Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that ...in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND
Options to treat elderly patients (≥65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without ...venetoclax, and supportive care. This multicenter, randomized, open‐label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA).
METHODS
Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was ≥0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow‐up phase.
RESULTS
The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1‐year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval CI, 5.6‐14 months) versus 4.1 months (95% CI, 2.7‐5.5 months; P = .005), respectively. The median event‐free survival was 4.9 months (95% CI, 2.8‐7 months) with AZA and 3 months (95% CI, 2.5‐3.5 months) with FLUGA (P = .001).
CONCLUSIONS
FLUGA achieved more remissions after 3 cycles, but the 1‐year OS rate was superior with AZA. However, long‐term outcomes were disappointing in both arms (3‐year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.
Azacitidine improves 1‐year overall survival in comparison with a semi‐intensive chemotherapy schedule (FLUGA). The complete remission/complete remission with incomplete blood count recovery rate after 3 cycles is lower in an azacitidine arm than a FLUGA arm, but the best response achieved is similar for the 2 groups.
Objective
To investigate the effect of an Enhanced Recovery After Surgery (ERAS) program on complications and length of stay (LOS) after radical cystectomy (RC) and to assess if the number and type ...of components of ERAS play a key role on the decrease of surgical morbidity.
Materials and methods
We analyzed the data of 277 patients prospectively recruited in 11 hospitals undergoing RC initially managed according to local practice (Group I) and later within an ERAS program (Group II). Two main outcomes were defined: 90-day complications rate and LOS. As secondary variables we studied 90-day mortality, 30-day readmission and transfusion rate.
Results
Patients in Group II had a higher use of ERAS measures (98.6%) than those in Group I (78.2%) (
p
< 0.05). Patients in Groups I and II experienced similar complications (70.5% vs. 66%,
p
= 0.42). LOS was not different between Groups I and II (12.5 and 14 days, respectively,
p
= 0.59). The risk of having any complication decreases for patients having more than 15 ERAS measures adopted RR = 0.815; 95% confidence interval (CI) 0.667–0.996;
p
= 0.045. Avoidance of transfusion and nasogastric tube, prevention of ileus, early ambulation and a fast uptake of a regular diet are independently associated with the absence of complications.
Conclusions
Complications and LOS after RC were not modified by the introduction of an ERAS program. We hypothesize that at least 15 measures should be applied to maximize the benefit of ERAS
Myxoid liposarcoma is classified in the group of sarcomas with adipose differentiation, which is the second most common group of sarcomas. However, myxoid liposarcoma is not a homogeneous entity, ...because the behavior and clinical course of these tumors can vary widely. This study aimed to describe the magnetic resonance imaging (MRI) features of myxoid liposarcomas and to determine whether the MRI features are associated with the histologic grade and can differentiate between low-grade and high-grade tumors and thus help in clinical decision making.
We studied 36 patients with myxoid liposarcomas treated at our center between 2010 and 2018. We analyzed clinical variables (age, sex, and tumor site) and MRI features (size, depth, borders, fatty component, myxoid component, non-fatty / non-myxoid component, apparent diffusion coefficient (ADC), and type of enhancement after the administration of intravenous contrast material). We correlated the MRI features with the histologic grade and the percentage of round cells.
In our series, patients with myxoid liposarcomas were mainly young adults (median age, 43 years). There were no differences between sexes; 97.2% were located in the lower limbs, 86.1% were deep, and 77.8% had well-defined borders. Of the 23 myxoid liposarcomas that contained no fat, 16 (69.6%) were high grade (p=0.01). All the tumors with a myxoid component of less than 25% were high grade (p=0.01); 83.3% of those with a non-fatty / non-myxoid component greater than 50% were high grade (p=0.03) and 61.5% had more than 5% round cells (p=0.01). Diffusion sequences were obtained in 14 of the 36 patients; ADC values were high (median, 2 x 10
mm
/s), although there were no significant associations between low-grade and high-grade tumors. Contrast-enhanced images were available for 30 (83.3%) patients; 83.3% of the tumors with heterogeneous enhancement were high grade (p=0.01).
MRI can be useful for differentiating between high- and low-grade myxoid liposarcomas and can help in clinical decision making.
Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug ...Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.
After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.
In terms of toxicities, non-PPT displayed 22% grade 3–4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.
Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.
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Pelvic organ prolapse is a condition with high prevalence in elderly women. With increasing life expectancy and a desire for improved quality of life, a rise in the frequency of ...surgical treatments for these women is anticipated. The aim is to compare complication, success, and satisfaction rates among elderly patients (aged >70 years) in comparison to younger women undergoing robotic sacrocolpopexy, thereby assessing the safety and efficacy of this surgery in this group of patients.
A prospective observational comparative study of 123 robotic sacrocolpopexies conducted between December 2016 and June 2022. Patients were stratified by age (cutoff point: 70 years). Baseline characteristics, type, and grade of prolapse, intra and postoperative data, complications, functional and anatomical outcomes, and satisfaction levels were collected.
Among the 123 patients, 62.6% were under 70 years old, while 37.4% were 70 years or older, exhibiting similar baseline characteristics, prolapse grade, and type. The percentages of intraoperative (6.5%) and postoperative complications (4.4–9%) were comparable in both age groups. Furthermore, success and satisfaction rates exceeded 90%, with no significant differences between women under and over 70 years during a two-year follow-up.
