Search

Background: Neoadjuvant treatment allows to better distinguish responders from non-responders, and to tailor post-neoadjuvant treatment according to tumor response in patients with HER2+ and triple-negative early breast cancer. For HR+/HER2- tumors, the pathologic complete response is less likely to occur, and residual disease is predictive of inferior recurrence-free or overall survival. Therefore, Ki-67 index, a prognostic biomarker in early breast cancer, is often used in clinical trials as an endpoint for evaluating response to neoadjuvant endocrine therapy (NET). In this systematic review and meta-analysis, we aim to assess if Ki-67 level after NET is associated with disease recurrence and/or survival. Methods: We conducted a systematic literature search of PubMed, Embase, CENTRAL, and conference proceedings (ASCO and ESMO annual meetings, ESMO Breast, and SABCS) up to June 28, 2022, to identify clinical trials or observational studies reporting Ki-67 index after NET in patients with HR+/HER2- early breast cancer treated with NET (PROSPERO number CRD42021282338). We excluded studies in which all patients received neoadjuvant chemotherapy, or from which separate data from patients receiving only NET was not retrieved. Here we report data from studies screened for the availability of the primary endpoint - recurrence-free survival (RFS), and the secondary endpoint - overall survival (OS), comparing patients with low Ki-67 versus high Ki-67 index after NET, as defined per each study. We performed a sensitivity analysis of the studies measuring the post-NET Ki-67 index in a pre-planned core biopsy. We used the Higgins I2 index to evaluate the heterogeneity between included studies, which did not reach statistical significance. Therefore, we used a fixed effects model to combine RFS and OS hazard ratios (HR) with 95% confidence intervals (CI). Results: We included 11 studies reporting data from 4,231 patients: nine clinical trials (n=3,926), one pooled analysis of two clinical trials (n=217), and one retrospective cohort study (n=88). Nine studies included only post-menopausal women (n=4,069), one included both post- and premenopausal women (n=88), and one included only premenopausal women (n=74). NET was aromatase inhibitor (AI) in four studies (n=3,359), tamoxifen or AI in four (n=465), tamoxifen in two (n=190), and one study with AI or fulvestrant (n=217). There were no studies with targeted agents combined with NET. No study restricted the use of adjuvant chemotherapy in high-risk patients. Three studies evaluated post-NET Ki-67 in a pre-planned core biopsy after a window of treatment of two to four weeks (n=3,348), while the other eight evaluated KI67 in the surgery specimen (n=883). The timing of post-NET evaluation ranged from 2 to 24 weeks. The median follow-up for RFS ranged between 37 and 95 months, and between 62 to 84 months for OS. We found a statistically significant association of adverse RFS (HR 2.43, 95% CI 1.99-2.98) and OS (2.66, 95% CI 1.65-4.28) with higher Ki-67 after NET. The sensitivity analysis of the three studies evaluating post-NET Ki-67 in a pre-planned core biopsy showed the same association with RFS (HR 2.41, 95% CI 1.77-3.30). These three studies did not report OS data. Conclusion: Our data reinforce the role of Ki-67 index after NET as a valuable biomarker of response or resistance to endocrine therapy in women with HR+/HER2- early breast cancer. Despite the use of adjuvant chemotherapy in most of the high-risk patients included in this analysis, the reduction of Ki-67 after NET is strongly associated with survival outcomes (RFS/OS), even after a short course of two to four weeks NET. Ki-67 index post-NET might be a useful tool to help tailoring the use of adjuvant chemotherapy in HR+/HER2-negative breast cancer patients, particularly in low-resource settings where the access to genomic assays is limited. Citation Format: Diogo Martins-Branco, Chiara Molinelli, Guilherme Nader Marta, Lieveke Ameye, Marianne Paesmans, Roberto Salgado, Philippe Aftimos, Evandro de Azambuja. Ki-67 index after neoadjuvant endocrine therapy as a prognostic biomarker in patients with HR+/HER2- early breast cancer: a systematic review and meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-07-01.

