Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid: a report from the Children's Oncology Group

Background

The components of therapy required for patients with INSS Stage 3 neuroblastoma and high‐risk features remain controversial.

Procedure

A retrospective cohort design was used to determine if intensive chemoradiotherapy with purged autologous bone marrow rescue (ABMT) and/or 13‐cis‐retinoic acid (13‐cis‐RA) improved outcome for patients with high‐risk neuroblastoma that was not metastatic to distant sites. We identified 72 patients with INSS Stage 3 neuroblastoma enrolled between 1991 and 1996 on the Phase 3 CCG‐3891 randomized trial. Patients were analyzed on an intent‐to‐treat basis using a log‐rank test.

Results

The 5‐year event‐free survival (EFS) and overall survival (OS) rates for patients with Stage 3 neuroblastoma were 55 ± 6% and 59 ± 6%, respectively (n = 72). Patients randomized to ABMT (n = 20) had 5‐year EFS of 65 ± 11% and OS of 65 ± 11% compared to 41 ± 11 (P = 0.21) and 46 ± 11% (P = 0.23) for patients randomized to CC (n = 23), respectively. Patients randomized to 13‐cis‐RA (n = 23) had 5‐year EFS of 70 ± 10% and OS of 78 ± 9% compared to 63 ± 12% (P = 0.67) and 67 ± 12% (P = 0.55) for those receiving no further therapy (n = 16), respectively. Patients randomized to both ABMT and 13‐cis‐RA (n = 6) had a 5‐year EFS of 80 ± 11% and OS of 100%.

Conclusion

Patients with high‐risk Stage 3 neuroblastoma have an overall poor prognosis despite aggressive chemoradiotherapy. Further studies are warranted to determine if myeloablative consolidation followed by 13‐cis‐RA maintenance therapy statistically significantly improves outcome. Pediatr Blood Cancer 2009;52:44–50. © 2008 Wiley‐Liss, Inc.     

Dose‐escalation is needed for gross disease in high‐risk neuroblastoma

1 Background

Locoregional failure is common after subtotal resection in high‐risk neuroblastoma. Although a dose of 21 Gy radiation therapy (RT) is standard for treatment of high‐risk neuroblastoma after gross total resection, the dose needed for local control of patients with gross residual disease at the time of RT is unknown. We sought to evaluate local control after 21–36 Gy RT in patients with high‐risk neuroblastoma undergoing subtotal resection.

2 Methods

All patients with high‐risk neuroblastoma who received RT to their primary site from 2000 to 2016 were reviewed. Of the 331 patients who received consolidative RT to their primary site, 19 (5.7%) underwent subtotal resection and were included in our analysis. Local failure (LF) was correlated with biologic prognostic factors and dose of RT.

3 Results

Median follow‐up among surviving patients was 6.0 years. Median RT dose was 25 Gy (range, 21 Gy–36 Gy). The 5‐year cumulative incidence of LF among all patients was 17.2%. LF at 5 years was 30% in those who received <30 Gy versus 0% in those who received 30–36 Gy (P = 0.12). There was a trend towards improved local control in patients with tumor size ≤10 cm at diagnosis (P = 0.12). The 5‐year event‐free and overall survival were 44.9% and 68.7%, respectively.

4 Conclusion

After subtotal resection, patients who received less than 30 Gy had poor local control. Doses of 30–36 Gy are likely needed for optimal control of gross residual disease at the time of consolidative RT in high‐risk neuroblastoma.     

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.     

Bronchiectasis following treatment for high‐risk neuroblastoma: A case series

High‐risk (HR) neuroblastoma remains a very challenging disease to treat and long‐term cure is only possible with intensive, multimodal treatment including chemotherapy, high‐dose therapy, radiotherapy, surgery, and immunotherapy. As a result, treatment‐related morbidity and late effects are common in survivors. This report outlines a case series of six patients who developed a chronic productive cough following treatment for HR neuroblastoma. High‐resolution computed tomography scanning confirmed the diagnosis of bronchiectasis. Two of the patients who have undergone immunological testing demonstrate hypogammaglobulinaemia and impaired vaccine response. Persistent cough in patients treated for neuroblastoma warrants investigation and consideration of immunological referral.     

