新生儿期起病的罕见肝窦阻塞综合征1例北大核心CSCD

患儿,男,1个月14 d,因腹胀2周,加重3 d入院。患儿生后曾有脐炎病史,体格检查示腹胀明显、腹壁静脉显露、肝脾触诊不满意,移动性浊音阳性。肝脏转氨酶轻度增高,肝脏超声及CT均提示门静脉肝内段及肝脏左中右静脉肝内段不显影、管腔闭塞、周边纤维增生,临床诊断为脐炎引发的肝窦阻塞综合征。入院后12 d患儿出现大量血性腹水,继发低血容量性休克、呼吸衰竭,家属放弃治疗后临床死亡。该文对新生儿期起病的肝窦阻塞综合征的诊断思路及多学科诊疗进行重点描述,并总结肝大、腹水的鉴别思路。     

Defibrotide for the treatment of hepatic veno‐occlusive disease/sinusoidal obstruction syndrome following nontransplant‐associated chemotherapy: Final results from a post hoc analysis of data from an expanded‐access program

1 Background

Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant‐associated chemotherapy. Following HSCT, VOD/SOS with multi‐organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post‐HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post‐HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded‐access treatment (T‐IND) program. A post hoc analysis of nontransplant‐associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented.

2 Procedure

Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended).

3 Results

Of the 1,154 patients in the T‐IND, 137 had nontransplant‐associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan–Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan–Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment‐related adverse events occurred in 26.8%.

4 Conclusions

In this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan–Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies.     

Defibrotide for the treatment of hepatic veno-occlusive disease in children

BACKGROUND: This retrospective report describes experience with defibrotide in children with hepatic veno-occlusive disease (HVOD) following hematopoietic progenitor cell transplant (HPCT) in a single institution. PROCEDURE: Children who had undergone HPCT between February 1999 and June 2001 and between July 2003 and September 2004 and who received defibrotide during their admission were identified. Demographic data and information regarding the clinical course of these patients were abstracted from their health records. RESULTS: Fourteen children (mean age: 9.3 years; range: 0.4-18.1) who underwent HPCT during the study period received defibrotide for the treatment of HVOD; nine were girls. Most patients underwent HPCT for hematologic malignancies (8/14) and received matched unrelated donor transplants (8/14). Conditioning regimens included cyclophosphamide with total body irradiation (5/14) and busulfan followed by cyclophosphamide (7/14). HVOD was diagnosed on transplant day -4 to +33 (median: +10.5); defibrotide was started on transplant day -4 to +40 (median: +12). The median initial defibrotide dose was 33 mg/kg/day (11-40 mg/kg/day); the median maximum defibrotide dose was 38.5 mg/kg/day (11-81 mg/kg/day). The median duration of defibrotide therapy was 16 days (4-37 days). Defibrotide was discontinued due to clinical improvement (9), death (3), drug unavailability (1), and neurological toxicity (1). Gastrointestinal hemorrhage was observed in two patients and intra-cranial hemorrhage was observed in one patient during defibrotide therapy. The survival rate to day +100 was 79%. CONCLUSIONS: Defibrotide appears to be an effective and relatively safe treatment for children with HVOD.     

Multifactorial analysis of opsoclonus‐myoclonus syndrome etiology (“Tumor” vs. “No tumor”) in a cohort of 356 US children

1 Background

Pediatric opsoclonus‐myoclonus syndrome (OMS) presents a paradox of etiopathogenesis: A neuroblastic tumor (NB) is found in only one half of the cases, the others are ascribed to infections or designated as idiopathic.

2 Method

From an IRB‐approved observational study of 356 US children with OMS, secondary analysis of “etiology” and related factors was performed on a well‐characterized cohort. The “Tumor” (n = 173) and “No Tumor” groups (n = 183), as defined radiologically, were compared according to multiple factors considered potentially differentiating. Data were analyzed retrospectively using parametric and nonparametric tests as indicated.

3 Results

Patients with NB were not distinguishable by prodromal symptoms, OMS onset age, gender, race/ethnicity, OMS severity, rank order of neurological sign appearance, or geographic distribution. Various CSF immunologic biomarker abnormalities of OMS did not vary in the presence or absence of a detectable tumor: frequency of six lymphocyte subsets, or concentrations of 18 cytokines/chemokines, cytokine antagonists, chemokine receptors, cell adhesion molecules, or neuronal/glial markers. Prior responsiveness to conventional immunotherapy was not contingent on tumor/no tumor designation.

4 Conclusions

Multiple convergent factors provide compelling empirical evidence and rationalize the concept that OMS is one neurological disorder, regardless of apparent etiology. Limitations to the current clinical etiologic classifications as paraneoplastic, parainfectious/post‐infectious, and idiopathic etiology require antigen‐based biological solutions to tease out the molecular pathophysiology of viral/tumoral mechanisms. Systematic studies, regardless of presumed etiology, will be necessary to find the highest‐yield combination of imaging approaches, screening for infectious agents, and new biomarkers. Two testable hypotheses for future research are presented.     

