Disparities in survival after trimodality therapy for esophageal adenocarcinoma.

Trimodality therapy with neoadjuvant chemoradiation followed by surgery has emerged as the standard of care for the treatment of locally advanced esophageal cancer. Yet, there is considerable variation in survival within this population. We sought to analyze factors associated with survival after trimodality therapy in esophageal adenocarcinoma. We identified 4,679 patients from the National Cancer Database (NCDB) of the American College of Surgeons who received chemotherapy and radiation prior to surgery for esophageal adenocarcinoma from 2006 to 2013. We excluded patients with stage IV disease and unknown pathological nodal status. We performed regression analyses using a Cox proportional hazards model to identify independent predictors of overall survival. On multivariate analysis, pathologic characteristics associated with decreased overall survival included stage, lymphovascular invasion, and positive surgical margins. Insurance status, age, and comorbidity index were also associated with decreased survival. We found that pathologically node-positive patients who received additional adjuvant chemotherapy were associated with improved survival. Compared to private insurance, Medicaid (HR 1.45, CI 1.22-1.73, P < 0.0001), Medicare (HR 1.17, CI 1.04-1.31, P = 0.0082), or having no insurance (HR 1.50, CI 1.17-1.92, P = 0.0012) were all negative predictors of overall survival. In patients with esophageal adenocarcinoma who have undergone trimodality therapy, a number of different factors are associated with overall survival. In particular, socioeconomic factors relating to access to care are independent predictors of survival. Despite receiving the standard of care, treatment disparities persist in this population of patients.

Prognostic significance of lymph node yield in ypN0 rectal cancer.

BACKGROUND: Neoadjuvant radiation therapy for locally advanced rectal adenocarcinoma decreases lymph node yield. This study investigated the association between survival and number of lymph nodes evaluated in patients with pathologically negative nodes after neoadjuvant therapy. METHODS: Patients with locally advanced rectal adenocarcinoma who underwent neoadjuvant therapy and had pathologically negative lymph nodes were included from the Surveillance, Epidemiology, and End Results (SEER) database over a 7-year interval (January 2004 to December 2010). Systematic dichotomization for optimal cut-off point identification was performed using statistical modelling. RESULTS: A total of 3995 patients met the inclusion criteria. The majority had T3 (66·7 per cent) and moderately differentiated (71·5 per cent) tumours. The median number of lymph nodes retrieved was 12 (i.q.r. 7-16). An optimal cut-off of nine lymph nodes was identified. Increasing age (P < 0·001), increasing T category (T4 versus T1, P < 0·001; T3 versus T1, P = 0·010), response to neoadjuvant therapy (P < 0·001) and number of nodes evaluated (P < 0·001) were significant factors for overall survival in univariable analysis. After adjustment in the multivariable model, the group with nine or more nodes examined had significantly better overall survival (hazard ratio (HR) 0·76, 95 per cent c.i. 0·65 to 0·88, P < 0·001; 5-year survival 83·2 versus 78·0 per cent) and cancer-specific survival (HR 0·76, 0·64 to 0·92, P = 0·004; 5-year survival 87·9 versus 85·1 per cent) than the group with one to eight nodes examined. CONCLUSION: Overall and cancer-specific survival were worse where fewer than nine lymph nodes were identified after neoadjuvant therapy for locally advanced rectal cancer.

Ratio of serum urea to serum creatinine in wild black bears.

In winter, the ratio of serum urea to serum creatinine is 10 or less in denning female and male bears. In midsummer it is 22 or more, similar to that of other mammals. However, in late summer and early fall, while food is available, the urea-to-creatinine ratio approaches or becomes 10 or less. The low value of this ratio appears to indicate the biochemical state of hibernation, and many bears are in this state weeks before they den.

Dose-response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys.

BACKGROUND AND PURPOSE: The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. EXPERIMENTAL APPROACH: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. KEY RESULTS: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. CONCLUSIONS AND IMPLICATIONS: The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.

The HRAS1 minisatellite locus and risk of ovarian cancer.

