Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

Incidence of childhood cancer in Latin America and the Caribbean: coverage, patterns, and time trends / Incidencia del cáncer infantil en América Latina y el Caribe: cobertura de los registros, patrones y tendencias a lo largo del tiempo / Incidência de câncer infantil na América Latina e no Caribe: cobertura, padrões e tendências temporais

ABSTRACT Objective. To provide a comprehensive overview of geographical patterns (2001-2010) and time trends (1993-2012) of cancer incidence in children aged 0-19 years in Latin America and the Caribbean (LAC) and interpret the findings in the context of global patterns. Methods. Geographical variations in 2001-2010 and incidence trends over 1993-2012 in the population of LAC younger than 20 years were described using the database of the third volume of the International Incidence of Childhood Cancer study containing comparable data. Age-specific incidence per million person-years (ASR) was calculated for population subgroups and age-standardized (WSR) using the world standard population. Results. Overall, 36 744 unique cases were included in this study. In 2001-2010 the overall WSR in age 0-14 years was 132.6. The most frequent were leukemia (WSR 48.7), central nervous system neoplasms (WSR 23.0), and lymphoma (WSR 16.6). The overall ASR in age group 15-19 years was 152.3 with lymphoma ranking first (ASR 30.2). Incidence was higher in males than in females, and higher in South America than in Central America and the Caribbean. Compared with global data LAC incidence was lower overall, except for leukemia and lymphoma at age 0-14 years and the other and unspecified tumors at any age. Overall incidence at age 0-19 years increased by 1.0% per year (95% CI [0.6, 1.3]) over 1993-2012. The included registries covered 16% of population aged 0-14 years and 10% of population aged 15-19 years. Conclusions. The observed patterns provide a baseline to assess the status and evolution of childhood cancer occurrence in the region. Extended and sustained support of cancer registration is required to improve representativeness and timeliness of data for childhood cancer control in LAC.

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RESUMO Objetivo. Apresentar uma visão abrangente dos padrões geográficos (2001 a 2010) e das tendências temporais (1993 a 2012) da incidência de câncer em crianças e jovens de 0 a 19 anos na América Latina e no Caribe (ALC) e interpretar os resultados no contexto de padrões mundiais. Métodos. Foram descritas variações geográficas de 2001 a 2010 e tendências de incidência de 1993 a 2012 na população com menos de 20 anos da ALC usando informações comparáveis da base de dados do terceiro volume do estudo International Incidence of Childhood Cancer. Foram calculadas taxas de incidência específica por idade por milhão de pessoas-ano (ASR, na sigla em inglês) para subgrupos populacionais e taxas padronizadas por idade usando a população padrão mundial (WSR, na sigla em inglês). Resultados. No total, foram incluídos 36 744 casos únicos. No período de 2001 a 2010, a WSR para todos os tumores combinados na faixa etária de 0 a 14 anos foi de 132,6. Os diagnósticos mais frequentes foram leucemia (WSR de 48,7), neoplasias do sistema nervoso central (WSR de 23,0) e linfoma (WSR de 16,6). A ASR para todos os tumores combinados na faixa etária de 15 a 19 anos foi de 152,3, e a maior taxa foi a de linfoma (ASR de 30,2). A incidência foi maior no sexo masculino do que no sexo feminino e maior na América do Sul do que na América Central e no Caribe. De modo geral, em comparação com as estimativas mundiais, a incidência na ALC foi menor, exceto para leucemia e linfoma entre 0 e 14 anos e para outros tumores e tumores não especificados em qualquer idade. A taxa de incidência na faixa etária de 0 a 19 anos aumentou em 1,0% ao ano (IC de 95% [0,6, 1,3]) entre 1993 e 2012. Os registros incluídos cobriam 16% da população de 0 a 14 anos e 10% da população de 15 a 19 anos. Conclusões. Os padrões observados servem de referência para avaliar o status e a evolução da ocorrência de câncer infantil na região. É necessário garantir um apoio ampliado e consistente aos registros de câncer para aprimorar a representatividade e a disponibilidade das informações em tempo adequado para o controle do câncer infantil na ALC.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Cost analysis of next-generation imaging in high-risk prostate cancer staging.

