KCNJ5 Mutation Contributes to Complete Clinical Success in Aldosterone-Producing Adenoma: A Study From a Single Center

ObjectiveThe KCNJ5 mutation is the most frequent mutation in aldosterone-producing adenoma (APA). We aimed to illustrate the relationship between KCNJ5 and prognosis after adrenalectomy as a guide for further treatment.MethodsOur study included 458 patients with APA. Tumor tissues were screened for somatic mutations in KCNJ5 hot-spot regions. We performed a retrospective analysis to identify correlations between KCNJ5 and clinical outcomes in 334 patients with adrenal venous sampling lateralization.ResultsSomatic KCNJ5 mutations were identified in 324 of 458 patients with APA (70.7%). Compared with the KCNJ5-wild type patients, patients with KCNJ5 mutations were younger, had a higher proportion of women, and had shorter durations of hypertension, lower body mass indexes (BMIs), and lower systolic blood pressure values (P < .05). During follow-up, among the 334 patients with APA with adrenal venous sampling lateralization, 320 (95.8%) presented complete biochemical success and 187 (56.0%) presented complete clinical success. One hundred eighty-seven patients with primary aldosteronism who achieved complete clinical success presented the following characteristics: age <40 years (78.7%), BMI <24 kg/m² (71.0%), hypertension duration <5 years (78.4%), females (66.9%), and KCNJ5 mutation (65.5%). A multivariate logistic regression analysis identified BMI, hypertension duration, and KCNJ5 mutation as independent predictors of complete clinical success.ConclusionThe prevalence of KCNJ5 mutations was 70.7%. KCNJ5 mutation is a protective factor of complete clinical success, while BMI and hypertension duration were risk factors of incomplete clinical success.     

Parathyroid Cystic Adenoma: A Systematic Review and Meta-Analysis

ObjectiveTo review diagnostic imaging modalities for parathyroid cystic adenomas (PCA). Since PCAs are a rare (0.5%-1%) subclass of parathyroid adenomas, and due to their cystic component, imaging modalities known to be efficient for diagnosing solid adenomas might fail in localizing them.MethodsWe conducted a systematic review using the PubMed and Cochrane databases for English articles on PCAs published between 1995 and 2020. A meta-analysis of the retrieved data was performed.ResultsOverall, 39 studies, reporting on a total of 160 patients, were included in the analysis. Two thirds (68%) of the patients were female, with a mean age of 53.9 years. A single cystic adenoma was detected in 98.1% of cases. The mean blood calcium corrected for albumin level was 12.6 ± 2.7 mg/dL, and the mean parathyroid hormone level was 565.5 ± 523.8 pg/mL. The mean PCA sizes as measured by ultrasound (US), computed tomography (CT), and ex vivo measurement were 4.8 ± 3.6, 5.2 ± 3.2, and 3.5 cm, respectively. The median weight was 8.1 g. PCA was detected in 86% of US examinations; 100% of US-guided fine needle aspiration, 4-dimensional computed tomography (4D-CT), or magnetic resonance imaging examinations; and 61% of 99m-technetium sestamibi scan with single-photon emission computed tomography ((99m)Tc-SPECT). (99m)Tc-SPECT showed a significantly lower diagnostic rate than US (odds ratio, 3.589), US-guided fine needle aspiration, CT combined with 4D-CT, and the combination of US, CT, 4D-CT, and magnetic resonance imaging (P < .001).ConclusionAlthough US and 4D-CT showed a significantly high rate in diagnosing PCA, (99m)Tc-SPECT showed a lower PCA diagnostic rate. These findings suggest that larger cystic lesions suspected as PCAs should be further evaluated using 4D-CT rather than (99m)Tc-SPECT.     

A Fatal Combination: A Thymidylate Synthase Inhibitor with DNA Damaging Activity

2′-deoxy-5-ethynyluridine (EdU) has been previously shown to be a cell poison whose toxicity depends on the particular cell line. The reason is not known. Our data indicates that different efficiency of EdU incorporation plays an important role. The EdU-mediated toxicity was elevated by the inhibition of 2′-deoxythymidine 5′-monophosphate synthesis. EdU incorporation resulted in abnormalities of the cell cycle including the slowdown of the S phase and a decrease in DNA synthesis. The slowdown but not the cessation of the first cell division after EdU administration was observed in all of the tested cell lines. In HeLa cells, a 10 μM EdU concentration led to the cell death in the 100% of cells probably due to the activation of an intra S phase checkpoint in the subsequent S phase. Our data also indicates that this EdU concentration induces interstrand DNA crosslinks in HeLa cells. We suppose that these crosslinks are the primary DNA damage resulting in cell death. According to our results, the EdU-mediated toxicity is further increased by the inhibition of thymidylate synthase by EdU itself at its higher concentrations.     

