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Estrogen receptor-positive (ER +) breast cancer accounts for approximately 75% of all breast cancers. Endocrine therapies, including selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER down-regulators (SERDs) provide substantial clinical benefit by reducing the risk of disease recurrence and mortality. However, resistance to endocrine therapies represents a major challenge, limiting the success of ER + breast cancer treatment. Mechanisms of endocrine resistance involve alterations in ER signaling via modulation of ER (e.g., ER downregulation, ESR1 mutations or fusions); alterations in ER coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators; regulation of signaling pathways; modulation of cell cycle regulators; stress signaling; and alterations in tumor microenvironment, nutrient stress, and metabolic regulation. Current therapeutic strategies to improve outcome of endocrine-resistant patients in clinics include inhibitors against mechanistic target of rapamycin (mTOR), cyclin-dependent kinase (CDK) 4/6, and the phosphoinositide 3-kinase (PI3K) subunit, p110α. Preclinical studies reveal novel therapeutic targets, some of which are currently tested in clinical trials as single agents or in combination with endocrine therapies, such as ER partial agonists, ER proteolysis targeting chimeras (PROTACs), next-generation SERDs, AKT inhibitors, epidermal growth factor receptor 1 and 2 (EGFR/HER2) dual inhibitors, HER2 targeting antibody-drug conjugates (ADCs) and histone deacetylase (HDAC) inhibitors. In this review, we summarize the established and emerging mechanisms of endocrine resistance, alterations during metastatic recurrence, and discuss the approved therapies and ongoing clinical trials testing the combination of novel targeted therapies with endocrine therapy in endocrine-resistant ER + breast cancer patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aimed to define the clinical course of anosmia in relation to other clinical symptoms., Methods: 135 patients with COVID-19 were reached by phone and subsequently included in the study. Olfactory functions were evaluated using a questionnaire for assessment of self-reported olfactory function. Patients were divided into four subgroups according to the presence of olfactory symptoms and temporal relationship with the other symptoms: group1 had only olfactory complaints (isolated, sudden-onset loss of smell); group2 had sudden-onset loss of smell, followed by COVID-19 related complaints; group3 initially had COVID-19 related complaints, then gradually developed olfactory complaints; and group4 had no olfactory complaints., Results: In total, 59.3% of the patients interviewed had olfactory complaints during the disease course. The olfactory dysfunction severity during COVID-19 infection was significantly higher in group1 compared to groups 2 and 3. In groups1-3, the odor scores after recovery from COVID-19 disease were significantly lower compared to the status prior to disease onset. The residual olfactory dysfunction was similar between groups1 and 2, but was more evident than group3. Mean duration for loss of smell was 7.8 ± 3.1 (2-15) days. Duration of loss of smell was longer in groups1 and 2 than in group3. Odor scores completely returned back to the pre-disease values in 41 (51.2%) patients with olfactory dysfunction. Rate of complete olfactory dysfunction recovery was higher in group3 compared to groups1 and 2., Conclusion: In isolated anosmia cases, anosmia is more severe, and complete recovery rates are lower compared to the patients who have other clinical symptoms., Level of Evidence: Level 4.

Purpose: In an effort to make olfactory training (OT) simpler, we designed an 'olfactory training ball' (OTB)-a baseball-size ball with four odor-containing tubes to use in OT. The study aimed to investigate the effects of OT with the OTB in comparison to classical OT with special attention to the effects of adherence to OT on olfactory outcome measures., Methods: Sixty patients with olfactory dysfunction following infections of the upper respiratory tract received OT either with classical methods-sniffing odors from jars (COT)-or the OTB for 12 weeks. Patients exposed themselves to the odors for 5 min twice daily. Adherence was measured with a modified version of the Morisky scale. Before and after OT, all patients underwent extensive olfactory testing using the Sniffin' Sticks test., Results: At the end of the 12 weeks of OT, TDI composite score (22.1 ± 2.8 vs. 19.9 ± 4.7, P = 0.044) and odor discrimination subtest scores (9.1 ± 1.8 vs.7.6 ± 2.5, P = 0.013) of the OTB group were significantly higher than that of the COT group. Adequate adherence to OT was significantly higher in patients receiving OTB when compared to those receiving COT (63% vs. 30%, P = 0.019)., Conclusion: The present study shows that a novel OT device, the OTB, provides better adherence to the training process compared to COT. Moreover, findings of the current study show that better adherence to the OT process is associated with better olfactory outcomes.