INTRODUCTION AND OBJECTIVE: Next-generation imaging (NGI) tests, such as choline PET/CT and PSMA PET, have shown to increase sensitivity in the detection of nodal and metastatic disease in prostate cancer. However, their use implies an increase in diagnostic costs compared to conventional imaging (CI) tests such as CT and bone scan. The aim of our study was to determine which diagnostic pathway is more cost-effective in high-risk prostate cancer. MATERIAL AND METHOD: Cost-effectiveness analysis of the available imaging tests (CI, Choline/PSMA PET) for the staging of high-risk prostate cancer. Sensitivity and specificity were estimated based on published evidence, and costs were collected from the Management Department. In order to carry out a cost-effectiveness analysis, five diagnostic pathways were proposed estimating the accurate diagnoses. RESULTS: PSMA PET was the most accurate diagnostic option. The CI diagnostic workup was the most economical and CI+PSMA the most expensive. Analyzing the diagnostic cost-effectiveness ratio, CI+PSMA proved to be the most expensive (€5627.30 per correct diagnosis) followed by PET PSMA (€4987.11), choline (€4599.84) and CI (€4444.22). CONCLUSIONS: PSMA PET is the most accurate strategy in staging distant disease in patients with high-risk prostate cancer. Radiotracer uptake tests such as CI have been shown to be the most cost-effective option, followed by choline and PSMA.

EXO1-mediated DNA repair by single-strand annealing is essential for BRCA1-deficient cells.

Deficiency for the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) leads to chromosomal instability and diseases such as cancer. Yet, defective HR also results in vulnerabilities that can be exploited for targeted therapy. Here, we identify such a vulnerability and show that BRCA1-deficient cells are dependent on the long-range end-resection factor EXO1 for survival. EXO1 loss results in DNA replication-induced lesions decorated by poly(ADP-ribose)-chains. In cells that lack both BRCA1 and EXO1, this is accompanied by unresolved DSBs due to impaired single-strand annealing (SSA), a DSB repair process that requires the activity of both proteins. In contrast, BRCA2-deficient cells have increased SSA, also in the absence of EXO1, and hence are not dependent on EXO1 for survival. In agreement with our mechanistic data, BRCA1-mutated tumours have elevated EXO1 expression and contain more genomic signatures of SSA compared to BRCA1-proficient tumours. Collectively, our data indicate that EXO1 is a promising novel target for treatment of BRCA1-deficient tumours.

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10-6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10-4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

Robot-assisted laparoscopic triple neurectomy for chronic inguinal pain: Description of the technique, our experience and preliminary results.

INTRODUCTION: Chronic inguinal pain or inguinodynia following hernioplasty is a relatively common complication that can be very incapacitating. Surgical treatment by triple neurectomy is a therapeutic option when previous treatments (oral/local therapy or neuromodulation) have failed. OBJECTIVE: Retrospective description of the surgical technique and results of laparoscopic and robot-assisted triple neurectomy for chronic inguinodynia. MATERIAL AND METHODS: We describe the inclusion/exclusion criteria as well as the surgical technique applied in 7 patients operated on at the University Health Care Complex of León (Urology Department) after failure of other treatment options. RESULTS: The patients presented chronic groin pain, reporting a preoperative pain VAS of 7.43 out of 10. After surgery, this score was reduced to 3.71 on the first postoperative day and to 4.2 points one year after surgery. Hospital discharge occurred 24 h after surgery with no relevant complications being reported. CONCLUSIONS: Laparoscopic or robot-assisted triple neurectomy is a safe, reproducible, and effective technique for the treatment of chronic groin pain refractory to other treatments.

Searching for a prognostic index in lupus nephritis.

BACKGROUND: Currently we do not have an ideal biomarker in lupus nephritis (LN) that should help us to identify those patients with SLE at risk of developing LN or to determine those patients at risk of renal progression. We aimed to evaluate the development of a prognostic index for LN, through the evaluation of clinical, analytical and histological factors used in a cohort of lupus. We have proposed to determine which factors, 6 months after the diagnosis of LN, could help us to define which patients will have a worse evolution of the disease and may be, more aggressive treatment and closer follow-up. METHODS: A retrospective study to identify prognostic factors was carried out. We have included patients over 18 years of age with a clinical diagnosis of systemic lupus erythematosus (SLE) and kidney involvement confirmed by biopsy, who are followed up in our centre during the last 20 years. A multi-step statistical approach will be used in order to obtain a limited set of parameters, optimally selected and weighted, that show a satisfactory ability to discriminate between patients with different levels of prognosis. RESULTS: We analysed 92 patients with LN, although only 73 have been able to be classified according to whether or not they have presented poor renal evolution. The age of onset (44 vs. 32; p = 0.024), the value of serum creatinine (1.41 vs. 1.04; p = 0.041), greater frequency of thrombocytopenia (30 vs. 7%; p = 0.038), higher score in the renal chronicity index (2.47 vs. 1.04; p = 0.015), proliferative histological type (100%) and higher frequency of interstitial fibrosis (67 vs. 32%; p = 0.017) and tubular atrophy (67 vs. 32%; p = 0.018) was observed between two groups. The multivariate analysis allowed us to select the best predictive model for poor outcome at 6 months based on different adjustment and discrimination parameters. CONCLUSION: We have developed a prognostic index of poor renal evolution in patients with LN that combines demographic, clinical, analytical and histopathological factors, easy to use in routine clinical practice and that could be an effective tool in the early detection and management.