Genetic Variants Associated with Colorectal Adenoma Susceptibility

BackgroundCommon low-penetrance genetic variants have been consistently associated with colorectal cancer risk.AimTo determine if these genetic variants are associated also with adenoma susceptibility and may improve selection of patients with increased risk for advanced adenomas and/or multiplicity (≥ 3 adenomas).MethodsWe selected 1,326 patients with increased risk for advanced adenomas and/or multiplicity and 1,252 controls with normal colonoscopy from population-based colorectal cancer screening programs. We conducted a case-control association study analyzing 30 colorectal cancer susceptibility variants in order to investigate the contribution of these variants to the development of subsequent advanced neoplasia and/or multiplicity.ResultsWe found that 14 of the analyzed genetic variants showed a statistically significant association with advanced adenomas and/or multiplicity: the probability of developing these lesions increased with the number of risk alleles reaching a 2.3-fold risk increment in individuals with ≥ 17 risk alleles.ConclusionsNearly half of the genetic variants associated with colorectal cancer risk are also related to advanced adenoma and/or multiplicity predisposition. Assessing the number of risk alleles in individuals within colorectal cancer screening programs may help to identify better a subgroup with increased risk for advanced neoplasia and/or multiplicity in the general population.     

Legume Consumption and Colorectal Adenoma Risk: A Meta-Analysis of Observational Studies

Background

The anticancer effects of legumes have been explored extensively, but evidence from epidemiologic studies on colorectal adenoma is controversial. We performed a meta-analysis to assess these issues.

Methods

A systemic search of several databases was conducted for relevant studies evaluating the relationship between legume intake and adenoma risk, with no language restriction, from January 1, 1966, to April 1, 2013.

Results

Three cohort and eleven case control studies with 8,380 cases and a total of 101,856 participants were included in the analysis; the pooled odds ratio (95% confidence interval) for the highest vs. lowest consumption categories was 0.83 (0.75–0.93), with moderate level of heterogeneity (I ² = 25.9% and P = 0.146) based on a random effects model. A decreased risk of adenoma was also observed in most of our subgroup meta-analyses.

Conclusions

Higher intake of legumes significantly reduced the risk of colorectal adenoma in our meta-analysis. Nevertheless, due to possible confounders and bias, further investigations are warranted to confirm this relationship.     

Concomitant therapy with Cineole (Eucalyptole) reduces exacerbations in COPD: A placebo-controlled double-blind trial

Background

The clinical effects of mucolytics in patients with chronic obstructive pulmonary disease (COPD) are discussed controversially. Cineole is the main constituent of eucalyptus oil and mainly used in inflammatory airway diseases as a mucolytic agent. We hypothesised that its known mucolytic, bronchodilating and anti-inflammatory effects as concomitant therapy would reduce the exacerbation rate and show benefits on pulmonary function tests as well as quality of life in patients with COPD.

Methods

In this double-blind, placebo-controlled multi-center-study we randomly assigned 242 patients with stable COPD to receive 200 mg of cineole or placebo 3 times daily as concomitant therapy for 6 months during winter-time. The frequency, duration and severity of exacerbations were combined as primary outcome measures for testing as multiple criteria. Secondary outcome measures included changes of lung function, respiratory symptoms and quality of life as well as the single parameters of the exacerbations.

Results

Baseline demographics, lung function and standard medication of both groups were comparable. During the treatment period of 6 months the multiple criteria frequency, severity and duration of exacerbations were significantly lower in the group treated with cineole in comparison to placebo. Secondary outcome measures validated these findings. Improvement of lung function, dyspnea and quality of life as multiple criteria were statistically significant relative to placebo. Adverse events were comparable in both groups.

Conclusion

Concomitant therapy with cineole reduces exacerbations as well as dyspnea and improves lung function and health status. This study further suggests cineole as an active controller of airway inflammation in COPD by intervening in the pathophysiology of airway inflammation of the mucus membrane.

