StarD7 deficiency switches on glycolysis and promotes mitophagy flux in C2C12 myoblasts.

StarD7 is a member of the START protein family required for phosphatidylcholine delivery to the mitochondria, thus key to maintain mitochondrial structure. Its deficiency has been associated with an impairment of cellular processes, such as proliferation and migration, and it has also been reported that it is needed in myogenic differentiation. Here, we show that StarD7 deficiency in C2C12 muscle cells results in the accumulation of abnormal mitochondria, a reduced number of mitochondria per cell area and increased glycolysis. In addition, StarD7-deficient cells undergo an increase in mitochondria-ER contact sites, reduced connexin 43 expression, and disturbances in lipid handling, evidenced by lipid droplet accumulation and decreased levels in phosphatidylserine synthase 1 and 2 expression. Interestingly, StarD7-deficient cells showed alterations in mitophagy markers. We observed accumulation of LC3B-II and BNIP3 proteins in mitochondria-enriched fractions and accumulation of autophagolysosomal and lysosomal vesicles in StarD7-deficient cells. Furthermore, live-cell imaging experiments of StarD7 knockdown cells expressing mitochondria-targeted mKeima indicated an enhanced mitochondria delivery into lysosomes. Importantly, StarD7 reconstitution in StarD7-deficient cells restores LC3B-II expression in mitochondria-enriched fractions at similar levels to those observed in control cells. Collectively, these findings suggest that StarD7-deficient C2C12 myoblasts are associated with altered cristae structure, disturbances in neutral lipid accumulation, glucose metabolism, and increased mitophagy flux. The alterations mentioned above allow for the maintenance of mitochondrial function.

Risk factors for major complications after surgical treatment of primary ileocecal Crohn's disease. A multicenter Latin American experience / Factores de riesgo para complicaciones mayores posteriores al tratamiento quirúrgico de la enfermedad de Crohn con afectación ileocecal. Trabajo retrospectivo, multicéntrico en América Latina

Introduction: Complications after ileocecal resection for Crohn's disease (CD) are frequent. The aim of this study was to analyze risk factors for postoperative complications after these procedures. Materials and methods: We conducted a retrospective analysis of patients treated surgically for Crohn's disease limited to the ileocecal region during an 8-year period at 10 medical centers specialized in inflammatory bowel disease (IBD) in Latin America. Patients were allocated into 2 groups: those who presented major postoperative complications (Clavien-Dindo>II), the “postoperative complication” (POC) group; and those who did not, the “no postoperative complication” (NPOC) group. Preoperative characteristics and intraoperative variables were analyzed to identify possible factors for POC. Results: In total, 337 patients were included, with 51 (15.13%) in the POC cohort. Smoking was more prevalent among the POC patients (31.37 vs 17.83; p=0.026), who presented more preoperative anemia (33.33 vs 17.48%; p=0.009), required more urgent care (37.25 vs 22.38; p=0.023), and had lower albumin levels. Complicated disease was associated with higher postoperative morbidity. POC patients had a longer operative time (188.77 vs 143.86min; p=0.005), more intraoperative complications (17.65 vs 4.55%; p<0.001), and lower rates of primary anastomosis. In the multivariate analysis, both smoking and intraoperative complications were independently associated with the occurrence of major postoperative complications. (AU)