The challenge of defining “ultra‐high‐risk” neuroblastoma

Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to determining appropriate treatment. Historically, most patients with high‐risk neuroblastoma (HR‐NBL) have been treated uniformly without further stratification. Attempts have been made to identify factors that can be used to risk stratify these patients and to characterize an “ultra‐high‐risk” (UHR) subpopulation with particularly poor outcome. However, among published data, there is a lack of consensus in the definition of the UHR population and heterogeneity in the endpoints and statistical methods used. This review summarizes our current understanding of stratification of HR‐NBL and discusses the complex issues in defining UHR neuroblastoma.     

The role of continuous renal replacement therapy in the management of acute kidney injury associated with sinusoidal obstruction syndrome following hematopoietic cell transplantation

Maintaining fluid balance, pre‐ and post‐MA‐HCT is essential and usually requires frequent administration of diuretics. Hepatic sinusoidal obstructive syndrome is potentially life‐threatening, especially when associated with AKI and MOF. This study describes six patients who developed AKI‐associated SOS and diuretic‐resistant FO who subsequently underwent CRRT using standardized management guidelines for fluid balance post‐HCT. Retrospective chart review was done for HCT patients between September 2011 and October 2013 at a tertiary care children's hospital. Thirty‐four patients underwent MA‐HCT in the study period. Six patients had SOS complicated by diuretic‐resistant FO and underwent CRRT. Defibrotide was used in three patients. Median time on CRRT was 10.5 days. Sixty‐six percent (N = 4 of 6) of patients had full resolution of SOS symptoms with a mortality rate of 34% (N = 2 of 6). Among patients who had full recovery of SOS symptoms, one patient developed AKI, end‐stage renal diseases and underwent kidney transplantation 34‐months post‐HCT. Thus, of six included patients, two died and one developed ESRD with only 50% (N = 3 of 6) good outcome. Use of a standardized, evidence‐based fluid balance protocol and early initiation of CRRT for HCT‐related AKI/SOS was associated with good outcomes.     

Longitudinal evaluation of liver stiffness in three pediatric patients with veno‐occlusive disease

Liver stiffness measurement by transient elastography is a non‐invasive ultrasound‐based technique used mainly for the evaluation of liver fibrosis in patients with chronic liver diseases. Some authors have suggested that it could be useful in the assessment of hepatic complications during hematopoietic stem cell transplant (HSCT), especially veno‐occlusive disease (VOD) or sinusoidal obstructive syndrome (SOS). Here, we present the evaluation of liver stiffness in three patients who developed severe hepatic VOD/SOS after HSCT. Liver stiffness measurement values were normal before transplant and afterward until the diagnosis of VOD/SOS when a dramatic increase was observed. After the VOD/SOS specific treatment, the values of stiffness showed a similar pattern of progressive reduction in all the three patients, with normalization after two weeks. In this report, we discuss the role of LSM in the management of patients after the diagnosis of VOD/SOS.     

Compliance with the “Baby‐friendly Hospital Initiative for Neonatal Wards” in 36 countries

In 2012, the Baby‐friendly Hospital Initiative for Neonatal Wards (Neo‐BFHI) began providing recommendations to improve breastfeeding support for preterm and ill infants. This cross‐sectional survey aimed to measure compliance on a global level with the Neo‐BFHI's expanded Ten Steps to successful breastfeeding and three Guiding Principles in neonatal wards. In 2017, the Neo‐BFHI Self‐Assessment questionnaire was used in 15 languages to collect data from neonatal wards of all levels of care. Answers were summarized into compliance scores ranging from 0 to 100 at the ward, country, and international levels. A total of 917 neonatal wards from 36 low‐, middle‐, and high‐income countries from all continents participated. The median international overall score was 77, and median country overall scores ranged from 52 to 91. Guiding Principle 1 (respect for mothers), Step 5 (breastfeeding initiation and support), and Step 6 (human milk use) had the highest scores, 100, 88, and 88, respectively. Step 3 (antenatal information) and Step 7 (rooming‐in) had the lowest scores, 63 and 67, respectively. High‐income countries had significantly higher scores for Guiding Principles 2 (family‐centered care), Step 4 (skin‐to‐skin contact), and Step 5. Neonatal wards in hospitals ever‐designated Baby‐friendly had significantly higher scores than those never designated. Sixty percent of managers stated they would like to obtain Neo‐BFHI designation. Currently, Neo‐BFHI recommendations are partly implemented in many countries. The high number of participating wards indicates international readiness to expand Baby‐friendly standards to neonatal settings. Hospitals and governments should increase their efforts to better support breastfeeding in neonatal wards.     

