Surgical outcomes of Turnbull-Cutait delayed coloanal anastomosis with pull-through versus immediate coloanal anastomosis with diverting stoma after total mesorectal excision for low rectal cancer: a systematic review and meta-analysis.

BACKGROUND: Theoretical advantages of Turnbull-Cutait pull-through delayed coloanal anastomosis (DCAA) are a reduced risk of anastomotic leak and therefore avoidance of stoma. Gradually abandoned in favor of immediate coloanal anastomosis (ICAA) with diverting stoma, DCAA has regained popularity in recent years in reconstructive surgery for low RC, especially when combined with minimally invasive surgery (MIS). The aim of this study was to perform the first meta-analysis, exploring the safety and outcomes of DCAA compared to ICAA with protective stoma. METHODS: A systematic search of MEDLINE, EMBASE, and CENTRAL and Google Scholar databases was performed for studies published from January 2000 until December 2020. The systematic review and meta-analysis were performed according to the Cochrane Handbook for Systematic Review on Interventions recommendations and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. RESULTS: Out of 2626 studies screened, 9 were included in the systematic review and 4 studies in the meta-analysis. Outcomes included were postoperative complications, pelvic sepsis and risk of definitive stoma. Considering postoperative complications classified as Clavien-Dindo III, no significant difference existed in the rate of postoperative morbidity between DCAA and ICAA (13% versus 21%; OR 1.17; 95% CI 0.38-3.62; p = 0.78; I2 = 20%). Patients in the DCAA group experienced a lower rate of postoperative pelvic sepsis compared with patients undergoing ICAA with diverting stoma (7% versus 14%; OR 0.37; 95% CI 0.16-0.85; p = 0.02; I2 = 0%). The risk of definitive stoma was comparable between the two groups (2% versus 2% OR 0.77; 95% CI 0.15-3.85; p = 0.75; I2 = 0%). CONCLUSIONS: According to the limited current evidence, DCAA is associated with a significant decrease in pelvic sepsis. Further prospective trials focusing on oncologic and functional outcomes are needed.

Ileal pouch-anal anastomosis with fluorescence angiography: a case-matched study.

AIM: An anastomotic leak in ileoanal pouch surgery may lead to pouch failure. Constructing a tension-free ileal pouch-anal anastomosis (IPAA) reduces this risk but can be technically challenging, balancing pouch vascularization with ileal mesenteric length and site of vessel ligation. Fluorescence angiography (FA) may help the clinician make a more balanced judgement. METHODS: Thirty-two patients undergoing minimally invasive completion proctectomy with FA-guided IPAA at two academic centres were matched and compared on a 1:1 basis to a historical group undergoing the same procedure without the use of this technique. RESULTS: Ligation of the ileocolic vessels was safely performed in 15/32 (47%) of FA patients compared with 5/32 (16%) of historical controls. One patient underwent intra-operative IPAA reconstruction after FA detected ischaemia. No anastomotic leak occurred with FA but there was only one in the historical controls (P = 0.31). The postoperative complication rate was similar between the two groups (P = 0.60). CONCLUSION: FA is applicable to IPAA surgery and may help to reduce perfusion-related anastomotic leaks. A prospective randomized trial is warranted.

Molecular epidemiology of methicillin resistant staphylococcus aureus colonizing the anterior Nares of school children of Udupi Taluk.

