Do NPM1 and FLT3-ITD mutations modify prognosis in patients treated with non-intensive regimens?

FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.

Multidisciplinary consensus document on the current treatment of bacille Calmette-Guérin-unresponsive non-muscle invasive bladder tumor.

Radical cystectomy is the current treatment of choice for patients with BCG-unresponsive non-muscle invasive bladder tumor (NMIBC). However, the high comorbidity of this surgery and its effects on the quality of life of patients require the investigation and implementation of bladder-sparing treatment options. These must be evaluated individually by the uro-oncology committee based on the characteristics of the BCG failure, type of tumor, patient preferences and treatment options available in each center. Based on FDA-required oncologic outcomes (6-month complete response rate for CIS: 50%; duration of response in responders for CIS and papillary: 30% at 12 months and 25% at 18 months), there is not currently a strong preference for one treatment over another, although the intravesical route seems to offer less toxicity. This work summarizes the evidence on the management of BCG-unresponsive NMIBC based on current scientific evidence and provides consensus recommendations on the most appropriate treatment.

La historia olvidada del alzhéimer: recordando a Oskar Fischer

Introducción: La Enfermedad de Alzheimer (EA), es una patología neurodegenerativa progresiva que afecta la memoria y otras funciones cognitivas. Hasta ahora no existen tratamientos curativos ni modificadores de la enfermedad, por lo que el manejo está centrado en la prevención y en el tratamiento de factores que puedan contribuir a su evolución; las herramientas farmacológicas son escasas y tienen efectos modestos en la ralentización de la enfermedad. Se propone realizar una breve biografía de Oskar Fischer, describir el conflicto con Alois Alzheimer que se identifica en documentos científicos y mencionar los principales elementos de la teoría de Oskar Fischer. Método: Se realizó una revisión narrativa en las bases de datos Scielo, PubMed y Lilacs, con los términos "Oskar Fischer" y se encontró quince artículos publicados entre 1906 a 2023, los cuales fueron resumidos por los autores GS y NR. El artículo fue posteriormente revisado por los demás autores. Resultados: Se organizaron en secciones, partiendo con una breve biografía del autor, su interacción con Alois Alzheimer y un resumen de su teoría; lo descrito por Oskar Fischer en términos de las estructuras de placas y ovillos se considera como una de las principales teorías fisiopatológicas de la EA. Conclusiones: Oskar Fisher hizo un aporte invaluable y planteó conceptos clásicos con respecto a la EA, que, si bien no le valieron para ser reconocido en la posteridad, han permitido que en las investigaciones posteriores sea de gran importancia repensar estos conceptos e incluir otras posibilidades e hipótesis, para continuar en la profundización del conocimiento de la enfermedad.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative pathology that affects memory and other cognitive functions. Until now, there are no curative or disease-modifying treatments, so management is focused on prevention and treatment of factors that may contribute to its evolution; pharmacological tools are scarce and have modest effects in slowing the disease. It is proposed to make a brief biography of Oskar Fischer, describe the conflict with Alois Alzheimer that is identified in scientific documents and mention the main elements of Oskar Fischer's theory. Method: A narrative review was carried out in the Scielo, PubMed and Lilacs databases, with the terms "Oskar Fischer" and fifteen articles published between 1906 and 2023 were found, which were summarized by the authors GS and NR. The article was subsequently reviewed by the other authors. Results: They were organized in sections, starting with a brief biography of the author, his interaction with Alois Alzheimer and a summary of his theory; what was described by Oskar Fischer in terms of the structures of plaques and tangles is considered one of the main pathophysiological theories of AD. Conclusions: Oskar Fisher made an invaluable contribution and raised classic concepts regarding AD, which, although they did not earn him recognition in posterity, have allowed subsequent research to be of great importance to rethink these concepts and include other possibilities and hypotheses, to continue deepening the knowledge of the disease.

Clinical Usefulness of Prostate-specific Membrane Antigen-ligand Positron Emission Tomography/Computed Tomography for the Detection of Prostate Cancer Biochemical Recurrence after Primary Radiation Therapy in Patients with Prostate-specific Antigen Below the Phoenix Threshold: Systematic Review and Meta-analysis.

