A Protective Role for Arachidonic Acid Metabolites against Advanced Colorectal Adenoma in a Phase III Trial of Selenium.

Oxylipins derived from arachidonic acid (ARA) have been implicated in the development of colorectal adenomas and colorectal cancer. The primary purpose of this work was to determine the relationship between plasma levels of oxylipins and colorectal adenoma characteristics at study entry, as well as with the development of a new adenoma during follow-up within a Phase III adenoma prevention clinical trial with selenium (Sel). Secondarily, we sought to determine whether the selenium intervention influenced plasma oxylipin levels. Four oxylipins were quantified in stored plasma samples from a subset of Sel study subjects (n = 256) at baseline and at 12-months. There were significantly lower odds of an advanced adenoma at baseline with higher prostaglandin E2 (PGE2), with an OR (95% CI) of 0.55 (0.33-0.92), and with 5-hydroxyeicosatetraenoic acid (5-HETE) ((0.53 (0.33-0.94)); and of a large adenoma with higher PGE2 ((0.52 (0.31-0.87)). In contrast, no associations were observed between any oxylipin and the development of a new adenoma during follow-up. Selenium supplementation was associated with a significantly smaller increase in 5-HETE after 12 months compared to the placebo, though no other results were statistically significant. The ARA-derived oxylipins may have a role in the progression of non-advanced adenoma to advanced, but not with the development of a new adenoma.

Correlation of perioperative biochemical variables with single adenoma weight in patients with primary hyperparathyroidism.

BACKGROUND: Single parathyroid adenoma is the main cause of primary hyperparathyroidism (PHPT), with surgery remaining the gold standard for its treatment. The ability to preoperatively predict the parathyroid adenoma size and could facilitate the decision about the extent of surgical exploration. It is reasonable to hypothesize that the perioperative levels of PHPT-related variables (i.e. calcium, parathormone, phosphate) may predict the adenoma weight or/and demonstrate whether the adenoma is successfully removed or not. Aim of this study is to explore the relationship between perioperative biochemical values and adenoma weight. Secondarily, we investigated the relationship between adenoma weight and uni-/bilateral neck exploration. METHODS: Retrospective study of all patients undergone surgery for primary hyperparathyroidism due to single adenoma in a tertiary university hospital in Germany during a 6-year period. Following variables were analyzed: preoperative serum calcium, phosphorus and parathormone, intraoperative parathormone before and after adenoma excision, intraoperative PTH decrease, postoperative serum calcium and parathormone (PTHpostop-pg/ml), calcium and PTH decrease. Bivariate correlations were calculated by the Spearman's correlation test at the 95% significance level. RESULTS: A total of 339 patients were included in the study. The median age of the patients was 60 years (range 21-90) and 77% were females. The median adenoma weight was 1 g (range 0.1-11). Adenoma weight correlated strong with maximum adenoma diameter (r = 0.72, p < 0.05), moderate with preoperative parathormone (r = 0.44) and parathormone decrease (r = 0.27), whereas there was no correlation with the intraoperative PTH decrease (r = 0.02). There was also a borderline (moderate to weak) correlation with pre- and postoperative calcium levels (r = 0.21 and r = 0.23 respectively) and a negative borderline correlation with phosphorus (r = - 0.21). Patients who required bilateral neck exploration, had significantly lighter adenomas (median weight 0.8 g vs 1.1 g, p = 0.005). CONCLUSIONS: We conclude that preoperative PTH levels may only serve as an approximate guide to adenoma weight, as direct preoperative prediction is not possible. Serum calcium levels, PTH and calcium decrease correlate only weak with adenoma weight. Patients who require bilateral neck exploration, have significantly (20-25%) lighter adenomas.

Surgical-pharmacological interactions in the treatment of acromegaly.

INTRODUCTION: Acromegaly requires a multimodal treatment approach that includes surgery by an expert pituitary neurosurgeon, pharmacological treatment with one or more of the available drugs and radiation therapy. These treatment alternatives are not mutually exclusive but rather complement each other when properly indicated in the individual patient. In this review, we summarize and analyze the available data concerning the choice of the surgical approach (microscopy vs. endoscopy) and the interactions between medical treatment with somatostatin analogs and pituitary surgery. AREAS COVERED: Technical aspects, complications and outcome of transsphenoidal surgery (TSS); Advantages and disadvantages of the microscopic and endoscopic approaches; Safety and efficacy of somatostatin analogs (SSA); Primary pharmacological therapy versus primary TSS; Benefits of the preoperative treatment with SSA; and the effect of surgical tumor debulking in the therapeutic response to SSA. EXPERT COMMENTARY: Continuing efforts at improving surgical techniques and at generating more efficacious pharmacological therapies for acromegaly are likely to improve the outcome of these patients. However, an integral approach of the patient aimed not only at achieving biochemical criteria of cure but also at treating the individual comorbidities is mandatory to improve the quality of life of these patients and to reduce their mortality rate.