Effect of hip hemiarthroplasty dislocation on mortality after hip fracture surgery. / [Artículo traducido] Efecto de la luxación de la prótesis parcial de cadera en la mortalidad tras la cirugía de fractura de cadera.

INTRODUCTION: Hip arthroplasty is the treatment of choice for displaced femoral neck fractures among the older population. The hip prosthesis dislocation is one of the most pointed potential complications after hip arthroplasty, but there is a lack of updated information on the effect of dislocation on the survival of older hip fracture patients so treated by hip hemiarthroplasty. We aim to evaluate the standalone effect of hip prosthesis dislocation after hip fracture hemiarthroplasty on patients' survival outcomes. MATERIALS AND METHODS: We conducted a retrospective multicenter study, including 6631 femoral neck fracture patients over 65 surgically treated by hemiarthroplasty. We made follow-up cut-offs 30-days, 6 weeks, 90-days, and one year after hospital discharge determining hip dislocation rate and patients' survival. RESULTS: The women population represented 78.7%, and the mean age of the population was 85.2 ± 6.7 years. Hip prosthesis dislocation incidence was 1.9% in the first 90-days after discharge, representing 91.54% of primary dislocations yearly noted. We reported statistically significant increased mortality rates of patients presenting at least one hip prosthesis dislocation event (from 16.0% to 24.6% at 90-day after discharge, and 29.5% to 44.7% at one year), and also significantly decreasing patient survival function at 90-day (P = .016) and one-year follow-up (P < .001). The recurrent dislocation events (26.15%) showed even higher mortality rates (up to 60.6%, p < .001). The multivariate Cox regression model determined that prosthesis dislocation was the only significant variable (P = .035) affecting patient survival, increasing the risk of dying before one year of follow-up by 2.7 times. DISCUSSION: Our study stands for the standalone hip prosthesis dislocation entailing a higher risk of death after hip fracture hemiarthroplasty in the older population.

Effect of hip hemiarthroplasty dislocation on mortality after hip fracture surgery.

INTRODUCTION: Hip arthroplasty is the treatment of choice for displaced femoral neck fractures among the older population. The hip prosthesis dislocation is one of the most pointed potential complications after hip arthroplasty, but there is a lack of updated information on the effect of dislocation on the survival of older hip fracture patients so treated by hip hemiarthroplasty. We aim to evaluate the standalone effect of hip prosthesis dislocation after hip fracture hemiarthroplasty on patients' survival outcomes. MATERIALS AND METHODS: We conducted a retrospective multicenter study, including 6631 femoral neck fracture patients over 65 surgically treated by hemiarthroplasty. We made follow-up cut-offs 30-days, 6 weeks, 90-days, and one year after hospital discharge determining hip dislocation rate and patients' survival. RESULTS: The women population represented 78.7%, and the mean age of the population was 85.2±6.7 years. Hip prosthesis dislocation incidence was 1.9% in the first 90-days after discharge, representing 91.54% of primary dislocations yearly noted. We reported statistically significant increased mortality rates of patients presenting at least one hip prosthesis dislocation event (from 16.0% to 24.6% at 90-day after discharge, and 29.5% to 44.7% at one year), and also significantly decreasing patient survival function at 90-day (p=0.016) and one-year follow-up (p<0.001). The recurrent dislocation events (26.15%) showed even higher mortality rates (up to 60.6%, p<0.001). The multivariate Cox regression model determined that prosthesis dislocation was the only significant variable (p=0.035) affecting patient survival, increasing the risk of dying before one year of follow-up by 2.7 times. DISCUSSION: Our study stands for the standalone hip prosthesis dislocation entailing a higher risk of death after hip fracture hemiarthroplasty in the older population.