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/., Introduction: Cancer care providers have faced many challenges in delivering safe care for patients during the COVID-19 pandemic. This cross-sectional survey-based study investigated the impact of the pandemic on clinical practices of Portuguese medical oncologists caring for patients with breast cancer. Methods: An anonymous online survey comprising 42 questions gathered information regarding COVID-19 testing, treatment in (neo)adjuvant and metastatic settings, and other aspects of breast cancer management. Practices before and during the pandemic were compared, and potential differences in outcomes according to respondents' regions, case volumes, and practice type were explored. Results: Of 129 respondents, 108 worked in the public health system, giving a representative national picture of the impact of the COVID-19 pandemic on breast cancer management. Seventy-one percent of respondents reported a reduction in visits for new cases of breast cancer, and there was a shift towards increased use of telemedicine. Clinical decision-making was largely unaffected in the most aggressive indications (i.e., triple-negative, HER2-positive, visceral crisis). The use of neoadjuvant therapy increased when access to surgery was difficult, whereas dose-dense regimens decreased, and cyclin-dependent kinase 4/6 inhibitor treatment decreased for less aggressive disease and increased for more aggressive disease. The use of oral formulations and metronomic chemotherapy regimens increased, and clinical trial participation decreased. Some differences by respondents' region and case volume were noted. Conclusion: Medical oncologists in Portugal implemented many changes during the COVID-19 pandemic, most of which were logical and reasonable responses to the current healthcare emergency; however, the true impact on patient outcomes remains unknown.

Background: The erythropoietin (EPO) receptor activation can stimulate tumor proliferation and may be implicated in resistance to anti-HER2 therapies. EPO administration can be used for the management of chemotherapy-induced anemia. We aim to assess if EPO intake during the adjuvant anti-HER2 treatment impacts the outcomes of HER2-positive early breast cancer (EBC) patients. Methods: For this post hoc analysis of the ALTTO trial (NCT00490139), we categorized two cohorts according to the use of EPO during adjuvant anti-HER2 treatment: i) at least one EPO dose (EPO-cohort) vs ii) no EPO (non-EPO-cohort). We compared their baseline characteristics to identify potential confounders. The primary endpoint disease-free-survival (DFS), and the secondary endpoint overall survival (OS) were compared between these two cohorts, with subgroup analysis according to menopausal status, tumor characteristics, and anti-HER2 treatment. Kaplan Meier method, log-rank test, and Cox regression model adjusted for confounders were performed for DFS and OS (removal criterion p2 cm (56.9%), positive nodal status (58.5%), positive hormone receptor (HR) status (61.8%), and poorly differentiated or undifferentiated histologic grade (64.2%). Baseline characteristics were similar in both cohorts, except for the timing of chemotherapy, for which 93.5% of patients from the EPO-cohort were enrolled in the concurrent designs (2/2B) vs 44.2% in the non-EPO-cohort (p Citation Format: Diogo Martins-Branco, Marie Kassapian, Véronique Debien, Rafael Caparica, Daniel Eiger, Urania Dafni, Charitini Andriakopoulou, Sarra El-Abed, Miguel Izquierdo, Malou Vicente, Saranya Chumsri, Martine Piccart-Gebhart, Alvaro Moreno-Aspitia, Ann Søegaard Knop, Janine Lombard, Evandro de Azambuja. The impact of erythropoietin administration concomitantly with adjuvant anti-HER2 treatment on the patients’ outcome: Sub-analysis of the ALTTO study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-14-05.