Expression of Selenoprotein Genes and Association with Selenium Status in Colorectal Adenoma and Colorectal Cancer.

Dietary selenium (Se) intake is essential for synthesizing selenoproteins that are important in countering oxidative and inflammatory processes linked to colorectal carcinogenesis. However, there is limited knowledge on the selenoprotein expression in colorectal adenoma (CRA) and colorectal cancer (CRC) patients, or the interaction with Se status levels. We studied the expression of seventeen Se pathway genes (including fifteen of the twenty-five human selenoproteins) in RNA extracted from disease-normal colorectal tissue pairs, in the discovery phase of sixty-two CRA/CRC patients from Ireland and a validation cohort of a hundred and five CRC patients from the Czech Republic. Differences in transcript levels between the disease and paired control mucosa were assessed by the Mann-Whitney U-test. GPX2 and TXNRD3 showed a higher expression and GPX3, SELENOP, SELENOS, and SEPHS2 exhibited a lower expression in the disease tissue from adenomas and both cancer groups (p-values from 0.023 to <0.001). In the Czech cohort, up-regulation of GPX1, SELENOH, and SOD2 and down-regulation of SELENBP1, SELENON, and SELENOK (p-values 0.036 to <0.001) was also observed. We further examined the correlation of gene expression with serum Se status (assessed by Se and selenoprotein P, SELENOP) in the Irish patients. While there were no significant correlations with both Se status markers, SELENOF, SELENOK, and TXNRD1 tumor tissue expression positively correlated with Se, while TXNRD2 and TXNRD3 negatively correlated with SELENOP. In an analysis restricted to the larger Czech CRC patient cohort, Cox regression showed no major association of transcript levels with patient survival, except for an association of higher SELENOF gene expression with both a lower disease-free and overall survival. Several selenoproteins were differentially expressed in the disease tissue compared to the normal tissue of both CRA and CRC patients. Altered selenoprotein expression may serve as a marker of functional Se status and colorectal adenoma to cancer progression.

Favorable surgical outcomes of aldosterone-producing adenoma based on lateralization by CT imaging and hypokalemia: a non-AVS-based strategy.

PURPOSE: To test the efficacy of a strategy based on CT imaging and clinical characteristics on lateralizing origin of excess aldosterone secretion in primary aldosteronism. PATIENTS AND METHODS: Consecutive patients with diagnosed primary hyperaldosteronism from June 2006 to July 2012 in our center underwent adrenal surgeries without pre-operational adrenal venous sampling (AVS) if all the three criteria were met: (1) round- or oval-shaped occupational lesion of low density after contrast enhancement with diameter >1 cm on CT scan was located in one adrenal gland; (2) unequivocally normal contralateral adrenal gland; (3) serum potassium level lower than 3.5 mmol/L. Subjects who had received operation were taken into analysis and follow-ups. RESULTS: One hundred and twenty-five patients fulfilled the criteria and were recruited into our research. One hundred and twenty-two operated patients (97.6%) experienced complete resolution of hypokalemia as well as resolution or improvement in hypertension with reduction in antihypertensive medication, while 3 patients (2.4%) failed to obtain normal kalemia and continued on spironolactone therapy. At a median of 65-month (range 21-93) follow-up of these 122 subjects, 27 patients dropped out (22.1%). The 95 responding patients reported no episodes of paralysis or confirmed hypokalemia or any supplementation of potassium. Multivariate linear correlation analysis showed that plasma potassium level was correlated inversely with tumor diameter (r = -0.258, 95% CI -0.076, -0.514, p = 0.037) and basal plasma aldosterone level (r = -0.251, 95% CI -0.040, -0.464, p = 0.042). CONCLUSIONS: Most patients with typical unilateral adrenal macroadenomas, normal contralateral glands and hypokalemia could attain favorable surgical therapeutic outcomes without pre-operational AVS lateralization.

Circulating insulin-like growth factor-related biomarkers: Correlates and responses to calcium supplementation in colorectal adenoma patients.

