Isolated hepatic perfusion for ocular melanoma metastasis: registry data suggests a survival benefit.

BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 35% of the patients, with the liver being the most common site for metastases. These metastases are generally refractory to systemic chemotherapy, and the median survival for patients with liver metastases is about 6 months. This phase II trial reports the experience of isolated hepatic perfusion (IHP) as a treatment option. METHOD: A total of 34 patients with isolated liver metastasis from ocular melanoma underwent IHP. An overall survival comparison was made using data retrieved from the National Patient Register managed by the Swedish National Board of Health and Welfare. RESULTS: An overall radiological response was seen in 68% of the patients, with 12% having a complete response. Time to local progression was 7 months; 68% of the patients developed extrahepatic metastases after a median of 13 months, and the median overall survival was 24 months. There was a significant survival advantage of 14 months (p = 0.029) when comparing these patients with a control group consisting of the longest surviving patients in Sweden with uveal melanoma liver metastases not treated with IHP. CONCLUSIONS: IHP is a treatment option with a high response rate and a potential survival benefit of more than 1 year. IHP should be considered an option in the treatment of uveal melanoma metastases. A randomized trial comparing IHP and best alternative care will start during 2013 (the SCANDIUM trial, ClinicalTrials.gov identifier NCT01785316).

Diagnostic incisional biopsies in clinically indeterminate choroidal tumours.

Most intraocular tumours are reliably diagnosed by a careful clinical examination combined with one or more non-invasive diagnostic techniques. However, in a small percentage of tumours, typically small and clinically amelanotic, the features are insufficiently distinct for a confident clinical diagnosis and tissue is required for diagnosis. We used a 23-G vitreous cutter to access the biopsy site in 43 patients with clinically indeterminate tumours. After retinotomy, an incisional choroidal biopsy yielded a specimen of ∼1 mm(3). Obtained tissue was routinely processed for light microscopy including an immunohistochemical panel of monoclonal antibodies. Adequate tissue for diagnosis was provided in 41/43 (95%) patients. The sensitivity and specificity to detect malignant disease were 0.97 and 1.00, respectively. The positive predictive value was 1.00. Complications included progression of pre-existing retinal detachment in 5/43 (12%) patients and transient rise in intraocular pressure to >40 mm Hg in 6/43 (14%) patients; 4 of these 6 patients had a pre-existing retinal detachment. No patient with a pre-operatively attached retina had a retinal detachment. We conclude that an incisional transretinal choroidal biopsy yields abundant material and may adequately confirm or exclude malignancy in patients with clinically indeterminate tumours. The complication rate can be minimised when patients with pre-existing retinal detachment are excluded from biopsy.

Time trends in the incidence of conjunctival melanoma in Sweden.

AIM: To study time trends in the incidence of conjunctival melanoma in Sweden. METHODS: All patients with conjunctival melanoma from 1960 to 2005 in Sweden were identified through the Swedish Cancer Registry, cross-checked against hospital files, and validated by histopathological review (97.5%) or detailed hospital records (2.5%). The crude and age-standardised incidences were estimated separately for each sex and the annual change in incidence over time was estimated using a regression model with logarithmic incidence numbers. Time trends for the largest diameter, thickness and location of the tumour when diagnosed were analysed. RESULTS: The age-standardised incidence of conjunctival melanoma increased significantly in men (n = 89) from 0.10 cases/million to 0.74 cases/million (p = 0.001) and in women (n = 81) from 0.06 cases/million to 0.45 cases/million (p = 0.007). The annual relative change in age-standardised incidence was 16.9% (95% confidence interval (CI) 12.2 to 21.6) in men and 19.5% (95% CI 9.3 to 29.7) in women. The age-specific incidence was higher in men and women > or = 65 years (1.48 and 1.39 cases/million, respectively) than in younger men and women (0.3 and 0.2 cases/million, respectively). During the period of study, tumours became smaller (p = 0.005) and thinner (p = 0.002) at the time of diagnosis and increasingly arose from parts of the conjunctiva exposed to ultraviolet radiation (p = 0.001). CONCLUSION: The incidence of conjunctival melanoma increased in Sweden during the period 1960 to 2005.

