RESUMEN
Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Inactivadores del Complemento , Hemoglobinuria Paroxística , Humanos , Hemoglobinuria Paroxística/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Adulto , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/efectos adversos , Inactivadores del Complemento/administración & dosificación , Anciano , Complemento C5/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
Background and purpose:
The management of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthalmology departments together with etiological investigations lacking a standardised protocol. However, CRAO is analogous to ischemic central nervous system stroke and is associated with increased stroke risk, thus, systemic thrombolysis treatment and multidisciplinary management can be beneficial. Since May 2022, at Semmelweis University CRAO patients diagnosed within 4.5 hours are given intravenous thrombolysis therapy and undergo etiologic workup based on current stroke protocols. Here we report our experience with the multidisciplinary, protocol-based management of CRAO in comparison with former non-protocol based ophthalmological conservative treatment.
. Methods:We reviewed CRAO patients’ data treated conservatively and with paracentesis within 6 hours at the Department of Ophthalmology between 2013 and 2022 including changes in visual acuity, neurological and cardiovascular findings compared to those in the thrombolysis project.
. Results:Of the 78 patients receiving non-protocol care, visual improvement was seen in 37% with natural course, 47% with conservative treatment and 47% with paracentesis. Four patients had significant carotid stenosis (2 underwent endarterectomy), 1 carotid dissection, 6 cardioembolism and 1 giant cell arteritis. Of the 4 patients within 4,5 hours, 3 gave their consent to the clinical trial and were treated with thrombolysis and underwent a full etiological assessment.
2 patients had improved visual acuity, 2 patients had significant carotid stenosis and underwent endarterectomy, 1 patient was started on anticoagulation for newly diagnosed atrial fibrillation.
CRAO patients presenting within 4,5 hours are rare and more patients are needed in our study to establish the efficacy of thrombolysis. However uniform protocollized evaluation helps identifying embolic sources thus, avoiding further and potentially more serious thromboembolic events.
.Asunto(s)
Estenosis Carotídea , Accidente Cerebrovascular Isquémico , Oclusión de la Arteria Retiniana , Accidente Cerebrovascular , Humanos , Terapia Trombolítica/métodos , Estenosis Carotídea/complicaciones , Estenosis Carotídea/terapia , Oclusión de la Arteria Retiniana/tratamiento farmacológico , Oclusión de la Arteria Retiniana/diagnóstico , Accidente Cerebrovascular/tratamiento farmacológico , Tratamiento ConservadorRESUMEN
OBJECTIVE: To study the relationship between neighborhood deprivation index (NDI) and markers of ovarian reserve and outcomes of controlled ovarian stimulation among young, healthy oocyte donors. DESIGN: Retrospective cohort study. PATIENTS: A total of 547 oocyte donors who underwent 905 oocyte retrieval cycles (2008-2020) at a private fertility center in Sandy Springs, Georgia, United States. INTERVENTIONS: Neighborhood deprivation index was calculated using principal component analysis applied to census-level measures of poverty, employment, household composition, and public assistance, which was then standardized and linked to donor information on the basis of donor residence. MAIN OUTCOME MEASURES: Markers of ovarian reserve, including antral follicle count (AFC) and antimüllerian hormone (AMH) levels, and outcomes of controlled ovarian stimulation including number of total and mature oocytes retrieved and ovarian sensitivity index (OSI) (defined as the number of oocytes retrieved/total gonadotropin dose × 1,000). Multivariable generalized estimating equations with Poisson and normal distribution were used to model the relationship between NDI and outcome measures adjusting for age, body mass index, and year of retrieval. RESULTS: The mean (SD) age of donors was 25.0 (2.8) years and 29% of the donors were racial or ethnic minorities. There were no associations between donor NDI and ovarian reserve markers. For every interquartile range increase in NDI, there was a reduction of -1.5% (95% confidence interval: -5.3% to 2.4%) in total oocytes retrieved although the effect estimate was imprecise. Associations of NDI with a number of mature oocytes retrieved and OSI were in a similar direction. We observed evidence for effect modification of the NDI and OSI association by donor race. There was a suggestive positive association between NDI and OSI in Black donors but no association in White donors. CONCLUSION: In this cohort of young, healthy, racially diverse oocyte donors, we found little evidence of associations between NDI and markers of ovarian reserve or outcomes of ovarian stimulation.
