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Rhabdoid meningiomas (RM) shows heterogeneous histological findings, and a wide variety of chromosomal copy number alterations (CNA) are associated with an unpredictable course of the disease. In this study, we analyzed a series of 305 RM samples from patients previously reported in the literature and 33 samples from 23 patients studied in our laboratory. Monosomy 22-involving the minimal but most common recurrent region loss of the 22q11.23 chromosomal region was the most observed chromosomal alteration, followed by losses of chromosomes 14, 1, 6, and 19, polysomies of chromosomes 17, 1q, and 20, and gains of 13q14.2, 10p13, and 21q21.2 chromosomal regions. Based on their CNA profile, RM could be classified into two genetic subgroups with distinct clinicopathologic features characterized by the presence of (1) chromosomal losses only and (2) combined losses and gains of several chromosomes. The latter displays a higher frequency of WHO grade 3 tumors and poorer clinical outcomes. This research was funded by Consejería de Sanidad JCYL, Gerencia Regional de Salud, Spain grant numbers GRS 2132/A/20 and GRS 2315/A/21 and Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain grant number CIBERONC CB16/12/00400.

OBJECTIVE To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first-line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti-VEGFR therapy in mRCC. PATIENTS AND METHODS SUNRISES, a randomised open-label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment-naive patients with clear-cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression-free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety. RESULTS Accrual was low due to the advent of new-generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1-year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm. CONCLUSIONS The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.

Bladder cancer; Muscle-invasive; Urothelial Cáncer de vejiga; Invasivo muscular; Urotelial Càncer de bufeta; Invasió muscular; Urotelial Most muscle-invasive bladder cancer (BC) are urothelial carcinomas (UC) of transitional origin, although histological variants of UC have been recognized. Smoking is the most important risk factor in developed countries, and the basis for prevention. UC harbors high number of genomic aberrations that make possible targeted therapies. Based on molecular features, a consensus classification identified six different MIBC subtypes. Hematuria and irritative bladder symptoms, CT scan, cystoscopy and transurethral resection are the basis for diagnosis. Radical cystectomy with pelvic lymphadenectomy is the standard approach for muscle-invasive BC, although bladder preservation is an option for selected patients who wish to avoid or cannot tolerate surgery. Perioperative cisplatin-based neoadjuvant chemotherapy is recommended for cT2-4aN0M0 tumors, or as adjuvant in patients with pT3/4 and or pN + after radical cystectomy. Follow-up is particularly important after the availability of new salvage therapies. It should be individualized and adapted to the risk of recurrence. Cisplatin–gemcitabine is considered the standard first line for metastatic tumors. Carboplatin should replace cisplatin in cisplatin-ineligible patients. According to the EMA label, pembrolizumab or atezolizumab could be an option in cisplatin-ineligible patients with high PD-L1 expression. For patients whose disease respond or did not progress after first-line platinum chemotherapy, maintenance with avelumab prolongs survival with respect to the best supportive care. Pembrolizumab also increases survival versus vinflunine or taxanes in patients with progression after chemotherapy who have not received avelumab, as well as enfortumab vedotin in those progressing to first-line chemotherapy followed by an antiPDL1/PD1. Erdafitinib may be considered in this setting in patients with FGFR alterations. An early onset of supportive and palliative care is always strongly recommended.

Protein misfolding diseases refer to a variety of disorders that develop as a consequence of the misfolding of proteins in various organs. The etiologies of Parkinson’s and Alzheimer’s disease remain unclear, but it seems that type two diabetes and other prediabetic states could contribute to the appearance of the sporadic forms of these diseases. In addition to amylin deposition, other amyloidogenic proteins implicated in the pathophysiology of neurodegenerative diseases could have important roles in the pathogenesis of this disease. As we have previously demonstrated the presence of α-synuclein deposits in the pancreas of patients with synucleinopathies, as well as tau and Aβ deposits in the pancreatic tissue of Alzheimer’s disease patients, we studied the immunoreactivity of amylin, tau and α-synuclein in the pancreas of 138 subjects with neurodegenerative diseases or type two diabetes and assessed whether the pancreatic β-cells of these subjects present cooccurrence of misfolded proteins. Furthermore, we also assessed the pancreatic expression of prion protein (PrP) in these subjects and its interaction, both in the pancreas and brain, with α-synuclein, tau, Aβ and amylin. Our study shows, for the first time, that along with amylin, pancreatic α-synuclein, Aβ, PrP and tau may contribute together to the complex pathophysiology of type two diabetes and in the appearance of insulin resistance in Alzheimer’s and Parkinson’s disease. Furthermore, we show that the same mixed pathologies that are observed in the brains of patients with neurodegenerative diseases are also present outside the nervous system. Finally, we provide the first histological evidence of an interaction between PrP and Aβ, α-synuclein, amylin or tau in the pancreas and locus coeruleus. These findings will shed more light on the common pathological pathways shared by neurodegenerative diseases and type two diabetes, benefiting the exploration of common therapeutic strategies to prevent or treat these devastating amyloid diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01171-0.