Feasibility and effectiveness of treatment strategy of tandem high‐dose chemotherapy and autologous stem cell transplantation in combination with 131I‐MIBG therapy for high‐risk neuroblastoma

This study was performed to evaluate the safety and effectiveness of tandem HDCT/ASCT combined with targeted radiotherapy using ¹³¹I‐MIBG for high‐risk neuroblastoma. Patients with high‐risk neuroblastoma were treated with 8 to 10 cycles of induction chemotherapy before tandem HDCT/ASCT. Patients received ¹³¹I‐MIBG treatment before the second HDCT/ASCT. Local radiotherapy and maintenance therapy were performed after tandem HDCT/ASCT. Between 2012 and 2016, 19 patients were diagnosed with high‐risk neuroblastoma in our institution and 18 of them received tandem HDCT/ASCT combined with ¹³¹I‐MIBG therapy. For the first HDCT/ASCT regimen, 12 patients received busulfan/melphalan and six patients received melphalan/etoposide/carboplatin. The second HDCT included ThioCy. The median dose of ¹³¹I‐MIBG was 17.2 mCi/kg for the first eight patients, while 12 patients in the latter period of the study received reduced dose of 10.7 mCi/kg. The 5‐year OS and EFS rates were 79% and 61%, respectively, for all 19 patients with high‐risk neuroblastoma, and 83% and 64%, respectively, for 18 patients who completed tandem HDCT/ASCT combined with ¹³¹I‐MIBG therapy. Six patients experienced disease relapse and five patients died. Treatment‐related mortality was not observed. Among 15 evaluable patients, 11 patients (73%) developed hypothyroidism, six patients (40%) had CKD, and six patients (40%) had growth failure. Hypothyroidism and growth failure were less frequent in patients who received reduced doses of ¹³¹I‐MIBG therapy. Tandem HDCT/ASCT combined with HD ¹³¹I‐MIBG therapy could be feasible for patients with high‐risk neuroblastoma with acceptable toxicity profiles and favorable outcomes.     

Langerhans cell histiocytosis in a patient with stage 4 neuroblastoma receiving oral fenretinide

Langerhans cell histiocytosis (LCH) has previously been reported in association with other malignancies. The pathogenesis of LCH and its relationship to other malignancies is poorly understood. We present a novel case of a child who developed an LCH bone lesion while receiving a Phase I protocol therapy with oral fenretinide/Lym‐X‐Sorb (4‐HPR/LXS) powder for neuroblastoma. Pediatr Blood Cancer 2009;53:1111–1113. © 2009 Wiley‐Liss, Inc.     

Nephrolithiasis in pediatric hematopoietic cell transplantation with up to 40 years of follow‐up

Background

Kidney stones have been reported to occur after childhood cancer, but little is known about kidney stones in children following hematopoietic cell transplantation (HCT). The objective of this retrospective study was to determine risk factors for the development of kidney stones and to describe the prevalence among survivors.

Procedure

The study included 1,343 childhood HCT patients. Mean follow‐up was 15.8 (1.0–40.0) years. Patients were treated with total body irradiation (TBI) (n = 948) or non‐TBI regimens. Methotrexate (MTX) for acute graft‐versus‐host disease (GVHD) prophylaxis was given as long‐course (n = 360), short‐course (n = 626), or none (n = 357). Prednisone for chronic GVHD therapy was received by 525 patients. Multivariate Cox regression models were used to estimate the hazard ratio (HR) of risk factors associated with kidney stones.

Results

Kidney stones developed in 51 patients, a median of 9.9 (0.2–29.4) years after first HCT, with a 30‐year cumulative incidence of 7.4%. Risk factors associated with kidney stones were TBI (HR = 2.2; P = 0.03), age at HCT (12–18 vs. <6 years, HR = 2.7; P = 0.01), MTX (long vs. none, HR = 3.6; P = 0.02), and prednisone (HR = 2.2; P = 0.008). Among 868 survivors, the prevalence of a history of kidney stones was 4.7%.

Conclusions

Survivors of childhood HCT have an increased risk of developing kidney stones. Pediatr Blood Cancer 2014;61:417–423. © 2013 Wiley Periodicals, Inc.     