Leukemic blasts with markers of four cell lineages in Down's syndrome (“megakaryoblastic leukemia”)

Among 16 patients with Down's syndrome (DS) and acute leukemia admitted to our department during a ten year period, 6 were diagnosed as acute megakaryoblastic leukemia (AMkL). The diagnosis was based on clinical and hematologic criteria, confirmed in three patients with the use of monoclonal antibodies (MoAb) specific for megakaryocytic antigens. In these three, and in a fourth patient, the leukemic blasts were positive for other myeloid, lymphoid and erythroid markers in MoAb testing. We suggest that AMkL in DS is a mixed lineage leukemia with blasts presenting a variety of cell surface antigens, indicating origin from an early progenitor cell with the capability of megakaryocytic differentiation. Of the 6 patients with AMkL, 4 treated with standard AML protocols are in complete continuing remission (CCR) with observation periods from 57+ to 148+ months. © 1993 Wiley-Liss, Inc.     

ToRCH “co‐infections” are associated with increased risk of abortion in pregnant women

ToRCH infections (toxoplasmosis, rubella, cytomegalovirus and Herpes simplex virus) have long been known to be associated with bad obstetric outcomes. However, little information is available about the impact of ToRCH co‐infections on the outcome of pregnancy. Hence, we tested the IgG and IgM antibodies to Toxoplasma gondii, Rubella, Cytomegalovirus and Herpes Simplex Virus among 81 pregnant women with abortion (case group) and 98 pregnant women with normal delivery (control group). In the single‐infection model, only CMV‐IgM seropositivity was significantly increased in case than control group (25.9% in case and 12.2 % in control, OR = 2.5, P = 0.019). In the co‐infection model, 14 patterns were recognized, but two patterns were significantly increased in the case than the control group. Co‐infection of T. gondii IgG + CMV IgM was 9.1‐fold increased in the case than the control group (8.6% in the case and 1% in control, OR = 9.1; P = 0.024). Also, co‐infection of T. gondii IgG + HSV IgG + CMV IgM was 7.7‐fold increased in case than the control group (7.4% in case and 1 % in control, OR = 7.7; P = 0.04). Although the OR of other co‐infections was higher in the case than the control group, the difference was not statistically significant. These findings indicate that ToRCH co‐infections are associated with increased risk of abortion than single infection. Hence, the rates of co‐infections should be considered in prenatal screening of ToRCH infections.     

Successful low‐dose radiotherapy treatment for Kasabach–Merritt syndrome

Kasabach–Merritt syndrome (KMS) is characterized by hemangioma associated with life‐threatening thrombocytopenia, and is a consumptive coagulopathy. Although treatments available include corticosteroids, α‐interferon, vincristine, and surgery, response may be unsatisfactory, and the mortality rate remains at approximately 30%. Although radiotherapy has been used effectively for KMS, it may cause growth retardation and secondary malignancy. We report a case of KMS in which hemangioma of the left thigh was successfully treated with low‐dose radiotherapy (6 Gy in six fractions, weekly) after failure of corticosteroid therapy. No significant late effects due to the radiotherapy were noted at 5 year follow up. Thus, low‐dose radiotherapy remains an important treatment method for KMS when patients fail to respond to other treatments.     

Mepolizumab—a novel option for the treatment of hypereosinophilic syndrome in childhood

Background

Mepolizumab was originally intended as a therapeutic agent for atopic asthma in adults, and consequently, little is known about its use in children. Up to now, corticosteroids have formed the basis of the initial treatment of hypereosinophilic syndromes and are shown to be effective in most patients. To analyze the effect of mepolizumab in children is the aim of this study.

Methods

We are reporting the experience of the effect of mepolizumab in 2 pediatric patients with hypereosinophilic syndrome that was not sufficiently controlled by other drugs. In addition, the literature regarding the treatment with mepolizumab in pediatric and adult patients is reviewed for the most important studies regarding safety and efficacy.

Results

Mepolizumab therapy showed in 2 pediatric patients with severe hypereosinophilic syndrome a safe and efficient therapeutic approach. No significant intolerances appeared. Furthermore, treatment with systemic corticosteroids was terminated, and therefore, severe side effects were avoided in our pediatric cases.

Conclusions

Anti‐IL‐5 antibodies, which can be applied without substantial drug intolerances, are a new, safe, and effective treatment option for pediatric patients with hypereosinophilic syndrome.     

Vesico‐amniotic shunting for lower urinary tract obstruction in a fetus with VACTERL association

Newborn cases of VACTERL association with lower urinary tract obstruction (LUTO) are rare and there have been no reports on those patients undergoing fetal therapy in English literature. We successfully performed vesico‐amniotic shunting in a fetus having LUTO caused by abnormality of the external genitalia at 16 weeks’ gestation. Although fetal karyotype was normal 46XY, follow‐up fetal ultrasound examinations revealed ventriculomegaly in the brain, a small stomach and a right multicystic dysplastic kidney. MRI at 31 weeks’ gestation suggested lobar type holoprosencephaly. Diagnosis of VACTERL association was confirmed postnatally. We consider that vesico‐amniotic shunting is indicated for a fetus of VACTERL association with LUTO if the parents wish the procedure after genetic counseling and explanations about the fetal conditions.