Outcomes of liver-first strategy and classical strategy for synchronous colorectal liver metastases in Sweden

Background

Patients with synchronous colorectal liver metastases (sCRLM) are increasingly operated with liver resection before resection of the primary cancer. The aim of this study was to compare outcomes in patients following the liver-first strategy and the classical strategy (resection of the bowel first) using prospectively registered data from two nationwide registries.

Assessment of ileal pouch inflammation by single-stool calprotectin assay

PURPOSE: Assessment of inflammation within the ileal pouch to establish a diagnosis of pouchitis requires both pouch endoscopy and biopsy because there can be a poor correlation between macroscopic and histologic assessments of inflammation. A simplified diagnostic test would be of clinical advantage. Calprotectin is a stable myelomonocytic protein, measurable in feces. It quantitatively relates to inflammation within the gastrointestinal tract. This study was designed to compare single and 24-hour stool measurements of calprotectin in patients with and without evidence of ileal pouch inflammation with endoscopic, histologic, and immunohistochemical indices. METHODS: Twenty-four-hour stool collections were made in ileal pouch patients, 9 with and 15 without (7 with ulcerative colitis and 8 with familial polyposis coli) evidence of pouch inflammation. First-morning stool concentration and total 24-hour calprotectin were quantified by use of a single step enzyme-linked immunosorbent assay. Biopsies from the reservoir were taken for conventional histology and scoring of intraepithelial neutrophil infiltrate. Cells positive for CD3, CD45RO, CD14, and CD15 within the lamina propria were quantified by use of immunohistochemistry. RESULTS: The mean first-morning stool calprotectin concentration correlated with the 24-hour level (r=0.91;P=<0.0001). The median single-stool calprotectin concentrations were 39 mg/l, 4 mg/l, and 8.5 mg/l (normal range, 0.2–10 mg/l) in patients with inflamed, noninflamed ulcerative colitis, and familial adenomatous polyposis, respectively. All nine patients with endoscopic and histologic evidence of pouch inflammation had raised stool calprotectin. Two of 15 patients without evidence of pouch inflammation had abnormal stool calprotectin. Single-stool calprotectin concentration correlated with the percentage of mature granulocytes (CD15;r=0.46;P=0.04) and activated macrophages (CD14;r=0.65;P=0.006), but not memory T cells (CD45RO;r=–0.05;P=0.4) within the lamina propria. CONCLUSION: Single first-morning stool calprotectin levels provide a quantitative measure of pouch inflammation, which may be helpful in the diagnosis and assessment of pouchitis.Supported by a grant from the Henry Smith Foundation.Presented at the Faulk symposium on the pelvic ileal reservoir in ulcerative colitis, Oxford, United Kingdom, April 17 to 19, 1997.     

Plasma metabolites associated with type 2 diabetes in a Swedish population: a case–control study nested in a prospective cohort

Aims/hypothesis

The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction.

Methods

We established a nested case–control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case–control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case–control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index.

Results

We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors.

Conclusions/interpretation

Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.

     

Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease.

BACKGROUND & AIMS: It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS: First, patients with quiescent Crohn's disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS: Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS: NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.     

Leukocyte adsorptive apheresis for the treatment of active ulcerative colitis: a prospective, uncontrolled, pilot study.

BACKGROUND AND AIMS: Active ulcerative colitis (UC) is characterized by infiltration of activated granulocytes and monocytes/macrophages (GM) within the large bowel mucosa. GM are major sources of inflammatory cytokines, and in UC they are elevated with increased survival time. We investigated the possibility that reducing the level of these cells might promote remission of active UC. METHODS: Thirty-one patients with active corticosteroid refractory (refractory) UC, mean age of 42 years, duration of UC 6 years, clinical activity index (CAI) of 15, disease activity index (DAI) of 10, and 8 corticosteroid naive patients (naive), mean age of 36 years, duration of UC 2 years, CAI of 11, DAI of 8 were recruited. Each patient was treated with up to 11 cycles of granulocyte and monocyte adsorptive apheresis over 11 weeks by using a 335-mL capacity column filled with cellulose acetate beads that adsorb GM. RESULTS: At week 12, 81% of refractory (CAI, 3; P < 0.001 and DAI, 4; P < 0.001) and 88% of naive (CAI, 1; P = 0.012 and DAI, 3; P = 0.011) patients achieved remission. Early relapse was not a feature, and at 12 months, 26 of 33 patients had maintained their remission. The treatment was well tolerated, and no severe side effects were observed. CONCLUSIONS: The outcome of this study suggests that reduction of circulating granulocytes and monocytes results in alleviation of inflammation and promotes clinical remission in patients with severe active UC that has not responded to intensive corticosteroid treatment. These data suggest that formal controlled studies are warranted.     

