Selection for surgery and survival of synchronous colorectal liver metastases; a nationwide study.

BACKGROUND: Resection of colorectal liver metastases (CRLM) is associated with improved survival but we currently have limited population-based data on selection for surgery. METHODS: Patients in the Swedish Colorectal Cancer Register reported with liver metastases at diagnosis in 2007-2011 were identified. Clinical characteristics including American Society of Anesthesiologists classification, type of hospital and health care region were retrieved. Linkage to the National Patient Register and Statistics Sweden provided information on liver resection and socioeconomic variables. RESULTS: Synchronous CRLM was found in 4243/27,990 (15.2%) patients, of whom 1094 (25.8%) also had concurrent lung metastases. Of 3149 patients with liver-only metastases, 556 (17.8%) were subjected to liver resection. The resection rate varied by subsite; right-sided 11.7%, left-sided 19.7% and rectal cancer 22.7% (p = 0.001). It varied by type of hospital 14.1-23.6%, by region 11.5-22.7%, and was 19.8% in men and 14.9% in women (all p < 0.001). The adjusted odds were 0.74 (0.59-0.93) for females, 0.58 (0.46-0.74) for general district and 0.50 (0.37-0.68) for district hospital patients, and there were large regional differences. Patients >75 years were very unlikely to receive liver surgery 0.22 (0.15-0.32). In patients subjected to liver surgery, median survival was 57 months, 5-year survival rate was 45.4%, and those with left-sided colon cancer had the best outcome (48.8%; p = 0.02). Five-year hazard ratio for patients not subjected to liver surgery was 4.3 (3.7-5.0). CONCLUSION: Nationwide outcome after resection of synchronous CRLM was impressing but ambiguous selection mechanisms and inaccessibility need to be resolved. The implications of subsite deserve further attention.

Socioeconomic inequalities in relative survival of rectal cancer most obvious in stage III.

INTRODUCTION: The association between socioeconomic status (SES) and relative survival of rectal cancer is little investigated. We hypothesized that the impact on risk of death by SES would be much smaller when differences in background mortality (comorbidity, lifestyle factors) were taken into account, i.e. in modelling relative survival of rectal cancer. METHODS: Individual data on civil status, education, and income were linked to the Swedish Rectal Cancer Registry 1995-2005 (n = 16,713). Specific life tables by socioeconomic group were used to calculate relative survival, and modelling included age, sex, stage, time period, and SES. The same covariates were applied in a Cox regression based on absolute survival. RESULTS: Stage distribution was associated with civil status, education, and income (p < 0.001). In spite of modelling based on relative survival, an increased risk of death was found for all other patients compared with those who were married, as well as for all other patients compared with those with the highest income. The pattern was fundamentally the same as in a Cox regression model, only the point estimates were slightly reduced using the relative approach. In stage-specific modelling of relative survival, income was of particular importance in stage III; the hazard ratio (HR) for lowest versus the highest income was 1.37 [95 % confidence interval (CI) 1.15-1.64]. There were also significant differences by income among patients who had a major surgical resection (stage IV excluded). CONCLUSION: Large and clinically relevant socioeconomic inequalities remained in stage-adjusted analyses of relative survival, also in a setting of universal healthcare and no screening program operating.

Heterogeneity of colon cancer patients reported as emergencies.

