Correlation Between Intraoperative and Pathological Findings for Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: This study aimed to examine the correlation between intraoperative and pathological findings for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) and to determine their prognostic significance. METHODS: Pathological reports of all colorectal cancer (CRC) patients undergoing CRS/HIPEC between 2009 and 2016 were retrospectively reviewed. Pathological specimens lacking tumor cells were defined as negative pathological specimens (NPS). The intraoperative peritoneal cancer index (PCI) and pathological PCI (excluding NPS) were calculated separately. Receiver operating characteristic (ROC) curves were applied to compare the prognostic value of intraoperative and pathological scoring systems. RESULTS: For 108 CRC patients, 113 CRS/HIPEC procedures were performed. Of 959 pathological specimens examined, 178 (18.6%) were NPS. Overall, 78 procedures (69%) showed NPS. In 52 procedures (46%), the pathological PCI differed from the intraoperative PCI (∆PCI > 0). The ROC areas for intraoperative PCI and pathological PCI were similar in predicting 1-year overall survival (OS), 2-year OS, and 1-year disease-free survival (all p values not significant). However, for the patients with NPS, the number of positive specimens (containing tumor tissue) was superior to intraoperative PCI in predicting 2-year OS (ROC under the curve areas, 0.69 vs. 0.58, respectively; p = 0.012). In addition, a subgroup of 15 patients with a high ∆PCI (≥ 3) had a more favorable median OS than a matched group of 30 patients with similar intraoperative PCI and a ∆PCI of 0 (median survival not reached vs. 21.6 months, respectively; p = 0.05). CONCLUSIONS: In the majority of CRC CRS/HIPEC procedures, NPS may be found. Among patients with NPS, pathological correlation may have a prognostic significance.

Implications of Stoma Formation as Part of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Formation of protective stoma as part of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) may be an effective tool in reducing anastomotic leak incidence. Our aim was to evaluate the incidence and implications of stoma formation during CRS-HIPEC and to examine whether a creation of protective stoma reduces the postoperative morbidity. METHODS: A cohort retrospective analysis of all CRS-HIPEC procedures performed between 2004 and 2016 was conducted. Predicting factors for stoma formation were assessed by comparing all patients who underwent stoma formation to those who did not; both groups were then restricted to cases with ≥2 bowel anastomoses and compared in terms of perioperative outcomes in order to determine whether protective stoma confers a morbidity benefit. RESULTS: One hundred and ninety-nine CRS-HIPEC procedures were performed on 186 patients. Thirty-four patients (17%) underwent stoma formation, 24 of them as protective stoma. Formation of a stoma was correlated with higher peritoneal carcinomatosis index score (13.6 ± 8 vs. 9.5 ± 7.7, p = 0.007), larger number of organs resected (p < 0.001), greater number of anastomoses (p < 0.001), prolonged operative time (8.1 ± 2.7 vs. 6.6 ± 2.2 h, p = 0.002), and prolonged hospital stay (12 vs. 8.5 days, p = 0.001). In procedures requiring ≥2 anastomoses, formation of protective stoma reduced the anastomotic leak rate (6 vs. 37%, p = 0.025), the morbidity rate (6 vs. 41%, p = 0.017), and reoperation rate (0 vs. 28%, p = 0.03). Overall, 15 patients (44%) underwent stoma reversal, 3 of whom had a complication treated non-operatively. CONCLUSIONS: Protective stoma should be considered in extensive CRS-HIPEC procedures requiring two or more bowel anastomoses in order to reduce the postoperative morbidity rate.

Postoperative complications and waiting time for surgical intervention after radiologically guided drainage of intra-abdominal abscess in patients with Crohn's disease.

