An Adrenal Incidentaloma Diagnosed as Dopamine-Secreting Pheochromocytoma: A Case Report

BackgroundDopamine-secreting pheochromocytomas are exceedingly rare.Case presentationA 28-year-old woman, who was admitted due to 4 hours of acute-onset abdominal pain, detected an adrenal mass incidentally. She was almost asymptomatic without a known family history. Laboratory assessments showed significant increases in dopamine levels of serum and 24-h urinary. By using preoperative a-adrenergic receptor blockers, she developed orthostatic hypotension and palpitations. When she underwent laparoscopic left adrenalectomy, she experienced rapid cyclic fluctuations in systolic blood pressure from 90 mmHg to 200 mmHg. Postoperatively, she exhibited prolonged hypotension, requiring vasopressor therapy and fluid replacement. According to histopathological diagnosis, it was a pheochromocytoma. Dopamine levels in 24-h urine and serum decreased to normal after operation. Analysis of specific gene SDHB, SDHD, RET, VHL and NF1 detected no pathogenic mutations.ConclusionPatients with dopamine-secreting pheochromocytomas are mostly asymptomatic, leading to a significant delay in diagnosis. There is a large possibility for dopamine-secreting pheochromocytomas to show a malignant tendency than the adrenergic and noradrenergic phenotypes. The a-adrenergic receptor blocker is not indicated for preoperative medical treatment because it can cause hypotension and cardiovascular failure. Calcium channel blockers or metyrosine may be better alternatives. All patients with pheochromocytomas should receive targeted genetic testing based on specific clinical features. SDHB, SDHD, RET, VHL and NF1 mutations are suggested for genetic testing of adrenal dopamine-secreting pheochromocytomas.     

Scale Can Improve the Clinical Value of Radiology Practices

Radiology is participating in the recent consolidation trend. Larger practices can invest in the infrastructure and teams to help improve the clinical value of the services they deliver. An example of national practice is provided that leverages its scale to promote clinical best practices aimed at reducing variability in the recommendations radiologists make for common imaging findings. This is accomplished by promoting the culture of learning and collaboration. In some initiatives, developing a machine learning tool to facilitate the application of clinical algorithms at the point of dictation facilitates the adoption of the recommendations. Regular feedback on practice and individual performance promotes improvement in performance and personal satisfaction of the clinicians. Cost savings through the reduction of unnecessary imaging studies or invasive procedures as well as improved outcomes through evidence-based follow-up have been achieved. In some cases, reductions in the rupture rate of abdominal aortic aneurysms have been realized through clinical follow-up programs. Embracing a culture of continuous learning through peer learning can lay the foundation for sharing clinical best practices. Having access to the benefits of scale in the form of investment in data, analytics, project management, and machine learning tools can facilitate the process of creating clinical value for our patients.     

Novel Scaled Average Bioequivalence Limits Based on GMR and Variability Considerations

PURPOSE: i) To develop novel approaches for the construction of bioequivalence (BE) limits incorporating both the intrasubject variability and the geometric mean ratio (GMR), and ii) to assess the performance of the novel approaches in comparison to several scaled BE procedures and the classic unscaled average BE. METHODS: Plots of the BE limits or the extreme GMR values accepted as a function of the coefficient of variation (CV) were constructed for published and the developed scaled procedures. Two-period crossover BE investigations with 12, 24, or 36 subjects were simulated with assumptions of a CV 10%, 20%, 30%, or 40%. The decline in the percentage of accepted studies was recorded as the true GMR for the two formulations was raised from 1.00 to 1.50. Acceptance of BE was evaluated by published and the developed scaled procedures, and, for comparison, by the unscaled average BE. RESULTS: Two GMR-dependent BE limits are proposed for the evaluation of average BE: i) BELscG1 with Ln(Upper, Lower BE limit) = +/-[(5 - 4GMR)0.496s + Ln(1.25)], and ii) BELscG2 with Ln(Upper, Lower BE limit) = +/-[(3 - 2GMR)(0.496s + Ln(1.25))], where s is the square root of the intrasubject variance. The range of BE limits becomes narrower as GMR values deviate from unity, and increases with variability. The two new approaches exhibit the highest statistical power at low CV values. At high levels of variability, BELscG1 and BELscG2 show high statistical power, as well as the lowest percentages of acceptance among the scaled methods when GMR = 1.25. The latter becomes more obvious when a large number of subjects is incorporated in the studies. CONCLUSIONS: The GMR and CV estimates of the BE study can be used in conjunction with the GMR vs. CV plot for the assessment of average BE. The new approaches, BELscG1 and BELscG2, appear to be highly effective at all levels of variation investigated.     