Peritonectomy with high voltage electrocautery generates higher levels of ultrafine smoke particles.

BACKGROUND: To adequately perform peritonectomy, the use of an electrocautery device at a high voltage is recommended. The aim of this study was to analyse the amount of airborne and ultrafine particles (UFP) generated during peritonectomy and to compare this with standard colon and rectal cancer surgery (CRC). METHOD: UFP was measured approximately 2-3 cm from the breathing area of the surgeon (personal sampling) and 3 m from where the electrocautery smoke was generated (stationary sampling) from 14 consecutive peritonectomy procedures and 11 standard CRC resections. The sampling was by P-Trak UFP counter that has the capacity to detect particle size ranging from 0.02 to 1 microm. RESULTS: The cumulative level of UFP of personal sampling in the peritonectomy group was higher (9.3 x 10(6) particle/ml/h (pt/ml/h)) than in the control group (4.8 x 10(5) pt/ml/h). A higher cumulative level of UFP in stationary sampling was observed in the PC group (2.6 x 10(6) pt/ml/h) than in the control group (3.9 x 10(4)pt/ml/h). CONCLUSION: Peritonectomy procedure with high voltage electrocautery generates elevated levels of UFP than standard CRC surgery does. The level of UFP produced by a peritonectomy is comparable to cigarette smoking. More efficient smoke evacuator systems are needed in order to reduce the levels of UFP generated during electrocautery surgery.

Association of HLA class I and class II antigen expression and mortality in uveal melanoma.

PURPOSE: Malignant transformation of cells is frequently associated with abnormalities in human leukocyte antigen (HLA) expression. These abnormalities may play a role in the clinical course of the disease, because HLA antigens mediate interactions of tumor cells with T cells and NK cells. Uveal melanoma is a highly malignant tumor of the eye and is characterized by a hematogenic spread to the liver. Little is known about the role of HLA expression in progression of this malignant disease. METHODS: In the present study HLA class I antigen, beta(2)-microglobulin (beta(2)-m), and HLA class II antigen expression was analyzed in primary uveal melanoma lesions by immunoperoxidase staining with monoclonal antibodies of 65 archival clinical samples. The results were correlated with the clinical course of the disease. RESULTS: HLA class I antigen expression and beta(2)-m expression were downregulated in 40 and 35 lesions, respectively. HLA class II antigens were expressed in 30 lesions. Patients with high HLA class I, including beta(2)-m, and HLA class II antigen expression in their primary melanoma lesions had a significantly decreased survival (P = 0.009, P < 0.001, and P = 0.006, respectively). CONCLUSIONS: The findings argue against a major role of cytotoxic T-lymphocyte (CTL)-mediated control of tumor growth in the clinical course of uveal melanoma and are compatible with a potential role of NK-cell-mediated control of hematogenic metastatic spread.

Enteroaggregative Escherichia coli as a major etiologic agent in traveler's diarrhea in 3 regions of the world.

Enteroaggregative Escherichia coli (EAEC) has been reported to cause traveler's diarrhea and persistent diarrhea in children in developing countries and in immunocompromised patients. To clarify the prevalence of EAEC in traveler's diarrhea, we studied 636 US, Canadian, or European travelers with diarrhea: 218 in Guadalajara, Mexico (June--August 1997 and 1998), 125 in Ocho Rios, Jamaica (September 1997--May 1998), and 293 in Goa, India (January 1997--April 1997 and October 1997--February 1998). Stool samples were tested for conventional enteropathogens. EAEC strains were identified by use of the HEp-2 assay. EAEC was isolated in 26% of cases of traveler's diarrhea (ranging from 19% in Goa to 33% in Guadalajara) and was second only to enterotoxigenic E. coli as the most common enteropathogen in all areas. Identification of EAEC reduced the number of cases for which the pathogen was unknown from 327 (51%) to 237 (37%) and explained 28% of cases with unknown etiology. EAEC was a major cause of traveler's diarrhea in 3 geographically distinct study areas.