BACKGROUND: In patients with active Crohn's disease (CD), treatment of intra-abdominal abscess usually comprises antibiotics and radiologically guided percutaneous drainage (PD) preceding surgery. The aim of this study was to investigate the risk of postoperative complications and identify the optimal time interval for surgical intervention after PD. METHODS: A multicentre, international, retrospective cohort study was carried out. Details of patients with diagnosis of CD who underwent ultrasonography- or CT-guided PD were retrieved from hospital records using international classification of disease (ICD-10) diagnosis code for CD combined with procedure code for PD. Clinical variables were retrieved and the following outcomes were measured: 30-day postoperative overall complications, intra-abdominal septic complications, unplanned intraoperative adverse events, surgical-site infections, sepsis and pathological postoperative ileus, in addition to abscess recurrence. Patients were categorized into three groups according to the length of the interval from PD to surgery (1-14 days, 15-30 days and more than 30 days) for comparison of outcomes. RESULTS: The cohort comprised 335 CD patients with PD followed by surgery. Median age was 33 (i.q.r. 24-44) years, 152 (45.4 per cent) were females, and median disease duration was 9 (i.q.r. 3.6-15) years. Overall, the 30-day postoperative complications rate was 32.2 per cent and the mortality rate was 1.5 per cent. After adjustment for co-variables, older age (odds ratio 1.03 (95 per cent c.i. 1.01 to 1.06), P < 0.012), residual abscess after PD (odds ratio 0.374 (95 per cent c.i. 0.19 to 0.74), P < 0.014), smoking (odds ratio 1.89 (95 per cent c.i. 1.01 to 3.53), P = 0.049) and low serum albumin concentration (odds ratio 0.921 (95 per cent c.i. 0.89 to 0.96), P < 0.001) were associated with higher rates of postoperative complications. A short waiting interval, less than 2 weeks after PD, was associated with a high incidence of abscess recurrence (odds ratio 0.59 (95 per cent c.i. 0.36 to 0.96), P = 0.042). CONCLUSION: Smoking, low serum albumin concentration and older age were significantly associated with postoperative complications. An interval of at least 2 weeks after successful PD correlated with reduced risk of abscess recurrence.

Climate change. Uncertainty and climate change assessments.

Clear and quantitative discussion of uncertainties is critical for public policy making on climate change. The recently completed report of the Intergovernmental Panel on Climate Change assessed the uncertainty in its findings and forecasts. The uncertainty assessment process of the IPCC should be improved in the future by using a consistent approach to quantifying uncertainty, focusing the quantification on the few key results most important for policy making. The uncertainty quantification procedure should be fully documented, and if expert judgment is used, a specific list of the experts consulted should be included.

Guanidination and nitroguanidination of staphylococcal enterotoxin B.

Guanidination of the free amino groups of staphylococcal enterotoxin B with 3,5-dimethyl-1-guanylpyrazole converted 31-32 of 33 epsilon-amino groups and 30% of the N-terminal residue. This product, although markedly reduced in solubility, suffered no gross change in conformation and retained full biological activity. A derivative prepared by reaction with O-methylisourea with only one lysyl residue unaltered lost most of its emetic activity. Nitroguanidination with 3,5-dimethyl-1-nitroguanylpyrazole converted up to 28 of the epsilon-amino groups and essentially all of the N-terminus. This material was greatly reduced in ability to produce emesis and like the O-methylisourea prepared guanidinated enterotoxin, gave only a line of partial identity in double diffusion. The loss of activity is attributed to unfolding and it is concluded that the free amino groups of enterotoxin B do not critically participate in either its antigenic determinants or its active center for emesis.

4-(Diphenylmethyl)-1-[(imino)methyl]piperidines as gastric antisecretory agents.

4-(Diphenylmethyl)-1-piperidinemethanimine (1) is a potent oral gastric antisecretory agent in rats but contains a strong anticholinergic component. Since a nonanticholinergic gastric antisecretory drug would be useful in the treatment of peptic ulcer disease, a program was initiated by us to find such an agent based on 1. Compound 1 contains structural elements common to the anticholinergics atropine and homatropine. Studies on the structure-activity relationships of these compounds and their derivatives have revealed certain modifications that diminish or abolish anticholinergic activity. The application of these modifications to the design of analogues of 1 afforded an antisecretory compound, 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine (3h, fenoctimine), which exhibited no anticholinergic activity. Fenoctimine is undergoing clinical trial as a gastric antisecretory drug.

Antisecretory activity of human, dog, and rat metabolites of fenoctimine.