IGG3 anti‐HLA donor‐specific antibodies and graft function in pediatric kidney transplant recipients

Anti‐HLA DSAs are associated with ABMR and graft loss in KT recipients, yet the influence of DSA IgG subclass on outcomes in pediatric KT recipients is not completely understood. We performed a single‐center retrospective chart review of pediatric KT recipients with anti‐HLA DSAs, aiming to study the association between specific DSA IgG subclasses and graft outcomes, including ABMR and significant graft dysfunction (graft loss or 50% decrease in eGFR). Thirty‐six patients (mean age 15.4y) with DSAs initially detected 1 month‐14.3 years post‐transplantation were followed for a median of 2.8 years. Rates of IgG1, 2, 3, and 4 subclass detection were 92%, 33%, 58%, and 25%, respectively. Twenty‐two patients (61%) had clinical ABMR, whereas 19% had subclinical ABMR, and 13 (36%) experienced significant graft dysfunction. Patients with IgG3+ DSAs had a higher risk of graft dysfunction compared with IgG3‐ patients (52% vs 13%, P = .03). In a multiple Cox proportional regression analysis, the presence of IgG3+ DSA was independently associated with significant graft dysfunction (HR 10.45, 95% CI 1.97‐55.55, P = .006). In conclusion, IgG3 subclass DSAs are associated with graft dysfunction and may be useful for risk stratification and treatment decisions in DSA‐positive pediatric KT recipients.     

Treatment‐related mortality in relapsed childhood acute lymphoblastic leukemia

1 Background

Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment‐related toxicity impacts survival.

2 Procedure

In this retrospective population‐based study, we described the causes of death and estimated the risk for treatment‐related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL‐92 and ALL‐2000 trials.

3 Results

Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment‐related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment‐related mortality were as follows: high‐risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3–3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3–9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17–9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment‐related causes.

4 Conclusions

Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.     

A phase II trial of a multi‐agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer

Background

Preclinical models show that an antiangiogenic regimen at low‐dose daily (metronomic) dosing may be effective against chemotherapy‐resistant tumors. We undertook a prospective, open‐label, single‐arm, multi‐institutional phase II study to evaluate the efficacy of a “5‐drug” oral regimen in children with recurrent or progressive cancer.

Procedure

Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21‐day cycles of low‐dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5‐drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed.

Results

One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days–21 years); 47 (49%) were female. Disease strata included high‐grade glioma (HGG, 21 patients), ependymoma (19), low‐grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty‐four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009).

Conclusion

The 5‐drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata. Pediatric Blood Cancer 2014;61:636–642. © 2013 The Authors Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.     

Ex vivo‐expanded donor CD4+ lymphocyte infusion against relapsing neuroblastoma: A transient graft‐versus‐tumor effect

High‐risk neuroblastoma has a poor prognosis despite multimodal treatment including high‐dose chemotherapy. A 7‐year‐old male with neuroblastoma received ex vivo‐expanded donor CD4⁺ T lymphocyte infusion (CD4⁺ DLI) after recurrence in the bone marrow following allogeneic hematopoietic stem cell transplantation from his HLA‐identical mother. The disease transiently responded to CD4⁺ DLI with reduction of tumor cells and a decrease of serum neuron‐specific enolase. The response was associated with development of continued high fever and an increase of cytotoxic T lymphocytes in peripheral blood. This case suggests a possibility of a graft‐versus‐tumor effect against neuroblastoma. Pediatr Blood Cancer 2009;52:895–897. © 2009 Wiley‐Liss, Inc.     

Elastase, α1‐proteinase inhibitor,and interleukin‐8 in pre‐dialyzed and hemodialyzed patients with chronic kidney disease

Background: Neutrophil elastase in complex with α₁‐proteinase inhibitor (NE‐α₁PI) and interleukin (IL)‐8 may serve as indicators of neutrophil activation and inflammatory stage. The aim of the study was to evaluate NE‐α₁PI, α₁‐PI, and IL‐8 levels in the blood of patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) or conservatively treated (CT). The influence of a single HD session on the investigated parameters was also assessed. Methods: Blood samples were obtained from two groups of hemodialyzed patients (children/young adults [group HD1, n= 8] and adults [group HD2, n= 13]), as well as 13 CT patients and a group of healthy subjects. The proteins were measured using enzyme‐linked immunosorbent assay or radial immunodiffusion. Results: There were no significant differences in NE‐α₁PI, α₁‐PI, and IL‐8 concentrations between the HD1 and HD2 patients. The levels of NE‐α₁PI were considerably higher than normal in both groups of HD patients (before and after the HD session) and in the CT patients. Higher titers of NE‐α₁PI (P < 0.05) and α₁‐PI (P < 0.01) were obtained in the adults during the course of HD. Increased NE‐α₁PI was positively correlated with α₁‐PI. The serum concentration of IL‐8 was significantly higher in the HD2 patients before and after dialysis than in the controls. Conclusions: The data indicate that in CKD patients, neutrophils are highly activated both in the pre‐dialyzed period and on regular HD. Contact with the dialysis membrane during HD causes a significant increase in blood NE‐α₁PI and α₁‐PI in adults, but not in children/young adults. NE‐α₁PI seems to be a much better indicator of an inflammatory state in CKD patients than free α₁‐PI or IL‐8.     