Diabetes mellitus is a strong negative prognostic factor in patients with myocardial infarction treated with thrombolytic therapy.

OBJECTIVES: To assess the long-term prognostic values of baseline demographic data, occurrence of vectorcardiographic signs of reperfusion, left ventricular function and coronary angiographic features. DESIGN: Longitudinal study of morbidity and mortality. SETTING: Coronary care unit at Danderyd Hospital, Stockholm, Sweden. SUBJECTS: A total of 222 patients (mean age 61 years) with a suspected acute myocardial infarction treated with thrombolysis were investigated and followed for 2-5 years (mean 1216 days). MAIN OUTCOME MEASURES: Death or a new myocardial infarction. RESULTS: Age above 55 years (P < 0.05), a previous diagnosis of diabetes mellitus (P < 0.005), hypertension (P < 0.05), heart failure (P < 0.001) and myocardial infarction (P < 0.05), a previous use of beta-blockers (P < 0.05) and an ejection fraction below 60% (P < 0.01) were predictors for death or a new myocardial infarction in univariate analysis. Sex, a previous history of smoking or angina pectoris, vectorcardiographic signs of reperfusion or degree of coronary artery disease had no prognostic values. In multivariate analysis including age above 55 years, a previous diagnosis of diabetes mellitus, hypertension and myocardial infarction, and an ejection fraction below 60%, only age (P < 0.05), diabetes mellitus (P < 0. 01) and ejection fraction (P < 0.05) were predictors for death or a new myocardial infarction. CONCLUSIONS: The results of the present study emphasize the importance of diabetes mellitus as a long-term prognostic risk factor in patients with myocardial infarction treated with thrombolysis. Further studies are needed to determine the mechanisms behind this increased risk.

Kidney donors don't regret: follow-up of 370 donors in Stockholm since 1964.

BACKGROUND: The aim of the study was to present the views of our kidney donors since 1964, at the time of donation, as well as later on--and to assess their current subjective health. METHODS: A total of 451 living-donor nephrectomies were performed on Swedish residents in Stockholm from April 1964 until the end of 1995. A questionnaire with 11 questions about the donation and a standardized health form (SF-36) were sent to all donors alive in 1997 (n=403). RESULTS: The mean age (+/-SD) of the donors was 61+/-14 years at follow-up and the time-since-donation was 12.5+/-7.7 years. The response rate was very good (92%). Current health, as assessed by form SF-36, was satisfactory. Donors scored somewhat better than those reported in a random sample of the Swedish population. The decision to donate had been easy: 86% made the decision themselves, without being pushed. Twenty-three percent thought that the nephrectomy had been troublesome. A higher percentage of young donors had felt that the postoperative period was difficult. Most donors (56%) stated that it had taken more than 2 months before they returned to a "normal" life, and 5% felt that they never completely recovered. Less than 1% of the donors regretted the donation. The commonest current medical prescription was antihypertensives (15%). The actual mean serum creatinine was 103+/-22 (range 48-219) micromol/L. CONCLUSIONS: The results indicate that the degree of health is at least as high as in the general population. The decision to donate was easy for most of the donors, but surgery and the recovery period were troublesome and lasted longer than expected. Kidney function was acceptable.

Emotional distress before coronary bypass grafting limits the benefits of surgery.