Asunto(s)
Donación de Oocito , Reserva Ovárica , Inducción de la Ovulación , Humanos , Femenino , Adulto , Reserva Ovárica/fisiología , Estudios Retrospectivos , Inducción de la Ovulación/métodos , Adulto Joven , Características de la Residencia , Recuperación del Oocito/estadística & datos numéricos , Resultado del Tratamiento , Georgia/epidemiología , PobrezaRESUMEN
Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.
Asunto(s)
Interferón alfa-2 , Interferón-alfa , Polietilenglicoles , Proteínas Recombinantes , Trombocitemia Esencial , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Interferón alfa-2/uso terapéutico , Interferón alfa-2/efectos adversos , Interferón-alfa/uso terapéutico , Interferón-alfa/efectos adversos , Polietilenglicoles/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/administración & dosificación , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/administración & dosificación , Trombocitemia Esencial/tratamiento farmacológico , Resultado del Tratamiento , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Inmunoterapia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma based on the results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis of this study. Eighty patients ≥18 years who had received one to three prior systemic therapies, and had Eastern Cooperative Oncology Group performance status 0-2 received up to 12 cycles of co-administered tafasitamab and lenalidomide, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy. At data cutoff on November 14, 2022, the objective response rate was 57.5%, with a complete response rate of 41.3% (n=33), which was consistent with prior analyses. With a median follow-up of 44.0 months, the median duration of response was not reached. The median progression-free survival was 11.6 months (95% confidence interval [95% CI]: 5.7-45.7) with a median follow-up of 45.6 months. The median overall survival was 33.5 months (95% CI: 18.3-not reached) with a median follow-up of 65.6 months. Patients who had received one prior line of therapy (n=40) showed a higher objective response rate (67.5%; 52.5% complete responses) compared to patients who had received two or more prior lines of therapy (n=40; 47.5%; 30% complete responses), but the median duration of response was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with those described in previous reports, were manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that the immunotherapy combination of tafasitamab and lenalidomide is well tolerated and has long-term clinical benefit with durable responses.
Asunto(s)
Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Humanos , Lenalidomida/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
Studies in mice and older, subfertile women have found that air pollution exposure may compromise female reproduction. Our objective was to evaluate the effects of air pollution on ovarian reserve and outcomes of ovarian stimulation among young, healthy females. We included 472 oocyte donors who underwent 781 ovarian stimulation cycles at a fertility clinic in Atlanta, Georgia, USA (2008-2019). Antral follicle count (AFC) was assessed with transvaginal ultrasonography and total and mature oocyte count was assessed following oocyte retrieval. Ovarian sensitivity index (OSI) was calculated as the total number of oocytes divided by total gonadotrophin dose × 1000. Daily ambient exposure to nitric oxide (NOx), carbon monoxide (CO), and particulate matter ≤ 2.5 (PM2.5) was estimated using a fused regional + line-source model for near-surface releases at a 250 m resolution based on residential address. Generalized estimating equations were used to evaluate the associations of an interquartile range (IQR) increase in pollutant exposure with outcomes adjusted for donor characteristics, census-level poverty, and meteorological factors. The median (IQR) age among oocyte donors was 25.0 (5.0) years, and 31% of the donors were racial/ethnic minorities. The median (IQR) exposure to NOx, CO, and PM2.5 in the 3 months prior to stimulation was 37.7 (32.0) ppb, 612 (317) ppb, and 9.8 (2.9) µg/m3, respectively. Ambient air pollution exposure in the 3 months before AFC was not associated with AFC. An IQR increase in PM2.5 in the 3 months before AFC and during stimulation was associated with -7.5% (95% CI -14.1, -0.4) and -6.4% (95% CI -11.0, -1.6) fewer mature oocytes, and a -1.9 (95% CI -3.2, -0.5) and -1.0 (95% CI -1.8, -0.2) lower OSI, respectively. Our results suggest that lowering the current 24-h PM2.5 standard in the US to 25 µg/m3 may still not adequately protect against the reprotoxic effects of short-term PM2.5 exposure.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Infertilidad , Reserva Ovárica , Adulto , Femenino , Humanos , Contaminantes Atmosféricos/toxicidad , Oocitos , Material Particulado/toxicidad , Adulto JovenRESUMEN