Introducción: Las complicaciones posteriores a resección ileocecal por enfermedad de Crohn (EC) son frecuentes. El objetivo de este estudio fue analizar los factores de riesgo para presentar complicaciones postoperatorias después de estos procedimientos. Materiales y métodos: Se realizó un análisis retrospectivo de los pacientes operados por EC limitada a la región ileocecal durante un período de 8 años en 10 centros especializados en enfermedad inflamatoria intestinal (EII) de América Latina. Los pacientes fueron divididos en 2 grupos, los que presentaron complicaciones postoperatorias mayores (Clavien-Dindo>II) (denominado grupo de complicaciones postoperatorias [POC]) y los que no (grupo sin complicaciones postoperatorias [NPOC]). Se analizaron las características preoperatorias y las variables intraoperatorias para identificar posibles factores relacionados con las POC. Resultados: Se incluyeron 337 pacientes, 51 (15,13%) en el grupo con POC. El grupo POC presentó mayor índice de tabaquismo (31,37 vs. 17,83; p=0,026), quienes presentaron más anemia preoperatoria (33,33 vs. 17,48%; p=0,009), urgencias (37,25 vs. 22,38; p=0,023) y menores niveles de albúmina. Los procedimientos por enfermedad complicada se asociaron con una mayor morbilidad postoperatoria. Los pacientes con POC tuvieron un tiempo operatorio más largo (188,77 vs. 143,86min; p=0,005), más complicaciones intraoperatorias (17,65 vs. 4,55%; p<0,001) y menores tasas de anastomosis primaria. En el análisis multivariado, tanto tabaquismo como complicaciones intraoperatorias se asociaron de forma independiente con la aparición de complicaciones mayores postoperatorias. (AU)

Early Salvage Chemo-Immunotherapy with Irinotecan, Temozolomide and Naxitamab Plus GM-CSF (HITS) for Patients with Primary Refractory High-Risk Neuroblastoma Provide the Best Chance for Long-Term Outcomes.

Patients with high-risk neuroblastoma (HR-NB) who are unable to achieve a complete response (CR) to induction therapy have worse outcomes. We investigated the combination of humanized anti-GD2 mAb naxitamab (Hu3F8), irinotecan (I), temozolomide (T), and sargramostim (GM-CSF)-HITS-against primary resistant HR-NB. Eligibility criteria included having a measurable chemo-resistant disease at the end of induction (EOI) treatment. Patients were excluded if they had progressive disease (PD) during induction. Prior anti-GD2 mAb and/or I/T therapy was permitted. Each cycle, administered four weeks apart, comprised Irinotecan 50 mg/m2/day intravenously (IV) plus Temozolomide 150 mg/m2/day orally (days 1-5); naxitamab 2.25 mg/kg/day IV on days 2, 4, 8 and 10, (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously was used (days 6-10). Toxicity was measured using CTCAE v4.0 and responses through the modified International Neuroblastoma Response Criteria (INRC). Thirty-four patients (median age at treatment initiation, 4.9 years) received 164 (median 4; 1-12) HITS cycles. Toxicities included myelosuppression and diarrhea, which was expected with I/T, and pain and hypertension, expected with naxitamab. Grade ≥3-related toxicities occurred in 29 (85%) of the 34 patients; treatment was outpatient. The best responses were CR = 29% (n = 10); PR = 3% (n = 1); SD = 53% (n = 18); PD = 5% (n = 5). For cohort 1 (early treatment), the best responses were CR = 47% (n = 8) and SD = 53% (n = 9). In cohort 2 (late treatment), the best responses were CR = 12% (n = 2); PR = 6% (n = 1); SD = 53% (n = 9); and PD = 29% (n = 5). Cohort 1 had a 3-year OS of 84.8% and EFS 54.4%, which are statistically significant improvements (EFS p = 0.0041 and OS p = 0.0037) compared to cohort 2. In conclusion, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant HR-NB, increasing long-term outcomes when administered early during the course of treatment.

Mechanisms of Modulation of Mitochondrial Architecture.

Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.

Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms.