BACKGROUND: Up to one-fourth of all colon cancer patients are reported as emergencies, and the aim of the present study was to scrutinize mode of presentation in this group. MATERIALS AND METHODS: All reported cases of emergency (n = 263) and randomly selected elective controls (1:2) of colon cancer in four Swedish counties 2006-2008 were eligible (n = 854). Symptoms and aspects of management were retrieved from surgery and primary care records. Outcomes were compared using Kaplan-Meier estimates and Cox regression. RESULTS: Among patients reported as emergencies, 158/263 (60 %) underwent operation within three days (acute), and 105 (40 %) after more than 3 days (subacute). In the latter group, 20/94 (21 %) had reported two symptoms, and 31/94 (33 %) had reported three or more symptoms associated with colon cancer to primary care during the last 12 months prior to surgery. In total, 46/105 (44 %) had already had an examination of the large bowel, and 52/105 (50 %) were stage IV, as opposed to 36/158 (23 %) in the acute group and 83/577 (15 %) in the elective group (p < 0.001). Mortality at 30 and 90 days was 15.2 and 35.6 % in the subacute group, 8.2 and 14.9 % in the acute group (p = 0.001), and 1.9 and 4.3 % in the elective group (p < 0.001); 5-year survival was 28.3, 40.1, and 57.8 %, respectively, in the three groups (p < 0.001). The hazard ratio, adjusted for age, sex, and stage, was 1.88 95 % confidence interval (CI) 1.5-2.4) for the acute group and 2.29 (95 % CI 1.7-3.1) for the subacute group. CONCLUSIONS: Colon cancer patients reported as emergencies but operated upon more than three days after admission had the worst outcome. Efforts to decrease the interval between admission and surgery is one important aspect of care, but wider attention must also be paid to this group of patients.

Emergency presentation and socioeconomic status in colon cancer.

BACKGROUND: Emergency presentation affects up to every fourth patient with colon cancer, and is associated with worse outcomes. The aim of this study was to investigate any association between socioeconomic status (SES) and mode of presentation in colon cancer. MATERIALS AND METHODS: Individually attained data on civil status, education and income were linked to quality registries for colon cancer in two large Swedish regions 1997-2006 (n = 12 293) and analyzed by logistic regression, adjusting for age, sex, stage, region and socioeconomic variables. RESULTS: The frequency of emergency presentation was 23%; 27.8% among patients above the age of 80, and 20.0% among patients aged 70-79 (p < 0.001). There was no difference between men and women (22.6% vs. 23.8%; p = 0.1). Among patients with stage IV colon cancer, 34.6% presented as emergencies. Odds ratio for an emergency presentation in unmarried patients was 1.24 (96% CI 1.04-1.48), and for unmarried patients above the age of 80, OR was 1.45 (95% CI 0.98-2.13). Among patients below the age of 70 with compulsory education only, OR was 1.22 (95% CI 0.98-1.48). For patients within the lowest income quartile (Q1), OR was 1.24 (95% CI 1.04-1.49). This was most pronounced in men (OR 1.34; 95% CI 1.40-1.72), in patients below the age of 70 (OR 1.36; 95% CI 1.02-1.82), and above the age of 80 (OR 1.41; 95% CI 1.00-1.98). CONCLUSION: Emergency presentation of colon cancer is consistently associated with socioeconomic factors, and this must be considered in efforts aimed at reducing the overall frequency of emergency cases.

A population-based audit of the clinical use of faecal occult blood testing in primary care for colorectal cancer.

AIM: Symptoms related to colorectal cancer (CRC) are common. We investigated the value of the faecal occult blood test (FOBT), when administered in primary care, in the diagnosis of CRC. METHOD: All patients who underwent a FOBT (Hemoccult II) at 20 public primary care centres in Sörmland County, Sweden, during 2000-2005, were included (n=9048). Linkage to the Swedish Cancer Registry identified all cases of CRC. Symptoms recorded at the time of the FOBT were retrieved from the patient records. The outcome from the FOBT to diagnosis and subsequent survival was compared between patients who were FOBT negative and patients who were FOBT positive. RESULTS: One-hundred and sixty-one patients were diagnosed with CRC within 2 years after undergoing a FOBT in primary care. These comprised 18% of all 917 patients diagnosed with CRC in the county during the study period. In 41 (25.4%) of the 161 patients the test was negative. Symptoms related to CRC were documented for 158 (98%) patients at the time the FOBT was administered. The median investigation time from the FOBT test to the diagnosis of CRC was 91 days: 80 days for FOBT-positive patients and 188 days for FOBT-negative patients (P<0.001). This difference was significant independent of age, sex and site of tumour. The hazard ratio for FOBT negativity, 3 years after the FOBT, when adjusted for age and sex, was 1.47 (95% CI, 0.81-2.68). CONCLUSION: Despite having suggestive symptoms, 41 (4.5%) of 917 CRC patients had a negative FOBT result in primary care. This was associated with diagnostic delay and, potentially, a worse outcome.