Robotic sacrocolpopexy is at least as effective and safe in women aged 70 years or older as in younger individuals, with no higher rates of intra and postoperative complications and similar rates of anatomical and subjective success.
El prolapso de órganos pélvicos es una patología con alta prevalencia en mujeres de edad avanzada. Con el aumento de la esperanza de vida y la búsqueda de una mejor calidad de vida se prevé un incremento en la frecuencia de tratamientos quirúrgicos en estas mujeres. El objetivo es comparar la tasa de complicaciones, éxito y satisfacción en pacientes de edad avanzada (>70 años) frente mujeres jóvenes intervenidas mediante colposacropexia robótica y así valorar la seguridad y eficacia de esta cirugía en dicho grupo de pacientes.
Estudio observacional prospectivo comparativo de 123 colposacropexias robóticas entre diciembre 2016 y junio 2022. Las pacientes fueron estratificadas según edad (punto de corte 70 años). Se recopilaron las características basales, tipo y grado de prolapso, datos intra y postoperatorios, complicaciones, resultados funcionales y anatómicos y grado de satisfacción.
Entre las 123 pacientes, el 62.6% tenía menos de 70 años, mientras que el 37.4% tenía 70 años o más, presentando características basales, grado y tipo de prolapso similares. Los porcentajes de complicaciones intraoperatorias (6.5%) y postoperatorias (4.4–9%) fueron comparables en ambos grupos de edad. Además, las tasas de éxito y satisfacción fueron superiores al 90%, sin diferencias significativas entre mujeres menores y mayores de 70 años durante un seguimiento de dos años.
La colposacropexia robótica es al menos tan eficaz y segura en mujeres de 70 años o mayores como en jóvenes sin mayor tasa de complicaciones intra y postoperatorias y con una tasa de éxito anatómico y subjetivo similar.
INTRODUCTIONPudendal nerve entrapment syndrome (PNE) is characterised by the presence of neuropathic pain in the pudendal nerve (PN) territory, associated or not with urinary, defecatory and sexual ...disorders. Surgical PN decompression is an effective and safe alternative for cases when conservative treatment fails. The aim of this study is to describe the first robot-assisted pudendal neurolysis procedure performed in our country. MATERIAL AND METHODSWe describe step by step the technique of robot-assisted laparoscopic neurolysis of the left PN performed with intraoperative neurophysiological monitoring on a 60-year-old patient diagnosed with left PNE. RESULTSThe procedure was performed satisfactorily without complications. After 24h, the patient was discharged from the hospital. We observed a 50% reduction in pain measured using the visual analogue scale 2 weeks after the procedure, which remained after 10 weeks of the neurolysis. CONCLUSIONSRobot-assisted neurolysis of the PN constitutes a feasible and safe approach, enabling better visualisation and accuracy in the dissection of the PN. Intraoperative neurophysiological monitoring is useful for locating the PN and for detecting intraoperative changes after the release of the nerve.
Background and ImportanceImmunotherapy has provided better responses and tolerance in the treatment of lung cancer than intravenous chemotherapy. However, it can also induce autoimmune adverse ...effects that could lead to hospital admission or death of the patient.Aim and ObjectivesTo analyse possible factors associated with the incidence of immune-related adverse events (iRAEs) in lung cancer (LC) patients treated with immune checkpoint inhibitors (ICI).Material and MethodsRetrospective analysis of patients with LC treated with ICI between 2015 and 2023 in a tertiary hospital. The variables collected from the clinical history were: age, sex, performance status, history of allergy/autoimmune disease, treatment with corticosteroids or antibiotics prior to the ICI, occurrence of iRAEs, type of toxicity and severity, laboratory variables (haemoglobin, neutrophil count, platelet count, LDH), date of progression and death. The association was determined using Chi-square tests and Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier methodResultsA total of 67 patients (74.6% men; mean age 68.6±9.4 years) treated with ICI were analysed. Of these, 49 developed at least one iRAE (73.1%), 37.3% from grade≥3. Statistically significant associations were found between appearance of skin toxicity and altered LDH levels (p=0.048), and musculoskeletal toxicity and ECOG≥2 (p=0.037). History of allergy/autoimmune disease and treatment with corticosteroids or antibiotics in the 3 months prior to the start of immunotherapy were associated with the appearance of liver toxicity (p=0.015 in all cases), asthenia (p=0.027; p=0.021; p=0.032) and musculoskeletal toxicity (p=0.006; p=0.006); p=0.005). Patients with iRAEs had longer PFS (14.8 vs. 3.3 months) and longer OS (19.2 vs. 2.9 months).Conclusion and RelevanceNo association was found between the proposed variables and the appearance of immune-related toxicity in general but a significant relation was found between altered LDH and skin toxicity, and between ECOG≥2 and musculoskeletal toxicity. Correlation was also found between a history of allergy or autoimmune disease and the consumption of antibiotics or corticosteroids with the appearance of hepatic, general or musculoskeletal toxicity.References and/or AcknowledgementsConflict of InterestNo conflict of interest.
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