) M; negative inotropic effects were observed at 10(-6) M. At 10(-5) M, both CP-96,345 and CP-96,344 decreased the amplitude of contraction of the rat portal vein, whereas at 10(-4) M, both compounds increased the frequency of contraction of this vessel. CP-96,345, at 5 x 10(-8) M, caused relaxation of precontracted pig coronary arteries. Since both CP-96,345 and CP-96,344 produced similar changes in haemodynamics and in the contractility of vascular and cardiac tissue, the cardiovascular effects of CP-96,345 are probably not related to NK1 receptor antagonism. As only the enantiomer with NK1 antagonistic activity inhibited cigarette smoke-induced plasma protein extravasation in rat trachea, CP-96,345 remains a useful tool for elucidating NK1 receptor-mediated responses, provided CP-96,344 is included as control.