Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder, characterized by the selective loss of nigrostriatal dopaminergic neurons, and the presence of intracellular insoluble proteinaceous inclusions, known as Lewy Bodies. Although PD etiopathogenesis remains elusive, the leading hypothesis for the death of specific groups of neurons establishes that mitochondrial dysfunction, alterations in the ubiquitin-proteasomal system (UPS), and oxidative stress are major events that act synergistically causing this devastating disease. In this review we will focus on mitochondrial impairment and its implications on proteasomal function and alpha-synuclein aggregation. We will address the role of mitochondria and proteasome cross-talk in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient therapy.

HER2-positive breast cancer represents 15%-20% of breast malignancies and is characterized by an aggressive behavior and high recurrence rates. Anti-HER2-directed agents represent the mainstay of treatment of patients with HER2-positive metastatic breast cancer (MBC). In this review we propose a treatment algorithm for patients with HER2-positive MBC based on the currently available literature on the topic. The combination of trastuzumab, pertuzumab and a taxane (THP) remains the preferred first-line therapy in most scenarios. Results of trials recently presented at the European Society for Medical Oncology (ESMO) Congress 2021 might have direct clinical impact in the second- and later-line settings. The randomized DESTINY-BREAST03 study compared trastuzumab deruxtecan (T-DXd) with trastuzumab emtansine (T-DM1) in patients previously treated with trastuzumab and a taxane. T-DXd significantly improved progression-free survival and showed a trend towards improved overall survival, establishing this agent as preferred second-line therapy. Treatment with T-DM1, or the combination of tucatinib, trastuzumab and capecitabine, are considered reasonable options after second-line therapy. For subsequent lines, trastuzumab duocarmazine, neratinib plus capecitabine or the continuation of trastuzumab with different chemotherapy partners are valid options. For patients experiencing disease relapse up to 6 months after completion of adjuvant therapy, as well as for those relapsing within 12 months from the completion of pertuzumab-based adjuvant treatment, we recommend T-DXd as preferred first-line option. For those relapsing between 6 and 12 months after non-pertuzumab-based adjuvant treatment, we recommend first-line THP. Finally, for patients with active brain metastasis, tucatinib-based combination represents a suitable second-line option.

Objective The aim of this work was to evaluate the role of Ubiquitin-Proteasome System (UPS) on mitochondrial-driven alpha-synuclein (aSN) clearance in in vitro, ex vivo and in vivo Parkinson disease (PD) cellular models. Method We used SH-SY5Y ndufa2 knock-down (KD) cells, PD cybrids and peripheral blood mononuclear cells (PBMC) from patients meeting the diagnostic criteria for PD. We quantified aSN aggregation, proteasome activity and protein ubiquitination levels. In PBMC of PD patients population we evaluated aSN levels in plasma and the influence of several demographic characteristics in the above mentioned determinations. Results We found that ubiquitin-independent proteasome activity was up-regulated in SH-SY5Y ndufa2 KD cells while a down regulation was observed in PD cybrids and PBMC. Moreover, we observed an increase in protein ubiquitination that correlates with a decrease in ubiquitin-dependent proteasome activity. Accordingly, proteasome inhibition prevented ubiquitin-dependent aSN clearance. Ubiquitin-independent proteasome activity was positively correlated with ubiquitination in PBMC. We also report a negative correlation of chymotrypsin-like activity with age in control and late-onset PD groups. Total ubiquitin content is positively correlated with aSN oligomers levels, which leads to an age-dependent increase of aSN ubiquitination in LOPD. Moreover, aSN levels are increased in the plasma of PD patients. Interpretation aSN oligomers are ubiquitinated and we identified an ubiquitin-dependent clearance insufficiency with accumulation of both aSN and ubiquitin. However, SH-SY5Y ndufa2 KD cells showed a significant up-regulation of ubiquitin-independent proteasomal enzymatic activity that could mean a cell rescue attempt. Moreover, we identified that UPS function is age-dependent in PBMC.

After the start of Lu-DOTA-TATE all patients achieved hypoglycaemia symptomatic control and had evident improvement of their quality of life. Three patients showed imagiological improvement suggesting reduced tumour load.