Objective To assess the antibody response in non-immunocompromised adults after two doses of BNT162b2. Methods Prospective, single-centre observational study in non-immunocompromised adults aged 18 years or more who received two doses of BNT162b2. The study contemplates analyses of serum samples collected 1.5, 3, 6, 9 and 12 months after the second dose of BNT162b2; results of the 1.5- and 3-month time-points are presented in this report. Antibodies against the receptor binding domain of the S1 subunit of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (anti-RBD antibodies) were measured using a commercial quantitative immunoassay. A threshold of 4160 AU/mL (corresponding to an ID50 of 1:250) was used as surrogate marker for serum neutralizing activity. Results Of 273 hospital workers who received two doses of BNT162b2, 260 (95%) agreed to participate in the study; 2/260 (0.8%) were excluded because of immunocompromised conditions. At the time of this report, 230/258 (89%) participants (mean age 46.0 years (SD 11.4 years); 143/230 (62%) female; 87/230 (38%) male) had completed 3 months of follow up after the second dose of BNT162b2. Thirty-six (16%) of the 230 had documented mild SARS-CoV-2 infection before receiving the first dose of BNT162b2. Median (interquartile range (IQR)) anti-RBD titres 1.5 months after vaccination were 9356 (5844–16 876) AU/mL; 3 months after vaccination, median anti-RBD titres had declined to 3952 (2190–8561) AU/mL (p < 0.001). Of 199/230 (86.5%) participants who had anti-RBD titres above 4160 AU/mL 1.5 months after the second dose of BNT162b2, only 95/230 (41%) maintained anti-RBD titres above this level 3 months after vaccination (p < 0.001). Conclusions The decline of anti-RBD antibodies 3 months after the second dose of BNT162b2 is of concern because it raises the possibility of a short-lived humoral immunity after vaccination. Booster doses of BNT162b2 might be required to maintain high titres of anti-RBD antibodies over time. pre-print 161 KB

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Aim To delineate the neurogenetic profiles of brain degeneration patterns in myotonic dystrophy type I (DM1). Methods In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (NDs) were intersected to large-scale transcriptome maps provided by the Allen Human Brain Atlas (AHBA). For validation, neuropathological and RNA analyses were performed in a small series of DM1 brain samples. Results Twofold: (1) From a list of preselected hypothesis-driven genes, confirmatory analyses found that three genes play a major role in brain degeneration: dystrophin (DMD), alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Neuropathological analyses confirmed a highly heterogeneous Tau-pathology in DM1, different to the one in Alzheimer's disease. (2) Exploratory analyses revealed gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. RNA analyses confirmed synaptic vesicle dysfunction. Conclusions The combination of large-scale transcriptome interactions with brain imaging and cognitive function sheds light on the neurobiological mechanisms of brain degeneration in DM1 that might help define future therapeutic strategies and research into this condition. We wish to thank Prof. Virginia Arechavala for providing us with an updated list of relevant genes in DM1, some of which were considered in our study. J.M.C. is funded by Ikerbasque: The Basque Foundation for Science and from the Ministerio de Economia, Industria y Competitividad (Spain) and FEDER (grant DPI2016-79874-R), and from the Department of Economic and Infrastructure Development of the Basque Country (Elkartek Program, KK-2018/00032 and KK-2018/00090). A.L. d. M. was founded by the Institute of Health Carlos III co-founded by Fondo Europeo de Desarrollo Regional-FEDER (grant PI17/01841), CIBERNED (grant 609), and La Caixa Foundation (grant HR17-00268). A. S. was founded by the Institute of Health Carlos III co-founded by Fondo Europeo de Desarrollo Regional-FEDER (grant PI17/01231), and the Basque Government (grant SAIO08-PE08BF01). A. J.M was partially funded by Euskampus Fundazioa and a predoctoral grant from the Basque Government (PRE_2019_1_ 0070). G.L. was founded by a predoctoral grant from the Basque Government (PRE_2016_1_0187). I.F. was founded from `la Caixa' Foundation under the agreement LCF/PR/HR19/52160007 and was also supported by the Ministry of Economy and Competiveness, Institute of Health Carlos III (co-funded by European Regional Development Fund, ERDF, a way to build Europe): FIS PI17/000809.