INTRODUCTION: Acute myeloid leukemia (AML) is a hematological malignancy with high mortality rate. The treatment is especially challenging in patients older than 65 years, which is the large majority of those. For patients unfit for intensive chemotherapy regimens, only palliative cytoreduction and basic supportive care used to be the options in our unit. However, from 2018, the azacitidine-venetoclax combination has been a new therapeutic alternative. This treatment resulted in marked survival benefit in clinical trials, however, its impact on the daily clinical practice and the entire patient population is unclear. OBJECTIVE: Our goal was to evaluate how the application of azacitidine-venetoclax changed the treatment and survival of AML patients in our practice. METHOD: We retrospectively analyzed the available clinical data of all AML patients treated consecutively between January 1, 2011 and December 31, 2021 at the 3rd Department of Internal Medicine (from 2020 onward called Department of Internal Medicine and Hematology), examining their treatment depending on the time period of therapy (2011-2017 and 2018-2021). Patients with acute promyelocytic leukemia were excluded. RESULTS: 423 patients were diagnosed during this period. The number of cases showed a marked increase: in the first 7 years of our study, 184 patients were diagnosed, while this rose to 239 during the subsequent 4 years. The median age of patients was 67.6 years, with more than 60% of patients aged over 65. An improving trend can be observed in the overall survival: between 2011 and 2017, the median overall survival was 4.8 ± 0.9 months, while between 2018 and 2021, it was 8.3 ± 1.4 months (p = 0.051). Moreover, in the case of patients over 65 there was a significant overall survival improvement: 3.1 ± 0.5 vs. 4.9 ± 0.6 months (p = 0,01). The main factor behind this improvement could be that a large proportion of over 65 patients previously only fit for supportive care could now be treated with azacitidine-venetoclax: the percentage of actively treated patients grew from 57.1% to 75.3% in the second period. CONCLUSION: The survival of patients unfit for curative therapy and older than 65 showed a steady increase which can be attributed to the introduction of new therapeutic alternatives. Orv Hetil. 2023; 164(45): 1787-1794.
Asunto(s)
Azacitidina , Leucemia Mieloide Aguda , Humanos , Anciano , Azacitidina/uso terapéutico , Azacitidina/efectos adversos , Estudios Retrospectivos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
OBJECTIVES: As jaw-tracking systems integrate into digital prosthetic workflows, their accuracy remains underexplored. This study aimed to evaluate the in vitro accuracy of a novel digital jaw-tracking system (Modjaw, Villeurbanne, France) by comparing its precision and trueness to that of an industrial scanner. METHODS: Upper and lower typodont models were scanned with an industrial-grade optical scanner (ATOS Q, Carl Zeiss GOM Metrology GmbH, Germany) to produce master scans. The models were placed in a phantom head with artificial joints to replicate five different intermaxillary relationships (IMRs). The 1, 2, 3, 4, and 5 mm IMR distances were stabilized by five silicone bites. The silicone bites were repositioned after each measurement. ATOS scanned the whole artificial joint with the models three times in each IMR to assess the precision of the repositioning (i.e., bite precision). The master scans were uploaded to Modjaw. Modjaw recorded the five IMR positions three times each to assess the precision of the Modjaw. Precision was calculated by aligning the scans within the same group, whereas Modjaw trueness was evaluated by aligning ATOS and Modjaw scans. The mean absolute distance (MAD) between aligned surfaces was calculated. The effect of IMR on the MAD was evaluated using a linear mixed model. RESULTS: The mean bite precision across the IMRs was 7.6 ± 0.53 µm. Modjaw precision over the IMRS was 9.7 ± 1.76 µm, and the trueness was 10.8 ± 1.40 µm. Increased IMRs up to 4 mm significantly increased the MAD from 6.5 to 8.5 µm for the bite precision, 4.8 to 15.7 µm Modjaw precision, and 7.1 to 14.9 µm for trueness. CONCLUSIONS: Modjaw excelled in accuracy, comparable to industrial scanners and superior to traditional methods. IMR elevation marginally deteriorates the accuracy. Future studies should extend to varied movements beyond centric relations and encompass the influence of intraoral scanners.
