RESUMEN
STUDY QUESTION: How does a gonadotrophin-releasing hormone (GnRH) agonist versus a GnRH antagonist protocol affect ovarian response when using an individualized fixed daily dose of follitropin delta for ovarian stimulation? SUMMARY ANSWER: The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS). WHAT IS KNOWN ALREADY: The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol. STUDY DESIGN, SIZE, DURATION: This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively). LIMITATIONS, REASONS FOR CAUTION: All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown. WIDER IMPLICATIONS OF THE FINDINGS: In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol. STUDY FUNDING/COMPETING INTEREST(S): The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40. TRIAL REGISTRATION DATE: 7 April 2019. DATE OF FIRST PATIENT'S ENROLMENT: 2 May 2019.
RESUMEN
This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared with FLOT alone (A:82% B:96%; P = .009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, P = 0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, P = 0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade ≥ 3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted.
Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/patología , Fluorouracilo , Leucovorina , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Factor A de Crecimiento Endotelial Vascular , RamucirumabRESUMEN
Androgen insufficiency under treatment with opioids, antidepressants and anticonvulsants in chronic pain diseases is a side effect with a high prevalence. It can lead to clinical metabolic alterations, adynamia, stress intolerance, anemia or osteoporosis and has a significant impact on the quality of life. Opioids, antidepressants and anticonvulsants affect the hypothalamic-pituitary-gonadal axis of sex hormones. A urologist, andrologist or endocrinologist should be involved in the treatment at an early stage. The recommendation of a differential therapeutic selection of certain substances is only indicative and does not meet evidential criteria. The indications for androgen substitution must be individualized and in consideration of the risk-benefit profile. Awareness of this side effect of an otherwise lege artis medicinal pain therapy must be sharpened and compulsory included in the differential diagnostic considerations.
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Analgésicos Opioides , Dolor Crónico , Analgésicos Opioides/efectos adversos , Andrógenos/uso terapéutico , Anticonvulsivantes/efectos adversos , Antidepresivos/efectos adversos , Enfermedad Crónica , Dolor Crónico/tratamiento farmacológico , Hormonas Esteroides Gonadales/uso terapéutico , Humanos , Calidad de VidaRESUMEN
RESEARCH QUESTION: Does oral probiotic supplementation influence the relative abundance of different vaginal microbiota in women experiencing infertility? DESIGN: A prospective, monocentric randomized controlled trial. To study the influence of probiotics on infertility, 80 patients with primary or secondary infertility were included. Patients were assigned to either a probiotic treatment or a control group. Participants in the treatment group (nâ¯=â¯40) took one sachet (2 g) a day of a defined probiotic supplement limiting Lactobacillus strains. Patients in the control group did not receive any additional probiotic supplements. Vaginal samples were taken on day 20 of the menstrual cycle and 4 weeks later, on day 20, of the consecutive cycle. Subsequently, 16s rRNA gene analysis of the vaginal samples was conducted. RESULTS: After the intervention phase, no effects on alpha diversity resulting from treatment could be observed. The between sample diversity of different women (beta diversity) at baseline had no effects of age, treatment group or body mass index. Primary or secondary sterility, however, had a significant effect on community. Three clusters (Lactobacillus crispatus, Lactobacillus iners and Lactobacillus gasseri) were identified as the leading representatives. Furthermore, patients treated with probiotics showed limited growth of Ureaplasma parvum compared with the control group (Pâ¯=â¯0.021). CONCLUSIONS: This study points to a possible protective effect of probiotic supplements on the vaginal microbiota. It is tempting to speculate that this effect assists in containing the growth of non-beneficial bacteria and helps to prevent or cure a dysbiotic vaginal flora.