Approximately 10% of ovarian cancers are due to mutations in highly penetrant inherited cancer susceptibility genes. The highly polymorphic HRAS1 minisatellite locus, located just downstream from the proto-oncogene H-ras-1 on chromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for cancers of the breast, colorectum, and bladder, and it was found that BRCAI mutation carriers with at least one rare HRAS1 allele have a greater risk of ovarian cancer than BRCA1 carriers with only common HRAS1 alleles. There are no conclusive studies of HRAS1 alleles in sporadic epithelial ovarian cancer. A case-control study of HRAS1 alleles was performed on DNA from 136 Caucasian patients with ovarian cancer and 108 cancer-free controls using conventional (Southern blot) and PCR-based methods to determine the frequency of rare HRAS1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression methods. A single degree of freedom test was used to assess the significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRAS1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated with a relative risk of 1.66 (95% CI, 0.91-3.01), whereas having two rare alleles increased the relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRAS1 allele types by the age of the case at diagnosis revealed that younger cases (<45 years) had a borderline statistically significant increased association with rare HRAS1 alleles compared to older cases (> or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRAS1 alleles contribute to ovarian cancer predisposition in the general population. Thus, the HRAS1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in both sporadic and hereditary ovarian cancer.

Reproductive factors and risk of intermediate- or high-grade B-Cell non-Hodgkin's lymphoma in women.

PURPOSE: The incidence rates of non-Hodgkin's lymphoma (NHL) unrelated to human immunodeficiency virus infection are lower for women than for men; yet, few factors have been identified that may account for this difference in risk. NHL is difficult to study epidemiologically because this disorder represents a group of malignancies that differ in terms of morphologic presentation, immunologic features, genetic characteristics, prognosis, and etiology. PATIENTS AND METHODS: We conducted a population-based case-control study in women to determine whether reproductive factors or hormonal exposures might be related to the risk of high- or intermediate-grade B-cell NHL. We interviewed 177 female residents of Los Angeles County who were diagnosed with high- or intermediate-grade B-cell NHL between 1989 and 1992; each case patient was individually matched on age and race to a control subject who lived in her neighborhood. RESULTS: Women who had used oral contraceptives had significantly lower risk of intermediate- or high-grade NHL (multivariate odds ratio [OR] = 0.47; 95% confidence interval [CI], 0.26 to 0.86) than women who had never used these compounds. Among parous women, those who had used lactation suppressants (which contain high levels of estrogen) had significantly lower risk of NHL (multivariate OR = 0.50; 95% CI, 0.29 to 0.85) than unexposed women. Postmenopausal women had a somewhat greater risk of NHL than premenopausal women, whereas those postmenopausal women who had used hormone replacement therapy (HRT) (primarily estrogen) had somewhat lower risk than those who had not used HRT. CONCLUSION: Exogenous estrogens seem to have a protective effect on the risk of high- and intermediate-grade B-cell NHL. Although the mechanisms for such protection are not known, alterations in immune reactivity, cytokine expression, or B-cell modulation may play a role.

Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716.

BACKGROUND: SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. METHODS: Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration. RESULTS: Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all subjects. CONCLUSIONS: SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.

Sympathoinhibitory response to clonidine is blunted in patients with heart failure.

To determine whether alpha2-adrenergic-mediated sympathoinhibition was altered in chronic heart failure, sympathoinhibitory sensitivity was assessed using the alpha2-adrenergic agonist clonidine in 7 patients with heart failure and in 10 healthy control subjects. Basal norepinephrine spillover was significantly higher in patients with heart failure (1.3+/-0.3 microg/min) than in control subjects (0.7+/-0.1 microg/min, P=.05). Compared with control subjects, the decrement in norepinephrine spillover to cumulative doses of clonidine (1, 2, and 3 microg/kg administered intravenously) was significantly less in patients with heart failure (P<.05). Blood pressure also tended to decrease less in patients with heart failure (P=.06). The doses of clonidine required to produce a 10% decrease in blood pressure and a 25% decrease in norepinephrine spillover were significantly higher in heart failure (P<.01 and P=.05, respectively). Thus, although clonidine lowers norepinephrine spillover significantly in patients with heart failure, such patients are less sensitive to clonidine than healthy control subjects. This difference in sensitivity suggests that doses of clonidine provide effective sympathoinhibition will need to be selected for studies that will evaluate the potential therapeutic effect of clonidine in heart failure.

Quantitation of energy expenditure by infrared thermography.