To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first-line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti-VEGFR therapy in mRCC.SUNRISES, a randomised open-label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment-naïve patients with clear-cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression-free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety.Accrual was low due to the advent of new-generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1-year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm.The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.

Aim Cabazitaxel (CBZ), a novel tubulin-binding taxane, improves overall survival in metastatic castration-resistant prostate cancer (mCRPC) that progresses during or after docetaxel treatment. We have designed a phase II study to evaluate the efficacy and safety of CBZ as a weekly schedule for ‘unfit’ mCRPC patients after docetaxel failure. Methods In this single arm phase II study. CBZ was weekly administered in 1-hour infusion on days 1, 8, 15 and 22, every 5 weeks at 10 mg/m2 to eligible ‘unfit’ patients; oral prednisone (5 mg) was administered twice a day. Circulating tumour cells (CTCs) were also collected. New treatment scheme was considered effective if at least 65% of patients met a clinical benefit criteria based on prostate-specific antigen (PSA)-progression-free survival (PFS) values at week 12. Results Seventy patients (median age: 73.9 years) were enrolled; overall, 71.4% had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2; and 84%, 16% and 11% had bone, liver and lung metastases, respectively. Objective partial response or stable disease was achieved in 61% of patients, while PSA responses of ≥50% and ≥80% were observed in 34.8% and 10.6%, respectively. The median PSA-PFS was 4.8 months; and 68.6% of patients had no progression at week 12. The most frequent grade 3/4 toxicities were neutropenia (2.8%), leukopenia (5.7%) and thrombocytopaenia (9%); no cases of febrile neutropenia were reported. Early CTC response was significantly correlated with PSA-PFS. Conclusions CBZ/prednisone administered weekly to ‘unfit’ mCRPC patients appears to be as effective as classical standard 3-week scheme (TROPIC study) but with significantly lower toxicities and better tolerance. Early CTC response appears to be valuable as an early end-point of therapeutic efficacy.

BACKGROUND Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer's disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity. OBJECTIVE To analyze HPSE and HPSE2 expressions at different stages of AD. METHODS RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain. RESULTS Both proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well. CONCLUSION Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative.

espanolEl Laberinto Hebb-Williams es una prueba utilizada para evaluar el aprendizaje espacial en animales. Aunque la capacidad espacial es una funcion cognitiva considerada sexodimorfica, donde los machos muestran una ventaja frente a las hembras, los resultados de los pocos estudios que evaluen diferencias de sexo en esta prueba no son concluyentes. Por ello, en este estudio nos propusimos comprobar si los ratones OF1 machos ejecutaban mejor que las hembras las tareas del Laberinto Hebb-Williams, y si esa ventaja era independiente de la dificultad del laberinto. Se utilizo la version reducida para ratones, la cual consta de 5 laberintos, 3 consi-derados faciles y 2 dificiles. Los resultados en general corroboraron una mejor ejecu-cion de los machos frente a las hembras, con tiempos de ejecucion y numero de errores mas reducidos y menor numero de ensayos para alcanzar el criterio de adquisi-cion. Sin embargo, estas diferencias de sexo no se dieron en todos los laberintos, manifestandose principal-mente en los laberintos faciles pero no en los dificiles. Se discuten posibles explicaciones a las diferencias entre machos y hembras en el aprendizaje de los laberintos en funcion de su dificultad, concluyendose que la categorizacion de la dificultad de los laberintos es dependiente del sexo. EnglishThe Hebb-Williams Maze is a test used to evaluate spatial learning in animals. Although sex differences in spatial ability have been observed in numerous species (males typically outperform females), inconclusive results have been obtained in the few studies that have used this test to assess male and female animals. This study investigated whether male OF1 mice performed better than OF1 mice on the Hebb-Williams Maze and whether any advantage was independent of the difficulty of the maze. We used a reduced version for mice, which consists of 5 mazes (3 easy and 2 difficult). In general, the results suggest that male mice performed better than female mice. The male mice showed shorter runtimes, a smaller number of errors, and fewer attempts to reach the criterion of acquisition. However, these sex differences were mainly found in the easy mazes but not in the difficult ones. We discuss the explanations for these differences in learning mazes based on their difficulty and conclude that the categorization of the difficulty of the mazes is sex-dependent.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