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Infertilidad Femenina/dietoterapia , Probióticos/farmacología , Infecciones por Ureaplasma/dietoterapia , Vagina/efectos de los fármacos , Vaginosis Bacteriana/dietoterapia , Adolescente , Adulto , Austria , Suplementos Dietéticos , Disbiosis/complicaciones , Disbiosis/dietoterapia , Femenino , Humanos , Infertilidad Femenina/microbiología , Lactobacillus/fisiología , Probióticos/administración & dosificación , Ureaplasma/efectos de los fármacos , Infecciones por Ureaplasma/complicaciones , Vagina/microbiología , Vaginosis Bacteriana/complicaciones , Adulto JovenRESUMEN
BACKGROUND: Despite publicised advice and warnings, there are only scant data on the non-indicated prescription of rapid-onset preparations of fentanyl (ROF) in non-cancer pain (NCP). Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation. OBJECTIVE: Initiated by the Working Group Cancer Pain and supported by the German Pain Society, a random sample survey was conducted to assess the non-indicated use of ROF. METHODS: The survey addressed attendees of pain conferences who were given the option to fill in the questionnaires outside the conference or online. Primary endpoints of the structured questionnaire were quantitative and qualitative items with regard to the prescription of ROF, while secondary endpoints were opioid-induced side effects. RESULTS: Obtaining a response rate of 44% (132/300) and an additional 51 online questionnaires revealed that 165 (90%) respondents had knowledge of non-indicated prescriptions or were involved in these. Of these, 65% were clinicians and 17% worked in an outpatient capacity. In all, 22% were trained pain or palliative physicians. Approximately 1205 patients were assessed indirectly. The main causes for dispensing ROF included NCP entities such as back pain (44%), neuropathic pain (33%), head or facial pain (12%), and dyspnea (5%) in cancer pain or lack of break-through pain or basic medication (44%). Sedation (32%), nausea/vomiting (31%), constipation (16%) and insufficient analgesia (31%) were the mostly commonly reported adverse effects. CONCLUSION: Despite the non-ambiguous indication for ROF, physicians often demonstrate inappropriate prescription behaviour. Iatrogenic misuse of ROF should be minimized. The rates of adverse effects of ROF seems to be in line with other opioids.
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Dolor en Cáncer , Médicos , Analgésicos Opioides/efectos adversos , Dolor en Cáncer/tratamiento farmacológico , Fentanilo/efectos adversos , Humanos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. METHODS: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group. INTERPRETATION: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. FUNDING: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Unión Esofagogástrica/patología , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/patología , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/administración & dosificación , Capecitabina/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Procedimientos Quirúrgicos del Sistema Digestivo , Supervivencia sin Enfermedad , Docetaxel/administración & dosificación , Docetaxel/uso terapéutico , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Neoplasias Gástricas/patología , Resultado del TratamientoRESUMEN
PURPOSE: This study investigated the potential of deep convolutional neural networks (CNN) for automatic classification of FP-CIT SPECT in multi-site or multi-camera settings with variable image characteristics. METHODS: The study included FP-CIT SPECT of 645 subjects from the Parkinson's Progression Marker Initiative (PPMI), 207 healthy controls, and 438 Parkinson's disease patients. SPECT images were smoothed with an isotropic 18-mm Gaussian kernel resulting in 3 different PPMI settings: (i) original (unsmoothed), (ii) smoothed, and (iii) mixed setting comprising all original and all smoothed images. A deep CNN with 2,872,642 parameters was trained, validated, and tested separately for each setting using 10 random splits with 60/20/20% allocation to training/validation/test sample. The putaminal specific binding ratio (SBR) was computed using a standard anatomical ROI predefined in MNI space (AAL atlas) or using the hottest voxels (HV) analysis. Both SBR measures were trained (ROC analysis, Youden criterion) using the same random splits as for the CNN. CNN and SBR trained in the mixed PPMI setting were also tested in an independent sample from clinical routine patient care (149 with non-neurodegenerative and 149 with neurodegenerative parkinsonian syndrome). RESULTS: Both SBR measures performed worse in the mixed PPMI setting compared to the pure PPMI settings (e.g., AAL-SBR accuracy = 0.900 ± 0.029 in the mixed setting versus 0.957 ± 0.017 and 0.952 ± 0.015 in original and smoothed setting, both p < 0.01). In contrast, the CNN showed similar accuracy in all PPMI settings (0.967 ± 0.018, 0.972 ± 0.014, and 0.955 ± 0.009 in mixed, original, and smoothed setting). Similar results were obtained in the clinical sample. After training in the mixed PPMI setting, only the CNN provided acceptable performance in the clinical sample. CONCLUSIONS: These findings provide proof of concept that a deep CNN can be trained to be robust with respect to variable site-, camera-, or scan-specific image characteristics without a large loss of diagnostic accuracy compared with mono-site/mono-camera settings. We hypothesize that a single CNN can be used to support the interpretation of FP-CIT SPECT at many different sites using different acquisition hardware and/or reconstruction software with only minor harmonization of acquisition and reconstruction protocols.