BACKGROUND: Brain metastases (BM) occur in up to 50% of patients (pts) with HER2+ metastatic breast cancer (MBC) and are associated with high morbidity and mortality. While the treatment outcomes of patients (pts) without BM are largely determined by their extra-cranial activity, the outcomes of pts with BM are also influenced by the treatment’s activity in the central nervous system (CNS). TKI-based regimens, have been incorporated into the management of pts with HER2+ MBC. This systematic review aims to assess the clinical outcomes of in pts with or without BM treated with TKI-containing regimens vs those treated with non-TKI-containing regimens. METHODS: A systematic literature search of PubMed, Embase, CENTRAL, and conference proceedings (ASCO, SABCS, ESMO, and ESMO Breast) up to June 20, 2021, was conducted to identify randomized clinical trials (RCT) comparing systemic therapies with anti-HER2 TKI-containing regimens and non-TKI-regimens in pts with HER2+ MBC (PROSPERO ID: CRD42021252332). Studies were screened for the availability of data on progression-free survival (PFS) and overall survival (OS) in subgroups of pts with and without BM at baseline. A random-effect model was used to calculate PFS and OS, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). The Higgins I2 index was used to evaluate the heterogeneity between studies. To assess whether the pooled HRs estimates were stable or strongly dependent on one or few studies, sensitivity analyses were conducted by interactively recalculating the pooled HRs estimates after exclusion of each single study. RESULTS: Of 1,671 identified records, 5 RCT were included involving 2,437 pts (490 with and 1,947 without BM at baseline). Intervention arms included tucatinib, lapatinib, pyrotinib or afatinib in combination with cytotoxic chemotherapy ± trastuzumab; control arms included cytotoxic chemotherapy ± trastuzumab or T-DM1. No trial evaluating neratinib met inclusion criteria. All trials allowed the inclusion of pts with stable and asymptomatic BM, while one (HER2CLIMB) also included pts with progressing/untreated BM. Previous treatment with trastuzumab was reported in 92.8% (n=2,262) of the pts. Regarding PFS, a non-statistically significant trend favoring TKI-containing regimens was observed both in pts with BM (HR 0.67, 95% CI 0.41-1.12, p=0.13) and without BM (HR 0.55, 95% CI 0.24-1.26, p=0.16). Substantial heterogeneity was detected in both subgroups (I2 = 64.4%, p=0.024 and I2 = 95.6%, p 0.001, respectively). Sensitivity analysis, excluding each study one by one, demonstrated a significant PFS benefit favoring TKI-containing regimens in pts with BM after the exclusion from the analysis of afatinib (Lux-Breast1), a non-HER2-specific TKI (HR 0.56, 95% CI 0.35-0.90, p=0.016), with no significant heterogeneity (I2 = 46.9%, p=0.13). Regarding OS, a non-statistically significant trend favoring non-TKI regimens was observed both in pts with BM (HR 1.28, 95% CI 0.48-3.40, p=0.62) and without BM (HR 1.02, 95% CI 0.53-1.98, p=0.94). Substantial heterogeneity was detected in both subgroups (I2 = 86.8%, p=0.001 and I2 = 85.7%, p=0.008, respectively). Sensitivity analysis showed no significant impact on OS after exclusion of each study one by one. No publication bias was detected by Egger’s test. CONCLUSION: Our results suggest a similar magnitude of OS and PFS benefit from anti-HER2 TKI-containing regimens in pts with or without BM. Sensitivity analysis including only trials that evaluated regimens containing tucatinib, lapatinib or pyrotinib demonstrated a significant PFS benefit favoring TKI-containing regimens in pts with BM, emphasizing the relevance of CNS involvement for the interpretation of the results of studies evaluating this class of agents. Citation Format: Guilherme Nader-Marta, Diogo Martins-Branco, Elisa Agostinetto, Marco Bruzzone, Marcello Ceppi, Matteo Lambertini, Nuria Kotecki, Ahmad Awada, Evandro de Azambuja. Efficacy of tyrosine kinase inhibitors (TKI) in the treatment of patients with HER2-positive (HER2+) breast cancer with or without brain metastases: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-03.

Purpose: This systematic review and meta-analysis aimed to evaluate the immune response to anti- SARS-CoV-2 prime-vaccination in patients with cancer. Methods: We performed a systematic literature search using PubMed, Embase, and Cochrane Library until 28/09/2021, and conference proceedings from ASCO and ESMO 2021 annual meetings. We screened for observational or interventional studies including subjects ≥ 16 years old with cancer diagnosis who were vaccinated against SARS-CoV-2. Prime-vaccination was defined as one dose of Ad26.COV2-S vaccine or two doses of BNT162b2, mRNA-1273, ChAdOx1-S or inactivated SARS-CoV-2 vaccine. The outcomes were humoral and adaptive immune responses (proportion of subjects with positive titers of antibody anti-SARS-CoV-2 spike protein and anti-SARS-CoV-2 cellular responses, respectively). Results: We included 89 records reporting data from 30, 183 subjects. The overall seropositive rate within the first month after complete anti- SARS-CoV-2 prime-vaccination was 80% [95% confidence interval (CI), 72-86%], 60% (95%CI, 53- 67%) in patients with hematological malignancies (HM) versus 94% (95%CI, 88-97%) in patients with solid malignancies (SM). The diagnosis of HM was significantly associated with a lower seropositive rate on multivariate meta-regression (odds ratio 0.35, 95% CI 0.18-0.69, HM versus both, p = 0.002). The overall humoral response was 49% (95% CI, 42-56%) after incomplete prime-vaccination and 79% (95% CI, 70-86%) at 2 months after complete prime-vaccination. These responses were also lower in patients with HM at these time points. The overall cellular response rate at any time after vaccination was 61% (95% CI, 44-76%). Conclusion: This meta-analysis provides compelling evidence of humoral and adaptive immune responses against SARS-CoV-2 in patients with cancer, which last for at least 2 months following complete prime-vaccination.