Objectives: In the PAOLA-1/ENGOT-ov25 primary analysis (NCT02477644), adding the PARP inhibitor olaparib to maintenance bevacizumab (bev) after first-line platinum-based chemotherapy with bev led to a significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with advanced high-grade ovarian cancer (HGOC), using modified RECIST v1.1 criteria (HR 0.59; 95% CI 0.49-0.72; P Methods: Pts with newly diagnosed, FIGO stage III-IV HGOC in response after platinum-based chemotherapy plus bev received bev (15 mg/kg q3w for 15 months) + olaparib (300 mg bid for 24 months) or pbo. Scans were performed every 24 weeks, or every 12 weeks if there was evidence of clinical or CA-125 progression. CA-125 levels were assessed every 12 weeks. Time to RECIST or CA-125 progression or death was a secondary endpoint; RECIST/CA-125 progression by biomarker status, response to initial therapy and CA-125 level at baseline were explored. Results: 537 pts were randomized to olaparib + bev and 269 to pbo + bev with median follow-up for PFS by RECIST/CA-125 of 24.2 vs 24.7 months (DCO 22 March 2019). In the ITT population, the benefit provided by olaparib + bev vs pbo + bev for PFS by RECIST/CA-125 (HR 0.58; 95% CI 0.48-0.70; P Download : Download high-res image (258KB) Download : Download full-size image Conclusions: Median PFS and HRs were consistent when progression was assessed by either RECIST or RECIST/CA-125 in PAOLA-1. Scans appear particularly important for detecting progression in HRD-positive pts, tBRCAm pts or pts with normal CA-125 levels at baseline as CA-125 levels did not seem to predict relapse in these pts. Results suggest that CA-125 surveillance alone may be sufficient to detect progression in most pts with abnormal baseline CA-125 levels when starting maintenance therapy.

11016 Background: Burn-Out Syndrome (BOS) is defined by (1) emotional and physical exhaustion; (2) cynicism and depersonalization; and (3) no personal nor professional fulfillment. It affects up to 78% of oncology-related workers (doctors, nurses and nurse-assistants, among others). This may decrease quality in both patient assistance and institutional processes. However, there is lack of resources for its diagnosis and management. Our objective is to: (1) determine the incidence of BOS in our team; (2) analyze potential causes; and (3) decrease in 20% the percentage of BOS affected workers. Methods: From October 2018 to November 2019, 20 nurses and nurse-assistants participated. Process map and Ishikawa fish-bone diagram were design to analyze BOS potential causes and to design appropriate interventions after Priority/pay-off matrix description. To do so, participants were asked to fulfill a personal detail questionnaire at the beginning, and adapted versions for the GHQ-12 and Maslach Index questionnaires after each intervention. To track the improvement process, a PDSA cycle was fulfilled and re-evaluated overtime. Project developed through the ASCO Quality Training Program and the Fundación ECO support. Results: Population main characteristics: 87% women, 47-year-old median age. 12 nurses, 6 working in the clinic. 90% with more than 5 years of experience in Oncology. At baseline, 75% healthy (GHQ-12), BOS cause risk: exhaustion 70%, depersonalization 45%, fulfillment 55%. Two interventions developed to improve exhaustion BOS risk: (1) ergonomy tips; and (2) self-assessment and self-help tools. 9 subjects lost after 2nd intervention. After interventions, 34% exhaustion risk reduction and 100% healthy workers (GHQ-12). Conclusions: After two interventions, we have achieved an improvement of 34% lowering the risk of suffering BOS among our workers. Health perception improved to 100%. The loss of 9 subjects after the 2nd intervention may be a bias when interpreting the final results. Giving the appropriate tools to medical oncology workers helps reduce BOS risk significantly

Background Laws refer that minors do not have the capability to give informed consent for their own medical attention. However, there are special conditions in which they are allowed to decide about their health. The greater the judgement and experience limitations in minors, the less weight is given to the values and objectives they express. Also, the more adverse consequences might be, the higher the level of authority that is demanded to decide on behalf of the minor, thus granting the State the capability to guarantee the well-being of the minor. Case report 12-year-old female patient with a diagnosis of acute lymphoblastic leukemia, with precarious social and family background; evolution of the disease obstructed by the disregard of the treatment due to her unsanitary and extreme poverty conditions. Both of her parents died soon after the start of the treatment and she was kept under the care of her half-sister of legal age. The work and the ethical dilemma of the pediatrician and the staff of Hospital Infantil de Mexico Federico Gomez are exposed within the building of support -networks with the objective of prioritizing the minor's well-being, without allowing family break-up or disintegration, thus succeeding in her recovery. Conclusions The case was submitted to the Hospital Bioethics Committee. Inter-institutional support networks were built in order to improve dynamics of the family, thus solving the needs of the minor. Despite the misfortune of the situation, the disease was successfully overcome.