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Aprendizaje Profundo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Procesamiento de Imagen Asistido por Computador/métodos , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Automatización , Femenino , Humanos , Masculino , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismoRESUMEN
BACKGROUND: Peritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC. METHODS: This prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery. RESULTS: Median follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms. CONCLUSIONS: Addition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy.
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Anticuerpos Biespecíficos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Biespecíficos/efectos adversos , Complejo CD3/antagonistas & inhibidores , Complejo CD3/genética , Docetaxel/administración & dosificación , Molécula de Adhesión Celular Epitelial/antagonistas & inhibidores , Molécula de Adhesión Celular Epitelial/genética , Femenino , Fluorouracilo/administración & dosificación , Gastrectomía , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Oxaliplatino/administración & dosificación , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/cirugía , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
INTRODUCTION: Food intolerance/malabsorption is caused by food ingredients, carbohydrates (mainly lactose and fructose), proteins (gluten), and biogenic amines (histamine) which cause nonspecific gastrointestinal and extra-intestinal symptoms. Here we focus on possible etiologic factors of intolerance/malabsorption especially in people with non-celiac gluten sensitivity (NCGS) or the so-called people without celiac disease avoiding gluten (PWCDAG) and histamine intolerance. METHODS: Recognizing the recently described symptoms of NCGS (PWCDAG) we review correlations and parallels to histamine intolerance (HIT). RESULTS: We show that intestinal and extra-intestinal NCGS (PWCDAG) symptoms are very similar to those which can be found in histamine intolerance. CONCLUSIONS: After a detailed diagnostic workup for all possible etiologic factors in every patient, a targeted dietary intervention for single or possibly combined intolerance/malabsorption might be more effective than a short-term diet low in fermentable oligo-, di- and monosaccharides and polyols (FODMAP) or the untargeted uncritical use of gluten-free diets.
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Dieta Sin Gluten , Intolerancia Alimentaria/etiología , Glútenes , Histamina , Enfermedad Celíaca , Intolerancia Alimentaria/dietoterapia , Humanos , Receptores HistamínicosRESUMEN
PURPOSE: Polar body biopsy (PBB) is a common technique in preimplantation genetic testing (PGT) to assess the chromosomal status of the oocyte. Numerous studies have been implemented to investigate the impact of biopsies on embryo development; however, information on embryo morphokinetics is still lacking. Hence, we investigated the impact of PBB on morphokinetic parameters in early embryo development. METHODS: Four hundred four embryos (202 PBB, 202 control) were retrospectively analyzed. Patients were stimulated with a gonadotropin-releasing hormone antagonist ovarian hyperstimulation protocol. After fertilization check, embryos were incubated in a time-lapse incubator. The groups were matched for maternal age at time of oocyte retrieval. RESULTS: Mean group times for reaching specific developmental time points showed no significant difference comparing embryos with PBB conducted and without. Likewise, further subdivision of the PBB group in euploid and aneuploid embryos revealed no differences in the early embryo morphokinetic development compared to the control group. Aneuploidy testing revealed a high prevalence of chromosomal aberrations for chromosomes 21, 4, 16, and 19. CONCLUSIONS: In conclusion, PBB does not impact the morphokinetic parameters of the embryo development. PBB can be safely applied without the risk of impairing the reproductive potential of the embryo and can be highly recommended as safe and practicable PGT approach, especially in countries with prevailing restrictions regarding PGT analysis.
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Blastocisto/metabolismo , Desarrollo Embrionario/genética , Morfogénesis/genética , Oocitos/metabolismo , Diagnóstico Preimplantación , Adulto , Aneuploidia , Biopsia , Hibridación Genómica Comparativa , Femenino , Fertilización In Vitro , Pruebas Genéticas , Humanos , Cinética , Edad Materna , Oocitos/crecimiento & desarrollo , Cuerpos Polares/metabolismo , Cuerpos Polares/patología , EmbarazoRESUMEN
Due to preexisting pain or surgically induced sensitization patients undergoing oncological surgery are predisposed for a postoperative high pain intensity with the risk of developing persistent pain. In oncological surgery, pain therapy should be adapted to the underlying pain mechanism. Different treatment principles should be applied in a graded concept of acute pain therapy. The rationale implies the "conventional" use of the WHO step scheme, the administration of opioids as PCA as well as regional analgesia and agents with anti-hypersensitizing properties. Anti-hypersensitizing and anti-neuropathic treatment principles may include the use of antidepressants, anticonvulsants, intravenous lidocaine and s-ketamine. Before using such treatment, pain mechanisms should be verified by an adequate pain diagnostic. The impact of perioperative regional analgesia on the oncological outcome is subject to controversy. Opioids reveal both: tumor promoting and tumor inhibiting properties.