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. ispartof: ONCOLOGY AND THERAPY vol:9 issue:2 pages:255-265 ispartof: location:New Zealand status: published

1543 Background: Patients (pts) with cancer have increased mortality from COVID-19 and their vaccination is crucial to prevent severe infection. We aimed to identify demographic and laboratory determinants of humoral immune responses to COVID-19 vaccination in pts with cancer and investigate differences in responses based on the vaccine platform. Methods: We searched for records in PubMed, Embase, and CENTRAL up to 28/09/21, as well as conference proceedings from ASCO and ESMO 2021. We included studies of pts ≥16 yr with a cancer diagnosis, who were vaccinated against SARS-CoV-2. Studies were excluded if ≥10% of the participants had other causes of immunosuppression or baseline anti-SARS-CoV-2 spike protein antibodies (Ab)/previous COVID-19 (PROSPERO ID: CRD42021282338). For this subgroup analysis of studies that reported a proportion of pts with cancer and positive Ab titers at any timepoint following complete vaccination, a random-effects model was used to estimate the humoral response rate (HRR) with 95% confidence intervals (CI). Results: We included 64 records, reporting data from 10,511 cancer pts. The HRR in the overall population and by subgroup are shown in Table. Elder patients with hematologic cancers (59%, CI 47-70%, N = 667) and patients with lymphopenia (50%, CI 25-75%, N = 111) or hypogammaglobulinemia (36%, CI 19-57%, N=226) were the subgroups with lower HRR. Male (77%, CI 69-84%, N = 2,659) and Asian (84%, CI 54-96%, N = 37) pts showed a trend to lower HRR when compared with females and other races, respectively. Pts vaccinated with mRNA vaccine platforms (79%, CI 74-83%, N = 9,404) had numerically higher HRR than those receiving the adenovirus vaccines (28%, CI 19-40%, N = 74). Conclusions: This study highlights demographic and laboratory determinants of weaker immune responses to SARS-CoV-2 vaccination, permitting better identification of more vulnerable pts. Despite the small number of pts included receiving adenovirus vaccines, these data also suggest prioritizing mRNA platform vaccination in pts with cancer. [Table: see text]

1537 Background: Patients (pts) with cancer are at increased risk of severe COVID-19. Both underlying malignancy and anti-cancer treatments influence the immune system, potentially impacting the level of vaccine protection achieved. Methods: A systematic literature search of PubMed, Embase, CENTRAL and conference proceedings (ASCO annual meetings and ESMO congress) up to 28/09/21, was conducted to identify studies reporting anti-SARS-CoV-2 spike protein immunoglobulin G seroconversion rates (SR) at any time point after complete COVID-19 immunization (mRNA- or adenoviral-based vaccines) in cancer pts. Complete immunization was defined as 1 dose of JNJ-78436735 vaccine or 2 doses of BNT162b2, mRNA-1273 or ChAdOx1 nCoV-19 vaccines. Subgroup analyses were performed to examine the impact of cancer diagnosis, disease stage, and anticancer therapies on the SR. Overall effects were pooled using random-effects models and reported as pooled SR with 95% confidence intervals (CI). Results: Of 1,548 identified records, 64 studies were included in this analysis reporting data from 10,511 subjects. The Table shows the SR in the overall population and specific subgroups. In pts with solid malignancies (SM), disease stage and primary site did not significantly impact the SR. In pts with hematologic malignancies (HM), SR were significantly lower in pts with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) compared to acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), and multiple myeloma (MM). Concerning the impact of cancer therapies on SR, pts with SM undergoing chemotherapy had numerically lower SR (N = 1,234, SR 87%, CI 81-92) compared to those treated with immune checkpoint inhibitors (N = 574, SR 94%, CI 88-97) or endocrine therapy (N = 326, SR 94%, CI 86-97) with or without another targeted therapy. Pts with HM treated with anti-CD20 therapy (within the last 12 months: N = 360, SR 7%, CI 2-20; or more than 12m: N = 175, SR 59%, CI 35-80), immune-modulating agents (BTK or BCL2 inhibitors) (N = 462, SR 47%, CI 32-64%) or other immunotherapies (anti-CD19/CART or anti-CD38) (N = 293, SR 37%, CI 23-53) had lower SR compared to pts treated with autologous (N = 353, SR 77%, CI 67-85) or allogenic stem cell transplantation (N = 509, SR 77%, CI 68-84). Conclusions: SR varies between cancer types and anticancer therapies with some cancer pts having low protection against COVID-19 even after complete vaccination. [Table: see text]