AIMS: After primary radiotherapy, biochemical recurrence is defined according to the Phoenix criteria as a prostate-specific antigen (PSA) value >2 ng/ml relative to the nadir. Several studies have shown that prostate-specific membrane antigen (PSMA)-ligand positron emission tomography/computed tomography (PET/CT) can help in detecting recurrence in patients with low PSA values. This study aimed to assess the detection rate and patterns of PSMA-ligand PET/CT uptake in patients with suspected biochemical recurrence after primary radiotherapy and with PSA levels below the Phoenix threshold. MATERIALS AND METHODS: The meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Articles providing data on patients with suspected prostate cancer recurrence after primary radiotherapy with a PSA value below the Phoenix threshold and who underwent PSMA-ligand PET/CT were included. Quality assessment was carried out using the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). RESULTS: In total, five studies were included, recruiting 909 patients (202 with PSA ≤2 ng/ml). The PSMA-ligand detection rate in the patients with ≤2 ng/ml ranged from 66 to 83%. The most frequent source of PSMA-ligand PET/CT uptake was local recurrence, followed by lymph node metastasis and bone metastasis. PSMA-ligand PET/CT uptake due to local-only recurrence was more likely in patients with PSA ≤2 ng/ml compared with PSA > 2 ng/ml: risk ratio 0.72 (95% confidence interval 0.58-0.89), P = 0.003. No significant differences were observed in the detection of PSMA-ligand uptake in other areas. Limitations include a lack of biopsy confirmation, cohort reports with small sample sizes and a potentially high risk of bias. CONCLUSION: A significant detection of PSMA-ligand-avid disease was observed in patients with PSA levels below the Phoenix threshold. There was a higher likelihood of detecting local-only uptake when the PSA value was ≤2 ng/ml. The findings suggest that a critical review of the Phoenix criteria may be warranted in the era of PSMA-ligand PET/CT and highlight the need for further prospective trials.

Feasibility of orbital friction stir welding on clad pipes of API X65 steel and Inconel 625.

Orbital friction stir welding (FSW) has been applied to clad pipes, which is certainly of interest to the oil and gas industry. In this context, an FSW system capable of performing sound joints in one pass with full tool penetration was developed. Orbital FSW was executed in 6 mm thick API X65 PSL2 steel clad pipes with 3 mm thick Inconel 625 using a polycrystalline cubic boron nitride (pcBN) tool. The metallurgical and mechanical properties of the joints were investigated. Sound joints with axial forces of 45-50 kN, tool rotational speeds of 400-500 rpm, and a welding speed of 2 mm/s were obtained, illustrating that the developed system can perform FSW joints without volumetric defects.

Congenital and Infantile Hemangiomas: Epidemiological, Clinical, and Treatment Characteristics Based on 3 Years' Experience at a Tertiary Care Hospital - A Retrospective Case Comparison and Review of the Literature. / Características clínico-epidemiológicas y consideraciones terapéuticas de los hemangiomas congénitos e infantiles de un hospital de tercer nivel durante un periodo de 3 años: estudio comparativo y revisión de la literatura.

Distinguishing between congenital and infantile hemangiomas is challenging, but essential for appropriate treatment. The immunohistochemical marker glucose transporter type 1 is helpful, but biopsies are uncommon in this setting. The aim of this retrospective study was to describe and compare epidemiological, clinical, and treatment characteristics of congenital and infantile hemangiomas diagnosed at a tertiary care hospital over 3 years. We studied 107 hemangiomas: 34 congenital hemangiomas (rapidly involuting, partially involuting, and noninvoluting), 70 infantile hemangiomas, and 3 hemangiomas pending classification. Superficial infantile hemangiomas of the head and neck were the most prevalent tumors. Congenital hemangiomas were most often located on the trunk. Studied risk factors were more common in patients with infantile hemangiomas. In this group of patients, treatment response was independent of sex, in vitro fertilization, lesion depth and location, and type of treatment.

Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria.

BACKGROUND: Azacitidine (AZA) is approved for the treatment of high-risk chronic myelomonocytic leukemia (CMML) of myelodysplastic (MD) subtype. Data of response rates using the specific response criteria for this disease are scarce. The aim of this study was to evaluate the response to AZA in patients diagnosed with CMML from the Spanish Registry of Myelodysplastic Syndromes (MDS) applying the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) response criteria. METHODS: We retrospectively studied 91 patients with CMML treated with at least one cycle of AZA from the Spanish Registry of MDS. As it was a real-world study, the response rate was evaluated between cycle 4 and 6, applying the MDS/MPN response criteria FINDINGS: The overall response rate at cycle 4-6 was 58%. Almost half of the patients achieved transfusion independence and one quarter showed clinical benefit, regardless of the CMML French-American-British (FAB) and World Health Organization (WHO) subtypes and CMML Specific Prognosis Scoring (CPSS) risk groups. Toxicity was higher in the MD-CMML subtype. INTERPRETATION: In our series, most CMML patients achieved an overall response rate with AZA according to the overlap-MDS/MPN response criteria regardless of the CMML FAB and WHO subtypes and CPSS risk groups. Thus, AZA may also be a treatment option for patients with the myeloproliferative CMML subtype and those with a lower-risk CPSS, but symptomatic.