This study investigated the effect of nicotinamide (NAM) supplementation on the development of brain inflammation and microglial activation in a mouse model of type 1 diabetes mellitus. C57BL/6J male mice, which were made diabetic with five consecutive, low-dose (55 mg/kg i.p.) streptozotocin (STZ) injections. Diabetic mice were randomly distributed in different experimental groups and challenged to different doses of NAM (untreated, NAM low-dose, LD, 0.1%; NAM high-dose, HD, 0.25%) for 25 days. A control, non-diabetic group of mice was used as a reference. The NAD+ content was increased in the brains of NAM-treated mice compared with untreated diabetic mice (NAM LD: 3-fold; NAM HD: 3-fold, p-value < 0.05). Immunohistochemical staining revealed that markers of inflammation (TNFα: NAM LD: -35%; NAM HD: -46%; p-value < 0.05) and microglial activation (IBA-1: NAM LD: -29%; NAM HD: -50%; p-value < 0.05; BDKRB1: NAM LD: -36%; NAM HD: -37%; p-value < 0.05) in brains from NAM-treated diabetic mice were significantly decreased compared with non-treated T1D mice. This finding was accompanied by a concomitant alleviation of nuclear NFκB (p65) signaling in treated diabetic mice (NFκB (p65): NAM LD: -38%; NAM HD: -53%, p-value < 0.05). Notably, the acetylated form of the nuclear NFκB (p65) was significantly decreased in the brains of NAM-treated, diabetic mice (NAM LD: -48%; NAM HD: -63%, p-value < 0.05) and inversely correlated with NAD+ content (r = -0.50, p-value = 0.03), suggesting increased activity of NAD+-dependent deacetylases in the brains of treated mice. Thus, dietary NAM supplementation in diabetic T1D mice prevented brain inflammation via NAD+-dependent deacetylation mechanisms, suggesting an increased action of sirtuin signaling.

Naxitamab Combined with Granulocyte-Macrophage Colony-Stimulating Factor as Consolidation for High-Risk Neuroblastoma Patients in First Complete Remission under Compassionate Use-Updated Outcome Report.

Naxitamab is an anti-GD2 antibody approved for the treatment of relapsed/refractory HR-NB. We report the survival, safety, and relapse pattern of a unique set of HR-NB patients consolidated with naxitamab after having achieved first CR. Eighty-two patients were treated with 5 cycles of GM-CSF for 5 days at 250 µg/m2/day (-4 to 0), followed by GM-CSF for 5 days at 500 µg/m2/day (1-5) and naxitamab at 3 mg/kg/day (1, 3, 5), on an outpatient basis. All patients but one were older than 18 months at diagnosis and had stage M; 21 (25.6%) pts had MYCN-amplified (A) NB; and 12 (14.6%) detectable MRD in the BM. Eleven (13.4%) pts had received high-dose chemotherapy and ASCT and 26 (31.7%) radiotherapy before immunotherapy. With a median follow-up of 37.4 months, 31 (37.8%) pts have relapsed. The pattern of relapse was predominantly (77.4%) an isolated organ. Five-year EFS and OS were 57.9% (71.4% for MYCN A) 95% CI = (47.2, 70.9%); and 78.6% (81% for MYCN A) 95% CI = (68.7%, 89.8%), respectively. EFS showed significant differences for patients having received ASCT (p = 0.037) and pre-immunotherapy MRD (p = 0.0011). Cox models showed only MRD as a predictor of EFS. In conclusion, consolidation with naxitamab resulted in reassuring survival rates for HR-NB patients after end-induction CR.

Risk factors for major complications after surgical treatment of primary ileocecal Crohn's disease. A multicentric Latin American experience.

INTRODUCTION: Complications after ileocecal resection for Crohn's disease (CD) are frequent. The aim of this study was to analyze risk factors for postoperative complications after these procedures. MATERIALS AND METHODS: We conducted a retrospective analysis of patients treated surgically for Crohn's disease limited to the ileocecal region during an 8-year period at 10 medical centers specialized in inflammatory bowel disease (IBD) in Latin America. Patients were allocated into 2 groups: those who presented major postoperative complications (Clavien-Dindo > II), the "postoperative complication" (POC) group; and those who did not, the "no postoperative complication" (NPOC) group. Preoperative characteristics and intraoperative variables were analyzed to identify possible factors for POC. RESULTS: In total, 337 patients were included, with 51 (15.13%) in the POC cohort. Smoking was more prevalent among the POC patients (31.37 vs. 17.83; P = .026), who presented more preoperative anemia (33.33 vs. 17.48%; P = .009), required more urgent care (37.25 vs. 22.38; P = .023), and had lower albumin levels. Complicated disease was associated with higher postoperative morbidity. POC patients had a longer operative time (188.77 vs. 143.86 min; P = .005), more intraoperative complications (17.65 vs. 4.55%; P < .001), and lower rates of primary anastomosis. In the multivariate analysis, both smoking and intraoperative complications were independently associated with the occurrence of major postoperative complications. CONCLUSION: This study shows that risk factors for complications after primary ileocecal resections for Crohn's disease in Latin America are similar to those reported elsewhere. Future efforts in the region should be aimed at improving these outcomes by controlling some of the identified factors.