Asunto(s)
Técnica de Impresión Dental , Modelos Dentales , Diseño Asistido por Computadora , Imagenología Tridimensional , SiliconasRESUMEN
OBJECTIVES: This study reports long-term outcomes from the open-label extension (OLE) period of the Phase I/II COMPOSER trial (NCT03157635) that evaluated crovalimab in patients with paroxysmal nocturnal haemoglobinuria, who were treatment-naive or switched from eculizumab at enrolment. METHODS: COMPOSER consists of four sequential parts followed by the OLE. The primary OLE objective was to assess long-term crovalimab safety, with a secondary objective to assess crovalimab pharmacokinetics and pharmacodynamics. Exploratory efficacy endpoints included change in lactate dehydrogenase (LDH), transfusion avoidance, haemoglobin stabilisation and breakthrough haemolysis (BTH). RESULTS: A total 43 of 44 patients entered the OLE after completing the primary treatment period. Overall, 14 of 44 (32%) experienced treatment-related adverse events. Steady state exposure levels of crovalimab and terminal complement inhibition were maintained over the OLE. During the OLE, mean normalised LDH was generally maintained at ≤1.5× upper limit of normal, transfusion avoidance was achieved in 83%-92% of patients and haemoglobin stabilisation was reached in 79%-88% of patients across each 24-week interval. Five BTH events occurred with none leading to withdrawal. CONCLUSIONS: Over a 3-year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved. Intravascular haemolysis control, haemoglobin stabilisation and transfusion avoidance were maintained, signifying long-term crovalimab efficacy.
Asunto(s)
Hemoglobinuria Paroxística , Humanos , Hemoglobinuria Paroxística/diagnóstico , Hemoglobinuria Paroxística/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Transfusión Sanguínea , Hemoglobinas , Duración de la Terapia , Hemólisis , L-Lactato DeshidrogenasaRESUMEN
The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10-4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax-rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.
Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Resistencia a Antineoplásicos/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Recurrencia , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mutación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Progresión de la EnfermedadRESUMEN
As the recent outbreak of coronavirus disease 2019 (COVID-19) has shown, viral infections are prone to secondary complications like invasive aspergillosis with a high mortality rate, and therefore the development of novel, effective antifungals is of paramount importance. We have previously demonstrated that 1-amino-5-isocyanonaphthalene (ICAN) derivatives are promising original drug candidates against Candida strains (Patent pending), even against fluconazole resistant C. albicans. Consequently, in this study ICANs were tested on Aspergillus fumigatus, an opportunistic pathogen, which is the leading cause of invasive and systematic pulmonary aspergillosis in immunosuppressed, transplanted and cancer- or COVID-19 treated patients. We have tested several N-alkylated ICANs, a well as 1,5-naphthalene-diisocyanide (DIN) with the microdilution method against Aspergillus fumigatus strains. The results revealed that the diisocyanide (DIN) was the most effective with a minimum inhibitory concentration (MIC) value as low as 0.6 µg mL-1 (3.4 µM); however, its practical applicability is limited by its poor water solubility, which needs to be overcome by proper formulation. The other alkylated derivatives also have in vitro and in vivo anti-Aspergillus fumigatus effects. For animal experiments the second most effective derivative 1-N, N-dimethylamino-5-isocyanonaphthalene (DIMICAN, MIC: 7-8 µg mL-1, 36-41 µM) was selected, toxicity tests were made with mice, and then the antifungal effect of DIMICAN was tested in a neutropenic aspergillosis murine model. Compared to amphotericin B (AMB), a well-known antifungal, the antifungal effect of DIMICAN in vivo turned out to be much better (40% vs. 90% survival after eight days), indicating its potential as a clinical drug candidate.
RESUMEN
While metastases are the most common intraocular malignancies, ocular metastases of renal cell carcinoma are rare. The most frequent primary malignancy of the eye is uveal melanoma. The common ocular localization is the choroid in both cases. The clinical differentiation of choroidal metastasis from renal cell carcinoma and choroidal melanoma malignum is a diagnostic challenge for the ophthalmologist. We present two cases where renal cell carcinoma had metastasized to the choroid. Enucleation was performed in a 61- and a 71-year-old male patient with suspected advanced choroidal malignant melanoma following biomicroscopic and B-scan ultrasonography examination. Histopathological examination confirmed clear-cell renal cell carcinoma in both cases. The clinical and ultrasonographic appearance of clear-cell renal cell carcinoma metastasis may mimic choroidal malignant melanoma, and may only be suspected if a primary renal cell carcinoma is already established.