Càncer de bufeta; Cistectomia; Quimioteràpia Cáncer de vejiga; Cistectomía; Quimioterapia Bladder cancer; Cystectomy; Chemotherapy The goal of this article is to provide recommendations about the management of muscle-invasive (MIBC) and metastatic bladder cancer. New molecular subtypes of MIBC are associated with specific clinical–pathological characteristics. Radical cystectomy and lymph node dissection are the gold standard for treatment and neoadjuvant chemotherapy with a cisplatin-based combination should be recommended in fit patients. The role of adjuvant chemotherapy in MIBC remains controversial; its use must be considered in patients with high-risk who are able to tolerate a cisplatin-based regimen, and have not received neoadjuvant chemotherapy. Bladder-preserving approaches are reasonable alternatives to cystectomy in selected patients for whom cystectomy is not contemplated either for clinical or personal reasons. Cisplatin-based combination chemotherapy is the standard first-line protocol for metastatic disease. In the case of unfit patients, carboplatin–gemcitabine should be considered the preferred first-line chemotherapy treatment option, while pembrolizumab and atezolizumab can be contemplated for individuals with high PD-L1 expression. In cases of progression after platinum-based therapy, PD-1/PD-L1 inhibitors are standard alternatives. Vinflunine is another option when anti-PD-1/PD-L1 therapy is not possible. There are no data from randomized clinical trials regarding moving on to immuno-oncology agents.

Laws refer that minors do not have the capability to give informed consent for their own medical attention. However, there are special conditions in which they are allowed to decide about their health. The greater the judgement and experience limitations in minors, the less weight is given to the values and objectives they express. Also, the more adverse consequences might be, the higher the level of authority that is demanded to decide on behalf of the minor, thus granting the State the capability to guarantee the well-being of the minor.12-year-old female patient with a diagnosis of acute lymphoblastic leukemia, with precarious social and family background; evolution of the disease obstructed by the disregard of the treatment due to her unsanitary and extreme poverty conditions. Both of her parents died soon after the start of the treatment and she was kept under the care of her half-sister of legal age. The work and the ethical dilemma of the pediatrician and the staff of Hospital Infantil de México Federico Gómez are exposed within the building of support -networks with the objective of prioritizing the minor's well-being, without allowing family break-up or disintegration, thus succeeding in her recovery.The case was submitted to the Hospital Bioethics Committee. Inter-institutional support networks were built in order to improve dynamics of the family, thus solving the needs of the minor. Despite the misfortune of the situation, the disease was successfully overcome.Las leyes refieren que los menores no tienen la capacidad para dar su consentimiento informado para su propia atención médica; sin embargo, hay condiciones especiales en las que se les permite determinar lo referente a su salud. Cuanto mayores sean las limitaciones de juicio y experiencia en los menores, menos peso se otorga a los valores y objetivos que expresan; cuanto más adversas sean las consecuencias, se deberá exigir un nivel más alto de autoridad para decidir en nombre del menor, dejando al Estado la capacidad de garantizar el bienestar del menor.Niña de 12 años con diagnóstico de leucemia linfoblástica aguda LI, con antecedentes familiares y sociales precarios; evolución entorpecida por el desapego al tratamiento y sus condiciones insalubres y pobreza extrema. Ambos padres fallecieron al poco tiempo de iniciar su tratamiento, quedando ella al cuidado de su medio hermana mayor de edad. Se exponen la labor y el dilema ético del oncólogo tratante y del personal del Hospital Infantil de México Federico Gómez en la creación de redes de apoyo con el objetivo de priorizar el bienestar de la menor, sin dar lugar al quebrantamiento y la desintegración familiar, consiguiendo exitosamente su recuperación.El caso fue sometido al Comité de Bioética Hospitalaria. Se formaron redes de apoyo interinstitucionales para intervenir en la dinámica familiar, resolviendo los requerimientos de la menor, y se consiguió con éxito superar la enfermedad.