Novel infusion strategy reduces severe adverse events caused by the anti-GD2 monoclonal antibody naxitamab.

Introduction: Anti-disialoganglioside 2 (anti-GD2) monoclonal antibodies (mAbs) are associated with Grade ≥3 (≥G3) adverse events (AEs) such as severe pain, hypotension, and bronchospasm. We developed a novel method of administering the GD2-binding mAb naxitamab, termed "Step-Up" infusion (STU), to reduce the risk of AEs of severe pain, hypotension, and bronchospasm. Methods: Forty-two patients with GD2-positive tumors received naxitamab under "compassionate use" protocols and administered via either the standard infusion regimen (SIR) or the STU regimen. The SIR comprises a 60-min infusion of 3 mg/kg/day on Day 1 of cycle 1 and a 30- to 60-min infusion on Day 3 and Day 5, as tolerated. The STU regimen uses a 2-h infusion on Day 1, initiated at a rate of 0.06 mg/kg/h during 15 min (0.015 mg/kg) and which increases gradually to a cumulative dose of 3 mg/kg; on Days 3 and 5, the 3-mg/kg dose is initiated at 0.24 mg/kg/h (0.06 mg/kg) and delivered in 90 min according to the same gradual-increase strategy. AEs were graded according to Common Terminology Criteria for Adverse Events version 4.0. Results: The frequency of infusions with an associated G3 AE was reduced from 8.1% (23/284 infusions) with SIR to 2.5% (5/202 infusions) with STU. The odds of an infusion being associated with a G3 AE reduced by 70.3% with STU vs. SIR (odds ratio: 0.297; p = 0.037). Mean serum naxitamab levels pre- and post-STU (11.46 µg/ml pre-infusion; 100.95 µg/ml post-infusion) were within the range reported for SIR. Discussion: The comparable pharmacokinetics of naxitamab during SIR and STU may indicate that switching to STU reduces G3 AEs without impact on efficacy.

FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells.

FTY720 is an FDA-approved sphingosine derivative drug for the treatment of multiple sclerosis. This compound blocks lymphocyte egress from lymphoid organs and autoimmunity through sphingosine 1-phosphate (S1P) receptor blockage. Drug repurposing of FTY720 has revealed improvements in glucose metabolism and metabolic diseases. Studies also demonstrate that preconditioning with this compound preserves the ATP levels during cardiac ischemia in rats. The molecular mechanisms by which FTY720 promotes metabolism are not well understood. Here, we demonstrate that nanomolar concentrations of the phosphorylated form of FTY720 (FTY720-P), the active ligand of S1P receptor (S1PR), activates mitochondrial respiration and the mitochondrial ATP production rate in AC16 human cardiomyocyte cells. Additionally, FTY720-P increases the number of mitochondrial nucleoids, promotes mitochondrial morphology alterations, and induces activation of STAT3, a transcription factor that promotes mitochondrial function. Notably, the effect of FTY720-P on mitochondrial function was suppressed in the presence of a STAT3 inhibitor. In summary, our results suggest that FTY720 promotes the activation of mitochondrial function, in part, through a STAT3 action.

Repetitive transcranial magnetic stimulation of primary motor cortex for stroke upper limb motor sequelae rehabilitation: A systematic review.