Impact of BK Polyomavirus Plasma Viral Load in Kidney Transplant Outcomes.

BACKGROUND: BK polyomavirus infection (BKVi) is an important cause of kidney transplant (KT) loss, but there is scarce evidence on the impact of BK plasma viral load on graft function and long-term KT survival. METHODS: A retrospective cohort study including all KT recipients with BKVi (BK viremia identified in ≥3 consecutive samples by polymerase chain reaction) in our center from January 2010 to December 2020 was performed. A case-control study (1:2) was performed. We grouped the cases according to their highest peak viral load: low-level viremia (<10,000 copies/mL) and high-level viremia (≥10,000 copies/mL). To identify risk factors for BKVi, a logistic regression analysis was achieved, and a multivariable Cox regression was used to describe risk factors for graft loss. RESULTS: A total of 849 KTs were performed, and 67 presented BKVi (low-level viremia, n = 35 and high-level viremia, n = 26). In logistic regression analysis male sex (odds ratio [OR], 4.226; 95% CI, 1.660-10.758, P = .002), age (OR, 1.047; 95% CI, 1.008-1.088; P = .018), and retransplant (OR, 4.162; 95% CI, 1.018-17.015; P = .047) were predictors of BKVi. Acute rejection was more frequent in the BKVi group (18% vs 4.9%, P = .004), and graft survival was lower in patients with BKVi and high-level viremia (P = .027). In Cox regression analysis, BKVi (hazard ratio, 3.657; 95% CI, 1.146-11.670; P = .029) and specific BKV (BK polyomavirus) high-level viremia (hazard ratio, 1.988; 95% CI, 1.012-3.907; P = .046) were predictors of shorter graft survival. CONCLUSIONS: BKV high-level viremia was associated with BKV nephropathy and poorer graft survival. Additionally, acute rejection is more frequent after BKVi. It is necessary to develop strategies safe and effective for these patients.

Prevalence of aphthous stomatitis in patients with inflammatory bowel disease after the treatment with monoclonal antibodies: a systematic review and meta-analysis.

BACKGROUND: Currently, the most frequently employed therapies in the treatment of inflammatory bowel diseases (IBD), i.e., Crohn's Disease (CD), Ulcerative Colitis (UC) or unclassified IBD (IBD-U) are monoclonal anti-TNFs and anti-integrin therapies, such as vedolizumab (VDZ). Forty-seven per cent of these patients present extra-intestinal manifestations, the second most prevalent being aphthous stomatitis (AS). The present study aims to investigate which of the two therapies is associated with a lower prevalence of AS after treatment. MATERIAL AND METHODS: An electronic search of the MEDLINE (via PubMed), Web of Science, SCOPUS, LILACS and OpenGrey databases was carried out. The criteria used were those described by the PRISMA Statement. The search was not temporarily restricted and was updated to January 2022. The quality assessment was analyzed using the JBI Prevalence Critical Appraisal Tool. RESULTS: After searching, 7 studies were included that met the established criteria. Of these, 6 analysed the prevalence of AS in CD patients and 4 in UC. A total of 1,744 patients were analysed (CD=1,477 patients; 84.69%; UC=267; 15.31%). The greatest reduction in AS prevalence was observed after anti-TNF therapy. The effect of these therapies on the prevalence of AS in patients with IBD-U could not be determined. CONCLUSIONS: Both biologic therapies achieve a reduction in the prevalence of AS in IBD patients (CD and UC). However, the best results were obtained in patients treated with anti-TNFs, possibly because VDZ is often used in patients who do not respond adequately to previous treatment with anti-TNFs and because of its intestinal specificity.

[Translated article] Implementation of a rapid recovery protocol in total knee arthroplasty. A randomised controlled trial.