The objective of this study was to adapt infrared thermography (IRT) to measure heat loss in human beings. IRT images were digitized and a mean body surface temperature was computed; heat losses caused by radiation, convection, and evaporation were calculated by using these data. Because subjects were standing during the procedure a small amount of heat was conducted through the feet; this heat was ignored. Total heat loss measured by IRT was not significantly different from values calculated from simultaneous indirect calorimetry (IC) determinations in fasting health subjects and in postsurgical patients receiving a constant infusion of energy. In healthy subjects, after eating the patterns of response to IRT and IC were as predicted from previous direct calorimetry data. Heat loss measured by IC increased first, 30 min postprandially, followed by an increase in heat loss at 60 min as measured by IRT. It was concluded that IRT as a noninvasive method can be used to quantitate heat loss in human beings.

Use of infrared thermographic calorimetry to determine energy expenditure in preterm infants.

BACKGROUND: Measurement of infant energy expenditure in the clinical setting is difficult and is rarely done. Both indirect and direct calorimetry require long measurement periods and frequent calibration. OBJECTIVE: The objective of this study was to validate in infants a newly developed method of determining energy expenditure, infrared thermographic calorimetry (ITC), against an established method, respiratory indirect calorimetry (IC). ITC measures mean infant body surface temperature. ITC was used in conjunction with heat loss theory to calculate radiant, convective, evaporative, and conductive heat losses and thereby determine total energy expenditure. DESIGN: Ten healthy preterm infants were studied by obtaining concurrent ITC and IC measurements over a 3.5-5.5-h study period. Continuous IC measurements were compared with ITC measurements taken every 10 min during study periods. IC values were summed over 10-min intervals covering the 5 min before and 5 min after each ITC measurement, to allow comparisons between the 2 methods. RESULTS: Comparison of paired ITC and IC mean measurements for all 10 infants over the entire study period showed no significant difference between the 2 methods. However, individual paired IC and ITC values were significantly different for 7 of 10 infants. The overall mean difference between the 2 methods was 1.3%. CONCLUSIONS: ITC is an accurate, noninvasive method for measurement of heat loss and energy expenditure in healthy preterm infants, and therefore it may be a useful clinical and research tool.

Protein metabolism during intensive physical training in the young adult.

Two groups of men consumed two levels of protein (1.4 and 2.8 g/kg body weight) during a 40-day experimental period. Physical activity and the sweat rates were fairly high during the entire experimental phase. Urinary nitrogen excretions remained fairly constant for both groups during the training and heavy physical activity periods. Nitrogen balances were positive exclusive or inclusive of the daily sweat nitrogen losses showing nitrogen retention. The essentially unchanged blood hemoglobin and serum protein levels showed that the control group was receiving an adequate protein intake to maintain nitrogen equilibrium, under conditions of fairly heavy physical acitvity. Although others may have suggested some compensatory reductions in the urinary excretion of nitrogen under conditions of profuse sweating, our data have not supported these conclusions. It appears that sweat losses of nutrients become relevant in determining requirements and will increase in importance as sweat rates are increased. The data again demonstrate that the nutrient losses during profuse sweating consitute an error that could seriously invalidate the accuracy of metabolic balance studies. In this study, although the men did increase body protein stores and muscle mass with high-protein diets, the additional body protein did not enhance physiological work performance. It is suggested that in this sutdy 100 g of protein/day was adequate for men performing fairly heavy work.

Pantothenic acid, coenzyme A, and human chronic ulcerative and granulomatous colitis.

To investigate further an apparent relationship between chronic ulcerative and granulomatous colitis and pantothenic acid deficiency, colonic tissues obtained at the time of colectomy in 29 patients with these disorders were assayed for pantothenic acid and for coenzyme A (CoA) activity. For comparison, normal colonic tissues free of pathological lesions were obtained from 31 patients having colectomy for carcinoma or diverticulitis. Plasma, red blood cells, and colonic mucosa were assayed microbiologically for free and total pantothenic acid. The activity of CoA in colonic mucosa was determined by assaying the acetylation of sulfanilamide. Concentrations of free, bound, and total pantothenic acid in blood and in colonic mucosa did not differ between the two groups of patients. Bound pantothenic acid increased linearly with total pantothenic acid. Colonic mucosa concentrated free pantothenic acid to about 50 times the level of blood, and pantothenic acid in red cells was similar to the concentration in plasma. Compared to normal gut mucosa, CoA activity was markedly low in mucosa from patients with chronic ulcerative or granulomatous disease despite the presence of normal amounts of free and bound pantothenic acid. A block in the conversion of bound pantothenic acid to CoA in diseased mucosa is suggested.