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) over the primary motor cortex (M1) has been used to treat stroke motor sequelae regulating cortical excitability. Early interventions are widely recommended, but there is also evidence showing interventions in subacute or chronic phases are still useful. OBJECTIVE: To synthetize the evidence of rTMS protocols to improve upper limb motor function in people with subacute and/or chronic stroke. METHODS: Four databases were searched in July 2022. Clinical trials investigating the effectiveness of different rTMS protocols on upper limb motor function in subacute or chronic phases post-stroke were included. PRISMA guidelines and PEDro scale were used. RESULTS: Thirty-two studies representing 1137 participants were included. Positive effects of all types of rTMS protocols on upper limb motor function were found. These effects were heterogeneous and not always clinically relevant or related to neurophysiological changes but produced evident changes if evaluated with functional tests. CONCLUSION: rTMS interventions over M1 are effective for improving upper limb motor function in people with subacute and chronic stroke. When rTMS protocols were priming physical rehabilitation better effects were achieved. Studies considering minimal clinical differences and different dosing will help to generalize the use of these protocols in clinical practice.

Acute myocarditis with transient myocardial thickening in two oncologic patients treated with anti-GD2 immunotherapy.

Immunotherapy has considerably improved clinical outcomes in different types of cancers but has also been associated with the development of myocarditis, especially with that mediated by immune checkpoint inhibitors. To the best of our knowledge, these are the first cases of myocarditis after anti-GD2 immunotherapy reported to date. We present two cases of paediatric patients who, after anti-GD2 infusion, presented severe myocarditis with myocardial hypertrophy detected on echocardiography and confirmed with cardiac magnetic resonance imaging. An increase in myocardial T1 and extracellular volume of up to 30% was observed with heterogeneous intramyocardial late enhancement. Myocarditis after anti-GD2 immunotherapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.

Lesiones metastásicas a glándula tiroides. Una serie de casos / Metastatic lesions to the thyroid gland. Case series

Las lesiones metastásicas representan hasta un 3 % de los tumores malignos de la glándula tiroides. La mayoría de los casos se originan de tumores de células renales y de pulmón. El abordaje diagnóstico implica una alta sospecha clínica en pacientes con primarios conocidos, sin embargo, puede ser la manifestación inicial de una enfermedad maligna extensa no diagnosticada hasta en un 20 % a 40 % de los pacientes. La biopsia por aguja fina ha demostrado buen rendimiento para el diagnóstico de los nódulos metastásicos. El pronóstico y la opción del tratamiento quirúrgico dependen del control local del primario y del estado de la enfermedad sistémica asociada, por lo tanto, debe ser individualizado. Por lo general, hasta un 80 % de los pacientes con compromiso de la tiroides tienen enfermedad metastásica multiorgánica, y la intención del tratamiento quirúrgico es con fines paliativos para prevenir las complicaciones derivadas de la extensión local de la enfermedad a las estructuras del tracto aerodigestivo superior en el cuello. Se presenta a continuación, una serie de seis casos de pacientes con lesiones metastásicas a glándula tiroides con primarios en riñón, mama y de melanomas

Metastatic lesions represent up to 3% of malignant tumors of the thyroid gland. Most cases originate from lung and renal cell tumors. The diagnostic approach implies a high clinical suspicion in patients with known primaries, however, it can be the initial manifestation of an extensive undiagnosed malignant disease in up to 20% to 40% of patients. Fine-needle biopsy has shown good performance for the diagnosis of metastatic nodules. The prognosis and the option of surgical treatment depend on the local control of the primary condition and the state of the associated systemic disease, therefore it must be individualized. In general, up to 80% of patients with thyroid involvement have multi-organ metastatic disease and surgical treatment is intended to be palliative to prevent complications resulting from local extension of the disease to structures of the upper aerodigestive tract in the neck. A case series of six patients with metastatic lesions to the thyroid gland with primaries in the kidney, breast and melanomas is presented below

Nek4 regulates mitochondrial respiration and morphology.