Fenoctimine (1a), a nonanticholinergic inhibitor of gastric acid secretion in dogs and rats, was evaluated as a gastric antisecretory agent in humans. In humans it exhibited weak antisecretory activity and caused anticholinergic-like side effects such as dry mouth and nasal passages. Studies of the metabolic fate of fenoctimine in humans, dogs, and rats provided structures of the resultant metabolites. These were synthesized and tested for antisecretory and anticholinergic activity. The human metabolites were all less active than fenoctimine as antisecretory agents, and some displayed significant anticholinergic activity. These results suggest that the unexpectedly weak effect of fenoctimine as a gastric antisecretory agent in humans, as well as anticholinergic effects, may be due to its extensive metabolism, which is different from that seen in dog and rat.

2-Mercaptoacetamidines as gastric antisecretory agents.

A series of N-substituted 2-mercaptoacetamidines was synthesized and evaluated for gastric antisecretory activity in dogs stimulated with gastrin tetrapeptide. The most potent analogues showed 80--95% inhibition of acid secretion after an oral dose of 8 mg/kg. Thus, these compounds represent a new structural type having significant antisecretory activity. Disulfides had essentially the same antisecretory potency as the corresponding mercaptoacetamidines, indicating a metabolic interconversion. Alkylation of the mercapto group decreased potency. Higher carboxamidine homologues such as 2- and 3-mercaptopropionamidines had very low activity. Hydroxyacetamidines and mercaptoacetamides also had low potency. Side effects observed with this series of compounds included emesis, tachycardia, and gastric bleeding.

Evaluation of a lipopeptide immunogen as a therapeutic in HIV type 1-seropositive individuals.

A 32-amino acid HIV-1 Gag immunogen was assessed for its ability to augment existing virus-specific CTL responses in chronically HIV-1-infected individuals. The immunogen was an HIV-1 synthetic lipopeptide conjugate composed of an N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R)-propyl-N-(R)-cysteinyl] group covalently coupled to a synthetic 32-amino acid Gag peptide containing at least 5 CTL epitopes known to be restricted by HLA-A33, -B8, -B27, -B35, and -Bw62. This potential immunotherapeutic was first determined to be safe in six HIV-1-seropositive subjects, with no adverse clinical effects noted during a 182-day period after administration of a dose of 350 microg. The immunogenicity of this lipopeptide conjugate was then assessed in a pilot study in nine HIV-1-seropositive volunteers with peripheral blood CD4+ lymphocyte counts of >500/microl. Three groups of individuals were studied: HLA-selected subjects who received 350 microg of the immunogen on days 0, 28, and 56 (four subjects); HLA-selected subjects who received a placebo according to a similar inoculation schedule (three subjects); and HLA-mismatched subjects who received the experimental immunogen (two subjects). All subjects were monitored for 26 weeks. After treatment, PBLs from two of the four HLA-selected subjects who received the experimental immunogen showed a transient increase in Gag peptide-specific bulk CTL activity. None of the placebo-vaccinated or vaccinated HLA-mismatched subjects showed any change in bulk Gag peptide-specific CTL activity. However, no consistent decrease in plasma HIV-1 RNA levels was noted in any of the subjects. The present study illustrates that this peptide formulation may not be a sufficiently potent immunogen to significantly augment HIV-1-specific CTLs and to decrease virus load in HIV-1-seropositive individuals.

Review article: alginate-raft formulations in the treatment of heartburn and acid reflux.