Asunto(s)
Carcinoma de Células Renales , Neoplasias de la Coroides , Melanoma , Anciano , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/cirugía , Neoplasias de la Coroides/diagnóstico por imagen , Neoplasias de la Coroides/cirugía , Humanos , Masculino , Melanoma/diagnóstico por imagen , Melanoma/cirugía , Neoplasias de la ÚveaRESUMEN
Despite the introduction of novel agents, multiple myeloma remains incurable for most patients, necessitating further therapeutic options. Venetoclax, a selective BCL-2 inhibitor, had shown promising results in patients with translocation t(11;14), but questions remain open about its optimal use. We have contacted all Hungarian haematology centers for their experience treating t(11;14) myeloma patients with venetoclax. 58 patients were reported. 37 received venetoclax in the relapsed/refractory setting with few or no other therapeutic options available. 21 patients started venetoclax as salvage after failing to achieve satisfactory response to first line therapy. In the relapsed/refractory setting objective response rate (ORR) was 94%, median progression-free survival (PFS) 10.0 months and median overall survival (OS) 14.6 months. In reinduction patients, ORR was 100%, median PFS and OS were not reached. Importantly, we found no adverse effect of high risk features such as deletion 17p or renal failure, in fact renal failure ameliorated in 42% of the cases, including three patients who became dialysis independent. Our study also reports the highest number of plasma cell leukemia cases successfully treated with venetoclax published in literature, with refractory plasma cell leukemia patients achieving a median PFS of 10.0 and a median OS of 12.2 months.
Asunto(s)
Mieloma Múltiple , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Humanos , Hungría , Mieloma Múltiple/tratamiento farmacológico , Sulfonamidas/uso terapéuticoRESUMEN
Vitrification, is an ultra-rapid, manual cooling process that produces glass-like (ice crystal-free) solidification. Water is prevented from forming intercellular and intracellular ice crystals during cooling as a result of oocyte dehydration and the use of highly concentrated cryoprotectant. Though oocytes can be cryopreserved without ice crystal formation through vitrification, it is still not clear whether the process of vitrification causes any negative impact (temperature change/chilling effect, osmotic stress, cryoprotectant toxicity, and/or phase transitions) on oocyte quality, which translates to diminished embryo developmental potential or subsequent clinical outcomes. In this review, we attempt to assess the technique's potential effects and the consequence of these effects on outcomes.
Asunto(s)
Oocitos , Vitrificación , Frío , Criopreservación , Crioprotectores/farmacologíaRESUMEN
Valved allografts and xenografts for reconstruction of the right ventricular outflow tract (RVOT) lack durability and do not grow. We report the first clinical use of a completely bioabsorbable valved conduit (Xeltis pulmonary valve - XPV) in children. Twelve children (six male), median age five (two to twelve) years and median weight 17 (10 to 43) kg, underwent RVOT reconstruction with the XPV. Diagnoses were: pulmonary atresia with ventricular septal defect (VSD) (n = 4), tetralogy of Fallot (n = 4), common arterial trunk (n = 3), and transposition of the great arteries with VSD and pulmonary stenosis (n = 1). All had had previous surgery, including prior RVOT conduit implantation in six. Two diameters of conduit 16mm (n = 5) and 18mm (n = 7) were used. At 24 months none of the patients has required surgical re-intervention, 9 of the 12 are in NYHA functional class I and three patients in NYHA class II. None of the conduits has shown evidence of progressive stenosis, dilation or aneurysm formation. Residual peak gradient of >40 mm Hg was observed in three patients, caused by kinking of the conduit at implantation in 1 and distal stenosis in the peripheral pulmonary arteries in 2 patients. Five patients developed severe pulmonary valve insufficiency (PI); the most common mechanism was prolapse of at least one of the valve leaflets. The XPV conduit is a promising innovation for RVOT reconstruction. Progressive PI requires however an improved design (geometry, thickness) of the valve leaflets.