Nek4 is a serine/threonine kinase which has been implicated in primary cilia stabilization, DNA damage response, autophagy and epithelial-to-mesenchymal transition. The role of Nek4 in cancer cell survival and chemotherapy resistance has also been shown. However, the precise mechanisms by which Nek4 operates remain to be elucidated. Here, we show that Nek4 overexpression activates mitochondrial respiration coupled to ATP production, which is paralleled by increased mitochondrial membrane potential, and resistance to mitochondrial DNA damage. Congruently, Nek4 depletion reduced mitochondrial respiration and mtDNA integrity. Nek4 deficiency caused mitochondrial elongation, probably via reduced activity of the fission protein DRP1. In Nek4 overexpressing cells, the increase in mitochondrial fission was concomitant to enhanced phosphorylation of DRP1 and Erk1/2 proteins, and the effects on mitochondrial respiration were abolished in the presence of a DRP1 inhibitor. This study shows Nek4 as a novel regulator of mitochondrial function that may explain the joint appearance of high mitochondrial respiration and mitochondrial fragmentation.

Mirror syndrome with noncompaction cardiomyopathy in the mother and fetus. Case report / Síndrome en espejo con miocardiopatía no compactada en la madre y el feto. Reporte de caso

Objective: To report the case of a pregnant woman with mirror syndrome associated with non-compaction cardiomyopathy in the mother and the fetus, in which antenatal medical treatment provided to the mother resulted in a favorable perinatal maternal outcome. Case presentation: A 16-year old primigravida with 33 weeks of gestation referred from a Level I institution to a private Level IV center in Medellín, Colombia, because of a finding of fetal hydrops on obstetric ultrasound. During hospitalization, the patient showed clinical and ultrasonographic signs of heart failure (dyspnea, edema and hypoxemia), with the diagnosis of hydrops fetalis (mirror syndrome) also confirmed. Diuretic treatment with furosemide was initiated in the mother, with subsequent improvement of the maternal condition as well as of the fetal edema. During the subacute postpartum period in the hospital, the presence of non-compaction cardiomyopathy was confirmed on cardiac nuclear magnetic resonance imaging in both the mother and the newborn. After discharge in adequated condition, they were included in the cardiovascular follow-up program for heart failure and congenital heart disease, respectively. Conclusion: A case of mirror syndrome associated with maternal and fetal non-compaction cardiomyopathy is presented. There is a limited number of reports on mirror syndrome due to cardiac anomalies (maternal and fetal), with weak treatment descriptions, pointing to the need for research in this area. It would be important to consider the diagnosis of non-compaction cardiomyopathy in fetuses with hydrops unrelated to isoimmunization or cardiac dysfunction, and approach these cases from a multi-disciplinary perspective.

Objetivo: reportar el caso de una gestante con síndrome en espejo asociada a miocardiopatía no compactada, tanto en la madre como el feto, en los que el tratamiento médico antenatal en la madre llevó a un resultado materno perinatal favorable. Presentación del caso: se describe el caso de una primigestante de 16 años, con 33 semanas de embarazo, remitida desde una institución de primer nivel de atención a una institución privada de cuarto nivel en la ciudad de Medellín, Colombia, por presentar feto con hidropesía en ultrasonido obstétrico de control. Durante la hospitalización, la paciente presentó signos clínicos y ecocardiográficos de falla cardiaca (disnea, edema e hipoxemia), a la vez que se confirmó el diagnóstico de Hydrops fetalis (síndrome en espejo). Se instauró tratamiento diurético con furosemida en la madre, logrando mejoría del cuadro materno y del edema fetal. En el puerperio mediato hospitalario se confirmaron la presencia de miocardiopatía no compactada en la resonancia magnética nuclear cardiaca, tanto de la madre como del recién nacido. Ambos egresaron en adecuadas condiciones y fueron vinculados al programa de seguimiento cardiovascular: falla cardiaca y de cardiopatía congénitas, respectivamente. Conclusión: se presenta un caso de síndrome en espejo asociado a miocardiopatía no compactada materna y fetal. Es limitado el número de reportes de síndrome en espejo por anomalías cardiacas (maternas y fetales) y pobre la descripción de los tratamientos realizados que surgen como temas a investigar. Sería importante considerar el diagnóstico de MNC en fetos con hidropesía no asociados a isoinmunización y con disfunción cardiaca, así como su atención por equipos multidisciplinarios.

