Abemaciclib: safety and effectiveness of a unique cyclin-dependent kinase inhibitor

Introduction: The discovery and the clinical availability of novel cyclin-dependent kinases 4 and 6 inhibitors have profoundly changed the therapeutic scenario of metastatic hormone receptor-positive breast carcinoma. Among these inhibitors, abemaciclib can induce potent and sustained cell cycle arrest and immune system stimulation. Areas covered: This review summarizes the safety profile and clinical efficacy data on abemaciclib alone or in combination with aromatase inhibitors or fulvestrant in metastatic hormone receptor-positive breast carcinoma. The management of patients treated with abemaciclib is the object of this paper. Expert opinion: As shown in phase 2 and 3 clinical trials on efficacy and tolerability, abemaciclib is a potentially convenient, safe, and effective agent for the treatment of patients with advanced hormone receptor-positive patients. Orally administered abemaciclib in combination with aromatase inhibitors or fulvestrant has the potential to allow significant improvement in survival outcomes, quality of life, response rate, and duration of response even in poor prognosis subgroups. Adequate patients’ information, clinical selection, and prompt, proactive management of side effects are mandatory

Using data differently and using different data

The lack of adequate measures is often an impediment to robust policy evaluation. We discuss three approaches to measurement and data usage that have the potential to improve the way we conduct impact evaluations. First, the creation of new measures, when no adequate ones are available. Second, the use of multiple measures when a single one is not appropriate. And third, the use of machine learning algorithms to evaluate and understand programme impacts. We motivate the relevance of each of the categories by providing examples where they have proved useful in the past. We discuss the challenges and risks involved in each strategy and conclude with an outline of promising directions for future work

BCR-ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein

Patients with chronic myeloid leukemia in whom tyrosine kinase inhibitors (TKIs) fail often present mutations in the BCR-ABL catalytic domain. We noticed a lack of substitutions involving 4 amino acids (E286, M318, I360, and D381) that form hydrogen bonds with ponatinib. We therefore introduced mutations in each of these residues, either preserving or altering their physicochemical properties. We found that E286, M318, I360, and D381 are dispensable for ABL and BCR-ABL protein stability but are critical for preserving catalytic activity. Indeed, only a "conservative" I360T substitution retained kinase proficiency and transforming potential. Molecular dynamics simulations of BCR-ABLI360T revealed differences in both helix αC dynamics and protein-correlated motions, consistent with a modified ATP-binding pocket. Nevertheless, this mutant remained sensitive to ponatinib, imatinib, and dasatinib. These results suggest that changes in the 4 BCR-ABL residues described here would be selected against by a lack of kinase activity or by maintained responsiveness to TKIs. Notably, amino acids equivalent to those identified in BCR-ABL are conserved in 51% of human tyrosine kinases. Hence, these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.This work was supported by an investigator grant to P.V. from Associazione Italiana per la Ricerca sul Cancro (AIRC) and by funding from the Biotechnology and Biological Sciences Research Council (BB/I023291/1 and BB/H018409/1 to AP and FF). P.B. is the recipient of an AIRC - Marie Curie fellowship

Correlation between adrenal function, growth hormone secretion, and insulin sensitivity in children with idiopathic growth hormone deficiency