BACKGROUND: Rapid recovery (RP) in total knee arthroplasty may increase the functionality while reducing costs. The aim of this study is to prove the benefits of a rapid recovery programme compared to our classic protocol. PATIENTS AND METHODS: We performed a RCT (NCT03823573) in patients undergoing otal knee arthroplasty. Intervention group (RP protocol) received local infiltration of levo-bupivacaine in the periarticular tissue and supervized ambulation 4-6h after surgery. Control (C) group received a femoral nerve block with levo-bupivacaine, while a drain was used. Ambulation after its removal. All the patients completed an Oxford Knee Score prior to surgery and 6 months after discharge. An ecodoppler to assess the presence of deep vein thrombosis was made 1 month after discharge. Minimum follow-up was of 6 months. RESULTS: A total of 175 patients were included in the trial (92 patients in the control group, 83 patients in the RP group). There were no differences in sex, age, implanted prosthesis, haemoglobin drop, need for transfusion, range of motion on discharge (C: 82.6°, RP: 85°) and at the end of the follow-up (C: 105.1, RP: 106.6), Oxford knee score improvement (C: 17.5 points; RP: 19.3 points), patient satisfaction or re-admissions at the emergency department (C: 7.6%; RP: 10.8%). Significancy was found on time of ischaemia (C: 81.29min; RP: 85.35min; p=.03), need for morphine shots (C: 19.7%; RP: 38.6%; p=.007), hospital stay (C: 3.84 days; RP: 2.54 days, p<.0001) and time until ambulation (C: 2.46 days; RP: 0.23 days; p<.0001). CONCLUSION: Rapid recovery protocols can reduce hospital stay without increasing complications or need for re-admission.

Adoptive NK Cell Transfer as a Treatment in Colorectal Cancer Patients: Analyses of Tumour Cell Determinants Correlating With Efficacy In Vitro and In Vivo.

Background: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC. Methods: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity. Results: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA- CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control. Conclusions: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.

Implementation of a rapid recovery protocol in total knee arthroplasty. A randomized controlled trial. / Implantación de un protocolo de recuperación precoz en artroplastia total de rodilla. Ensayo clínico aleatorizado.

BACKGROUND: Rapid recovery (RP) in total knee arthroplasty may increase the functionality while reducing costs. The aim of this study is to prove the benefits of a rapid recovery program compared to our classic protocol. PATIENTS AND METHODS: We performed a RCT (NCT03823573) in patients undergoing otal knee arthroplasty. Intervention group (RP protocol) received local infiltration of levo-bupivacaine in the periarticular tissue and supervized ambulation 4-6h after surgery. Control (C) group received a femoral nerve block with levo-bupivacaine, while a drain was used. Ambulation after its removal. All the patients completed an Oxford Knee Score prior to surgery and 6 months after discharge. An ecodoppler to assess the presence of deep vein thrombosis was made one month after discharge. Minimum follow-up was of 6 months. RESULTS: A total of 175 patients were included in the trial (92 patients in the control group, 83 patients in the RP group). There were no differences in sex, age, implanted prosthesis, hemoglobin drop, need for transfusion, range of motion on discharge (C: 82.6°, RP: 85°) and at the end of the follow-up (C: 105.1, RP: 106.6), Oxford Knee Score improvement (C: 17.5 points; RP: 19.3 points), patient satisfaction or re-admissions at the emergency department (C: 7.6%; RP: 10.8%). Significancy was found on time of ischemia (C: 81.29min; RP: 85.35min; P=0.03), need for morphine shots (C: 19.7%; RP: 38.6%; P=0.007), hospital stay (C: 3.84 days; RP: 2.54 days, P<0.0001) and time until ambulation (C: 2.46 days; RP: 0.23 days; P<0.0001). CONCLUSION: Rapid recovery protocols can reduce hospital stay without increasing complications or need for re-admission.

POLRMT as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients.

Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of POLRMT (OR = 5.76, P = 2.23 × 10-5). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the risk allele had a decreased expression of POLRMT in heart tissue that may cause an impaired capacity to maintain a healthy mitochondrial population in cardiomyocytes under stressful conditions, as is treatment with epirubicin. This finding suggests a novel molecular mechanism involved in the development of AIC and may improve our ability to predict patients who are at risk.

Immune cells fold and damage fungal hyphae.

Innate immunity provides essential protection against life-threatening fungal infections. However, the outcomes of individual skirmishes between immune cells and fungal pathogens are not a foregone conclusion because some pathogens have evolved mechanisms to evade phagocytic recognition, engulfment, and killing. For example, Candida albicans can escape phagocytosis by activating cellular morphogenesis to form lengthy hyphae that are challenging to engulf. Through live imaging of C. albicans-macrophage interactions, we discovered that macrophages can counteract this by folding fungal hyphae. The folding of fungal hyphae is promoted by Dectin-1, ß2-integrin, VASP, actin-myosin polymerization, and cell motility. Folding facilitates the complete engulfment of long hyphae in some cases and it inhibits hyphal growth, presumably tipping the balance toward successful fungal clearance.

Genetically determined telomere length and multiple myeloma risk and outcome.

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10-6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.