Comparison of low‐dose and high‐dose cosyntropin stimulation testing in children

Background: There is no consensus among pediatric endocrinologists in using low‐dose (LD) versus high‐dose (HD) cosyntropin to test for secondary/tertiary adrenal insufficiency. This paper compares LD and HD cosyntropin stimulation testing in children for evaluation of hypothalamic‐pituitary‐adrenal axis (HPAA) and suggests a new peak cortisol cut‐off value for LD stimulation testing to avoid false positivity. Methods: Data of 36 children receiving LD (1 µg) and HD (249 µg) cosyntropin consecutively during growth hormone (GH) stimulation testing were analyzed in two groups. Group A were patients who passed GH stimulation testing and were not on oral, inhaled or intranasal steroids (intact hypothalamic‐pituitary axis, n= 19). Group B were patients who failed GH stimulation testing and/or were on oral, inhaled or intranasal steroids (impaired hypothalamic‐pituitary axis, n= 17). Results: In group A, the mean peak cortisol response in LD cosyntropin was 18.5 ± 2.4 µg/dL and that for the HD cosyntropin was 24.8 ± 3.1 µg/dL (r: 0.76, P≤ 0.05). In group B, the mean peak cortisol response in LD cosyntropin was 15.7 ± 6.1 µg/dL and that for HD cosyntropin was 21.7 ± 7.9 µg/dL (r: 0.98, P≤ 0.05). When a standard cut‐off of 18 µg/dL was used, 37% of the patients with intact HPAA failed LD cosyntropin testing, but a cut‐off of 14 µg/dL eliminated false positive results. Conclusions: LD cosyntropin stimulation testing results should be interpreted cautiously when used alone to prevent unnecessary long‐term treatment. Using a lower cut‐off for LD (≥14 µg/dL) seems to avoid false positive results and still detects most cases of impaired HPAA.     

Outcome of antibody‐mediated rejection compared to acute cellular rejection after pediatric heart transplantation

Outcomes of ACR after pediatric HTx have been well described, but less has been reported on outcomes of AMR. We compared the clinical characteristics and cardiovascular outcomes (composite end‐point of death, retransplantation, or allograft vasculopathy) of pediatric HTx recipients with AMR, ACR, and no rejection in a retrospective single‐center study of 104 recipients. Twenty were treated for AMR; 15 were treated for ACR. Recipients with AMR had an increased frequency of congenital heart disease (90% vs ACR 67% vs no rejection 59%, P = .03), homograft (68% vs 7% vs 18%, P < .001), HLA sensitization (45% vs 13% vs 13%, P = .008), and positive cross‐match (30% vs 7% vs 9%, P = .046). AMR caused hemodynamic compromise more often than ACR (39% vs 4%, P = .02). AMR recipients had worse cardiovascular outcome than recipients with ACR or no rejection (40% vs 20% vs 8.6%, P = .003). In bivariate Cox analysis, AMR (HR 4.1, CI 1.4‐12.0, P = .009) and ischemic time (HR 1.6, CI 1.1‐2.3, P = .02) were associated with worse cardiovascular outcome; ACR was not. In summary, pediatric HTx recipients who develop AMR have worse cardiovascular outcome than recipients who develop only ACR or experience no rejection at all.     

Failure of MIBG scan to detect metastases in SDHB‐mutated pediatric metastatic pheochromocytoma

¹²³I‐meta‐iodo benzyl guanidine (MIBG) scans are considered the gold standard imaging in neuroblastoma; however, flouro deoxy glucose positron emission tomography (FDG‐PET) scans have increased sensitivity in adults with pheochromocytoma/paraganglioma. We describe a pediatric patient initially considered to have localized neuroblastoma based on anatomical imaging and ¹²³I‐MIBG scan, but subsequent investigations revealed germline succinate dehydrogenase complex iron sulfur subunit B (SDHB) mutation–associated pheochromocytoma with multiple FDG‐avid skeletal metastases. We then compared ¹²³I‐MIBG and FDG‐PET scans in children with metastatic pheochromocytoma/paraganglioma. FDG‐PET was superior to ¹²³I‐MIBG scan for the detection of skeletal metastases (median number of skeletal lesions detected 10 [range 1–30] vs. 2 [range 1–26], respectively; P = 0.005 by t‐test). FDG‐PET should be considered the functional scan of choice in children with pheochromocytoma/paraganglioma.     