BACKGROUND: The inclusion of large, heterogeneous groups of patients for coronary bypass grafting (CABG) surgery has resulted in a more mixed treatment outcome. Thus it becomes important to identify patients who are less likely to benefit from surgery or who may require additional support to improve treatment outcome. The aim of the present study was to examine whether psychological status measured before CABG can contribute to prediction of short- and long-term outcomes of the surgery. METHODS AND RESULTS: One hundred seventy-one consecutive patients from two large university hospitals in Stockholm completed a psychosocial questionnaire before being scheduled for surgery. One year after CABG, patients again completed the questionnaire. Follow-up of medical charts was conducted during the first 3 years after surgery. All major cardiac events (cardiac death, definite myocardial infarction, revascularization, and unstable angina verified by angiography or myocardial scintigraphy) were recorded. Although the overall effect of surgery was excellent in the majority of cases, the patients exhibiting a high degree of distress (anxiety, depression, and tiredness) before surgery assessed their status as being much worse both before the operation and at the 1-year follow-up. Equally important was the fact that patients considered distressed before surgery had significantly higher rates of cardiac events (16%) in the 3-year follow-up period compared with nondistressed patients (5%) (chi-square=5.11, degrees of freedom=1, p < 0.02). CONCLUSIONS: Systematic evaluation and treatment of emotional distress in the candidates for coronary revascularization may be expected to result in more optimal subjective results and a reduction in the number of serious cardiac events after surgery.

Positional cloning of ZNF217 and NABC1: genes amplified at 20q13.2 and overexpressed in breast carcinoma.

We report here the molecular cloning of an approximately 1-Mb region of recurrent amplification at 20q13.2 in breast cancer and other tumors and the delineation of a 260-kb common region of amplification. Analysis of the 1-Mb region produced evidence for five genes, ZNF217, ZNF218, and NABC1, PIC1L (PIC1-like), CYP24, and a pseudogene CRP (Cyclophillin Related Pseudogene). ZNF217 and NABC1 emerged as strong candidate oncogenes and were characterized in detail. NABC1 is predicted to encode a 585-aa protein of unknown function and is overexpressed in most but not all breast cancer cell lines in which it was amplified. ZNF217 is centrally located in the 260-kb common region of amplification, transcribed in multiple normal tissues, and overexpressed in all cell lines and tumors in which it is amplified and in two in which it is not. ZNF217 is predicted to encode alternately spliced, Kruppel-like transcription factors of 1,062 and 1,108 aa, each having a DNA-binding domain (eight C2H2 zinc fingers) and a proline-rich transcription activation domain.

Helicobacter pylori seropositivity is not associated with inflammatory parameters, lipid concentrations and degree of coronary artery disease.

OBJECTIVES: To determine the prevalence of chronic infection with Helicobacter pylori (HP) in patients with established coronary artery disease (CAD) and in healthy controls. Furthermore, to investigate whether HP infection is associated with inflammatory parameters, lipid concentrations and degree and progression of CAD. DESIGN: A case-control study combined with a prospective angiographic study. SETTING: Stockholm Metropolitan Area, Sweden. PATIENTS AND METHODS: A material consisting of 92 young men aged 40.9 +/- 3.2 (mean +/- SD) years, with previous myocardial infarction and documented coronary atherosclerosis, and 95 healthy sex-matched controls, aged 43.2 +/- 3.0 (mean +/- SD) years, with similar socio-economic status and ethnic background was analysed for the prevalence of HP seropositivity, plasma concentrations of the inflammatory parameters fibrinogen, tumour necrosis factor alpha and orosomucoid, and serum concentrations of lipids. The impact of HP seropositivity on degree and progression of CAD, as assessed by quantitative coronary angiography, was also determined. RESULTS: The study population of mainly Scandinavian origin had a low prevalence of HP seropositivity in comparison with previously published European populations. No significant increase in HP seropositivity was found in patients compared with controls (42.2 vs. 32.6%). Furthermore, HP infection was not associated with increased levels of inflammatory parameters, lipid concentrations or with degree of angiographically determined CAD at baseline, or progression of CAD and clinical events over 5 years. CONCLUSIONS: HP infection is not associated with inflammatory parameters and lipid concentrations and could not be confirmed as a risk factor for CAD.

Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease.