Disturbances of speech prosody following right hemisphere infarcts

The ability to perceive and express emotional, as well as number of linguistic prosodic qualities of speech was tested in 20 Swedish-speaking patients with right-sided cortical, as well as purely subcortical brain infarcts, and in 18 normal controls. The infarcts were assessed by clinical neurological examination, and by CT, EEG, and measurements of regional cerebral blood flow (rCBF). In the patients the identification of emotional messages was disturbed, as well as the identification and production of several linguistic prosodic qualities. The study supports the claim that prosodic impairment could be linguistic in nature, and not secondary to affective disorder. The total degree of anatomical and functional disturbance of the right hemisphere played a role for both the ability to identify emotional messages and for identification of two of the linguistic prosodic qualities tested. However, it was not possible to find support for the hypothesis that the organization of prosody in the right hemisphere mirrors that of propositional speech on the left side.     

Binding of the Aliphatic Halides 1,2-Dihromoethane and Chloroform in the Rodent Vaginal Epithelium

Abstract: Whole-body and light microscopic autoradiography were used to study the binding of 1,2-dibromo(¹⁴C)ethane (¹⁴C-DBE) and ¹⁴C-chloroform (¹⁴C-CF) in the mouse and rat vaginal epithelium in vitro and in vivo. In pregnant mice, mice pretreated with pregnant mare's serum gonadotropin (PMSG) or ovariectomized mice primed with medroxyprogesterone, a high level of bound ¹⁴C-DBE metabolites were present in the epithelium, while in ovariectomized oestradiol-primed mice or intact oestradiol-primed mice, the binding was low. Similar results were obtained with ¹⁴C-CF, although the level of binding generally was lower than that observed after ¹⁴C-DBE-exposure. No binding of ¹⁴C-DBE-metabolites was observed in the juvenile rat vaginal epithelium, whereas a high binding was present in the PMSG-primed adult rat vaginal epithelium. Collectively, these data show that ¹⁴C-DBE and ¹⁴C-CF are transformed in situ to metabolites that are irreversibly bound to the vaginal epithelium. The results also suggest that the activating enzyme is under endocrine control and has a low activity in the juvenile and oestradiol-primed adult animal.     

Influence of lesions of the noradrenergic locus coeruleus system on the cerebral metabolic response to bicuculline-induced seizures

The objective of the present study was to explore if lesions of the ascending noradrenergic pathways, originating in the locus coeruleus, modulate the cerebral metabolic response to bicuculline-induced seizures in rats. Bilateral noradrenergic lesions were performed by 6-hydroxydopamine injections in the caudal mesencephalon, 12–22 days before seizures were induced in animals ventilated on N₂O:O₂ (75:25). After 5 min of seizures the brain was frozen in situ and cerebral cortex and hippocampus were sampled for analysis. Labile phosphates, glycolytic metabolites, cyclic nucleotides, and free fatty acids were measured. In another series, lesioned animals were used for measurements of cerebral oxygen consumption.The noradrenergic lesions neither modified the electroencephalographically recorded seizure discharge, nor did they alter cerebral oxygen consumption or cerebral energy state. However, when compared to sham-operated animals, those with noradrenergic lesions had significantly higher (115% and 68%) glycogen concentrations and lower (50% and 52%) cyclic AMP concentrations in cerebral cortex and hippocampus, respectively, demonstrating the marked influence of noradrenergic activity on adenylate cyclase activity and glycogenolysis. The lesions failed to modulate the rise in free fatty acids in the cerebral cortex, or the cyclic GMP concentrations in the cerebral cortex and hippocampus. Thus, increased noradrenergic activity during status epilepticus does not seem responsible for lipolysis or for activation of guanylate cyclase.     

Micropuncture evaluation of the importance of perivascular pH for the arteriolar diameter on the brain surface

Summary A micropipette technique was used to induce local changes of the bicarbonate concentration of the cerebro-spinal fluid surrounding arterioles on the exposed cerebral cortex of anaesthetized rats and cats. Injection volumes of a few nanoliters caused circumscribed and pronounced changes of the diameter of the arterioles under study: mock spinal fluid without bicarbonate dilated, while a solution containing 25 meq/l of bicarbonate constricted the vessels. In such experiments the localpCO₂ of the arteriolar wall remains practically constant, since it is set by thepCO₂ of the arterial blood and of the cerebral tissue. Hence the microinjections essentially consisted in a local change of the pH of the fluid surrounding a small segment of a cerebral arteriole. Since metabolic changes of the nervous tissue changes the periarteriolar pH, it is probable that local pH induced vasomotor changes of the type reported here participate in the so called metabolic regulation of the cerebral blood flow which underlies the local adaptation of the cerebral blood flow to changing functional demands.Supported by the Deutsche Forschungsgemeinschaft.