Circulating insulin-like growth factor 1 (IGF-1) may be directly associated with colorectal cancer risk, and IGF binding protein 3 (IGFBP-3) is one of the most abundantly expressed binding proteins in various cancers. Calcium intakes, primarily from food, have been directly associated with circulating IGF-1, but whether supplemental calcium affects IGF-1 and IGFBP-3 is unknown. We tested the effects of 1.0 and 2.0 g of supplemental elemental calcium daily on circulating IGF-1 and IGFBP-3 concentrations in colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193). IGF-1 and IGFBP-3 were quantified using enzyme-linked immunoassay and quantitative Western ligand blot, respectively. We also assessed cross-sectional associations of these biomarkers with participants' baseline characteristics. We found no appreciable effect of calcium relative to placebo on circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio. Mean IGF-1 concentrations were 11.1% higher in those with greater milk intakes (P = 0.05). Mean IGF-1 and IGFBP-3 concentrations were, respectively, 18.0% (P = 0.003) and 16.5% (P = 0.01) higher in men and were monotonically lower with increasing age (both P = 0.01). IGFBP-3 was 17.7% higher among those with higher relative to no alcohol consumption (P = 0.04). While these results support previous findings that IGF-1 concentrations are higher with greater milk intakes, and IGF-1 and IGFBP-3 concentrations differ according to sex and age, they provide no evidence to suggest that supplemental calcium appreciably affects circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio in sporadic colorectal adenoma patients.

Parathyroid Adenomas in Adults and Adolescents. Critical Appraisal and Surgical Strategy in 18 Cases.

Background: Our study underline scarcity of isolated case reports or small case series of parathyroid adenoma (PA) published in autochthonous medical literature,their variable clinical expression among the "historic" varieties but also the diagnostic difficulties and delays of diagnosis as well consecration of surgery as the golden therapeutic standard of this disorder. PATIENTS AND METHOD: Demographic, clinical presentations, laboratory and imaging data, operative findings and procedures together with pathology account and outcome from the case reports of 18 patients with documented PHP were retrospectively analyzed. Results: The male/female ratio was 1/5, with ages ranging from 16 to 58 (mean 46) years. Renal stones (n=9) and bone sufferings (n=6) were the most common modes of presentation. To these were added psychiatric and neuromuscular complaints, digestive disorders (pancreatitis and peptic ulcer) arterial hypertension and presence of a palpable nodule. Mean serum calcium and phospho-rus, alkaline phosphatase and PTH dosage together with parathyroid ultrasound and 99m Tc sestamibi scintigraphy are the most useful parameters for diagnosis. Eighteen adenomectomies were performed of which bilateral neck exploration was done in 16 patients and minimally invasive approach in the remaining two cases. In 9 situations concomitant thyroid exeresis for associated lesions or tactical purpose were done. Pathology revealed single adenoma consisting of main and oxyphil cells in 17 cases. In one case an atypical adenoma was identified and in another case three years after removal of a benign adenoma the subject presented a clinical ipsilateral recurrence which provided to be a carcinoma. Postoperative clinical and humoral outcome was favorable in all situations less the case of carcinoma which died after 14 months. Conclusions: Despite the rarity and difficulties of diagnosis in cases of PA, practitioners must be aware of potential existence of these lesions in order to apply as early and appropriate treatment where surgery is the gold standard.

Iron intake, serum iron indices and risk of colorectal adenomas: a meta-analysis of observational studies.

To provide a quantitative assessment of the association between iron intake, serum iron indices and the risk of colorectal adenoma (CRA), we summarised the evidence from observational studies. Relevant studies were identified in MEDLINE and EMBASE until 31 March 2015. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were pooled with a random-effects model. A total of 10 articles, involving 3318 subjects with CRA, were used in this meta-analysis. The SRR of CRA was 0.83 (95% CI: 0.71-0.98; Pheterogeneity  = 0.694, I2  = 0) for the highest versus the lowest level of dietary iron intake. The SRR was 0.93 (95% CI: 0.62-1.42) for total (dietary and supplemental) iron intake, 1.23 (95% CI: 1.03-1.48) for haem iron intake and 0.73 (95% CI: 0.54-0.97) for supplemental iron intake. Serum iron indices were not associated with CRA risk (serum ferritin: SRR = 1.16, 95% CI: 0.81-1.66; serum iron: SRR = 1.02, 95% CI: 0.75-1.38; serum transferrin saturation: SRR = 1.01; 95% CI: 0.82-1.50). Increased intake of haem iron is associated with significantly increased risk of CRA, whereas intake of non-haem or supplemental iron is inversely associated with risk of CRA. Limited data indicate null associations between serum iron indices and CRA risk.