Asunto(s)
Bioprótesis , Defectos del Tabique Interventricular , Prótesis Valvulares Cardíacas , Válvula Pulmonar , Transposición de los Grandes Vasos , Obstrucción del Flujo Ventricular Externo , Niño , Preescolar , Constricción Patológica , Femenino , Defectos del Tabique Interventricular/cirugía , Humanos , Masculino , Válvula Pulmonar/diagnóstico por imagen , Válvula Pulmonar/cirugía , Resultado del Tratamiento , Obstrucción del Flujo Ventricular Externo/cirugíaRESUMEN
Összefoglaló. Bevezetés: A colorectalis eredetu májáttétek (CRCLM-ek) kuratív célú kezelésében elsodleges a sebészi reszekció. A mutét elott különbözo képalkotó vizsgálatok végezhetok, az egyik ilyen speciális vizsgálat a májsejtspecifikus kontrasztanyaggal végzett MR-vizsgálat. Célkituzés: Tanulmányunkban a májsejtspecifikus kontrasztanyaggal végzett MR-vizsgálat helyét és szerepét vizsgáltuk a májsebészeti gyakorlatban colorectalis áttétes betegek esetében. Módszer: Az Uzsoki Utcai Kórház Sebészeti-Onkosebészeti Osztályán 2017. 01. 01. és 2019. 12. 31. között CRCLM miatt májreszekcióra kerülo betegek adatait elemeztük. Retrospektív módon vizsgáltuk a betegek általános sebészeti és onkosebészeti paramétereit, a képalkotó diagnosztikai eredményeket, a mutéti adatokat és a patológiai leleteket. Eredmények: 132, CRCLM miatt operált betegbol 73 szoliter áttét (55%), míg 59 beteg (45%) többszörös áttét miatt került mutétre. 94 betegnél (71%) történt májsejtspecifikus MR-vizsgálat. Szoliter áttét esetén 60%-ban, multiplex áttétek esetén 85%-ban történt májsejtspecifikus MR-vizsgálat (p = 0,02). A szoliter áttétes betegek 8%-ában, míg a multiplex áttétes betegek 39%-ában mutatott további áttétet a májspecifikus kontrasztanyaggal végzett MR-vizsgálat (p = 0,001). A betegek 5%-ában igazolódott fals pozitivitás és 6%-ában fals negativitás a májsejtspecifikus MR-vizsgálat során. 264 góc vizsgálata alapján a májspecifikus kontrasztanyaggal végzett MR-vizsgálat szenzitivitása CRCLM esetén 95%-os, míg pozitív prediktív értéke 93%-os volt vizsgálatunkban. Következtetés: A májsejtspecifikus kontrasztanyaggal végzett MR-vizsgálat hasznos diagnosztikai módszer a CRCLM-ek sebészi reszekciója elott. Leginkább többszörös áttétek esetén, preoperatív szisztémás onkológiai kezelést követoen, illetve más képalkotó vizsgálaton igazolt eltunt áttét esetén javasolható az alkalmazása. Orv Hetil. 2021; 162(50): 2010-2016. INTRODUCTION: Liver resection is the only curtive treatment option of colorectal cancer liver metastases (CRCLMs). While different diagnostic modalities are available before surgery, a specific diagnostic tool is the liver-specific contrast-enhanced MRI. OBJECTIVE: The purpose of this study was to evaluate the role of liver-specific contrast-enhanced MRI before resection of colorectal liver metastases. METHOD: Patients with CRCLM, resected at the Department of Surgical Oncology, Uzsoki Teaching Hospital, between 01. 01. 2017 and 31. 12. 2019 were enrolled in our study. Clinical data, diagnostic, intraoperative and pathological findings were analyzed in a retrospective setting. RESULTS: 132 CRCLM patients were resected in this period, 73 patients had solitary (55%), and 59 patients (45%) had multiple metastases. Liver-specific contrast-enhanced MRI was performed in 94 patients (71%). 60% of the patients with solitary and 85% of the patients with multiple CRCLM had liver-specific contrast-enhanced MRI (p = 0.02). Compared to other modalities, liver-specific contrast-enhanced MRI showed additional metastases in 8% of the patients with solitary, and in 39% of the patients with multiple metastases (p = 0.001). Liver-specific contrast-enhanced MRI had a 5% false-positivity and a 6% false-negativity rate. 264 leasions were analyzed, and the sensitivity of the liver-specific contrast-enhanced MRI was 95% with a predictive positive value of 93%. CONCLUSION: Liver-specific contrast-enhanced MRI is a useful diagnostic tool in CRCLM patients before liver resection. It is highly recommended in the case of multiple metastases, after preoperative chemotherapy and in the case of disappearing metastases. Orv Hetil. 2021; 162(50): 2010-2016.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Neoplasias Colorrectales/cirugía , Hepatectomía , Humanos , Neoplasias Hepáticas/cirugía , Imagen por Resonancia Magnética , Estudios RetrospectivosRESUMEN
In cancer therapy, immunogenic cell death eliminates tumor cells more efficiently than conventional apoptosis. During photodynamic therapy (PDT), some photosensitizer (PS) targeting lysosomes divert apoptosis to the immunologically more relevant necrosis-like cell death. Acridine orange (AO) is a PS targeting lysosome. We synthesized a new compound, 3-N,N-dimethylamino-6-isocyanoacridine (DM), a modified AO, aiming to target lysosomes better. To compare DM and AO, we studied optical properties, toxicity, cell internalization, and phototoxicity. In addition, light-mediated effects were monitored by the recently developed QUINESIn method on nuclei, and membrane stability, morphology, and function of lysosomes utilizing fluorescent probes by imaging cytometry in single cells. DM proved to be a better lysosomal marker at 405 nm excitation and lysed lysosomes more efficiently. AO injured DNA and histones more extensively than DM. Remarkably, DM's optical properties helped visualize shockwaves of nuclear DNA released from cells during the PDT. The asymmetric polar modification of the AO leads to a new compound, DM, which has increased efficacy in targeting and disrupting lysosomes. Suitable AO modification may boost adaptive immune response making PDT more efficient.