Emergency presentation of colon cancer is most frequent during summer.

AIM: The frequency of emergency colon cancer (ECC) was determined using a reproducible definition of 'emergency' to analyse the impact of mode of presentation on long-term prognosis and to search for risk factors for an emergency presentation. METHOD: All patients with colon cancer treated at one Swedish GDH between 1996 and 2005 (N = 604) were eligible. Patients admitted through the emergency room, operated on within three days and with an emergency condition confirmed at surgery were classified as ECC. Survival was analysed by Kaplan-Meier estimates and risk of death by Cox regression. RESULTS: The rate of ECC was 97/585 (17%). Patients with ECC were older (median 77 vs 74, P = 0.02), they had more stage III and IV cancers (65%vs 47%; χ(2) = 9.4, P < 0.001) and had a cancer located in the caecum less often (20%vs 33%, χ(2) = 4.3 P = 0.04). ECC were most frequent between June and August (36%), whereas elective cases were evenly distributed throughout the year (χ(2) = 7.8; P = 0.049), Crude 5-year survival was 18% in ECC and 38% in the elective group (P < 0.001). The hazard ratio for death within five years in ECC, with 30-day mortality excluded and adjusted for age and sex was 2.25 (95% CI; 1.42-3.55). CONCLUSION: Emergency presentation of colon cancer is an independent and adverse risk factor for long-term survival. The causes of a seasonal variation need to be clarified.

Socioeconomic inequalities in the use of radiotherapy for rectal cancer: a nationwide study.

UNLABELLED: Preoperative radiotherapy (PRT) in rectal cancer reduces the risk of local recurrence by at least half but the influence of the socioeconomic status of patients on the use of PRT is little investigated in Europe. METHODS: Individually attained data on civil status, education and income were linked to the Swedish Rectal Cancer Registry 1995-2005 (n=16,713) and analysed by logistic regression. RESULTS: Forty-six percentage of the patients received PRT and the crude rate varied with age, gender, civil status, education and income as well as with sublocalisation, stage, type of hospital and health care region. In a multivariate analysis, all civil status groups had PRT to a lesser extent compared with married patients; odds ratio (OR) for unmarried patients was 0.67 (95% confidence interval (CI) 0.59-0.76). Patients with secondary and university education had PRT to the same extent as those with compulsory school (OR 1.04 (0.94-1.15) and 0.92 (0.81-1.06)). The use of PRT was associated with income; OR for patients with income Q1 versus Q4 was 0.76 (0.67-0.86). The inequalities by civil status and income remained unchanged also in groups with a relatively stronger indication for adjuvant radiotherapy, i.e. younger patients and in low rectal cancer. CONCLUSION: Unmarried and low-income patients are at increased risk for not receiving PRT in rectal cancer. Comorbidity may explain some differences but increased awareness of the role of non-medical variables for the use of PRT is warranted.

Sphincter preservation in rectal cancer is associated with patients' socioeconomic status.