Comparing metabolite profiles of habitual diet in serum and urine.

BACKGROUND: Diet plays an important role in chronic disease etiology, but some diet-disease associations remain inconclusive because of methodologic limitations in dietary assessment. Metabolomics is a novel method for identifying objective dietary biomarkers, although it is unclear what dietary information is captured from metabolites found in serum compared with urine. OBJECTIVE: We compared metabolite profiles of habitual diet measured from serum with those measured from urine. DESIGN: We first estimated correlations between consumption of 56 foods, beverages, and supplements assessed by a food-frequency questionnaire, with 676 serum and 848 urine metabolites identified by untargeted liquid chromatography mass spectrometry, ultra-high performance liquid chromatography tandem mass spectrometry, and gas chromatography mass spectrometry in a colon adenoma case-control study (n = 125 cases and 128 controls) while adjusting for age, sex, smoking, fasting, case-control status, body mass index, physical activity, education, and caloric intake. We controlled for multiple comparisons with the use of a false discovery rate of <0.1. Next, we created serum and urine multiple-metabolite models to predict food intake with the use of 10-fold crossvalidation least absolute shrinkage and selection operator regression for 80% of the data; predicted values were created in the remaining 20%. Finally, we compared predicted values with estimates obtained from self-reported intake for metabolites measured in serum and urine. RESULTS: We identified metabolites associated with 46 of 56 dietary items; 417 urine and 105 serum metabolites were correlated with ≥1 food, beverage, or supplement. More metabolites in urine (n = 154) than in serum (n = 39) were associated uniquely with one food. We found previously unreported metabolite associations with leafy green vegetables, sugar-sweetened beverages, citrus, added sugar, red meat, shellfish, desserts, and wine. Prediction of dietary intake from multiple-metabolite profiles was similar between biofluids. CONCLUSIONS: Candidate metabolite biomarkers of habitual diet are identifiable in both serum and urine. Urine samples offer a valid alternative or complement to serum for metabolite biomarkers of diet in large-scale clinical or epidemiologic studies.

Alcohol Consumption-Related Metabolites in Relation to Colorectal Cancer and Adenoma: Two Case-Control Studies Using Serum Biomarkers.

Alcohol is a known carcinogen that may be associated with colorectal cancer. However, most epidemiologic studies assess alcoholic beverage consumption using self-reported data, leading to potential exposure misclassification. Biomarkers of alcohol consumption may provide an alternative, complementary approach that reduces misclassification and incorporates individual differences in alcohol metabolism. Therefore, we evaluated the relationship between previously identified alcohol consumption-related metabolites and colorectal cancer and adenoma using serum metabolomics data from two studies. Data on colorectal cancer were obtained from a nested case-control study of 502 US adults (252 cases, 250 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Data on colorectal adenoma were obtained from a case-control study of 197 US adults (120 cases, 77 controls) from the Navy Colon Adenoma Study. Unconditional multivariable logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for eight alcohol consumption-related metabolites identified in a previous analysis: ethyl glucuronide; 4-androstene-3beta,17beta-diol disulfate 1; 5-alpha-androstan-3beta,17beta-diol disulfate; 16-hydroxypalmitate; bilirubin (E,Z or Z,E); cyclo (-leu-pro); dihomo-linoleate (20:2n6); and palmitoleate (16:1n7). We found no clear association between these alcohol consumption-related metabolites and either endpoint. However, we did observe an inverse association between cyclo (-leu-pro) and colorectal adenoma that was only observed in the highest metabolite quantile (OR 4th vs. 1st Quantile = 0.30, 95% CI: 0.12-0.78; P-trend = 0.047), but no association for colorectal cancer. In conclusion, there were no adverse associations between alcohol consumption-related metabolites and colorectal cancer or adenoma.

Focused parathyroidectomy without intra-operative parathyroid hormone monitoring for primary hyperparathyroidism: results in a low-volume hospital.