RESUMEN
Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetoen gyógyíthatatlan betegség, ezért nagy klinikai jelentoségük van az eredményes mento kezeléseknek. A szájon át adható elso proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekbol álló kombináció, mely hazánkban 2015 áprilisától kezdodoen a "Named Patient Program" keretén belül vált elérhetové relabált, refrakter myeloma multiplexes betegek kezelésére. Célkituzés: Kutatásunk célja az ixazomib-lenalidomid-dexametazon kezelés mellett a hosszú távon progressziómentes túlélok célzott vizsgálata. Módszer: A program keretében összesen 7 centrumban 80 visszaeso beteg részesült e triplet kezelésben, adataikat retrospektíven elemeztük. Leíró statisztikai és Kaplan-Meier-analízist végeztünk. Eredmények: A betegek nagyobb hányada reagált: 63,75%-os válaszarány mellett 14 (17,5%) betegnél nem volt terápiás válasz/stabil betegség alakult ki, és 15-nél (18,75%) a betegség a kezelés mellett is progrediált. A progressziómentes túlélés a teljes betegcsoportban 10,6 hónapnak adódott, ugyanakkor 16 beteg (18,75%) két éven túl progressziómentesnek bizonyult, sot közülük 11-nél a betegség még 3 év után sem progrediált. Tanulmányunkban a fenti, hosszú távú túlélo betegcsoport tulajdonságait tárjuk fel. Megbeszélés: A folyamatos terápia a myeloma multiplex kezelésében meghatározóvá vált. Ezért fontos ismernünk, hogy kik lehetnek azok a betegek, akik különösen sokat profitálnak egy bizonyos terápiából. A hosszú távon progressziómentes túlélok között az immunglobulin-nehézláncot érinto transzlokációk vagy triszómiák közül (trend szintjén) az utóbbiak kedvezobb progressziómentes túléléssel bírtak, de progressziómentes platót mindkét betegcsoportban észleltünk. A betegség tumortömegét méro nemzetközi stádiumbeosztás (ISS) nem jelezte elore a hosszú túlélést. Gyógyszerelhagyáshoz vezeto mellékhatást a hosszú távú túlélo csoportban egyet sem regisztráltunk; az észlelt mellékhatások nagy része enyhe volt. Következtetések: Munkánk során az ixazomib-lenalidomid-dexametazon kombinációt effektívnek és biztonságosnak találtuk relabált, refrakter myeloma multiplex kezelésére, mely a betegek mintegy hatodánál több éven át eredményesen alkalmazható. Cikkünkkel a hazai beteganyagon szerzett tapasztalatainkat szeretnénk megosztani a COVID-19-világjárvány alatt különösen aktuálissá vált, tisztán orális terápiás lehetoségrol. Orv Hetil. 2021; 162(36): 1451-1458. INTRODUCTION: Despite great advances in therapy, multiple myeloma is still a largely incurable disease, therefore the importance of salvage therapies is paramount. The first oral proteasome inhibitor ixazomib in combination with lenalidomide-dexamethasone is a tolerable, orally administered regime, which has become available for Hungarian relapsed, refractory multiple myeloma patients from April 2015 in the Named Patient Program. OBJECTIVE: Our goal was to investigate the long-time progression-free surviving patient population treated with the ixazomib-lenalidomide-dexamethasone triplet. METHOD: We retrospectively studied a total of 80 patients from 7 centers who received the triplet combination. Survival analyses were performed. RESULTS: Two-third of the patients responded: the overall response rate was 63.75%. 14 patients (17.5%) did not respond/had stable disease and 15 patients (18.75%) outright progressed upon therapy. Although progression-free survival was only 10.6 months for the entire patient cohort, the disease in a subgroup of 16 patients did not progress within two years. In fact, 11 of them were still in sustained remission after 3 years of therapy. Our goal was to analyze the characteristics of this subgroup. DISCUSSION: The idea of long-term therapy of multiple myeloma is gaining widespread acceptance. Therefore it is important to know which patients may benefit the most from certain therapies. Among these 16 long-term responder patients, reciprocal translocation of the immunoglobulin heavy chain seemed to lack an adverse impact on progression-free survival; comparable to trisomies, both curves had a progression-free plateau. The International Staging System (ISS) score at the start of therapy did not predict long-term survivorship. Most of the side effects in this subgroup were mild, manageable, none led to therapy discontinuation. CONCLUSION: Ixazomib-lenalidomide-dexamethasone was confirmed to be an effective and safe combination for relapsed, refractory multiple myeloma, and one-sixth of the treated patients were able to receive it for several years, effectively. This fully oral therapeutic option is at its best during the present COVID-19 pandemic. Orv Hetil. 2021; 162(36): 1451-1458.