Nutritional status of a group of alcoholics before and after admission to an alcoholism treatment unit.

The nutritional status of the alcoholic has been presumed to be less than adequate because of the large quantity of alcohol ingested. Most reports have focused on the derelict alcoholic. In contrast, the patients in this investigation are more representative of the usual alcoholic population. The pretreatment dietary histories of 58 alcoholics were compared with their actual dietary intake while they were hospitalized for the treatment of alcoholism. Comparisons were also made between dietary intake by history and Recommended Dietary Allowances. The mean calorie, protein, fat, and carbohydrate intake of the patients was adequate and was well within the Recommended Dietary Allowances ranges. After the patients stopped drinking, they increased their intake of all major nutrients, especially carbohydrates. A subgroup of 11 patients whose recent dietary intake by history was corroborated by their urinary nitrogen excretion had no change in total caloric intake after they stopped drinking.

Sucrose sensitivity of patients with coronary artery disease.

Various loads of simple carbohydrates were fed to 148 patients with known coronary-artery disease (CAD) for 4 days in the Clinical Research Center. The 148 patients were grouped according to the diet regimen tested-sucrose (low and high), glucose, and fructose. A high-sucrose diet was fed to 29 control subjects. Diets containing 2 g of simple carbohydrate (predominantly either sucrose or glucose) per kilogram of body weight per day had no significant effect on fasting plasma glucose, serum triglycerides, or serum free fatty acids. However, diets containing 4 g of simple carbohydrate (predominantly sucrose) or 2 g fructose per kilogram of body weight per day produced a significant rise in serum triglycerides with decreases in fasting plasma glucose and free fatty acids. Serum cholesterol diminished in all the diet groups, probably because of the decrease fat and cholesterol intakes. The increase of serum triglycerides in CAD patients receiving simple carbohydrate at the 4-g/kg rate was significantly greater than in the normal control subjects fed the same diet, suggesting a sensitivity of CAD patients to this stimulus. No significant correlation could be demonstrated between changes in serum triglycerides and the extent of CAD (one, two, or three vessels) as determined from coronary angiograms.

Alterations in vitamin A and thyroid hormone status in anorexia nervosa and associated disorders.

Vitamin A and thyroid hormone status was investigated in 27 patients with anorexia nervosa. Subjects were divided into three groups based on eating behavior and serum carotene concentrations: anorexic (dietary restriction), normal carotene; anorexic, elevated serum carotene; bulimic, elevated serum carotene. All bulimic subjects fulfilling selection criteria were hypercarotenemic (weight loss and reduced metabolic rate). Data were compared to normal healthy volunteers. Serum retinol and retinol-binding protein levels were normal in all subjects whereas retinyl esters were elevated in the hypercarotenemic groups. Hypercarotenemia was primarily a result of elevation of vitamin A active carotenoids, especially beta-carotene. Diet was excluded from the etiology of hypercarotenemia. Thyroid hormones T4 and T3 were significantly depressed in hypercarotenemic groups and rT3 increased. A concomitant alteration in vitamin-hormone status is observed with progressive metabolic alterations: low T3, T4, and elevated retinyl esters in subjects with the hypercarotenemia associated with anorexia nervosa.

Depression of plasma cholesterol in men by consumption of baked products containing soy protein.

The effects of soy-protein consumption with and without soy fiber on plasma lipids in 26 mildly hypercholesterolemic men were studied. Four, 4-wk dietary treatments included 50 g protein and 20 g dietary fiber from soy flour (SF), isolated soy protein/soy cotyledon fiber (ISP/SCF), ISP/cellulose (ISP/C), or nonfat dry milk/C (NFDM/C) in conjunction with a low-fat, low-cholesterol diet. Plasma total cholesterol (TC) concentrations were lowest for both ISP dietary treatments compared with baseline (P < 0.05) and NFDM/C (P < 0.01). SF also led to lower TC compared with NFDM/C (P < 0.05). LDL-cholesterol values were lowest for both ISP treatments compared with NFDM/C (P < 0.01), but lower compared with baseline only with ISP/SCF (P < 0.05). Apolipoprotein B was lowest when ISP/C was fed, compared with baseline, SF, and NFDM (P < 0.05). HDL-cholesterol and total triglycerides (TG) were not affected. Results indicate that 50 g ISP is effective in lowering TC, LDL-C, and apolipoprotein B while maintaining HDL concentrations in mildly hypercholesterolemic men.