BACKGROUND: Decision making regarding the choice of surgical procedure in rectal cancer is complex. It was hypothesized that, in addition to clinical factors, several aspects of patients' socioeconomic background influence this process. METHODS: Individually attained data on civil status, education and income were linked to the Swedish Rectal Cancer Registry 1995-2005 (16 713 patients) and analysed by logistic regression. RESULTS: Anterior resection (AR) was performed in 7433 patients (44.5 per cent), abdominoperineal resection (APR) in 3808 (22.8 per cent) and Hartmann's procedure in 1704 (10.2 per cent). Unmarried patients were least likely (odds ratio (OR) 0.76, 95 per cent confidence interval (c.i.) 0.64 to 0.88) and university-educated men were most likely (OR 1.30, 1.04 to 1.62) to have an AR. Patients with the highest income were more likely to undergo AR (OR 0.80, 0.85 and 0.86 respectively for first, second and third income quartiles). Socioeconomic differences in the use of AR were smallest among the youngest patients. Unmarried patients were more likely (OR 1.21, 95 per cent c.i. 1.00 to 1.48) and university-educated patients less likely (OR 0.78, 95 per cent c.i. 0.63 to 0.98) to have an APR. CONCLUSION: The choice of surgical strategy in rectal cancer is not socioeconomically neutral. Confounding factors, such as co-morbidity or smoking, may explain some of the differences but inequality in treatment is also plausible.

Inhibition of lipid peroxidation by spin labels. Relationships between structure and function.

Inhibition of lipid peroxidation by nitroxide radicals and their corresponding hydroxylamines was investigated. The nitroxides were either oxazolidines or piperidines, differing in substitution of the backbone of the molecule (a five or six-membered ring structure, respectively). Concentration requirements for 50% inhibition of microsomal lipid peroxidation varied from 340 to 6 microM for the nitroxides, and from 120 to 3 microM for the hydroxylamines, correlating with lipophilicity and chemical structure. Intramembrane concentrations required for 50% inhibition was independent of lipophilicity when peroxidation was initiated with ADP-Fe2+ but increased with lipophilicity when peroxidation was initiated with t-butylhydroperoxide. During studies of the kinetics of the inhibition, two modes were seen: a delay or a decreased rate of the process. The former mode was seen with the more lipophilic inhibitors. The mechanism of inhibition was similar for all nitroxides and consisted of the following three major components: blocking of primary initiation, prevention of secondary (peroxide-dependent) initiation, and scavenging of various lipoid radicals in the membrane, the major mode of action of the hydroxylamines. Inhibitory efficiency was interpreted in terms of steric hindrance, diffusibility, regeneration of inhibitor, and ability to interact with hydrophilic sites in a hydrophobic environment.

Detection of oxygen radicals during reperfusion of intestinal cells in vitro.

The nitroxide OXANO. (2-Ethyl-2,5,5-trimethyl-3-oxazolidinoxyl) which in its reduced form, OXANOH (2-Ethyl-1-hydroxy-2,5,5-trimethyl-3-oxazolidine), is capable of reacting with short-lived radicals, forming a secondary stable radical, was used for ESR-detection of radical production in isolated cells. The properties of OXANO. and OXANOH in terms of stability in cellular and subcellular systems, membrane permeability and effects on cellular viability were evaluated. Ischemia and reperfusion was simulated in vitro in a preparation of cells from rat intestinal mucosa by incubation at high density (4 X 10(8) cells/ml) under an atmosphere of nitrogen for 25 min and resuspended with fresh oxygenated buffer containing 5 mM OXANOH. A significant increase in radical formation during the 15 min reperfusion period studied was obtained in cells exposed to ischemia compared to control cells incubated at normal density under an atmosphere of oxygen. The addition of 5 microM of the scavenging enzyme superoxide dismutase reduced the radical formation by 50%. The time sequence of the superoxide formation was calculated as the difference in radical production in the presence and absence of superoxide dismutase.

Peroxidase-catalyzed oxidation of eugenol: formation of a cytotoxic metabolite(s).