Trial registration

ISRCTN07600011     

Thyrotropin-Secreting Adenoma in a Patient with Primary Hypothyroidism

ObjectiveTo describe a patient who developed a thyrotropin (TSH)-Secreting adenoma in the setting of primary hypothyroidism.MethodsWe report the clinical, laboratory, and radiologic findings of a patient with a history of primary hypothyroidism who presented with headache, a bitemporal visual field deficit, and elevated TSH despite long-term levothyroxine therapy. We discuss the diagnostic challenges of this case and review the relevant literature.ResultsA54-year-old woman with a history of primary hypothyroidism presented with a 3-year history of headache and a week of worsening vision. Imaging revealed a heterogeneous sellar mass elevating the optic chiasm. Her serum TSH was 46.5 mIU/L and free thyroxine concentration was 0.1 ng/dL. The differential diagnosis included pituitary hyperplasia and a TSH-secreting adenoma in a patient with primary hypothyroidism. The pathologic characteristics of the tumor were consistent with the latter.ConclusionIn a patient with an elevated TSH concentration and a previous diagnosis of hypothyroidism, it is important to consider other entities besides medication noncompliance. TSH-secreting adenomas can also cause elevated levels of TSH. (Endocr Pract. 2011;17: e135-e139)     

A theoretical explanation of “Concomitant resistance”

Concomitant resistance is a tumor growth dynamic which results when the growth of a second tumor implant is inhibited by the presence of the first. Recently, we modeled tumor growth in the presence of a regenerating liver after partial hepatectomy (Michelson and Leith,Bull. Math. Biol. 57, 345–366, 1995), with an interlocking pair of growth control triads to account for the accelerated growth observed in both tissues. We also modeled tumor dormancy and recurrence as a dynamic equilibrium achieved between proliferating and quiescent subpopulations. In this paper those studies are extended to initially model the concomitant resistance case. Two interlocking model systems are proposed. In one an interactive competition between the tumor implants is described, while in the other purely proportional growth inhibition is described. The equilibria and dynamics of each system when the coefficients are held constant are presented for three subcases of model parameters. We show that the dynamic called concomitant resistance can be real or apparent, and that if the model coefficients are held constant, the only way to truly achieve concomitant resistance is by forcing one of the tumors into total quiescence. If this is the true state of the inhibited implant, then a non-constant recruitment signal is required to insure regrowth when the inhibitor mass is excised. We compare these theoretical results to a potential explanation of the phenomenon provided by Prehn (Cancer Res. 53, 3266–3269, 1993).     

Challenging artificial genetic systems: thymidine analogs with 5-position sulfur functionality

Eight different polymerases, chosen from evolutionary families A (Taq, Tfl, HotTub and Tth) and B (Pfu, Pwo, Vent and Deep Vent), were examined for their ability to incorporate 5-position modified 2′-deoxyuridine derivatives that carry a protected thiol group appended via different linkers containing either three or four carbon atoms. This represents the first attempt to incorporate the thiol functionality into DNA via enzymatic synthesis. Each polymerase–substrate combination was evaluated using a hierarchy of increasingly more difficult challenges, starting with incorporation of a single derivative, proceeding to incorporation of two derivatives at adjacent sites and non-adjacent sites, then examining the ability of the polymerase to accept the derivative within the template, and concluding with a challenge involving PCR. The evaluation of thiol-bearing 2′-deoxyuridine derivatives was then extended to consider their chemical stabilities. Stability was found to be less than satisfactory when the thiol functionality has a ‘propargylic’ relationship to the unsaturation in the linker. The best polymerase–appendage combination used the polymerase from Pyrococcus woesei (Pwo) and the 5′-tBu-SS-CH₂-CH₂-CC- linker. This pair supported PCR amplification and therefore should have value in artificial in vitro selection experiments. Indeed, we discovered that Pwo and Pfu preferred the derivative triphosphate over TTP, the natural substrate, in competition studies. These studies confirm an earlier suggestion that membership of an evolutionary family of polymerases is a partial predictor of the ability of the polymerase to accept 5-modified 2′-deoxyuridines. Considerable differences are displayed by different members within a polymerase family, however. This remains curious, as the ability of the polymerase to replicate natural DNA with high fidelity and its propensity to exclude unnatural analogs are presumed to be correlated.