Cancer cases are growing in an exponential way, likewise the prices of new cancer drugs. Continuing in this way, in the near future, it will be impossible to provide optimum care for all cancer patients. Therefore, it is important to establish mechanisms that enable the National Health Systems to provide the best options of treatment, either through the elaboration of decision-binding frameworks or through other initiatives that guarantee the best quality care for all oncology patients to overcome, in the best possible way, this difficult illness. Here, we review current proposals that have been established by different cancer organizations worldwide, their similarities, their differences and whether they are helpful in a real clinical setting. Facing present reality and despite these organizations' huge efforts, these proposals are not being implemented at all and it does not seem feasible that they will in the short run. In the same way, we support and argue why oncologists should have a crucial and a preponderant role to establish the best way of guaranteeing an equal access to the latest oncology care.

249 Background: Burn-Out Syndrome (BOS) is defined by: emotional and physical exhaustion; cynicism and depersonalization; and no personal nor professional fulfillment. With increasing incidence, it impacts negatively in the patient attention quality and the quality of institutional processes. Few experiences reported about its incidence and impact in Medical Oncology. Lack of resources for its diagnosis and management. Our objective was to determine the incidence of the BOS in our workers, analyze its causes and try to reduce in 20% the percentage of workers suffering or at risk of suffering BOS. Developed as a Quality Training Program (ASCO - ECO Foundation) project. Methods: 23 nurses/nurse-assistants Medical Oncology Department at University General Hospital of Valencia fulfilled anonymized questionnaire with personal details, GHQ-12 evaluation and Maslach index questions, at baseline and after intervention. Causes of BOS analyzed and process map and Ishikawa fish-bone scheme designed. Interventions carried in consequence. Results: 23 subjects, 87% women, 47 year-old median age. 14 nurses, 8 working in the clinic. 90% with more than 5 years of experience in Oncology. At baseline, 75% GHQ-12 good health. Maslech index: 70%, 45% and 55% in risk (medium+high) of BOS related to exhaustion, depersonalization or fulfillment, respectively. In exhaustion, 35% medium risk, 35% high risk of BOS. After priority-matrix development, ergonomy tips and self-improvement tools were identified as the adequate interventions to improve exhaustion risk. After ergonomy tips intervention, 90% GHQ-12 good health, 15% exhaustion medium risk, 50% exhaustion high risk, 65% at risk of BOS related to exhaustion. An improvement of 5% lowering the risk of suffering Burn-Out Syndrome among our workers was achieved Conclusions: BOS risk is complex due to answer subjectivity. We have healthier workers (GHQ-12), but although levels of exhaustion have decreased mildly, those who were already exhausted are worse than before (Maslach Index). Possible causes: renovation work on Clinic, labor instability, local holidays during project. Additional self-improvement tools sessions are now being held.

e20661 Background: FGFR1 gene amplifications are observed in squamous (sq) non-small cell lung cancer (NSCLC) and may suggest tractable oncogenic dependency. However, their value in predicting clinical activity of FGFR inhibitors is unclear. We explored tumor FGFR1-3 mRNA expression levels to select patients (pts) for treatment with rogaratinib, an oral, potent, small-molecule inhibitor of FGFR1-4. The first-in-human study of rogaratinib included pts with all NSCLC histologies. Methods: Pts with refractory advanced NSCLC were screened for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples, and FGFR1-3 overexpression was defined by pre-specified cut-offs. Pts received rogaratinib 800 mg BID on a continuous 21-day cycle. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1 after cycles 2, 5, and 8. Results: 260 NSCLC biopsies were screened for FGFR1-3 tumor mRNA expression; 244 (93.8%) were evaluable. FGFR1-3 mRNA overexpression was found in 47% of sq NSCLC, and only 14% of non-sq NSCLC, with FGFR3 being the most commonly overexpressed subtype. 40 FGFR mRNA-positive pts were enrolled and treated. Rogaratinib was well tolerated; hyperphosphatemia (75%), diarrhea (53%), and decreased appetite (35%) were the most frequent treatment-emergent adverse events. Events were mostly mild or moderate. 36 treated pts were evaluable for response. The overall response rate was 5.6% (2 partial responses, 1 lasting for > 16 months). Disease control rate was 64%. Disease stabilization was seen in pts with mRNA overexpression across all FGFR subtypes and also in pts who failed prior lines of therapy, including anti-PD-L1. Molecular studies are ongoing to identify additional predictors of response to improve pt selection. Conclusions: Rogaratinib has a favorable safety and tolerability profile and clinical activity in pts with refractory FGFR1-3 tumor mRNA-positive NSCLC. It has potential for further exploration in combination with other agents. A clinical trial is currently enrolling FGFR mRNA-overexpressing pts with advanced and pre-treated sq NSCLC. Clinical trial information: NCT03762122.