The oxidation of eugenol (4-allyl-2-methoxyphenol) by horseradish peroxidase was studied. Following the initiation of the reaction with hydrogen peroxide, eugenol was oxidized via a one-electron pathway to a phenoxyl radical which subsequently formed a transient, yellow-colored intermediate which was identified as a quinone methide. The eugenol phenoxyl radical was detected using fast-flow electron spin resonance. The radicals and/or quinone methide further reacted to form an insoluble complex polymeric material. The stoichiometry of the disappearance of eugenol versus hydrogen peroxide was approximately 2:1. The addition of glutathione or ascorbate prevented the appearance of the quinone methide and also prevented the disappearance of the parent compound. In the presence of glutathione, a thiyl radical was detected, and increases in oxygen consumption and in the formation of oxidized glutathione were also observed. These results suggested that glutathione reacted with the eugenol phenoxyl radical and reduced it back to the parent compound. Glutathione also reacted directly with the quinone methide resulting in the formation of a eugenol-glutathione conjugate(s). Using 3H-labeled eugenol, extensive covalent binding to protein was observed. Finally, the oxidation products of eugenol/peroxidase were observed to be highly cytotoxic using isolated rat hepatocytes as target cells.

Prostaglandin synthase catalyzed metabolic activation of p-phenetidine and acetaminophen by microsomes isolated from rabbit and human kidney.

The metabolism of p-phenetidine in microsomes from rabbit kidney and the metabolism of acetaminophen and p-phenetidine in human kidney microsomes to protein binding metabolites were examined. Microsomal preparations from rabbit kidney medulla catalyzed the irreversible arachidonic acid-dependent binding of p-[14C]phenetidine to tissue protein. This was not observed in similar preparations from kidney cortex or if the microsomal protein was denatured. The Km (60 microM) of the binding reaction indicated that the enzymatic processes responsible for the binding have very high affinity for p-phenetidine. Indomethacin inhibited the binding to medullary microsomal protein whereas the inclusion of catalase and superoxide dismutase did not affect protein binding. Linolenic acid hydroperoxide was very effective in supporting binding whereas tertiary butylhydroperoxide and H2O2 were less effective. The binding in the presence of hydroperoxides was not sensitive to indomethacin or metyrapone. The binding ratio of 14C-ring to 14C-ethyl labeled p-phenetidine using rabbit kidney medulla microsomal protein was 2:1 suggesting that the binding species may be p-phenetidine quinone-imine and quinone-diimine dimers which have been shown previously to be products of the peroxidatic oxidation of p-phenetidine. The inclusion of reduced glutathione in incubations containing p-[14C] phenetidine, rabbit kidney medulla microsomes and arachidonic acid resulted in a decrease in radioactivity bound to protein and an increase in radioactivity in the aqueous phase after extraction. Thin-layer chromatography of the aqueous phase revealed the presence of reduced glutathione conjugates of the previously identified reactive dimers of p-phenetidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoradiography of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): uptake in the monoaminergic pathways and in melanin containing tissues.

A recently discovered neurotoxic compound, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, has been found to cause a parkinsonian-like syndrome in man and monkey, but not in laboratory animals such as rat, mouse and guinea pig. MPTP seems to selectively destroy the melanin containing dopaminergic cells in pars compacta of substantia nigra. Lower mammalian species do not have melanin in these cells, which indicates that the presence of neuromelanin may be of importance for the development of MPTP-induced lesions. By means of whole-body autoradiography of 3H-MPTP in mice, accumulation and retention was observed in the dopaminergic pathways, in locus caeruleus and in structures in the medulla oblongata and spinal cord. A high uptake was also seen in melanin-containing tissues such as in the eyes of pigmented mice. MPTP has earlier been found to have high affinity in vitro for dopamine melanin, which is similar to the pigment in substantia nigra. The typical features of the MPTP-induced neurotoxicity with destruction of pigmented nerve cells and development of parkinsonism may be to to accumulation and retention of MPTP and its metabolites in these cells. In species with pigmented nerve cells, such as man and monkey, the accumulation may be much more pronounced because of the melanin affinity of MPTP and its metabolites.

Biotransformation of terodiline I. Identification of metabolites in dog urine by mass spectrometry.