CONTEXT: Community associated methicillin resistant Staphylococcus aureus (CA-MRSA) cause serious skin and soft tissue infections including necrotizing fasciitis and necrotizing pneumonia. Production of Panton Valentine Leucocidine (PVL) toxin is implicated in its enhanced virulence. A variant of epidemic MRSA-15 (EMRSA-15) which produces PVL toxin has been isolated and characterized by pulsed-field gel electrophoresis (PFGE) method from the Indian population both in hospital and community settings. AIMS: Identify the epidemiological type of MRSA colonizing the anterior nares of school children in Udupi taluk. SETTINGS AND DESIGN: The study population included children of the age group of 5-16 years belonging to the Udupi taluk of Karnataka, India. A total of 1503 children were screened for MRSA colonization during July 2009 to December 2010. MATERIALS AND METHODS: PVL assay, Staphylococcal Cassette Chromosome (SCC) mec typing and PFGE typing were carried out with all the MRSA isolates. STATISTICAL ANALYSIS USED: Frequency distribution of different variables was assessed by SPSS. RESULTS: Among the 1.1% of MRSA, 58.8% (10/17) of isolates were positive for pvl and 41.7% (7/17) were identified as SCC mec type IV. PFGE patterns of all the strains were identical with Indian variant EMRSA-15; however they were different from classical EMRSA-15 in 3-4 bands. CONCLUSIONS: The Indian variant EMRSA-15 gains much epidemiological relevance owing to the acquisition of pvl gene. In spite of low prevalence of nasal colonization of MRSA, emergence of the virulent Indian variant EMRSA-15 in our community is a worrisome fact to be reckoned with.

Comparison of single-dose oral grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men. The STD Study Group.

In a randomized open study, 351 male patients with uncomplicated gonorrhea were given single oral doses of grepafloxacin (400 mg) or cefixime (400 mg). In the 299 microbiologically evaluable patients, urethral infections were cured in 99% (147 of 149) of those receiving grepafloxacin and 97% (145 of 150) of those given cefixime. Eradication rates for both regimens were 100% in the 16% (47 of 299) of participants who were infected with penicillin-resistant Neisseria gonorrhoeae and 97% in the 21% (62 of 299) of participants infected with tetracycline-resistant strains. Grepafloxacin is a well-tolerated alternative to cefixime for treatment of uncomplicated gonorrhea in males.

Pharmacokinetics of grepafloxacin after oral administration of single and repeat doses in healthy young males.

The pharmacokinetics of grepafloxacin in healthy male subjects following single oral administration of doses ranging from 200 to 1200 mg, and following repeated oral administration of 400 and 800 mg doses are reported. Plasma levels of grepafloxacin reached a peak within 2 hours (on average) following drug administration and then declined bi-exponentially with concentrations being detectable (> 5 micrograms/L) in the plasma for at least up to 72 hours postdose. The high values for the apparent volume of distribution (5 to 8 L/kg) suggested extensive distribution of grepafloxacin in the tissues. Only a small percentage of the administered dose (ranging from 6% to 9.5%) was recovered in the urine as unchanged grepafloxacin, suggesting that metabolism, rather than urinary excretion, is the major elimination route. The half-life of grepafloxacin was about 12 hours after single doses and about 15 hours after repeat doses. The trough levels increased significantly over the first 3 days of repeat administration; thereafter, the changes were small, with steady-state being reached by the fifth day. The area under the concentration-time curve (AUC24 h) values observed on days 7 and 14 of repeat administration, at each dose level, were similar, suggesting that steady-state is maintained. The area values increased more than proportionally after administration of increasing single and repeat doses, suggesting nonlinear kinetics. The elimination half-life and renal clearance did not change with increasing doses. Saturation in the metabolism of grepafloxacin and possibly in the distribution into a peripheral compartment, as suggested by a decrease in the total plasma clearance and in the apparent volume of distribution, could be the origin of the nonlinear kinetics. However, this deviation from linearity is unlikely to be of clinical significance, since it was very small over the recommended range of therapeutic doses (400 to 600 mg once daily). Compared with other quinolones, grepafloxacin showed the longest half-life and the highest apparent volume of distribution. These features, together with the excellent bactericidal activity of grepafloxacin, support the recommended dosage regimen of grepafloxacin for the treatment of respiratory tract infections and sexually transmitted diseases.

Effect of age and gender on the pharmacokinetics of grepafloxacin.