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Neoplasias/cirugía , Manejo del Dolor/métodos , Dolor Postoperatorio/terapia , Humanos , Hipertensión/etiología , Hipertensión/terapia , Dimensión del Dolor , Dolor Postoperatorio/tratamiento farmacológico , Resultado del TratamientoRESUMEN
The Eph kinases, EphA4 and EphB1, and their ligand, ephrinB1, have been previously reported to be present in platelets where they contribute to thrombus stability. Although thrombus formation allows for Eph-ephrin engagement and bidirectional signaling, the importance specifically of Eph kinase or ephrin signaling in regulating platelet function remained unidentified. In the present study, a genetic approach was used in mice to establish the contribution of signaling orchestrated by the cytoplasmic domain of EphB2 (a newly discovered Eph kinase in platelets) in platelet activation and thrombus formation. We conclude that EphB2 signaling is involved in the regulation of thrombus formation and clot retraction. Furthermore, the cytoplasmic tail of this Eph kinase regulates initial platelet activation in a contact-independent manner in the absence of Eph-ephrin ligation between platelets. Together, these data demonstrate that EphB2 signaling not only modulates platelet function within a thrombus but is also involved in the regulation of the function of isolated platelets in a contact-independent manner.
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Coagulación Sanguínea/fisiología , Plaquetas/enzimología , Activación Plaquetaria/fisiología , Receptor EphB2/metabolismo , Transducción de Señal/fisiología , Animales , Plaquetas/citología , Ratones , Ratones Transgénicos , Receptor EphB2/genéticaRESUMEN
OBJECTIVE: Thiol isomerases facilitate protein folding in the endoplasmic reticulum, and several of these enzymes, including protein disulfide isomerase and ERp57, are mobilized to the surface of activated platelets, where they influence platelet aggregation, blood coagulation, and thrombus formation. In this study, we examined the synthesis and trafficking of thiol isomerases in megakaryocytes, determined their subcellular localization in platelets, and identified the cellular events responsible for their movement to the platelet surface on activation. APPROACH AND RESULTS: Immunofluorescence microscopy imaging was used to localize protein disulfide isomerase and ERp57 in murine and human megakaryocytes at various developmental stages. Immunofluorescence microscopy and subcellular fractionation analysis were used to localize these proteins in platelets to a compartment distinct from known secretory vesicles that overlaps with an inner cell-surface membrane region defined by the endoplasmic/sarcoplasmic reticulum proteins calnexin and sarco/endoplasmic reticulum calcium ATPase 3. Immunofluorescence microscopy and flow cytometry were used to monitor thiol isomerase mobilization in activated platelets in the presence and absence of actin polymerization (inhibited by latrunculin) and in the presence or absence of membrane fusion mediated by Munc13-4 (absent in platelets from Unc13d(Jinx) mice). CONCLUSIONS: Platelet-borne thiol isomerases are trafficked independently of secretory granule contents in megakaryocytes and become concentrated in a subcellular compartment near the inner surface of the platelet outer membrane corresponding to the sarco/endoplasmic reticulum of these cells. Thiol isomerases are mobilized to the surface of activated platelets via a process that requires actin polymerization but not soluble N-ethylmaleimide-sensitive fusion protein attachment receptor/Munc13-4-dependent vesicular-plasma membrane fusion.