Nine metabolites of terodiline (N-tert-butyl-4,4-diphenyl-2-butylamine) have been identified in dog urine by various chromatographic techniques and mass spectrometry. The main metabolic pathway is aromatic hydroxylation, leading to the quantitatively most important metabolite, N-tert-butyl-4-(4-hydroxyphenyl)-4-phenyl-2-butylamine, and to two dihydroxylated metabolites, one mono substituted in both rings (N-tert-butyl-4,4'-bis(4-hydroxyphenyl)-2-butylamine), and one disubstituted in one ring (N-tert-butyl-4-(3,4-dihydroxyphenyl)-4-phenyl-2-butylamine). The latter is further metabolized by methylation, forming N-tert-butyl-4-(4-hydroxy-3-methoxyphenyl)-4-phenyl-2-butylamine, the second most abundant metabolite. Still another metabolite is formed by hydroxylation in the tert-butyl group to N-(2-hydroxymethyl-2-propyl)-4,4-diphenyl-2-butylamine. A very minor dihydroxylated metabolite results from oxidation both in an aromatic ring and in the tert-butyl group, giving N-(2-hydroxymethyl-2-propyl)-4-(4-hydroxyphenyl)-4-phenyl-2-butylamine. Oxidation of the carbon adjacent to the nitrogen and subsequent deamination gives the two ketones 4-(4-hydroxyphenyl)-4-phenyl-2-butanone and 4-(4-hydroxy-3-methoxyphenyl)-4-phenyl-2-butanone. Reduction of the carbonyl function in the former yields the corresponding alcohol, 4-(4-hydroxyphenyl)-4-phenyl-2-butanol. Some unchanged terodiline is also present. All metabolites formed by functionalization appear to be extensively conjugated, presumably with glucuronic acid.

Reactive products formed by peroxidase catalyzed oxidation of p-phenetidine.

The nature of the reactive metabolites formed during HRP/H2O2 catalyzed oxidation of p-phenetidine was investigated. Interaction with DNA measured as the induction of DNA single strand breaks and DNA binding resulted in a time-dependent decrease in the interaction and could be related to the primary oxidation of p-phenetidine. Oxygen uptake observed during p-phenetidine metabolism in the presence of GSH also exhibited such a correlation. GSH-conjugate formation and protein binding on the other hand exhibited an initial increase and did not appear to be directly related to primary p-phenetidine oxidation since maximal interaction was obtained when p-phenetidine had been completely metabolized. The GSH-conjugate and protein binding ratio of ring labelled to ethyl labelled p-phenetidine of approx. 2:1 indicated that these reactive metabolites(s) may be dimer(s) whose formation presumably involved loss of one ethoxy group of p-phenetidine. Accordingly formation of ethanol, indicative of ethoxy group elimination, could be observed during p-phenetidine metabolism. Only one metabolite generated from p-phenetidine oxidation exhibited a concentration dependent binding to protein. This metabolite also reacted with GSH to form water-soluble conjugates. Prior reduction of the metabolite by ascorbic acid prevented this conjugate formation. The mass spectral fragmentation pattern of the reactive protein- and GSH-binding metabolite was compatible with the structure N(4-ethoxyphenyl)-p-benzoquinoneimine.

Metabolism of Oxybutynin: establishment of desethyloxybutynin and oxybutynin N-oxide formation in rat liver preparation using deuterium substitution and gas chromatographic mass spectrometric analysis.

Oxybutynin is rapidly metabolized in rat liver microsomes. Two major primary oxidation products were identified as N-desethyl oxybutynin and oxybutynin N-oxide. Deuterium substituted substrate was used to aid the identification. N-Desethyl oxybutynin was characterized by gas chromatography electron impact mass spectrometry as its trifluoroacetamide derivative and oxybutynin N-oxide was indicated by the presence of a decomposition product, 2-oxo-3-butenyl-2 cyclohexyl-2-phenylglycolate, as elucidated from the gas chromatographic mas spectrometric analysis. The formation of this product from synthetic oxybutynin N-oxide was verified and occurs by two consecutive rearrangements upon thermolysis of the unstable N-oxide. Attempted titanous chloride reduction of oxybutynin N-oxide resulted in the formation of the hydrolytic products 2-cyclohexyl-2-phenylglycolic acid and 4-diethylamino-2-butynol.