Alginate-based raft-forming formulations have been marketed word-wide for over 30 years under various brand names, including Gaviscon. They are used for the symptomatic treatment of heartburn and oesophagitis, and appear to act by a unique mechanism which differs from that of traditional antacids. In the presence of gastric acid, alginates precipitate, forming a gel. Alginate-based raft-forming formulations usually contain sodium or potassium bicarbonate; in the presence of gastric acid, the bicarbonate is converted to carbon dioxide which becomes entrapped within the gel precipitate, converting it into a foam which floats on the surface of the gastric contents, much like a raft on water. Both in vitro and in vivo studies have demonstrated that alginate-based rafts can entrap carbon dioxide, as well as antacid components contained in some formulations, thus providing a relatively pH-neutral barrier. Several studies have demonstrated that the alginate raft can preferentially move into the oesophagus in place, or ahead, of acidic gastric contents during episodes of gastro-oesophageal reflux; some studies further suggest that the raft can act as a physical barrier to reduce reflux episodes. Although some alginate-based formulations also contain antacid components which can provide significant acid neutralization capacity, the efficacy of these formulations to reduce heartburn symptoms does not appear to be totally dependent on the neutralization of bulk gastric contents. The strength of the alginate raft is dependant on several factors, including the amount of carbon dioxide generated and entrapped in the raft, the molecular properties of the alginate, and the presence of aluminium or calcium in the antacid components of the formulation. Raft formation occurs rapidly, often within a few seconds of dosing; hence alginate-containing antacids are comparable to traditional antacids for speed of onset of relief. Since the raft can be retained in the stomach for several hours, alginate-based raft-forming formulations can additionally provide longer-lasting relief than that of traditional antacids. Indeed, clinical studies have shown Gaviscon is superior to placebo, and equal to or significantly better than traditional antacids for relieving heartburn symptoms. Alginate-based, raft-forming formulations have been used to treat reflux symptoms in infants and children, and in the management of heartburn and reflux during pregnancy. While Gaviscon is effective when used alone, it is compatible with, and does not interfere with the activity of antisecretory agents such as cimetidine. Even with the introduction of new antisecretory and promotility agents, alginate-rafting formulations will continue to have a role in the treatment of heartburn and reflux symptoms. Their unique non-systemic mechanism of action provides rapid and long-duration relief of heartburn and acid reflux symptoms.

FMRFamide enhances acetylcholine-induced contractions of guinea pig ileum.

Isolated guinea pig ilea were contracted with acetylcholine (ACh) in the absence and presence of the neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2). FMRFamide (0.17-17 microM) enhanced ACh-induced contractions (observed as a leftward shift of the dose-response curve and increase in Emax) with maximal effect at 1.7 microM. FMRFamide had no effect when administered alone. These results extend the demonstration of a FMRFamide/ACh interaction to mammalian tissue and support the concept that FMRFamide, or mammalian equivalents, could play a modulatory role in mammals.

A-18-famide and F-8-famide, endogenous mammalian equivalents of the molluscan neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2), inhibit colonic bead expulsion time in mice.

Morphine and the two endogenous mammalian FMRFamide (Phe-Met-Arg-Phe-NH2)-related peptides known as morphine-modulating neuropeptides, F-8-Famide (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) and A-18-Famide (Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe -NH2), were administered intracerebroventricularly (ICV) to mice and the effect of each on colonic bead expulsion time was measured. Each of the three compounds delayed expulsion of a 3 mm glass bead placed in the distal colon. A-18-Famide was more potent than F-8-Famide [ED 50 = 2.3 micrograms (1.2 nmole) and 13.9 micrograms (13.0 nmole), respectively]. A-18-Famide: 1) did not block morphine-induced delay of bead expulsion time, and 2) was blocked by simultaneous administration (ICV) of 1.0 microgram of the competitive opiate antagonist naloxone. These data demonstrate apparent opioid modulatory or agonist-like, rather than antagonist-like, properties of A-18-Famide and F-8-Famide.

Mu and delta, but not kappa, opioid agonists induce contractions of the canine small intestine in vivo.

Extraluminal strain gage transducers were sutured along the transverse axis of the duodenum in order to monitor circular muscle contractile activity in the pentobarbital anesthetized dog. Administration by intravenous bolus of a variety of mu- and delta-directed opioid ligands resulted in a dose-dependent increase in duodenal contractile activity. In contrast, all kappa-directed ligands were devoid of stimulatory activity. Naloxone reversed the effects of normorphine and [Met5]enkephalin but was 20 times more effective against normorphine than [Met5]enkephalin. Based on the inactivity of all kappa ligands examined and the differential potency of naloxone against [Met5]enkephalin and normorphine, we suggest that this model may be useful in the classification of opioid ligands as to their receptor selectivity in vivo. Further, these data indicate that the stimulation of duodenal contractile activity is not mediated by enteric kappa receptors.