Background Immune checkpoint inhibitors (ICI) have changed the paradigm of advanced malignant melanoma (MM). Several prognostic factors, mostly linked to inflammation, have been under scope to better select patients for such therapies. We aimed to build and apply a prognostic score in this setting. Methods Baseline characteristics and outcomes on 147 patients with advanced MM treated with an anti-PD1 (nivolumab or pembrolizumab) in monotherapy, between Jan-2016 and Oct-2019, in the 1st, 2nd or 3rd line setting were collected from two centres in Portugal. Data cut-off for follow-up was May-2020. Cox proportional hazards regression was used to identify independent prognostic factors for OS. Results With a median FU of 28.93 months (95% CI [22.52–33.54]), mOS for the whole cohort was 14.75 months (95% CI, [10.80–18.71]). Overall, 43 and 104 patients were treated with nivolumab and pembrolizumab, respectively. We identified four adverse prognostic factors that were independent predictors of bad prognosis: number of metastatic sites >2 (p 2x upper limit of normal) (p Conclusions Using easily accessible parameters from our daily practice, we propose the MELImmune prognostic score for advanced MM patients treated with anti-PD1 in monotherapy that could be incorporated to the daily clinical practice and clinical trials. We further aim to validate this score in an independent larger sample. Ethics Approval The study was approved by both institutions’ Ethics Committee.

Context: Patients with chronic obstructive pulmonary disease (COPD) and lung cancer report several symptoms at the end of life and may share palliative care needs. However, these disease groups have distinct health care use. Objectives: To compare the frequency and length of hospitalizations during the last month of life between patients with COPD and lung cancer, assessing the main characteristics associated with these outcomes. Methods: Data were retrieved from the Portuguese Hospital Morbidity Database. Deceased patients in a public hospital from mainland Portugal (2010-2015), with COPD as the main diagnosis of the last hospitalization (n = 2942) were sex and age matched (1:1) with patients with lung cancer. The association of patients' main diagnosis, and individual, hospital and area of residence characteristics, on frequency (>1) and length (>14 days) of end-of-life hospitalizations were quantified through adjusted odds ratio (OR) and respective 95% confidence intervals (CIs). Results: Hospitalizations for >14 days during the last month of life were more likely for lung cancer patients than COPD patients (OR = 1.12; 95% CI = 1.00-1.25). Among patients with COPD, male sex (OR = 1.50; 95% CI = 1.25-1.80) and death in a large hospital (OR = 1.82; 95% CI = 1.41-2.35) were positively associated with longer hospitalizations; the occurrence of >1 hospitalization and hospitalizations for >14 days were less likely among those from rural areas (OR = 0.72, 95% CI = 0.55-0.94; OR = 0.67, 95% CI = 0.54-0.83, respectively). In patients with lung cancer, male sex was negatively associated with longer hospitalizations (OR = 0.82; 95% CI = 0.69-0.98). Conclusion: At the end of life, patients with lung cancer had longer hospitalizations than patients with COPD, and the main characteristics associated with the frequency and length of hospitalizations differed according to the patients' main diagnosis. This study was funded by national funding from the Foundation for Science and Technology, under the Unidade de Investigação em Epidemiologia do Instituto de Saúde Pública da Universidade do Porto (EPIUnit, info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/04750/2020/PT). An individual PhD grant attributed to A. R. C. (SFRH/BD/102181/2014) was funded by Foundation for Science and Technology and the Programa Operacional Capital Humano. This work was also supported by the Fundação Calouste Gulbenkian as part of the DINAMO Project (grant number: 127988 to B. G.) and the Núcleo Regional do Sul da Liga Portuguesa Contra o Cancro (43/2015 and 35/2016 to D. M. B.).