Cytotoxicity and DNA damage evaluation of TiO2 and ZnO nanoparticles. Uptake in lung cells in culture.

The cytotoxicity and DNA damage of titanium dioxide and zinc oxide nanoparticles (TiO2 and ZnO NPs) have been studied in a human lung carcinoma cell line (A549) after 24 h exposure. TiO2 and ZnO NPs had mean diameters of 12.9 ± 2.8 and 24.1 ± 8.0 nm, respectively. ZnO NPs reduced cell viability from 250 µg/mL, increasing reactive oxygen species (ROS) and decreased GSH/GSSG ratio. The comet assay detected DNA damage from 50 µg/mL. TiO2 NPs induced cytotoxicity and DNA damage from 50 to 100 µg/mL, respectively, along with a decrease of the GSH/GSSG ratio. Both particles were found inside the cells, within membrane-bound vesicles. The internalization mechanism is promoted partially by caveolae-mediated endocytosis and, in the case of TiO2 NPs, also by macropinocytosis.

Recent advances in neoadjuvant immunotherapy for urothelial bladder cancer: What to expect in the near future.

Urothelial bladder cancer (UC) is the most common malignancy involving the urinary system and represents a significant health problem. Immunotherapy has been used for decades for UC with intravesical bacillus Calmette-Guérin (BCG) set as the standard of care for non-muscle-invasive bladder cancer (NMIBC). The advent of immune checkpoint inhibitors (ICIs) has completely transformed the treatment landscape of bladder cancer enabling to expand the treatment strategies. Novel ICIs have successfully shown improved outcomes on metastatic disease to such an extent that the standard of care paradigm has changed leading to the development of different trials with the aim of determining whether ICIs may have a role in early disease. The localized muscle-invasive bladder cancer (MIBC) scenario remains challenging since the recurrence rate continues to be high despite all therapeutic efforts. This article will review the current experience of ICIs in the neoadjuvant setting of UC, the clinical trials landscape and finally, an insight of what to expect in the immediate and mid-term future.

Evaluation of health care-associated infections following radical cystectomy. / Estudio de las infecciones relacionadas con la asistencia sanitaria tras la realización de cistectomía radical.

INTRODUCTION AND OBJECTIVE: Radical cystectomy is a complex surgery with a high rate of complications including infections, which lead to increased morbidity and mortality, longer hospital stay and higher costs. The aim of this work is to evaluate health care-associated infections (HAIs) in these patients, as well as associated microorganisms, antibiotic resistance profiles and risk factors. MATERIAL AND METHODS: Prospective study from 2012 to 2017. Epidemiologic variables, comorbidities and surgical variables are collected. The microorganisms involved and antibiotic susceptibility patterns are analyzed. RESULTS: 122 patients. Mean age 67 (SD:18,42). Mean hospital stay 23.5 days (18.42). HAIs rate of 45%, with predominant urinary tract infections (43%) and surgical wound infections (31%). Positive cultures in 78.6% of cases. Increased isolation of Enterococcus (18%) and Escherichia coli (13%). Forty-three percent of microorganisms were resistant to amoxicillin/ampicillin, 23% to beta-lactamases and 36% to quinolones. Empirical treatment was adequate in 87.5%. Hospital stay is increased (17 days, p< 0.05) due to HAIs. Lower rate of infectious complications in the laparoscopic vs. open approach (p< 0.001) and in orthotopic vs. ileal conduit diversion (p = 0.04) CONCLUSIONS: We found a high rate of HAIs in our radical cystectomy series, with predominant urinary tract and surgical wound infections. E.coli and Enterococcus spp. are the most frequently isolated microorganisms, with high rates of resistance to some commonly used antibiotics.

Current treatments for BCG failure in non-muscle invasive bladder cancer (NMIBC). / Tratamientos actuales tras fracaso a BCG en cáncer de vejiga no músculo-invasivo.