A differentiation between peripheral and central neurokinin receptors using phenoxybenzamine.

Concentrations of phenoxybenzamine ranging from 0.33-33 micron produced a competitive block of kassinin-, neurokinin A- and neurokinin B-induced contractions of the guinea-pig ileum with pA2 values of 6.6, 5.6 and 6.2, respectively. Physalaemin- and substance P-induced contractions were insensitive to phenoxybenzamine treatment. Differences in sensitivity to phenoxybenzamine and pA2 values suggest the existence of at least two and possibly three neurokinin receptors in the guinea-pig ileum. Injected intrathecally to mice, phenoxybenzamine blocked neurokinin-induced, but not bombesin- or somatostatin-induced, reciprocal hind limb scratching. Phenozybenzamine was 6-32 times more effective in blocking neurokinin B-induced scratching than substance P, kassinin, physalaemin or neurokinin A-induced scratching. These results suggest that multiple peripheral and central neurokinin receptors can be differentiated from one another by phenoxybenzamine treatment. They also suggest the existence of a distinct neurokinin B receptor in the mouse spinal cord and the apparent identification of a third neurokinin receptor in the guinea-pig ileum.

Tachykinin-like central activity of neuromedin K in mice.

Neuromedin K, a decapeptide isolated from porcine spinal cord and suggested to have tachykinin-like activity in vitro, produced reciprocal hind-limb scratching when injected intrathecally to mice. Neuromedin K was 20-60 times less potent in producing scratching (on a molar basis) than substance P, kassinin, eledoisin or physalaemin. The activity of neuromedin K was blocked by the substance P antagonist [D-Pro2D-Trp7.9]substance P at doses of antagonist which effectively blocked the activity of the other tachykinins. These data provide the first evidence for tachykinin-like activity of neuromedin K in the central nervous system.

Central and peripheral administration of serotonin produces opposite effects on mouse colonic propulsive motility.

The effects of central or peripheral administration of serotonin on colonic expulsion time (CE) of a glass bead were evaluated after i.p. or free hand i.c.v. administration to mice. Serotonin (5-HT) caused an inhibition of CE when administered centrally but stimulated propulsion after i.p. administration. Several selective serotonin agonists were then tested. Inhibition after i.c.v. administration was produced by 8-OH-DPAT (5-HT1a), RU-24969 (5-HT1b), and 2-methyl serotonin (5-HT3), but not DOI (5-HT2) which augmented propulsion. Relative potencies for inhibition (ED50S) were RU (0.9 micrograms, 3.9 nM) greater than 8-OH-DPAT (3 micrograms, 9.1 nM) greater than 5-HT (7.8 micrograms, 20.1 nM) greater than 2-methyl serotonin (43 micrograms, 140 nM). After i.p. administration 5-HT stimulated propulsive motility (ED50 = 16.1 micrograms, 41.4 nM) while 8-OH-DPAT (ED50 = 55 micrograms, 167 nM) and RU-24969 (ED50 = 54 micrograms, 236 nM) inhibited. DOI and 2-MS had no dose-related activity. The finding that several of the serotonin receptor agonists were capable of inhibiting propulsive motility either by i.p. or i.c.v. administration is a new finding and may help to explain drug-induced constipating activity in man. No selective agonist completely mimicked the effect of serotonin.

The effect of Phe-Met-Arg-Phe-NH2 (FMRFamide) on morphine-induced inhibition of colonic propulsive motility in mice.

Morphine and the molluscan neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) were administered to mice alone or in combination intracerebroventricularly (i.c.v.) and the effect on colonic propulsive motility was measured. Both morphine (1.0 microgram, i.c.v.) and FMRFamide (10 and 50 micrograms, i.c.v.) delayed expulsion of a 3 mm glass bead placed in the distal colon of mice compared to vehicle-treated controls. The inhibitory effects of morphine and FMRFamide on expulsion time were additive at the doses used and individually blocked by naloxone. These data suggest that FMRFamide does not antagonize this nonanalgesic effect of morphine, but appears to have opioid agonist properties.