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Plaquetas/enzimología , Membrana Celular/enzimología , Megacariocitos/enzimología , Activación Plaquetaria , Proteína Disulfuro Isomerasas/sangre , Actinas/sangre , Animales , Plaquetas/efectos de los fármacos , Proteínas Sanguíneas/deficiencia , Proteínas Sanguíneas/genética , Calnexina/sangre , Membrana Celular/efectos de los fármacos , Genotipo , Humanos , Megacariocitos/efectos de los fármacos , Fusión de Membrana , Proteínas de la Membrana/sangre , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Activación Plaquetaria/efectos de los fármacos , Proteína Disulfuro Isomerasas/biosíntesis , Transporte de Proteínas , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/sangreRESUMEN
PURPOSE: The aim of the present study was to develop a standard operating procedure (SOP) for the collection, transport, and storage of human cumulus cells, follicular fluid, blood serum, seminal plasma, embryo culture supernatant, and embryo culture supernatant control obtained within the IVF process under approved protocols and written informed consent from participating patients. The SOP was developed at the Kinderwunsch Institut Schenk, Dobl, Austria, together with Biobank Graz of the Medical University of Graz, Austria. METHODS: The SOP provides comprehensive details of laboratory procedures and sampling of the different fluids within the IVF process. Furthermore, information on sample coding, references of involved laboratory techniques (e.g., oocyte retrieval with a Steiner-TAN needle), ethical approvals, and biobanking procedures are presented. RESULTS: The result of the present study is a standard operating procedure. CONCLUSIONS: The SOP ensures a professional way for collection and scientific use of IVF samples by the Kinderwunsch Institut Schenk, Dobl, Austria, and Biobank Graz of the Medical University of Graz, Austria. It can be used as a template for other institutions to unify specimen collection procedures in the field of reproductive health research.
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Bancos de Muestras Biológicas , Líquidos Corporales/citología , Fertilización In Vitro , Técnicas Reproductivas Asistidas , Adulto , Células del Cúmulo/citología , Técnicas de Cultivo de Embriones , Femenino , Líquido Folicular/citología , Humanos , Recuperación del Oocito , Semen/citología , Suero/citologíaRESUMEN
PURPOSE: Anti-Mullerian hormone (AMH) is commonly known as the most potent marker for ovarian reserve due to its decline as female age increases. While serum AMH (sAMH) levels have been intensively investigated, there is less data regarding AMH concentrations in follicular fluid (FF), since FF has usually been designated as waste product during oocyte collection in assisted reproductive technologies. This pilot study investigated follicle AMH concentrations (fAMH) of several follicles per ovary, individually collected with the Steiner-Tan needle, and compared them to sAMH concentrations in women undergoing IVF treatment. We hypothesized that there is no difference of fAMH concentrations in individual follicles and that these concentrations resemble the sAMH value of the patient. METHODS: Patients were stimulated with a gonadotropin-releasing hormone antagonist ovarian hyperstimulation protocol. On the day of oocyte retrieval, serum samples and FF from all individual follicles from one stimulated IVF cycle were collected and individually analyzed for AMH concentrations. RESULTS: Intracyclic mean fAMH values (n follicle = 2-14) were significantly correlated to sAHM values (ρ = 0.85, p < 0.001) and showed a trend to be negatively associated with age (ρ = -0.43, p = 0.06). Mean intrapatient fAMH concentrations differed significantly (p < 0.001). Furthermore, significant correlations of sAMH with individual fAMH values of the first five follicles of each patient were observed. CONCLUSIONS: In conclusion, our results clearly showed that individual fAMH concentrations reflected sAMH values and that fAMH concentrations did not significantly differ within one patient. In future studies, it will be interesting to correlate individual fAMH values to the respective embryo development and overall pregnancy outcome in order to improve IVF treatments and to refrain from embryo overproduction.