The effects of age and gender on the pharmacokinetics of the oral fluoroquinolone grepafloxacin were examined in 48 healthy middle-aged and elderly individuals, of whom half were male and half were female. Participants were stratified into 4 groups (each with n = 12), aged 40 to 49 years, 50 to 59 years, 60 to 69 years, and > 70 years. All received oral grepafloxacin 600 mg once daily for 7 days, and pharmacokinetic parameters were measured on days 1 and 7. Mean plasma grepafloxacin concentrations were consistently higher in females than in males. Peak concentrations, area under the concentration-time curve, apparent volume of distribution and apparent total clearance (but not renal clearance) differed significantly in females and males. There were no significant gender differences in the elimination half-life values. Further analysis of the data suggests that the gender-related pharmacokinetic differences were primarily due to differences in bodyweight, in particular to differences in lean body mass. The only parameters that changed significantly with age were renal clearance and the proportion of the dose excreted unchanged in the urine, but no clear trend was observed, and there was no correlation with creatinine clearance. We conclude that age and gender have no clinically significant effect on the pharmacokinetics of grepafloxacin. Dose adjustment on the basis of these factors does not therefore seem necessary.

Effect of food and gastric pH on the bioavailability of grepafloxacin.

Two open crossover studies were conducted to investigate the effects of food or concomitant treatment with the histamine H2-receptor antagonist famotidine on the pharmacokinetics of the new fluoroquinolone grepafloxacin. Each study involved 16 healthy male volunteers. In the first study, participants received grepafloxacin 600 mg, either after fasting or after consumption of a standard high-fat meal. There were no significant differences in any pharmacokinetic parameter under the fasting or nonfasting conditions. In the second study, participants received grepafloxacin 400 mg, either alone or after infusion of famotidine 20 mg; additional doses of famotidine were given, if necessary, to maintain intragastric pH above 6. Famotidine treatment had no significant effect on grepafloxacin pharmacokinetics. The results of these studies indicate that neither food nor the elevation of gastric pH influence the absorption or bioavailability of grepafloxacin. Therefore, grepafloxacin can be administered with or without food.

Grepafloxacin pharmacokinetics in individuals with hepatic dysfunction.

The pharmacokinetics of grepafloxacin, a new broad spectrum fluoroquinolone antibiotic, were studied in 2 trials involving 14 healthy volunteers, 10 individuals with mild (Child-Pugh Class A) impairment of liver function, and 12 with moderate (Child-Pugh Class B or C) hepatic impairment. All participants received an oral dose of grepafloxacin 400 mg, daily for 7 days, and plasma and urine grepafloxacin concentrations were measured over 7 days. The pooled data from participants with impaired liver function showed that, compared with healthy individuals, peak plasma grepafloxacin concentrations, area under the plasma concentration-time curve and proportion of the dose excreted in the urine were increased. In addition, apparent total clearance was reduced in the presence of hepatic dysfunction. Peak concentrations were increased by 36% and 48% in individuals with Class A and B disease, respectively; the corresponding reductions in clearance were 33% and 55%, respectively. Child-Pugh scores and components of the scores showed no correlation with any pharmacokinetic variables. Based on these findings, we recommend a daily grepafloxacin dose of 400 mg in patients with mild hepatic impairment, irrespective of the severity of infection. Grepafloxacin should not be used in patients with moderate or severe liver disease.

Effect of renal impairment on the pharmacokinetics of grepafloxacin.