IntroductionThere is growing concern about the aggressiveness of cancer care at the end of life (ACCEoL), defined as overly aggressive treatments that compromise the quality of life at its end. Recognising the most affected patients is a cornerstone to improve oncology care. Our aim is to identify factors associated with ACCEoL for patients with cancer dying in hospitals.MethodsAll adult patients with cancer who died in public hospitals in mainland Portugal (January 2010 to December 2015), identified from the hospital morbidity database. This database provided individual clinical and demographic data. We obtained hospital and region-level variables from a survey and National Statistics. The primary outcome is a composite ACCEoL measure of 16 indicators. We used multilevel random effects logistic regression modelling (p<0·05).ResultsWe included 92 155 patients: median age 73 years; 62% male; 53% with metastatic disease. ACCEoL prevalence was 71% (95% CI 70% to 71%). The most prevalent indicators were >14 days in the hospital (43%, 42–43) and surgery (28%, 28–28) in the last 30 days. Older age (p<0·001), breast cancer (OR 0·83; 95% CI 0·76 to 0·91), and metastatic disease (0·54; 95% CI 0·50 to 0·58) were negatively associated with ACCEoL. In contrast, higher Deyo-Charlson Comorbidity Index (p<0·001), gastrointestinal and haematological malignancies (p<0·001), and death at cancer centre (1·31; 95% CI 1·01 to 1·72) or hospital with medical oncology department (1·29; 95% CI 1·02 to 1·63) were positively associated with ACCEoL. There was no association between hospital palliative care services at the hospital of death and ACCEoL.ConclusionClinical factors related to a better understanding of disease course are associated with ACCEoL reduction. Patients with more comorbidities and gastrointestinal malignancies might represent groups with complex needs, and haematological patients may be at increased risk because of unpredictable prognosis. Improvement of hospital palliative care services could help reduce ACCEoL, particularly in cancer centres and hospitals with medical oncology department, as those services are usually under-resourced, thus reaching few.

Coronavirus disease 2019 (COVID-19) has resulted in millions of deaths globally. The pandemic has had a severe impact on oncology care and research. Patients with underlying cancer are more vulnerable to contracting COVID-19, and also have a more severe clinical course following the infection. The rollout of COVID-19 vaccines in many parts of the world has raised hopes of controlling the pandemic. In this editorial, the authors outline key characteristics of the currently approved COVID-19 vaccines, provide a brief overview of key emerging issues such as vaccine-induced immune thrombotic thrombocytopenia and SARS-CoV-2 variants of concern, and review the available data related to the efficacy and side effects of vaccinating patients with cancer.

Cellular homeostasis relies on quality control systems so that damaged biologic structures are either repaired or degraded and entirely replaced by newly formed proteins or even organelles. The clearance of dysfunctional cellular structures in long-lived postmitotic cells, like neurons, is essential to eliminate, per example, defective mitochondria, lipofuscin-loaded lysosomes and oxidized proteins. Short-lived proteins are degraded mainly by proteases and proteasomes whether most long-lived proteins and all organelles are digested by autophagy in the lysosomes. Recently, it an interplay was established between the ubiquitin-proteasome system and macroautophagy, so that both degradative mechanisms compensate for each other. In this article we describe each of these clearance systems and their contribution to neuronal quality control. We will highlight some of the findings that provide evidence for the dysfunction of these systems in Alzheimer's and Parkinson's diseases. Ultimately, we provide an outline on potential therapeutic interventions based on the modulation of cellular degradative systems.

135 Background: Immunotherapy (IO) has changed the disease course of metastatic malignant melanoma (mMM). Prognostic biomarkers are lacking, but high neutrophil-lymphocyte ratio (NLR) has been correlated with poor outcome. Lymphocyte-monocyte ratio (LMR) and platelet-lymphocyte ratio (PLR) are also readily available. This study aimed to investigate the prognostic value of NLR, LMR and PLR. Methods: Retrospective cohort of mMM patients (pts) treated with anti PD-1 blockade in 2 centers, between Jan ’13-Aug ’18. Baseline and 6-week (6 w) blood counts were collected. Cut-offs for NLR, LMR and PLR were defined based on literature and ROC curve method. Progression free survival (PFS; primary outcome) and overall survival (OS) were calculated using log rank test. Uni and multivariate analysis were performed using cox-regression model. Results: Baseline characteristics: 83 pts with median age 65.5 years (range 21-90), 77% BRAFwt, 98% PS-ECOG 0-1, 51% LDH >ULN, 5% on steroids. Median NLR 2.7 (IQR 2.1-3.8), LMR 3.1 (2.1-4.3) and PLR 160.8 (98.3-216.4). The majority of pts (65%) were treated with pembrolizumab. With a median follow-up of 6.2 months (m), median PFS was 7.3 m (CI 5.5-9.2) and median OS was 15.9 m (13.4-18.4). In the multivariate model, baseline NLRhigh (≥3.0) and PLRhigh (≥180.0) were associated with worse PFS (HR 2.04, CI 1.11-3.77; p=0.02; and HR 2.50, CI 1.37-4.57; p=0.003). Baseline LMRhigh (≤2.1) was associated with worse PFS (HR 1.886, CI 1.019-3.488; p=0.043) only on the univariate analysis. At 6 w, 16 out of 39 pts with baseline NLRhigh presented a decrease in NLR. This was associated with better PFS (HR 0.24, CI 0.09-0.62; p=0.003). Inversely, an increase ≥20% in NLR or PLR was associated with progression (HR 3.65, CI 1.99-6.72, p < 0.001; and HR 3.99, CI 2.01-7.91, p < 0.001). Conclusions: Our data showed that NLR and PLR, as surrogates for systemic inflammation, might be used as prognostic biomarkers for melanoma patients treated with IO. Decreasing NLR in pts with previously high NLR, has a 76% risk reduction of progression. In clinically challenging situations, these biomarkers may help the clinician in an earlier therapeutic orientation.