Síndrome en espejo con miocardiopatía no compactada en la madre y el feto. Reporte de caso / Mirror syndrome with noncompaction cardiomyopathy in the mother and fetus. Case report

Objetivo: reportar el caso de una gestante con síndrome en espejo asociada a miocardiopatía no compactada (MNC), tanto en la madre como el feto, en los que el tratamiento médico antenatal en la madre llevó a un resultado materno perinatal favorable. Presentación del caso: se describe el caso de una primigestante de 16 años, con 33 semanas de embarazo, remitida desde una institución de primer nivel de atención a una institución privada de cuarto nivel en la ciudad de Medellín, Colombia, por presentar feto con hidropesía en ultrasonido obstétrico de control. Durante la hospitalización, la paciente presentó signos clínicos y ecocardiográficos de falla cardiaca (disnea, edema e hipoxemia), a la vez que se confirmó el diagnóstico de Hydrops fetalis (síndrome en espejo). Se instauró tratamiento diurético con furosemida en la madre, logrando mejoría del cuadro materno y del edema fetal. En el puerperio mediato hospitalario se confirmaron la presencia de miocardiopatía no compactada en la resonancia magnética nuclear cardiaca, tanto de la madre como del recién nacido. Ambos egresaron en adecuadas condiciones y fueron vinculados al programa de seguimiento cardiovascular: falla cardiaca y de cardiopatía congénitas, respectivamente. Conclusión: se presenta un caso de síndrome en espejo asociado a miocardiopatía no compactada materna y fetal. Es limitado el número de reportes de síndrome en espejo por anomalías cardiacas (maternas y fetales) y pobre la descripción de los tratamientos realizados que surgen como temas a investigar. Sería importante considerar el diagnóstico de MNC en fetos con hidropesía no asociados a isoinmunización y con disfunción cardiaca, así como su atención por equipos multidisciplinarios.

ABSTRACT Objective: To report the case of a pregnant woman with mirror syndrome associated with noncompaction cardiomyopathy in the mother and the fetus, in which antenatal medical treatment provided to the mother resulted in a favorable perinatal maternal outcome. Case presentation: A 16-year old primigravida with 33 weeks of gestation referred from a Level I institution to a private Level IV center in Medellín, Colombia, because of a finding of fetal hydrops on obstetric ultrasound. During hospitalization, the patient showed clinical and ultrasonographic signs of heart failure (dyspnea, edema and hypoxemia), with the diagnosis of hydrops fetalis (mirror syndrome) also confirmed. Diuretic treatment with furosemide was initiated in the mother, with subsequent improvement of the maternal condition as well as of the fetal edema. During the subacute postpartum period in the hospital, the presence of non-compaction cardiomyopathy was confirmed on cardiac nuclear magnetic resonance imaging in both the mother and the newborn. After discharge in adequated condition, they were included in the cardiovascular follow-up program for heart failure and congenital heart disease, respectively. Conclusion: A case of mirror syndrome associated with maternal and fetal non-compaction cardiomyopathy is presented. There is a limited number of reports on mirror syndrome due to cardiac anomalies (maternal and fetal), with weak treatment descriptions, pointing to the need for research in this area. It would be important to consider the diagnosis of non-compaction cardiomyopathy in fetuses with hydrops unrelated to isoimmunization or cardiac dysfunction and approach these cases from a multidisciplinary perspective.

Naxitamab combined with granulocyte-macrophage colony-stimulating factor as consolidation for high-risk neuroblastoma patients in complete remission.