Endothelin-1, -2 and -3 directly and big-endothelin-1 indirectly elicit an abdominal constriction response in mice.

When injected intraperitoneally into mice, endothelins ET-1, ET-2, ET-3 and big-endothelin-1[1-38] (big-ET-1[1-38]) produced a dose-related, robust and easily quantified abdominal constriction response within 20 min. The ED50 values for this response were 0.026, 0.005, 0.131, and 0.043 mg/kg, respectively. Hence, this test could provide a convenient in vivo endpoint for endothelin activity. The results also imply that ET-1, ET-2, ET 3 or big-ET-1[1-38] may be nociceptive under certain conditions. Morphine (4 mg/kg, s.c.) administered 30 min prior completely blocked the response produced by ET-1. Thus, in conjunction with other indicators, the test may also serve as an in vivo screen for agents useful in the treatment of abdominal or visceral pain. The effect of big-ET-1[1-38], but not ET-1, was blocked by pretreatment with the enzyme inhibitor phosphoramidon (10 mg/kg, s.c., 30 min prior), implying that the big-ET-1[1-38] must first be enzymatically cleaved, presumably to ET-1, in order to elicit the abdominal constriction response. This test might also serve as a discriminative antinociceptive screen, because the response to ET-1 was not blocked by acetaminophen (400 mg/kg, p.o.), ibuprofen (75 mg/kg, p.o.) or indomethacin (1.0 mg/kg, p.o.).

Differentiation of multiple neurokinin receptors in the guinea pig ileum.

We have studied the selectivity and competitiveness of three neurokinin antagonists and atropine against substance P, neurokinin A, and neurokinin B. DPDTNLE-NB, [D-Pro2, D-Trp6,8, Nle10]-neurokinin B is a competitive antagonist of neurokinin B (pA2 = 5.5), but not substance P or neurokinin A. DPDT-SP ([D-Pro2,Trp7,9]-substance P), competitively blocks substance P (pA2 = 6.9) and neurokinin B (pA2 = 6.8), but not neurokinin A. Spantide ([D-Arg1, D-Trp7,9, Leu11]-substance P) competitively blocks substance P (pA2 = 6.7) and at a log unit higher concentration blocks neurokinin A (pA2 = 5.8), but does not block neurokinin B. Atropine is a competitive antagonist of neurokinin B (pA2 = 9.0) at ten times the concentration needed to block acetylcholine (pA2 = 10.1), but does not inhibit the other neurokinins. These results support the hypothesis of multiple neurokinin receptors in the guinea pig ileum and indicate that the site of neurokinin B, but not substance P or neurokinin A is predominantly on intramural neurons. This indirect stimulation appears to be dependent on the release of acetylcholine. Neurokinin B also has activity on smooth muscle receptors since the contractile response could not be completely antagonized by atropine. There appear to be two smooth muscle neurokinin receptors on the basis of results obtained with DPDT-SP and spantide, one predominantly responsive to substance P and the other to neurokinin A. Only spantide appeared to have any effect on the neurokinin A receptor and that was at a much higher concentration than that needed to block substance P.

Vasorelaxant effect of the potassium channel activator, RWJ 29009, is tissue selective.

Potassium channel activators have potential cardioprotective properties, in part due to their ability to increase coronary blood flow. We compared the vasorelaxant properties of potassium channel activators, a calcium channel blocker (nicardipine) and a direct smooth muscle relaxant (sodium nitroprusside) in the canine coronary artery, the femoral artery and the saphenous vein precontracted with 0.03 microM endothelin-1. In the circumflex coronary artery, RWJ 29009, a novel and potent potassium channel activator, maximally relaxed the precontracted rings with an EC50 of 1.9 nM. Cromakalim (EC50 = 220 nM) and nitroprusside (EC50 = 109 nM) were also active. Nicardipine (EC50 = 16.6 nM) produced only a 70% relaxation at 1 microM concentration. In both femoral artery and saphenous vein, all agents relaxed the precontracted rings only at much higher concentrations, and the relaxations were only 75% of maximal relaxation. The results show that while all vasodilators preferentially relax the coronary artery, potassium channel activators appear to be the most selective and potent of these agents.