Grepafloxacin is mainly (approximately 90%) excreted by nonrenal mechanisms. The effect of renal impairment on the pharmacokinetics of grepafloxacin was evaluated in an open-label study involving 20 adults, 15 of whom had some degree of renal impairment (creatinine clearance 7.5 to 64.0 ml/min). Of these 15, 3 had mild renal impairment, 6 had moderate renal impairment, and 6 had severe renal impairment. Grepafloxacin 400 mg was administered orally once daily for 7 days, and pharmacokinetic parameters were measured on days 1 and 7. The results show that both renal clearance and the amount of grepafloxacin excreted unchanged in urine, on day 1 and day 7, were significantly lower in individuals with severe renal impairment compared with those who were healthy. Renal clearance was 0.50 +/- 0.05 ml/min/kg in healthy individuals vs 0.15 +/- 0.05 ml/min/kg in patients with severe renal impairment on day 1, while the corresponding values on day 7 were 0.46 +/- 0.04 ml/min/kg vs 0.14 +/- 0.08 ml/min/kg, respectively. The percentage of grepafloxacin excreted unchanged in urine on day 1 was 5.1 +/- 3.0 in the healthy individuals and 1.5 +/- 0.7 in those with severe renal impairment. On day 7, the corresponding values were 7.9 +/- 1.9 and 2.9 +/- 2.2. No other significant pharmacokinetic differences occurred between the 2 groups. Accumulation during multiple dose administration did not vary with the degree of renal impairment. We conclude that the pharmacokinetics of grepafloxacin are not significantly different in individuals with varying degrees of renal impairment. Hence, dose adjustment is not necessary during treatment of patients with renal dysfunction.

Theophylline and warfarin interaction studies with grepafloxacin.

Two phase I trials, each involving 16 healthy adult volunteers, were performed to investigate possible interactions between grepafloxacin and theophylline or warfarin. In the theophylline study, grepafloxacin 600 mg was administered once daily for 10 days to 12 volunteers who were receiving a maintenance dose of theophylline. This dose of theophylline was designed to produce mean serum theophylline concentrations of 7.5 mg/L; 4 volunteers received theophylline plus placebo. Pharmacokinetic parameters of theophylline were determined before grepafloxacin treatment and on day 10 of grepafloxacin or placebo administration. Peak theophylline concentrations and the area under the concentration-time curve increased significantly during grepafloxacin treatment, and apparent total clearance of theophylline was reduced by approximately 50%. No changes were observed in the placebo group and theophylline appeared to have no effect on the pharmacokinetics of grepafloxacin. In the warfarin study, grepafloxacin 600 mg was given once daily for 14 days to volunteers receiving a maintenance dose of warfarin. Warfarin was discontinued during the last 4 days of grepafloxacin administration. The pharmacodynamics of warfarin did not change after administration of grepafloxacin. Similarly, warfarin had no significant effect on the pharmacokinetics of grepafloxacin. We conclude that during treatment with grepafloxacin maintenance, doses of theophylline should be reduced by 50%, and we recommend that serum concentrations of theophylline be monitored during treatment with grepafloxacin. However, no dose adjustment is necessary for grepafloxacin when it is coadministered with theophylline, and dose adjustment does not seem to be required in concomitant treatment with grepafloxacin and warfarin.

Efficacy and safety of grepafloxacin 600 mg daily for 10 days in patients with community-acquired pneumonia.

The efficacy and safety of grepafloxacin in treating patients with community-acquired pneumonia (CAP) was assessed in an open-label, noncomparative study. Patients (N = 273) received grepafloxacin 600 mg QD for 10 days. A total of 237 patients (87%) completed the study. In assessable patients, the clinical success rate at follow-up (4 to 6 weeks after the last dose) was 89% (211/238 patients). In microbiologically assessable patients, the eradication rate at follow-up was 95% (86/91 isolates). Grepafloxacin was highly effective in the treatment of bacterial CAP caused by Streptococcus pneumoniae (irrespective of penicillin susceptibility), Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, and Staphylococcus aureus and in the therapy of atypical pneumonia caused by Mycoplasma pneumoniae and Legionella pneumophila. Grepafloxacin was well tolerated, with the most frequently reported drug-related adverse events being taste perversion and nausea. Grepafloxacin 600 mg QD for 10 days was highly effective and well tolerated in the treatment of patients with CAP.

Randomized, double-blind, comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia.