Combined deficiency of glucose-6-phosphatase and fructose-1, 6-diphosphatase. Studies of glucagon secretion and fuel utilization.

An adult woman with hypoglycemia, hyperlactatemia, hyperuricemia, hypertriglyceridemia, hyperketonemia and inability to make new glucose from galactose, fructose, glycerol and alanine was found to have no hepatic glucose-6-phosphatase and deficient fructose-1,6-diphosphatase. Nonautonomous hyperglucagonemia was demonstrated and shown to contribute to the hyperlactatemia and hyperketonemia. A paradoxic hyperlactatemic response to glucose and galactose was observed. Studies of substrate utilization showed prompt adaptation to changes in dietary supply of energy which probably accounted for her never having experienced symptoms of hypoglycemia.

Nutrient intake and serum cholesterol level in normal children 6 to 16 years of age.

A study of 103 healthy, white schoolchildren who were between 6 and 16 years of age revealed no positive correlation between the level of serum cholesterol and the mean daily amount of total calories, cholesterol, fat, saturated fat, or sugar in the diet.

Recombinant pro-urokinase requires heparin for optimal clot lysis and restoration of blood flow in a canine femoral artery thrombosis model.

Heparin is often used as an adjunct to thrombolytic therapy in order to prevent reocclusion of the patent vessels in patients with thrombotic disease. Controversy exists as to whether heparin is required for effective clot lysis with tissue-type plasminogen activator, while in vitro data and small scale clinical trials have suggested an enhancement of pro-urokinase efficacy by heparin. The present study was conducted to determine whether heparin pre-treatment is required to produce optimal clot lysis and blood flow restoration in response to recombinant pro-urokinase (r-proUK). In four groups of dogs, blood clots labelled with 125Iodine were formed in the femoral artery and were monitored continuously for loss of counts as an indicator of clot lysis. Femoral artery blood flow was measured simultaneously. Group 1 received vehicle (n = 5), while group 2 was given vehicle + heparin (n = 6; 500 U bolus + 350 U/h). This dose of heparin increased the activated partial thromboplastin time (APTT) by at least 1.5 times the control level for the 4 h observation period. Group 3 received r-proUK alone at a dose of 100,000 U/kg (50% given as a 1-min bolus injection, 50% as a 30 min infusion) (n = 8), while group 4 was treated with the same dose of r-proUK in the presence of heparin as described (n = 8).2

Comparison of dose regimens for the administration of recombinant pro-urokinase in a canine thrombosis model.

Pro-urokinase represents an important addition to the array of thrombolytic drugs currently available for clinical use because of its high clot specificity but distinctly different mechanism compared with that of t-PA. Recombinant pro-urokinase (r-proUK) is a single-chain precursor of high molecular weight urokinase which has been expressed in a mouse myeloma cell line. The present study was conducted to determine the dosing regimen which would produce optimal clot lysis and restoration of blood flow 2 h after treatment with r-proUK, using a dog model of arterial thrombosis. Efficacy was indicated by lysis of a radio-labelled clot which was formed in the heat-damaged femoral arteries of 39 male beagle dogs. The animals were divided into six heparinized treatment groups, each receiving one of five dosing regimens or the vehicle for r-proUK. The total dose (80,000 U/kg) was divided into an initial loading bolus, followed by either a second bolus or by infusions for various time periods, as shown below: Group Treatment Regimen % Lysis 1 r-proUK Bolus/bolus, 50%/50% at 0 and 15 min 52 +/- 7 2 r-proUK Bolus/bolus, 50%/50% at 0 and 30 min 62 +/- 7 3 r-proUK Bolus/infusion, 20%/80% infused to 30 min 41 +/- 8 4 r-proUK Bolus/infusion, 20%/80% infused to 60 min 66 +/- 5 5 r-proUK Bolus/infusion, 50%/50% infused to 30 min 73 +/- 4 6 Vehicle Bolus/infusion, 50%/50% infused to 30 min 12 +/- 6 It was concluded that optimal clot lysis and restoration of femoral flow was accomplished using a regimen in which 50% of the dose was given as a bolus, followed immediately by the remaining 50% given as a 30 min intravenous infusion (Group 5). At the dose used in this study, r-proUK did not produce degradation of fibrinolytic or hemostatic plasma proteins.