BACKGROUND: The role of routine intra-operative parathyroid hormone monitoring for sporadic primary hyperparathyroidism is contentious. Satisfactory results can be achieved in high-volume centres. The results of low-volume hospitals are rarely studied. METHODS: A retrospective, non-comparative study was conducted. From November 2002 to October 2012, 105 patients with clinically sporadic primary hyperparathyroidism underwent focused parathyroidectomy without intra-operative parathyroid hormone monitoring. Single adenoma was localised on pre-operative ultrasonography or sestamibi scan. The cure rate, surgical complication rate and pathology findings were evaluated. RESULTS: Most of the operations (63.8 per cent) were performed under local anaesthesia. All but two patients (98.1 per cent) were cured after surgery. There was only one case of double adenomas. No recurrent hyperparathyroidism was observed after a mean follow up of 56.9 months. Surgical complications comprised two cases (1.9 per cent) of transient vocal fold palsy and one case (1.0 per cent) of permanent vocal fold palsy. Seven patients (6.7 per cent) suffered temporary hypocalcaemia. CONCLUSION: Satisfactory results of focused parathyroidectomy without routine intra-operative parathyroid hormone monitoring for appropriately selected primary hyperparathyroidism cases can be attained in a low-volume hospital.

Gender- and site-specific differences of colorectal neoplasia relate to vitamin D.

BACKGROUND: The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion. AIM: To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors. METHODS: One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded. RESULTS: Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016). CONCLUSIONS: A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.

C-reactive protein and risk of colorectal adenomas or serrated polyps: a prospective study.

Serum C-reactive protein (CRP) is a sensitive marker of systemic inflammation. Because there is a well-recognized relationship between local inflammation and colorectal cancer, we aimed to evaluate whether serum CRP levels were associated with the occurrence of colorectal adenomas and serrated polyps using data from a large adenoma prevention trial. A total of 930 participants with a history of colorectal adenomas were enrolled in a randomized trial of calcium supplementation (1,200 mg/day) for the prevention of colorectal adenomas. Outcomes in this analysis are metachronous adenomas (and advanced neoplasms specifically), and serrated polyps at follow-up colonoscopy. High-sensitivity CRP levels were measured 1 year following baseline colonoscopy. Multivariate analysis was performed to estimate risk ratios (RR) using Poisson regression, controlling for potential confounders. We measured serum CRP levels in 689 participants (mean CRP, 3.62 ± 5.72 mg/L). There was no difference in CRP levels with respect to calcium versus placebo treatment assignment (P = 0.99). After adjustment for potential confounders, we found no association between CRP level and risk of recurrent adenoma or advanced lesion [quartile 4 vs. quartile 1: RR, 95% confidence interval (CI) = 0.99 (0.73-1.34) and 0.92 (0.49-1.75), respectively]. Similarly, no association was seen between CRP levels and risk of serrated polyps or proximal serrated polyps [quartile 4 vs. quartile 1: RR (95% CI) = 1.32 (0.85-2.03) and 1.19 (0.54-2.58), respectively]. In conclusion, this large prospective colorectal adenoma chemoprevention study found no significant relationship between CRP levels and occurrence of adenomas, advanced neoplasms, or serrated polyps.

Determinants of serum T4 and T3 at the time of diagnosis in nosological types of thyrotoxicosis: a population-based study.

OBJECTIVE: To characterize thyroid hormone levels at the time of diagnosis in the nosological types of thyrotoxicosis diagnosed in the population and to analyze determinants for serum thyroxine (T4) and tri-iodothyronine (T3). DESIGN: Population-based study of thyrotoxicosis at disease onset. METHODS: In the period 1997-2000, we prospectively identified all patients diagnosed with incident primary overt thyrotoxicosis in a Danish population cohort and classified patients into ten well-defined nosological types of disease (n=1082). Untreated levels of serum T3, T4, and T3:T4 ratio were compared and related to sex, age, level of iodine deficiency, smoking status, alcohol intake, iodine supplement use, co-morbidity, and TSH receptor antibodies (TRAbs) in multivariate models. RESULTS: Graves' disease (GD) patients had much higher levels of T3 and higher T3:T4 ratio at diagnosis compared with other thyrotoxic patients, but with a profound negative association between hormone levels and age. In GD, patients diagnosed in the area with more severe iodine deficiency had lower levels of T3 and T4. TRAb-negative GD patients had biochemically mild thyrotoxicosis. Higher age was also associated with lower degree of biochemical thyrotoxicosis in nodular toxic goiter. We found no association between serum T3 and T4 and sex, smoking habits, iodine supplements, alcohol intake, or co-morbidity in any type of thyrotoxicosis. CONCLUSIONS: The study gives new insight into the hormonal presentation of thyrotoxicosis and showed that young age, positive TRAb levels, but also residency in the area with higher iodine intake was positively associated with biochemical disruption in GD.

Selenium and colorectal adenomas risk: a meta-analysis.