Designs for dose–escalation trials with quantitative responses

In a dose–escalation trial for a new drug, each successive dose is tested on a new cohort of volunteer subjects, so that if any dose produces severe adverse reactions then higher doses are not tested. However, if there are other differences between the cohorts, such as differences in environmental health factors, type of person or experimental procedure, then these differences may obscure the differences between doses. Therefore, cohorts should be fitted in the analysis, as either fixed or random effects. I suggest that, if this is done, then there are three simple principles that reduce variance (i) allocating no more than half the subjects in any cohort to any single dose; (ii) subject to safety constraints, using as many different doses as possible in each cohort; (iii) using one more cohort than the number of doses, without increasing the total number of subjects. Using these principles, I propose some new designs that conform to the safety rules of traditional dose–escalation trials while reducing the variance of the estimators of differences between the doses by a factor of two or more, for the same number of subjects. Copyright © 2009 John Wiley & Sons, Ltd.     

Two‐stage designs versus European scaled average designs in bioequivalence studies for highly variable drugs: Which to choose?

The usual approach to determine bioequivalence for highly variable drugs is scaled average bioequivalence, which is based on expanding the limits as a function of the within‐subject variability in the reference formulation. This requires separately estimating this variability and thus using replicated or semireplicated crossover designs. On the other hand, regulations also allow using common 2 × 2 crossover designs based on two‐stage adaptive approaches with sample size reestimation at an interim analysis. The choice between scaled or two‐stage designs is crucial and must be fully described in the protocol. Using Monte Carlo simulations, we show that both methodologies achieve comparable statistical power, though the scaled method usually requires less sample size, but at the expense of each subject being exposed more times to the treatments. With an adequate initial sample size (not too low, eg, 24 subjects), two‐stage methods are a flexible and efficient option to consider: They have enough power (eg, 80%) at the first stage for non‐highly variable drugs, and, if otherwise, they provide the opportunity to step up to a second stage that includes additional subjects.     

Algorithms for evaluating reference scaled average bioequivalence: power,bias, and consumer risk

The determination of the bioequivalence between highly variable drug products involves the evaluation of reference scaled average bioequivalence. The European and US regulatory authorities suggest different algorithms for the implementation of this approach. Both algorithms are based on approximations reflected in lower than the achievable power or higher than the nominal consumer risk of 5%. To overcome these deficiencies, a new class of algorithms, the so‐called Exact methods, was earlier introduced. However, their applicability was limited. We propose 2 modifications which make their computation simpler and also applicable with any study design. Four algorithms were evaluated in simulated 3‐period and 4‐period bioequivalence studies: Hyslop's approach recommended by the US FDA, the method of average bioequivalence with expanding limits requested by the European EMA, and 2 versions of the new Exact methods. At small sample sizes, the Exact methods had substantially higher statistical power than Hyslop's algorithm and had lower consumer risk than the method of average bioequivalence with expanding limits. Similarly to the Hyslop's algorithm, higher than 5% consumer risk was observed only with either unbalanced study design or with additional regulatory requirements. The improved Exact algorithms compare favorably with the alternative procedures. They are based on the bias correction method of Hedges. The recognition that the scaled difference statistics is measured with bias has important practical implications when results of pilot bioequivalence studies are evaluated and, at the same time, calls for the revision of the statistical theory of RSABE and its related methods.     

Albizia lebbeck seed methanolic extract as a complementary therapy to manage local toxicity of Echis carinatus venom in a murine model

Context and objective: Viperid venom-induced chronic local-toxicity continues even after anti-snake venom treatment. Therefore, traditional antidote Albizia lebbeck L. (Fabaceae) seed extract was tested against Echis carinatus S. (Viperidae) venom (ECV)-induced local toxicity to evaluate its complementary remedy.