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Hormona Antimülleriana/sangre , Fertilización In Vitro , Líquido Folicular/metabolismo , Técnicas Reproductivas Asistidas , Adulto , Hormona Antimülleriana/aislamiento & purificación , Implantación del Embrión , Femenino , Líquido Folicular/química , Humanos , Recuperación del Oocito , Reserva Ovárica/fisiología , Embarazo , Índice de Embarazo , Progesterona/sangreRESUMEN
BACKGROUND: A daily injection of low-molecular-weight heparin (LMWH) is often prescribed to women with unexplained recurrent pregnancy loss (RPL), although evidence suggesting a benefit is questionable. OBJECTIVE: To determine whether LMWH increases ongoing pregnancy and live-birth rates in women with unexplained RPL. DESIGN: Controlled, multicenter trial with randomization using minimization conducted from 2006 to 2013. (ClinicalTrials.gov: NCT00400387). SETTING: 14 university hospitals and perinatal care centers in Germany and Austria. PATIENTS: 449 women with at least 2 consecutive early miscarriages or 1 late miscarriage were included during 5 to 8 weeks' gestation after a viable pregnancy was confirmed by ultrasonography. INTERVENTION: Women in the control group received multivitamin pills, and the intervention group received vitamins and 5000 IU of dalteparin-sodium for up to 24 weeks' gestation. MEASUREMENTS: Primary outcome was ongoing pregnancy at 24 weeks' gestation. Secondary outcomes included the live-birth rate and late pregnancy complications. RESULTS: At 24 weeks' gestation, 191 of 220 pregnancies (86.8%) and 188 of 214 pregnancies (87.9%) were intact in the intervention and control groups, respectively (absolute difference, -1.1 percentage points [95% CI, -7.4 to 5.3 percentage points]). The live-birth rates were 86.0% (185 of 215 women) and 86.7% (183 of 211 women) in the intervention and control groups, respectively (absolute difference, -0.7 percentage point [CI, -7.3 to 5.9 percentage points]). There were 3 intrauterine fetal deaths (1 woman had used LMWH); 9 cases of preeclampsia or the hemolysis, elevated liver enzyme level, and low platelet count (HELLP) syndrome (3 women had used LMWH); and 11 cases of intrauterine growth restriction or placental insufficiency (5 women had used LMWH). LIMITATION: Placebo injections were not used, and neither trial staff nor patients were blinded. CONCLUSION: Daily LMWH injections do not increase ongoing pregnancy or live-birth rates in women with unexplained RPL. Given the burden of the injections, they are not recommended for preventing miscarriage. PRIMARY FUNDING SOURCE: Pfizer Pharma.
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Aborto Habitual/prevención & control , Anticoagulantes/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Anticoagulantes/administración & dosificación , Dalteparina/uso terapéutico , Femenino , Heparina de Bajo-Peso-Molecular/administración & dosificación , Humanos , Inyecciones Subcutáneas , Nacimiento Vivo , Embarazo , Vitaminas/uso terapéuticoRESUMEN
Erlotinib with bevacizumab showed promising activity in recurrent nonsquamous (NS) nonsmall cell lung cancer (NSCLC). The INNOVATIONS study was designed to assess in first-line treatment of unselected cisplatin-eligible patients this combination compared to cisplatin, gemcitabine and bevacizumab. Stage IIIB/IV patients with NS-NSCLC were randomised on erlotinib (150â mg daily) and bevacizumab (15â mg·kg(-1) on day 1, every 3â weeks) (EB) until progression, or cisplatin (80â mg·m(-2) on day 1, every 3â weeks) and gemcitabine (1250â mg·m(-2) on days 1 and 8, every 3â weeks) up to six cycles and bevacizumab (15â mg·kg(-1) on day 1, every 3â weeks) (PGB) until progression. 224 patients were randomised (EB n=111, PGB n=113). The response rate (12% versus 36%; p<0.0001), progression-free survival (median 3.5 versus 6.9â months; hazard ratio (HR) 1.85, 95% CI 1.39-2.45; p<0.0001) and overall survival (median 12.6 versus 17.8â months; HR 1.41, 95% CI 1.01-1.97; p=0.04) clearly favoured PGB. In patients with epidermal growth factor receptor mutations (n=32), response rate, progression-free survival and overall survival were not superior with EB. Platinum-based combination chemotherapy remains the standard of care in first-line treatment of unselected NS-NSCLC. Molecular targeted approaches strongly mandate appropriate testing and patient selection.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Clorhidrato de Erlotinib/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Desoxicitidina/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Receptores ErbB/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , GemcitabinaRESUMEN
PURPOSE: To analyze the 3-month life expectancy rate in pancreatic cancer (PC) patients treated within prospective trials from the German AIO study group. PATIENTS AND METHODS: A pooled analysis was conducted for patients with advanced PC that were treated within five phase II/III studies conducted between 1997 and 2017 (Gem/Cis, Ro96, RC57, ACCEPT, RASH). The primary goal for the current report was to identify the actual 3-month survival rate, a standard inclusion criterion in oncology trials. RESULTS: Overall, 912 patients were included, 83% had metastatic and 17% locally advanced PC; the estimated median overall survival (OS) was 7.1 months. Twenty-one percent of the participants survived < 3 months, with a range from 26% in RC57 to 15% in RASH. Significant predictors for not reaching 3-month OS were > 1 previous treatment line (p < 0.001) and performance status (p < 0.001). CONCLUSIONS: Despite the definition of a life expectancy of > 3 months as a standard inclusion criterion in clinical trials for advanced PC, a significant proportion of study patients does not survive > 3 months. TRIAL REGISTRATION NUMBERS: NCT00440167 (AIO-PK0104), NCT01729481 (RASH), NCT01728818 (ACCEPT).