Selenium, as an important component of some antioxidants, has been suggested to have protective effects against colorectal adenomas. This meta-analysis examined the association between selenium level in blood and risk of colorectal adenomas. Data from 7 studies (3 cross-sectional studies, 3 case-control studies, 1 nested case-control study) published before December 2011 was included in this meta-analysis. Fixed and random-effects model was explored to calculate odds ratio (OR) and 95% confidence intervals (CI). Heterogeneity among studies was measured using Cochrane Q-test together with the I (2) statistic. There was a significant inverse correlation between selenium level and colorectal adenomas risk according to fixed-effects model. The overall OR of highest selenium level to lowest for colorectal adenomas is 0.67 (95% CI: 0.55-0.81). Heterogeneity was moderate among the pooled studies (P = 0.05 for the Q test, I (2) = 48%). These results suggested a protective effect of selenium for colorectal adenomas. Some factors, such as age, gender, smoking, and characteristics of the adenomas need to be further considered within the association between selenium levels and risk of colorectal adenomas.

Determination of the minimal essential serum folate concentration for reduced risk of colorectal adenoma.

BACKGROUND & AIMS: There are no data regarding basal folate levels in patients without colorectal adenoma. This study aimed to determine the minimum serum folate concentration that associates with reduced risk of colorectal adenoma. METHODS: 1510 consecutive patients underwent total colonoscopy for suspected colorectal lesions after barium enema examination. Prior to colonoscopy, history of alcohol consumption was noted and blood serum analyzed for folate and vitamin B12 levels. Polypoid lesions were evaluated histologically. We excluded patients with anemia, history of colonoscopy, overconsumption of alcohol, or malignancies. In all, 458/1510 patients (male/female; 258/200, 40-75 years) were determined eligible. Variables were compared between patients with adenoma and those without adenoma. RESULTS: Serum folate concentration was the variable with the most significant statistical variation between males with adenoma (8.0 ng/ml) and males without adenoma (9.2) (p = 0.001). Serum folate concentrations in females with adenoma did not differ significantly from those in females without adenoma (10.7 versus 10.9). When subjects were stratified into groups according to serum folate, we found no significant difference in the prevalence of adenoma in patients with folate levels greater than 8.0 ng/ml. CONCLUSION: Patients with serum folate concentrations above 8.0 ng/ml had the lowest risk of developing colorectal adenoma.

Serum salicylate levels and risk of recurrent colorectal adenomas.

BACKGROUND: Intake of aspirin is associated with reduction in risk of colorectal adenoma and carcinoma. Some plants contain salicylates, and individuals not taking aspirin may have measurable salicylate levels. However, the association between serum salicylate level and recurrence of adenoma in nonusers of aspirin has not been studied. METHODS: We measured serum salicylate levels in participants in a randomized controlled trial with calcium supplementation for the prevention of colorectal adenomas. Generalized linear models were used to assess the association between serum levels and adenoma risk during the follow-up period of the trial. RESULTS: We did not find an association with recurrence of adenomas or advanced adenomas with serum salicylate levels at year 1 among nonusers of aspirin. There was no effect modification of the chemopreventive effect of calcium supplementation in reducing risk of recurrent adenomas or advanced adenomas. CONCLUSIONS: Among nonusers of ASA, serum salicylate levels are not associated with risk of recurrence of adenomas. IMPACT: Serum salicylate levels can be detected in individuals not taking aspirin, but the levels may be too low to confer protection from risk of recurrent adenomas.

A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of colorectal adenoma patients.

In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n=92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P=0.03) and CYP24A1 expression decreased 21% (P=0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P=0.01) and CYP27B1 expression increased 159% (P=0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P=0.13) and CaR expression increased 24% (P=0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.

Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa.

Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.

Hiperparatiroidismo primario con normocalcemia, una asociación de diagnóstico complejo: a propósito de un caso clínico / Normocalcemic hyperparathyroidism: report of one case

We report a 59 years old female with a history of nephrolithiasis and progressive worsening of her bone mineral density. High serum PTH levels were detected, with normal serum calcium. Causes of secondary hyperparathyroidism were discarded. The patient was followed during six years, period in which she maintained elevated serum PTH and normal serum calcium. During the second year of follow up, hydrochlorothiazide was indicated. Serum calcium raised progressively and after six years, it became abnormally high. The patient was subjected to a total left lobe and subtotal right lobe thyroidectomy. The surgeon found a 1.6 mm diameter left parathyroid nodule. After surgery the patient is asymptomatic and is receiving levothyroxine supplementation.