This randomized, multicentre, double-blind, double-dummy study assessed the efficacy and safety of 7 or 10 day regimens of grepafloxacin, 600 mg od, compared with amoxycillin, 500 mg tds, in the treatment of community-acquired pneumonia (CAP). A total of 264 patients were recruited at 43 centres (127 received grepafloxacin and 137 received amoxycillin), of whom 207 patients (78%) completed the study. Clinical and microbiological efficacy were assessed at the end-of-treatment visit (3-5 days after the last dose) and at the follow-up visit (28-42 days after the last dose). At follow-up, patients in the evaluable population treated with grepafloxacin demonstrated a clinical response rate (76%; 87/114) equivalent to that seen with amoxycillin (74%, 85/111, 95% CI = -12%, 10%) while, in the intent-to-treat population with a documented bacterial pathogen, the clinical success rate in the grepafloxacin group (78%, 29/37) was significantly higher than in the amoxycillin group (58%, 28/48), 95% CI = 2%, 43%). In patients from the evaluable population in whom the pathogens were documented the clinical success rate favoured grepafloxacin, compared with amoxycillin (79%, 26/33 versus 63%, 26/42, respectively; 95% CI = -5.2%, 38.1%). Microbiological eradication with grepafloxacin was statistically superior to amoxycillin in the evaluable population; the success rate was 89% (32/36) in the grepafloxacin group compared with 71% (32/45) for the amoxycillin group (95% CI = 2%, 37%). The pathogens most commonly isolated from patients were Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae. The success rates for infections caused by S. pneumoniae and H. influenzae at follow-up were higher with grepafloxacin than with amoxycillin. Grepafloxacin was well tolerated, with a safety profile comparable to that of amoxycillin. The therapeutic judgement of patients and investigators at the patient's last visit, as well as the assessment of individual respiratory signs and symptoms, yielded comparable results with both treatments. The results of this study indicate that grepafloxacin, 600 mg od for 7-10 days, is equivalent to or better than amoxycillin, 500 mg tds for 7-10 days in achieving a successful clinical and microbiological response in the treatment of patients with CAP.

Immunoscintigraphy with 111In-satumomab pendetide in patients with colorectal adenocarcinoma: performance and impact on clinical management.

PURPOSE: The role of immunoscintigraphy with 111In-satumomab pendetide in the medical and/or surgical management of colorectal cancer patients was evaluated in a multicenter trial. METHODS: This 103 patient study population included 46 individuals with rising serum carcinoembryonic antigen levels and otherwise negative diagnostic evaluation, 29 patients with known recurrence, presumed to be isolated and resectable, and 28 patients for whom standard diagnostic tests provided equivocal information. RESULTS: No adverse reactions were noted following intravenous administration of 1 mg of satumomab pendetide radiolabeled with approximately 5 mCi of 111In. Thirty percent of patients developed human anti-mouse antibodies postinfusion. In the 84 patients for whom correlation with histopathologic, diagnostic, and/or clinical findings was available, antibody imaging demonstrated a sensitivity of 73 percent in patients with confirmed tumor (36/49) and negative results for all 35 patients with no evidence of malignancy. Occult disease was detected in 18 patients. CONCLUSION: 111In-satumomab pendetide immunoscintigraphy was helpful in the medical and/or surgical management of 45 (44 percent) patients and provided information unavailable from other diagnostic modalities.

Immunoscintigraphy in patients with colorectal, ovarian, and prostate cancer. Results with site-specific immunoconjugates.