176 Background: Cabazitaxel (CBZ) improves overall survival in mCRPC that progresses during or after docetaxel treatment. CABASEM is a phase II study to evaluate the efficacy and safety of a weekly schedule of CBZ for 'unfit' (ECOG2, previous neutropenic fever with docetaxel, or radiotherapy to

198 Background: Different treatments efficacy for mCRPC when progression after docetaxel x 6 cycles + ADT (as CHAARTED scheme) are unknown as all pivotal trials where performed in patients who progressed to mCPRC after ADT. Methods: A retrospective analysis of 175 mCRPC patients of 10 spanish hospitals who were treated with docetaxel + ADT as first line treatment was performed. Patients characteristics at diagnosis (age, gleason) and at progression to mCRPC were analyzed (PSA, presence of visceral mets, type of progression). As efficacy endpoints, clinical and objective response, and survival from progression to mCRPC were analyzed. Results: Median age at diagnosis 65.2 years old (range 44-84). Metastatic at diagnosis 173. Bone metastasis 155 (88,5%), visceral 31 (17.7%), gleason >7 130 (74,3%), number docetaxel cycles: 6 (80%), 5 (5,7%)

El proceso de toma de decisiones en las unidades de terapia intensiva pediatrica (UTIP) se sustenta en un marco cientifico, legal y etico, el cual suele ser mas complejo que en la practica para adultos e involucra a los padres o tutores, en consecuencia, debe ser resuelto con seriedad, con calma y rigor metodologico. Se diseno una encuesta por expertos, con aplicacion anonima y voluntaria, en forma no institucional, en la que se plantearon cuestiones referentes a dilemas bioeticos generados en los servicios de UTIP y los procedimientos para su solucion. La aplicacion de este instrumento fue el metodo Delphi, en dos rondas. Los resultados mas importantes, entre otros, consistieron en reconocer que la totalidad de los medicos encuestados enfrentan en su unidad dilemas eticos, siendo el mas frecuente la obstinacion terapeutica, en un 32%, resultado que se enlaza al de la dificultad de establecer el diagnostico de paciente terminal, en un 13%. Incluir materias de bioetica y toma de decisiones con contenido moral en la formacion de estos profesionistas, asi como implementar la comunicacion asertiva entre el equipo de salud y la familia, y promover el funcionamiento adecuado de comites de bioetica hospitalarios con funciones consultivas de emergencia, son propuestas que emergen de las conclusiones de este estudio.

Lewy bodies are the hallmark of Parkinson disease and their sophisticated analysis will undoubtedly elucidate the pathogenic process. They have been studied by using different microscopic tools. The authors have used atomic force microscopy (AFM) to study the ultramicrotom cut postmortem brain tissue of Parkinson disease patients. Under the same preparation conditions, they have found aggregated fibrillary nanostructures in Lewy bodies, as well as a loss of connections between neurons located in other parts of the substantia nigra. Although these results are preliminary and descriptive in nature, this paper reports the application of a novel and intriguing technique. Further studies including the study of cortical LB and Lewy neurites will be needed to determine the full potential of AFM in the study of the pathogenesis of cell death in Parkinson disease and other synucleinopathies.

Background The co-occurrence of the c.709-1G > A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. Methods and findings We compared clinical characteristics of 14 patients who carried the c.709-1G > A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G > A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T-patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked beta-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). Conclusions In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question. F.M., P.S.J. and S.E.L. receive funding from the Tau Consortium. F.C. receives funding from the Generalitat de Catalunya (grant 2014 SGR 866). P.S.J. receives funding from ISCIII (PI12/02288). This work was also supported by the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Resumen El Grupo de Trabajo de Neurooncologia (GTNO) de la SENEC ha encargado a los miembros del comite de neurooncologia del Hospital Universitario Donostia de San Sebastian (Espana) la elaboracion del presente documento, para que sirva como Guia del consenso establecido en el seno del GTNO y recomendacion propuesta en todos los hospitales, publicos o privados, que manejan esta patologia. Es obligado la constitucion y funcionamiento normalizado de comites de neurooncologia en todos los centros con servicio de neurocirugia, y lo expuesto a continuacion debe contemplarse a la luz de las condiciones particulares de los mismos, con las variaciones pertinentes segun los recursos diagnosticos y terapeuticos. Nos presentan a continuacion el ejemplo de la constitucion, funcionamiento y experiencia que han contraido en mas de 8 anos de trabajo multidisciplinar en pacientes con tumores cerebrales.