BACKGROUND: Naxitamab is a humanized anti-disialoganglioside (GD2) monoclonal antibody approved for treatment of bone/bone marrow refractory high-risk neuroblastoma (HR-NB). Compassionate use (CU) expanded access program at Hospital Sant Joan de Deu permitted treatment of patients in complete remission (CR). We here report the survival, toxicity, and relapse pattern of patients in first or second CR treated with naxitamab and sargramostim (GM-CSF). PROCEDURE: Seventy-three consecutive patients with HR-NB (stage M at age >18 months or MYCN-amplified stages L1/L2 at any age) were treated in first or second CR. Treatment comprised five cycles of subcutaneous (SC) GM-CSF for 5 days at 250 µg/m2 /day (days -4 to 0), followed by naxitamab + SC GM-CSF for 5 days at 500 µg/m2 /day (days 1-5). Naxitamab was infused over 30 minutes at 3 mg/kg/day, days 1, 3, and 5, outpatient. RESULTS: Fifty-five patients were in first CR and 18 in second CR. Seventeen patients had MYCN-amplified NB and 11 detectable minimal residual disease in the bone marrow. Fifty-eight (79.5%) patients completed therapy. Four (5%) experienced grade 4 toxicities and 10 (14%) early relapse. Three-year event-free survival (EFS) 58.4%, 95% CI = (43.5%, 78.4%) and overall survival (OS) 82.4%, 95% CI = (66.8%, 100%). First CR patients 3-year EFS 74.3%, 95% CI = (62.7%, 88.1%), and OS 91.6%, 95% CI = (82.4%, 100%). EFS is significantly different between first and second CR (p = .0029). The pattern of relapse is predominantly (75%) of an isolated organ, mainly bone (54%). Univariate Cox models show prior history of relapse as the only statistically significant predictor of EFS but not OS. CONCLUSIONS: Consolidation with naxitamab and GM-CSF resulted in excellent survival rates for HR-NB patients in CR.

Clinical and Pathological Evidence of Anti-GD2 Immunotherapy Induced Differentiation in Relapsed/Refractory High-Risk Neuroblastoma.

BACKGROUND: Neuroblastic tumors (NBTs) originate from a block in the process of differentiation. Histologically, NBTs are classified in neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). Current therapy for high-risk (HR) NB includes chemotherapy, surgery, radiotherapy, and anti-GD2 monoclonal antibodies (mAbs). Anti-GD2 mAbs induce immunological cytoxicity but also direct cell death. METHODS: We report on patients treated with naxitamab for chemorefractory NB showing lesions with long periods of stable disease. Target lesions with persisting 123I-Metaiodobenzylguanidine (MIBG) uptake after 4 cycles of immunotherapy were further evaluated by functional Magnetic Resonance Imaging (MRI) and/or Fluorodeoxyglucose (FDG)-positron emission tomography (PET). MIBG avid lesions that became non-restrictive on MRI (apparent diffusion coefficient (ADC) > 1) and/or FDG-PET negative (SUV < 2) were biopsied. RESULTS: Twenty-seven relapse/refractory (R/R) HR-NB patients were enrolled on protocol Ymabs 201. Two (7.5%) of the 27 showed persistent bone lesions on MIBG, ADC high, and/or FDG-PET negative. Forty-four R/R HR-NB patients received chemo-immunotherapy. Twelve (27%) of the 44 developed persistent MIBG+ but FDG-PET- and/or high ADC lesions. Twelve (86%) of the 14 cases identified were successfully biopsied producing 16 evaluable samples. Histology showed ganglioneuroma maturing subtype in 6 (37.5%); ganglioneuroma mature subtype with no neuroblastic component in 4 (25%); differentiating NB with no Schwannian stroma in 5 (31%); and undifferentiated NB without Schwannian stroma in one (6%). Overall, 10 (62.5%) of the 16 specimens were histopathologically fully mature NBTs. CONCLUSIONS: Our results disclose an undescribed mechanism of action for naxitamab and highlight the limitations of conventional imaging in the evaluation of anti-GD2 immunotherapy clinical efficacy for HR-NB.