The treatment of choice for high-risk non-muscle invasive bladder cancer (NMIBC) is bacillus Calmette-Guérin (BCG). However, when this fails, the indicated treatment is radical cystectomy. In recent years, trials are being developed with various drugs to avoid this surgery in patients with BCG failure. The aim of this article is to update the treatments under study for bladder preservation in this patient population. Non-systematic review, searching PubMed with the terms "Bladder cancer", "Non-muscle invasive bladder cancer", "NMIBC", "BCG", "BCG-refractory", "Mitomycin C", "MMC", "Hyperthermia", "Electromotive Drug Administration", "EMDA". We used the search engines clinicaltrials.gov and clinicaltrialsregister.eu to find clinical trials. The only intravesical drug approved by the Food and Drug Administration (FDA) for carcinoma in situ (CIS) after failure to BCG is Valrubicin. Recently, the FDA has approved intravenous Pembrolizumab, following the publication of preliminary data from the KEYNOTE-057 study. Atezolizumab has demonstrated similar preliminary efficacy results. Only microwave-induced chemohyperthermia and EMDA-MMC (Electromotive Drug Administration) are recognized as alternatives in European guidelines. Other options under investigation are taxanes and gemcitabine, alone or in combination, recombinant viruses and device-assisted intravesical chemohyperthermia. The results of new drugs are promising, with a large number of trials underway. Knowing the mechanisms of resistance to BCG is essential to explore new therapeutic options.

New immunotherapies for high-risk non-muscle invasive bladder cancer: Current state and future perspectives. / Nuevas inmunoterapias en el cáncer de vejiga no músculo-invasivo de alto riesgo: estado actual y perspectivas de futuro.

BACKGROUND: The standard treatment for high-risk non-muscle invasive bladder tumors (NMIBT) is transurethral resection of the bladder and BCG instillations. However, responses are limited, and new therapeutic alternatives for these patients are required. The results of checkpoint inhibitors in advanced tumors have led to interest in the use of these molecules in NMIBT. METHODS: We conducted a search on PubMed using the terms «bladder cancer¼ and «check point inhibitors¼. We have used the search engines clinicaltrials.gov and clinicaltrialsregister.eu for the search of clinical trials. RESULTS: There are currently 5 trials in progress on BCG untreated patients. There are no results available. As for BCG non-responders, there are 15 ongoing trials, two of them with preliminary results: Keynote 057, with promising results with pembrolizumab, which has led the FDA to approve its use in January 2020, and SWOG S1605, which has shown similar results with atezolizumab. Other trials are using intravesical administration of these drugs, which is an attractive option if it is effective for cancer control. CONCLUSIONS: Checkpoint inhibitors offer a new possibility for patients who do not respond to BCG. These will probably be used in the future for previously BCG untreated patients. Preliminary data from clinical trials show promising results. A good understanding of these molecules by urologists and the creation of multidisciplinary teams are crucial in order to offer the best therapeutic alternatives to these patients.

Nucleic acids complexation with cationic elastin-like polypeptides: Stoichiometry and stability of nano-assemblies.

Positively charged elastin-like polypeptides (ELPs) were synthesized for the compaction of genetic material. A recombinant ELP (VPGXG)40 with X = V,M (3:1) was post-modified in two steps to introduce chemoselectively either primary or secondary amine pendant groups at each methionine residue. Positively charged ELPs were characterized by SDS-PAGE, size exclusion chromatography, 1H NMR, potentiometric titrations and dynamic light scattering to assess their purity and determine their degree of functionalization, molecular weight, isoelectric point and thermo-responsive behaviour. Electrostatic complexation between the different ELP derivatives and nucleic acids was studied to determine the stoichiometry of ELPS/nucleic acids complex formation, and to find optimal conditions leading to stable nanoparticles with controlled size and surface potential. The stability of these complexes was investigated in the presence of salts at physiological concentrations and in the presence of surfactant. This study revealed that two regimes of stable nanoparticles in terms of size and charge can be obtained from the electrostatic complexation between the primary amine containing ELP derivative, ELP(-NH2), and plasmid DNA. Resulting complexes were found to be stable to dissociation for charge ratios up to 2.5 under physiological salt concentrations (154 mM NaCl), showing that plasmid DNA was completely condensed by the polycationic ELP and protected against electrolyte-mediated dissociation.

Analysis of referrals after a synergic work between Primary Care and Urology. Impact of joint protocol implementation and a continuing education program in our healthcare area. / Evolución de las derivaciones desde Atención Primaria a Urología tras la creación de un grupo de trabajo y la instauración de protocolos y cursos de formación continuada.