The standard for differentiating between dementia subtypes is currently based on neuropathological changes and follows traditional nosological classifications. However, the high incidence of comorbid neuropathologies complicates the differentiation between dementia diagnoses in the clinic. The aim of this study was to investigate the grades of agreement between clinical and neuropathological diagnoses in neurodegenerative disorders, to compare them with rates found in previous studies, and to propose implications for dementia diagnostics. Patients, who donated their brains to the Brain Bank of Navarre (Pamplona, Spain), had been diagnosed with a neurodegenerative disorder during life (clinical diagnosis) and postmortem (neuropathological diagnosis). We studied a sample of patients with a short average time interval between the last clinical assessment and death (4.6 months). Overall, there was a mean grade of agreement of 44.0% between the clinical diagnosis and the pure neuropathological diagnosis (i.e., without co-morbid neuropathological disorders). This grade of agreement differed between dementia subtypes: e. g., 85% for prion disease, 49% for Alzheimer's disease, and 0% for Lewy body dementia. Our data confirm that co-occurrence of multiple neuropathological disorders is very common in individuals with dementia, and that the underlying neuropathology often differs from the neuropathology implied by the clinical diagnosis. These findings support a multidimensional approach to diagnosing dementia, in which dementia syndromes are not categorized into diagnostic subtypes, but are seen as syndromes characterized by a combination of various neuropathological dimensions.

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license., Mammalian cells exhibit a frequent pericentrosomal Golgi ribbon organization. In this paper, we show that two AKAP450 N-terminal fragments, both containing the Golgi-binding GM130-interacting domain of AKAP450, dissociated endogenous AKAP450 from the Golgi and inhibited microtubule (MT) nucleation at the Golgi without interfering with centrosomal activity. These two fragments had, however, strikingly different effects on both Golgi apparatus (GA) integrity and positioning, whereas the short fragment induced GA circularization and ribbon fragmentation, the large construct that encompasses an additional p150glued/MT-binding domain induced separation of the Golgi ribbon from the centrosome. These distinct phenotypes arose by specific interference of each fragment with either Golgi-dependent or centrosome-dependent stages of Golgi assembly. We could thus demonstrate that breaking the polarity axis by perturbing GA positioning has a more dramatic effect on directional cell migration than disrupting the Golgi ribbon. Both features, however, were required for ciliogenesis. We thus identified AKAP450 as a key determinant of pericentrosomal Golgi ribbon integrity, positioning, and function in mammalian cells., Funding was provided by the Ministerio de Ciencia e Innovación (grants BFU2009-07182 and CSD2009-00016) and Junta de Andalucía (grant P07-CVI-03199) to R.M. Rios and C. Caballero. M.P. Gavilan is a Ministerio de Ciencia e Innovación–Juan de la Cierva fellow.

Neurodegenerative diseases that course with dementia represent a public health problem that is growing in importance, mostly due to the aging of the population. Imaging techniques provide essential diagnostic and prognostic information. Some classifications of these diseases have recently been modified through the incorporation of histological, immunohistochemical, and genetic criteria. This article reviews the different radiological and pathological aspects of the most common diseases that course with dementia. We studied brains from our community's tissue bank with postmortem MRI and posterior histological examination and illustrate this exposition with images from the radiopathologic correlation.

Alterations in the proteasome activity in the CNS have been described during aging. However, a detailed study of all proteasome subunits is actually lacking. We have analyzed, in vivo, the age-related modifications in the molecular composition of hippocampal proteasomes. We found that the immunoproteasome/proteasome ratio was increased in aged hippocampus. The processing of the low-molecular-mass protein (LMP)7/beta(5i) subunit, practically absent in young hippocampus, was increased in aged animals. Among the potential factors underlying these modifications we evaluated the neuroinflammation and the transcription factor Zif268. Lipopolysaccharide (LPS)-induced neuroinflammation in young rats, up-regulated the expression of immunoproteasome subunits and increased the processing of the LMP7/beta(5i) protein. Moreover, the hydrophobicity of cellular peptides, analyzed by liquid chromatography, increased in both, young LPS-injected animals and aged rats, suggesting that immunoproteasomes including the LMP7/beta(5i) subunit could, at least in part, account for this modification. Also, the mRNA expression of the transcription factor Zif268, which down-regulates the immunoproteasome subunit LMP7/beta(5i) by binding to sequences within the promoter regions, was decreased in both, aged hippocampus and young LPS-injected animals. Finally, we found that spatial memory training in young animals, a situation in which the expression of Zif268 is increased, modified the mRNA expression of the constitutive and catalytic subunits in an opposite manner. Based on present data, we propose that the age-related increases in the content of hippocampal immunoproteasome is mostly because of neuroinflammatory processes associated to aging.