Elevated plasma levels of triglyceride-rich lipoproteins, a decreased high-density lipoprotein (HDL) cholesterol concentration, hyperinsulinemia, and impaired fibrinolytic function frequently aggregate in patients with premature coronary heart disease (CHD). Experimental studies suggest that the cytokine tumor necrosis factor alpha (TNFalpha) produced by adipocytes plays a part in the regulation of triglyceride and glucose metabolism. The present study examined whether TNFalpha is implicated in these metabolic and fibrinolytic disturbances in young postinfarction patients. TNFalpha levels were determined in two groups of young (age <45 years) male postinfarction patients (n = 92 and 60) and in matched, population-based control subjects (n = 63). Plasma TNFalpha was higher in patients than in controls (4.1 +/- 1.6 v2.5 +/- 0.4 pg/mL, P < .0001). In hyperlipidemic patients, TNFalpha levels correlated significantly with the concentrations of very-low-density lipoprotein (VLDL) triglyceride and cholesterol and negatively with HDL cholesterol. Treatment with bezafibrate decreased VLDL triglycerides and increased HDL cholesterol, but did not affect TNFalpha levels. The TNFalpha concentration also correlated significantly with fasting glucose and proinsulin concentrations, as well as glucose and proinsulin levels after glucose ingestion. In contrast, no relations were found with the insulin level or degree of insulin resistance. The present results provide clinical evidence for a basic role of TNFalpha in hypertriglyceridemia, glucose intolerance, and the etiology of premature CHD.

Design features of a five-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT).

Young survivors of myocardial infarction represent a poignant challenge to clinical research on atherogenic mechanisms and factors predisposing to and precipitating coronary thrombosis. Young male postinfarction patients are characterized by heavy smoking, dyslipoproteinaemias involving very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL), a family history of premature coronary artery disease, hyperinsulinaemic responses to oral and intravenous glucose challenges, an elevated plasma fibrinogen concentration and defective fibrinolytic function. Based on the multiplicity of metabolic and haemostatic disturbances present in these patients, a double-blind, randomized, placebo-controlled angiographic trial was initiated to determine whether bezafibrate, a clofibrate analogue, retards the progression or facilitates regression of premature coronary atherosclerosis. Men under the age of 45 years who survived a first myocardial infarction were screened for participation in the study. A fasting serum cholesterol value > or = 5.2 mmol/l and/or serum triglycerides > or = 1.6 mmol/l after three months of dietary treatment and angiographically demonstrable lesions in at least one coronary segment were required for inclusion. Treatment with diet and bezafibrate (200 mg t.i.d.) or matching placebo is continued for five years during which time re-angiography is performed after two years and at the end of the study. The primary aim of the trial is a comparison between the bezafibrate and placebo groups for change in mean minimum luminal diameter between the baseline and five-year coronary angiograms. This report presents the design features of the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) and a review of current knowledge of mechanisms underlying premature coronary atherosclerosis and myocardial infarction at a young age.

Bronchial reactivity, lung function, and serum immunoglobulin E in smoking-discordant monozygotic twins.

Smokers with chronic bronchitis and/or chronic obstructive pulmonary disease (COPD) have been reported to have an increased bronchial reactivity (BR). It has been discussed whether increased BR is a risk factor for the development of COPD in smokers. We studied 10 monozygotic twin pairs who were discordant for tobacco smoking by means of histamine provocation tests, lung function tests, and serum samples for total IgE. The smokers had a mild obstructive ventilatory impairment, with FEV1 significantly lower than that of the partner both when it was determined from the flow-volume loops (3.2 +/- 1.0 L for smokers and 3.4 +/- 0.8 L for nonsmokers) and by the Vitalograph spirometer (3.5 +/- 1.0 L for smokers and 3.8 +/- 0.8 L for nonsmokers). Forced midexpiratory flow (FEF25-75%) and forced expiratory flow at 75 to 85% of vital capacity (FEF75-85%) were both significantly lower in the smokers (p < 0.05). The alveolar plateau phase N2-delta test and lung clearing index in the multibreath nitrogen washout test were both significantly affected in the smokers (p < 0.05 and p < 0.01, respectively). We found no significant difference in histamine reactivity between smokers and nonsmokers and no correlation between differences in reactivity and differences in lung function within pairs. Total serum IgE was significantly higher in the smokers than in their nonsmoking siblings. These data suggest that obstructive ventilatory impairment and raised serum IgE are earlier and more constant manifestations of tobacco smoking than increased bronchial reactivity. Thus, bronchial hyperreactivity does not seem to be a major risk factor for the development of early airways obstruction in smokers.