Purpose Patients with growth hormone deficiency (GHD) demonstrate an increased cortisol/cortisone ratio which could potentially explain the metabolic features of GHD, while GH treatment (GHT) could increase the cortisol metabolism. Methods In 35 children (27 M, mean age 10.1 years) with idiopathic GHD at baseline and after 12 months of GHT and in 25 controls, in addition to metabolic parameters, we assessed adrenal function by morning serum cortisol, its peak, and its area under the curve (AUCCOR) during insulin tolerance test (ITT). Results A cortisol peak <18 \ub5g/dl was shown in 22 and 31% of GHD children at baseline and after GHT, respectively. At baseline, GHD children had lower fasting glucose (p < 0.001) and ISI-Matsuda (p = 0.042), with concomitant higher Homa-IR (p = 0.006) and morning cortisol (p = 0.012) than controls. Morning cortisol was negatively correlated with GH (p < 0.001), fasting glucose (p < 0.001) and ISI-Matsuda (p < 0.001) and positively with Homa-IR (p = 0.010). Both cortisol peak and AUCCOR were negatively correlated with GH (all p < 0.001) and ISI-Matsuda (p = 0.016 and p = 0.001, respectively). After 12 months of GHT, a significant increase in fasting glucose (p < 0.001), and Homa-IR (p = 0.011) was documented, with a concomitant decrease in morning cortisol (p = 0.002), AUCCOR (p = 0.038), total (p = 0.003) and LDL-cholesterol (p = 0.016). No significant correlations were found among cortisol levels and all parameters were investigated. Conclusions Cortisol levels correlate with GH secretion and with many metabolic parameters in GHD children, while the metabolic effects during GHT are mainly due to GHT per se and less to cortisol reduction

Goitre and Iodine Deficiency in Europe

The prevalence of endemic iodine-deficiency goitre in Europe has been reduced in many areas by the introduction of iodination programmes. Recent reports, however, show that goitre remains a significant problem and that its prevalence has not decreased in a number of European countries. Hetzel1 has pointed out that the high global prevalence of iodine-deficiency disorders could be eradicated within 5-10 years by introduction of an iodised salt programme. The current World Health Organisation recommendations for iodine intake are between 150 and 300 μg/da

Practical Approach to the Diagnosis of the Vulvo-Vaginal Stromal Tumors: An Overview

Background: The category of the "stromal tumors of the lower female genital tract" encompasses a wide spectrum of lesions with variable heterogeneity, which can be nosologically classified on the basis of their morphologic and immunohistochemical profiles as deep (aggressive) angiomyxoma (DAM), cellular angiofibroma (CAF), angiomyofibroblastoma (AMFB) or myofibroblastoma (MFB). Despite the differential diagnosis between these entities being usually straightforward, their increasingly recognized unusual morphological variants, along with the overlapping morphological and immunohistochemical features among these tumours, may raise serious differential diagnostic problems. Methods and Results: The data presented in the present paper have been retrieved from the entire published literature on the PubMed website about DAM, CAF, AFMB and MFB from 1984 to 2021. The selected articles are mainly represented by small-series, and, more rarely, single-case reports with unusual clinicopathologic features. The present review focuses on the diagnostic clues of the stromal tumours of the lower female genital tract to achieve a correct classification. The main clinicopathologic features of each single entity, emphasizing their differential diagnostic clues, are discussed and summarized in tables. Representative illustrations, including the unusual morphological variants, of each single tumour are also provided. Conclusion: Awareness by pathologists of the wide morphological and immunohistochemical spectrum exhibited by these tumours is crucial to achieve correct diagnoses and to avoid confusion with reactive conditions or other benign or malignant entities

TWO CASES OF NON-ALCOHOLIC WERNICKE ENCEPHALOPATHY SUCCESSFULLY TREATED BY THIAMINE REPLACEMENT: DIAGNOSTIC AND THERAPEUTIC CONSIDERATIONS

Wernicke\u2019s encephalopathy (WE) is an acute neurologi- cal disorder, due to a lack of thiamin (vitamin B1) which is observed mainly in alcoholic patients. Unfortunately, the syn- drome is underestimated in clinical practice and most often recognized only on autopsy, especially among non-alcoholics. The common clinical picture include mental status changes, ocular dysfunction, and gait ataxia. Treatment consists of timely thiamine replacement through intravenous infusion. We describe the case of two patients who developed a non-alcoholic WE post-surgical, regressed completely after intravenous infusion of thiamine. These cases suggest intere- sting diagnostic and therapeutic implications