Materials and methods: Soxhlet extraction of A. lebbeck seeds was performed with the increasing polarity of solvents (n-hexane to water); the extract was screened for phytochemicals (alkaloids, anthraquinones, flavonoids, glycosides, phenolics, saponins, steroids and tannins). In preliminary in vitro analysis, A. lebbeck methanolic extract (ALME) demonstrated significant inhibition of ECV proteases, the major enzyme–toxin responsible for local- toxicity. Therefore, in vitro neutralizing potential of ALME was further evaluated against hyaluronidases and phospholipase A₂ (1:1–1:100 w/w). In addition, alleviation of ECV induced characteristic local- toxicity [haemorrhage (i.d.) and myotoxicity (i.m.)] was determined in mice.

Results: ALME contained high concentrations of phenolics and flavonoids and demonstrated significant in vitro inhibition of ECV protease (IC_50?=_?36.32?μg, p?<?0.0001) and hyaluronidase (IC_50?=_?91.95?μg, p?<?0.0001) at 1:100 w/w. ALME significantly neutralized ECV induced haemorrhage (ED_50?=_?26.37?μg, p?<?0.0001) and myotoxicity by significantly reducing serum creatinine kinase (ED_50?=_?37.5?μg, p?<?0.0001) and lactate dehydrogenase (ED_50?=_?31.44?μg, p?=?0.0021) levels at 1:50 w/w.

Discussion and conclusion: ALME demonstrated significant neutralization of ECV enzymes that contribute in local tissue damage and haemostatic alterations. The study scientifically supports the anecdotal use of A. lebbeck in complementary medicine and identifies ALME as principle fraction responsible for antivenom properties.     

The 4-hook anchor coaxial needle with scaled suture is superior to the double spring coil for preoperative localization

BackgroundPreoperative localization of small size pulmonary nodules is challenging, but it is necessary for surgical resection of early lung cancer. As a new device for preoperative localization, the 4-hook-anchor coaxial needle with scaled suture was tentatively applied in our department to improve the effect of preoperative localization. However, double spring coil, as a proven positioning technology, used to be our preferred method in the past. We did a retrospective single-centre research driven by the interest on which one should be the first choice for preoperative localization among these two approaches.MethodsWe performed a retrospective analysis on 100 patients undergoing surgery with the new coaxial needle from 2019 to 2020, and 98 patients undergoing double spring coil from 2017 to 2019. The duration of localization, success rate, operation time, intraoperative bleeding, and positioning-related complications of these two groups of patients were examined in this study.ResultsThere were no significant differences between the two groups of patients in terms of the success rate. However, the new coaxial needle seemed to be able to shorten the duration of preparative localization and operation time by accelerating the efficiency of exploring small nodules intraoperatively, and also decreased the risk of positioning-related pneumothorax and pulmonary hemorrhage. The logistic analysis indicated that the puncture depth was an independent risk factor for overall complications. Meanwhile, previous lung diseases and positioning time were independent risk factors for pneumothorax, besides pneumorrhagia and depth of penetration as well.ConclusionsThe new coaxial needle can save time for both radiologists and thoracic surgeons, while reducing the risk of positioning-related complications. We support its application clinically instead of the double spring coil.     

Statistical evaluation of the scaled criterion for drug interchangeability

ABSTRACT

As more and more generic drug products become available in the marketplace, it is a concern whether these generic drug products can be used interchangeably in terms of their quality, safety, and efficacy. The United States Food and Drug Administration (FDA) indicates that an approved generic drug product can serve as a substitute for the innovative drug product. The FDA, however, does not indicate that approved generic drug products can be used interchangeably even if they are bioequivalent to the same innovative drug product. In the past decade, several criteria for assessing interchangeability were proposed in regulatory guidances and/or literature. Chow, Xu, and Endrenyi proposed a scaled criterion for drug interchangeability (SCDI), which takes both intra-subject variability and subject-by-drug variability into consideration. In this paper, the performance of this criterion is statistically evaluated by deriving the upper confidence limit of the test statistic and extrapolating expression of the power to facilitate sample size calculation. The performance of SCDI is also compared with that of the criterion for assessment of individual bioequivalence (IBE) for addressing drug switchability recommended by the FDA, which also takes into account the subject-by-drug variability, under various parameter specifications.