Methylations in hemoglobin from monozygotic twins discordant for cigarette smoking: hereditary and tobacco-related factors.

Dose monitoring of exogenous methylators by measurement of N-methylvaline in hemoglobin (Hb) is rendered difficult due to a relatively high, variable background in unexposed persons. A kinetic study indicates intracellular S-adenosylmethionine to be a main source of these background methylations. A comparison of twin pairs indicates that the variation in methylvaline levels is partly hereditary (P less than 0.001). Therefore, in a study of monozygotic twin pairs discordant for tobacco smoking the resolving power of the monitoring was increased and in vivo doses of methylators from the smoke could be more easily monitored through their adducts to Hb. Probably, twin studies offer a useful tool for the identification and quantification of electrophiles of endogenous and exogenous origin.

The Balbiani ring 3 gene in Chironomus tentans has a diverged repetitive structure split by many introns.

A set of approximately 15 secretory proteins is synthesized by the salivary gland cells in the midge Chironomus tentans. These proteins are secreted but do not form insoluble fibers until they are transported out of the gland lumen. A Balbiani ring (BR) gene family consisting of four genes (BR1, BR2.1, BR2.2 and BR6) have previously been shown to encode four of these proteins, sp-I a to d, with relative molecular weights of 1 x 10(6). Each BR gene contains an uninterrupted block in which about 100 repeats are tandemly arranged. The repeats are virtually identical and efficient homogenization mechanisms must operate within each block. Here we describe a new BR gene, the BR3 gene, which according to structural similarities may belong to the BR gene family, but at the same time exhibits a strikingly different structure. The gene encodes a 10.9 kb transcript that contains 38 introns and is spliced into a 5.5 kb mRNA. The mRNA is translated into a cysteine-rich 185 kDa major component of the gland secretion. The coding sequence in the gene is built from diverged repeats in which mainly the cysteine codons are preserved and the sequence is split by the introns into 17 to 678-bp long exons. The introns are located at defined positions in relation to the repeat structure. In sharp contrast to the uninterrupted array of identical repeats in the BR1-BR6 genes, the repeats in the BR3 gene are not efficiently homogenized and have diverged extensively from each other. We propose that the splitting of the repeat structure into variable sized exons prevents homogenizations dependent on unequal aligning of homologous sequences.

Comparative studies of antibiotic therapy after penetrating abdominal trauma.

Two prospective, randomized trials of the efficacy of antibiotic regimens after penetrating abdominal trauma demonstrated that a combination of clindamycin and tobramycin was superior to cefamandole or cefoxitin in preventing postinjury wound infection but that no difference could be demonstrated between combination therapy (clindamycin plus tobramycin) and moxalactam. Infection was more likely to occur after a gunshot wound or with a high injury severity score and occurred after the 10th postinjury day only in those patients who received cefamandole or cefoxitin. There was a higher incidence of culture of B. fragilis in the latter groups as well as infections due to resistant organisms. Short-term antibiotic therapy for 72 hours with either tobramycin plus clindamycin or moxalactam appears adequate for the majority of patients after gunshot or knife wounds. The costs of these regimens to the patient were similar in our hospital. The most important single factor, however, in maintaining low infection rates after penetrating injury to the abdominal cavity is appropriate and timely surgical management.

Mechanisms of host defense in well nourished patients with chronic alcoholism.

Tests of immune function were performed on five recently abstinent, well nourished,and disease-free patients with chronic alcoholism. No significant defects in adherence, metabolic, or bactericidal activity of polymorphonuclear leukocytes were found when compared to sex-matched controls. Antibody-dependent and natural killer cellular cytotoxicity of monocyte-macrophages and lymphocytes also were normal. These data support the concept that immunity might be intact in the group of patients with chronic alcoholism who are recently sober, well nourished, and free of underlying disease.