Asunto(s)
Compuestos de Boro/uso terapéutico , Dexametasona/uso terapéutico , Glicina/uso terapéutico , Lenalidomida/uso terapéutico , Mieloma Múltiple , Glicina/análogos & derivados , Humanos , Mieloma Múltiple/tratamiento farmacológico , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
Összefoglaló. Az akut coronaria szindrómán (ACS) átesett betegek kezelésének alappillére a kettos (aszpirin + klopidogrél ) thrombocytaaggregáció-gátló kezelés. Az immunthrombocytopeniás purpurás (ITP-s) betegek - és különösen azok, akik refrakter ITP miatt thrombopoetinanalóg kezelésben részesülnek - külön elbírálást igényelnek. 50-100 G/l thrombocytaszám közötti és vérzéses szövodménnyel nem rendelkezo ACS-s betegeken a gyógyszerkibocsátó stent beültetését követoen kettos thrombocytaaggregáció-gátló kezelést csak 1 hónapig kell alkalmazni (ez az idotartam átlagos vérzéses rizikójú betegeken 1 év), majd klopidogrél-monoterápia javasolt. Munkánk során a 2015. január 1. és 2020. október 1. között a Semmelweis Egyetem I. Belgyógyászati Klinikáján kezelt ITP-s betegek körében vizsgáltuk az ACS elofordulását és lefolyását. Klinikánkon az elmúlt 5 évben gondozott, 168 ITP-s beteg közül 3 beteg esetében alakult ki ACS. A refrakter ITP kezelésének részeként mind a 3 beteg thrombopoetinanalóg - (2 beteg romiplosztim-, 1 beteg eltrombopág-) kezelésben részesült. A 3 ITP-s betegünk egyikénél sem alakult ki vérzéses szövodmény a thrombopoetinanalóg-kezelés és a thrombocytaaggregáció-gátlás mellett. Elso betegünk esetében 5 év alatt három alkalommal alakult ki ACS (egy ízben fémstentet és két alkalommal gyógyszerkibocsátó stentet kapott). A második betegnél két alkalommal (1 év különbséggel), a harmadik betegnél egy esetben történt gyógyszerkibocsátó stent beültetése. ITP és ACS együttes fennállása esetén az akut és a hosszú távú gyógyszeres kezelés egyéni mérlegelést igényel. Ezen speciális betegcsoport számára a kezelési irányelv kidolgozása megfontolandó. Orv Hetil. 2021; 162(33): 1335-1340. Summary. Dual antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel is essential in the treatment of acute coronary syndrome (ACS). Immune thrombocytopenic purpura (ITP) patients - and especially those receiving thrombopoietin analog (TPO) treatment - deserve special attention. In ACS patients with platelet counts between 50 G/L and 100 G/L and no bleeding symptoms, DAPT is indicated for 1 month after the placement of new generation drug-eluting stents (the length of treatment is 1 year in the case of patients with average bleeding risk) followed by clopidogrel monotherapy. In patients with average bleeding risk, DAPT is recommended for 1 year after the ACS. Our aim was to investigate the incidence and outcome of ACS in ITP patients, who were treated in our clinic between 1st January 2015 and 1st October 2020. Out of 168 patients treated for ITP, 3 patients suffered from ACS in the last 5 years. These patients received TPO treatment (2 patients subcutan romiplostim, 1 patient oral eltrombopag). None of these ITP patients treated with DAPT and with TPO analog suffered from bleeding complications. 1 patient developed ACS three times within the last 5 years (he received bare-metal stent once and drug-eluting stent twice). Drug-eluting stent was placed once in the third, and twice (with 1 year difference) in the second patient. Acute and long-term medication of patients suffering from both ITP and ACS is a challenging task and needs individual evaluation. Establishment of treatment guidelines for this special group is warranted. Orv Hetil. 2021; 162(33): 1335-1340.