RESUMEN
PURPOSE: This trial evaluates the addition of the PD-L1 antibody atezolizumab (ATZ) to standard-of-care fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) as a perioperative treatment for patients with resectable esophagogastric adenocarcinoma (EGA). METHODS: DANTE started as multicenter, randomized phase II trial, which was subsequently converted to a phase III trial. Here, we present the results of the phase II proportion, focusing on surgical pathology and safety outcomes on an exploratory basis. Patients with resectable EGA (≥cT2 or cN+) were assigned to either four preoperative and postoperative cycles of FLOT combined with ATZ, followed by eight cycles of ATZ maintenance (arm A) or FLOT alone (arm B). RESULTS: Two hundred ninety-five patients were randomly assigned (A, 146; B, 149) with balanced baseline characteristics between arms. Twenty-three patients (8%) had tumors with microsatellite instability (MSI), and 58% patients had tumors with a PD-L1 combined positive score (CPS) of ≥1. Surgical morbidity (A, 45%; B, 42%) and 60-day mortality (A, 3%; B, 2%) were comparable between arms. Downstaging favored arm A versus arm B (ypT0, 23% v 15% [one-sided P = .044]; ypT0-T2, 61% v 48% [one-sided P = .015]; ypN0, 68% v 54% [one-sided P = .012]). Histopathologic complete regression rates (pathologic complete response or TRG1a) were higher after FLOT plus ATZ (A, 24%; B, 15%; one-sided P = .032), and the difference was more pronounced in the PD-L1 CPS ≥10 (A, 33%; B, 12%) and MSI (A, 63%; B, 27%) subpopulations. Complete margin-free (R0) resection rates were relatively high in both arms (A, 96%; B, 95%). The incidence and severity of adverse events were similar in both groups. CONCLUSION: Within the limitations of the exploratory nature of the data, the addition of ATZ to perioperative FLOT is safe and improved postoperative stage and histopathologic regression.
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Adenocarcinoma , Anticuerpos Monoclonales Humanizados , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/uso terapéutico , Docetaxel/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/patología , Fluorouracilo/efectos adversos , Leucovorina/efectos adversos , Terapia Neoadyuvante/métodos , Oxaliplatino/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patologíaRESUMEN
Functional abdominal pain disorders (FAPDs) are among the most common types of chronic pain disorders in children. FAPD symptoms are characterized by chronic abdominal pain and changed bowel movements. The pathophysiology of FAPDs in children is unknown, but these conditions may have an imprecise clinical overlap to food intolerance/malabsorption. We report on 51 consecutive children (23/28 males/females; median age 15.3 years) with investigated FAPDs from 2017 to 2022 in this retrospective pilot study. Small intestinal biopsies in children demonstrated the association of lactase and diamine oxidase (DAO), which prompted us to perform hydrogen (H2) breath tests for lactose intolerance (LIT) and determine serum DAO for the evaluation of histamine intolerance (HIT) in pediatric patients with FAPDs. To complete the food intolerance/malabsorption evaluation tests, we included a search for antibodies against tissue transglutaminase to find celiac disease (CD), performed H2 breath tests to detect fructose malabsorption (FM), and conducted a search for IgA antibodies against H. pylori infection. The results demonstrate that all 51 children evaluated were diagnosed with food intolerance/malabsorption and/or various combinations thereof. Seven children showed FM, eight of the children had HIT, and eight children had LIT. The other children had combinations: thirteen children (25.5%) had HIT and LIT, seven children (9.8%) had FM with HIT, five children (13.7%) had FM and LIT, and three children (5.9%) had a triple combination of FM, HIT, and LIT. By describing this method of personalized investigation for food intolerance/malabsorption in children with FAPDs, we demonstrate that functional abdominal pain disorders may be associated with food intolerance/malabsorption. After such diagnosis in this pediatric population, a registered dietitian helped to establish a reduction and/or exclusion diet individually tailored to their symptomatology.