Insulinomas are a rare type of pancreatic neuroendocrine tumours characterized by insulin hypersecretion. They are considered malignant when metastases are present. Traditional therapies often promote only temporarily symptomatic relief and may be associated with severe adverse effects. There is scarce experience in treating malignant insulinomas with peptide receptors radionuclide therapy (PRRNT). We describe PRRNT results in four patients with inoperable malignant insulinomas with poorly controllable hypoglycaemia. All patients received therapy with 177Lu-DOTA-TATE after conventional therapies failed in controlling disease progression and symptoms. The activity administered per cycle was 4.8–7.4 GBq. The interval between cycles was 10–16 weeks. Haematology, liver and kidney function tests were performed before treatment initiation and 5 and 10 weeks after each cycle. Patient 1 presented significant clinical benefit for 13 months after PRRNT, with imaging improvement. Patient 2 obtained reduction of the number and severity of hypoglycaemic episodes during 15 months after therapy. Patient 3 is asymptomatic since PRRNT first cycle performed 23 months ago and revealed significant imaging improvement. Patient 4 had resolution of hypoglycaemia only 3 days after PRRNT first cycle and today, 16 months after therapy, the disease seems to be in remission and the patient maintains euglycaemic state. PRRNT was well tolerated, with only hematologic grade 2 toxicity in patient 1 and mild kidney toxicity in patient 3. After the start of 177Lu-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.

Background: Communication is present in all encounters in care and of importance to create a caring relation. A good relation between patients, next of kin and health care staff is crucial, not lea ...

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.

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's 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 patient population we evaluated the aSN levels in the 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 downregulation 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 oligomer 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 a ubiquitin-dependent clearance insufficiency with the 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.

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.

68 Background: There is growing concern about the aggressiveness of cancer care at the end of life (ACCEoL). Recognizing the most affected patients is a cornerstone to improve this public health unmet need. Our aim is to identify factors associated with ACCEoL for cancer patients dying in hospitals. Methods: Cohort study of adults with ICD9CM diagnosis of cancer, who died in public hospitals in mainland Portugal (Jan'10 - Dec'15), identified from the hospital morbidity database (HMD). HMD provided individual clinical and demographic data. The primary outcome is a composite ACCEoL measure of 16 indicators, expanding an earlier framework, validated by an expert panel. We obtained hospital and area-level variables from a hospital survey and National Statistics. We used multilevel random effects logistic regression modelling (p < 0.05). Results: We included 92,155 patients: median age 73 yo; 61.9% male; 53.0% metastatic. ACCEoL prevalence was 71.1%. The most prevalent indicators were > 14 days in hospital (42.7%) and surgery in last 30 days (27.8%). Older age (p < 0.001), breast cancer (OR 0.83; 95%CI 0.76-0.91) and metastatic disease (0.54; 0.50-0.58) were associated with less ACCEoL. In contrast, higher Deyo-Charlson comorbidity index (p < 0.001), gastrointestinal (GI) and hematological malignancies (p < 0.001), and death at a cancer center (1.31; 1.01-1.72) or hospital with medical oncology (MO) dept. (1.29; 1.02-1.63) were associated with higher ACCEoL. There was no association between existence of hospital palliative care services (HPCS) at the hospital of death and ACCEoL. Conclusions: Our study confirmed that clinical factors related with better understanding of disease course are associated with ACCEoL reduction. Patients with more comorbidities and GI malignancies might represent groups with complex needs, and hematological patients may be at increased risk because of unpredictable prognosis. It is important to better understand how to reduce ACCEoL in cancer centers and hospitals with MO dept.; improvement of HPCS could be an answer as these services are usually under-resourced, thus reaching few.

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.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, often diagnosed at an advanced stage when the most potentially curative strategies are no longer effective. Advances in the understanding of tumor biology are opening new paths for the prevention and treatment of HCC, through the development of new targeted therapies. The design of drugs that block different growth-promoting pathways, activate apoptotic pathways may also open new horizons in the treatment of HCC. The aim of this study was to test the efficacy of new targeted drugs involved in signalling pathways, such as farnesiltransferase (L-744832) and mTOR inhibitors (everolimus) in a HCC cell line (HUH-7 cells). The HUH-7 cells were cultured in absence and presence of different concentrations of L-744832 and everolimus. The antiproliferative effect was assessed by the Alamar Blue assay and cell death by optic microscopy and flow cytometry. Our results showed that farnesiltransferase and mTOR inhibitors had an antiproliferative and cytotoxic effects in monotherapy in a dose and time dependent manner, inducing cell death preferentially by apoptosis. On, the other hand, the combination of L-744832 and everolimus with conventional anticarcinogenic drugs demonstrated a higher antiproliferative and cytotoxic effect for lower doses than the IC50 used in monotherapy (addition or potentiation synergism). These results suggested that farnesiltransferase and mTOR inhibitors may constitute a new potential therapeutic approach in HCC either in monotherapy or in association with conventional therapies.