Application of monoclonal antibody (MoAb) technology to cancer management is discussed by reviewing the development and clinical evaluation of two MoAb-based immunoscintigraphic agents (111In-satumomab pendetide [OncoScint CR/OV-In] and 111In-CYT-356; Cytogen Corporation, Princeton, NJ). Both agents were prepared using a site-specific MoAb modification method that preserves the immunoreactivity of the radiolabeled immunoconjugate. 111In-satumomab pendetide is an 111In-labeled conjugate of the murine MoAb B72.3, which is directed to TAG-72, an antigen expressed by the majority of adenocarcinomas. By providing information that complements the results of standard radiographic diagnostic modalities, this imaging agent can aid in the treatment of patients with colorectal or ovarian cancer. Immunoscintigraphy with 111In-satumomab pendetide has been shown to assist in medical-surgical management by detecting occult extrahepatic lesions, clarifying equivocal results of other diagnostic imaging tests, and evaluating the extent and resectability of known tumor lesions. 111In-CYT-356 is an 111In-labeled conjugate of the murine MoAb 7E11-C5.3, which is reactive with prostatic carcinoma, benign prostatic hypertrophy, and, to a lesser extent, normal prostatic tissue. Results of preliminary clinical investigations suggest that 111In-CYT-356 immunoscintigraphy can be useful for the presurgical staging of prostatic carcinoma and for the detection of occult distant disease in patients with negative or equivocal results on standard imaging tests. Results with these site-specifically radiolabeled immunconjugates demonstrate the clinical utility of MoAb-based imaging agents in the treatment of patients with solid tumors.

The effect of food on ciramadol bioavailability in normal subjects.

Eleven healthy volunteers completed a study to compare the relative bioavailability to orally administered ciramadol in a fasting versus postprandial state. A single oral dose of 30 mg of ciramadol was administered on two separate occasions, 2 weeks apart, in a randomized crossover study. A mono- or biexponential pharmacokinetic equation with first-order absorption was applied to analyse the serum data for each subject. Significant differences were found in peak time (tmax) and absorption time (tabs) whereas the mean AUCs for the two modes of administration were not significantly different. The relative bioavailability (F) of the drug when administered in the postprandial state with respect to the fasting state was 96 per cent. It is thus concluded that ingestion of food has no effect on the extent of absorption of ciramadol; however, food may alter its rate of absorption.

Parametric effects in the discrimination of intracranial stimulation: some methodological and analytical issues.

Rats were implanted with electrodes in the medial forebrain bundle at the level of the lateral hypothalamus. Electrical stimulation was established as a conditioned stimulus for responding in a modified two-way active shock avoidance procedure. Stimulus generalization experiments were conducted to determine the effects of pulse frequency, current intensity, pulse duration, and of train duration. It was found that the discriminative stimulus properties of the electrical stimulation co-varied in an orderly manner with variations in each of the parameters. The generalization data sets of frequency, intensity, and train duration could be fitted by linear functions in log-linear coordinates; the effects of pulse duration generated a biphasic gradient. An analysis in terms of charge revealed that train duration had the lowest slope, whereas frequency and intensity generated equally steep functions. The most striking differences occurred among conditions which were similar in terms of current intensity, pulse duration and number of pulses, but which differed in the temporal patterning of pulses. Some methodological and analytical aspects of discrimination and generalization with intracranial stimulation are discussed.

Facilitation of self-stimulation in rats by methadone.

The effects of morphine and its derivatives on self-stimulation behavior have been widely studied. In those experiments which have used multiple injections (over days) and multiple post-injection tests (within days), the typical findings includes a depression of responding after the initial injections followed by a facilitation of responding on subsequent days. There have been only a few reports which have tested the effects of methadone in this paradigm. Some investigators have observed only depression of self-stimulation while others have reported both the transient depression and the subsequent facilitation generally obtained with morphine. In the present experiment we administered either 5 mg/kg or 10 mg/kg methadone IP over a five day period and tested MFB-LH self-stimulation at 2, 4, 6, 8, 10 and 23 hours post-injection. Compared to saline controls, the 10 mg/kg dose produced the typical opiate-induced changes in self-stimulation, i.e., an initial depression which lasted for two hours on the first two days but was replaced by significant facilitation by hour 4 of day 3. This facilitation persisted for at least 10 hours on all 5 days of the experiment. Except for a transient (days 2-3) depression of self-stimulation, 5 mg/kg was without effects. The present experiment demonstrates that methadone does facilitate self-stimulation but that its ability to do so is highly dose-dependent.