OBJECTIVE: To analyse the evolution and adequacy of referrals from Primary Care to Urology, after the implementation of referral protocols on the most frequent urological diseases and the establishment of a continuing education program. MATERIAL AND METHODS: A Primary Care-Urology work group was created in 2011. Initially, performance and clinical practice protocols in prostatic pathology (BPH and PSA) were established. These were supported by training sessions for primary care physicians. After analysing the effect of the mentioned joint work, 3more (scrotal pathology, urinary tract infections and urinary incontinence) were included. We analysed and compared the referrals and their adequacy before and after the establishment of the protocols. RESULTS: The most common referral causes were symptoms of the lower urinary tract due to BPH, which initially represented 22.8% of the total, and decreased to 16.9%. After the introduction of the new algorithms, we observed a decrease in referrals for scrotal pathology (13-14% to 7.8%), an increase in urinary incontinence referrals (3% al 10.3%) and those related to urinary tract infections remained stable. The adequacy to the protocols improved progressively: LUTS from 46% to 65.3%; PSA from 55% to 84.4% and urinary incontinence from 66.2% to 73.1%. Adequacy in scrotal pathology decreased (de 67.1% a 63.3%), while in UTI it stayed much the same (around 76%). CONCLUSIONS: The joint work between Urology and Primary Care achieves an improvement in referrals adequacy regarding the most frequent urological pathologies.

Preventing the recurrence of depression with a Mediterranean diet supplemented with extra-virgin olive oil. The PREDI-DEP trial: study protocol.

BACKGROUND: The role of dietary patterns in the prevention of unipolar depression has been analyzed in several epidemiological studies. The primary aims of this study are to determine the effectiveness of an extra-olive oil-enriched Mediterranean diet in reducing the recurrence of depression and improving the symptoms of this condition. METHODS: Multicenter, two-arm, parallel-group clinical trial. Arm 1, extra-virgin olive oil Mediterranean diet; Arm 2, control group without nutritional intervention. Dieticians are in charge of the nutritional intervention and regular contact with the participants. Contacts are made through our web platform ( https://predidep.es/participantes/ ) or by phone. Recurrence of depression is assessed by psychiatrists and clinical psychologists through clinical evaluations (semi-structured clinical interviews: Spanish SCID-I). Depressive symptoms are assessed with the Beck Depression Inventory. Information on quality of life, level of physical activity, dietary habits, and blood, urine and stool samples are collected after the subject has agreed to participate in the study and once a year. DISCUSSION: To the best of our knowledge, the PREDI-DEP trial is the first ongoing randomized clinical trial designed to assess the role of the Mediterranean diet in the prevention of recurrent depression. It could be a cost-effective approach to avoid recurrence and improve the quality of life of these patients. TRIAL REGISTRATION: The study has been prospectively registered in the U.S. National Library of Medicine ( https://clinicaltrials.gov ) with NCT number: NCT03081065.

Overactive bladder symptom bother and health-related quality of life in patients with systemic lupus erythematosus and primary Sjögren syndrome.

OBJECTIVE: The objective of this paper is to assess overactive bladder (OAB) symptom bother (SB) and health-related quality of life (HRQL) among patients with systemic lupus erythematosus (SLE) and primary Sjögren syndrome (pSS). METHODS: We recruited adult SLE and pSS patients and two groups of age- and sex-matched controls. We applied the OAB questionnaire-short form (OABq-SF) to all participants to assess SB and HRQL and collected clinical information relevant for OAB. We compared the OABq-SF scores for SB and HRQL between patients and controls using univariate and multivariate linear regression analysis. RESULTS: We recruited 95 rheumatic patients (68 SLE, 27 pSS) and 231 controls. Compared to controls SLE patients showed higher OABq-SF SB scores (22.6 ± 20.4 vs 14.7 ± 17.0, p = 0.004) and lower HRQL scores (89.8 ± 15.8 vs 93.8 ± 11.4, p = 0.044). On multivariate analysis SLE was significantly associated with a higher SB score (ß-coefficient 7.13, p = 0.008) and tended to be associated with worse HRQL values (ß-coefficient -3.53, p = 0.055). Patients with pSS had numerically higher mean SB scores (22.8 ± 22.5 vs 16.2 ± 18.0, respectively, p = 0.107) and lower HRQL scores (91.0 ± 10.7 vs 93.2 ± 11.6, respectively, p = 0.369), although these differences were not statistically significant. Diagnosis of pSS was not significantly associated with SB or HRQL scores on univariate or multivariate analysis. CONCLUSIONS: Patients with SLE have significantly worse OAB-SB and poorer HRQL compared to controls. A similar trend was seen for pSS patients, especially for SB. These findings suggest that clinically subtle OAB symptoms may be present in rheumatic patients for whom, later on, bladder pain syndrome may occur.