Verbal short‐term memory span in children: long‐term modality dependent effects of intrauterine growth restriction

Background: Recent reports showed that children born with intrauterine growth restriction (IUGR) are at greater risk of experiencing verbal short‐term memory span (STM) deficits that may impede their learning capacities at school. It is still unknown whether these deficits are modality dependent. Methods: This long‐term, prospective design study examined modality‐dependent verbal STM functions in children who were diagnosed at birth with IUGR (n = 138) and a control group (n = 64). Their STM skills were evaluated individually at 9 years of age with four conditions of the Visual–Aural Digit Span Test (VADS; Koppitz, 1981 ): auditory–oral, auditory–written, visuospatial–oral and visuospatial–written. Cognitive competence was evaluated with the short form of the Wechsler Intelligence Scales for Children – revised (WISC‐R95; Wechsler, 1998 ). Results: We found IUGR‐related specific auditory‐oral STM deficits (p < .036) in conjunction with two double dissociations: an auditory‐visuospatial (p < .014) and an input–output processing distinction (p < .014). Cognitive competence had a significant effect on all four conditions; however, the effect of IUGR on the auditory‐oral condition was not overridden by the effect of intelligence quotient (IQ). Conclusions: Intrauterine growth restriction affects global competence and inter‐modality processing, as well as distinct auditory input processing related to verbal STM functions. The findings support a long‐term relationship between prenatal aberrant head growth and auditory verbal STM deficits by the end of the first decade of life. Empirical, clinical and educational implications are presented.     

Use of oral immunoglobulins to treat diarrhea in pediatric kidney transplant recipients—Single‐center experience and review of the literature

Effective treatment modalities for diarrhea in solid organ transplant recipients are lacking. We evaluated the effect of oral IgG on clinical course of diarrhea in pediatric kidney transplant recipients. We retrospectively studied all pediatric kidney transplant recipients who required hospitalization for diarrhea between January 1, 2015, and December 31, 2017. We divided the recipients into two groups based on whether they had received oral IgG to treat diarrhea. Sixteen pediatric kidney transplant recipients required hospitalization for diarrhea over 3 years. Median age at admission was 9.25 years (IQR:12.54). Fifty‐six percent of recipients were male, and 81% were white. Four patients received oral IgG for prolonged diarrhea. Oral IgG recipients had longer diarrheal duration before admission (median (days) 14.5 vs1; P .02), a trend for greater weight loss at admission (median (kilogram) 1.4 vs 0.2; P .3), and a trend for higher acute kidney injury (>75% reduction in glomerular filtration rate: 100% vs 42%; P .36). Diarrhea resolved completely in 3 (75%) oral IgG recipients and 7 (58%) non‐oral IgG patients by discharge (P .99). One oral IgG recipient showed partial improvement but also had biopsy evidence of mycophenolate‐induced colitis. All patients tolerated oral IgG well. No patients required re‐hospitalization within 30 days of discharge. Oral IgG may be used safely and effectively to treat prolonged diarrhea in pediatric kidney transplant recipients. A larger, randomized, prospective study is needed to further assess the efficacy of oral IgG in the treatment of diarrhea.     

Severe lung injury and lung biopsy in children post‐hematopoietic stem cell transplantation: The differences between allogeneic and autologous transplantation

To review outcome of children post‐allogeneic (allo) and autologous (auto) SCT with severe lung injury who had lung biopsy and to determine whether the diagnoses provided by lung biopsy had an impact on outcome. Retrospective study was carried out from January 2000 to June 2010. Nine hundred and eighteen children (0–18 yr) received SCT (allo 476, auto 442), and 59 biopsies were performed in 48 patients. Most common result of lung biopsy was non‐infectious inflammation and recurrent disease in allo‐ and autorecipients, respectively. In a multivariate analysis, survival of allorecipients who had management change was inferior (p = 0.002; HR: 3.12). These patients were extremely sick, and management change was the last attempt to stabilize their respiratory status. There was a trend toward superior survival for children who had biopsy after 100 days following SCT (p = 0.09; HR: 0.55) and a trend toward inferior survival for those with proven infections within two wk of biopsy (p = 0.07; HR: 2.14). Only 31% of allorecipients and 25% of autorecipients survived. There were no biopsy‐related complications. Lung biopsy itself appears to be well tolerated, although requiring a biopsy seems to carry a poor prognosis; this seems to be due to different causes, auto (relapse), allo (non‐infectious inflammation).     

Caries‐, Candida‐ and Candida antigen/antibody frequency in children after heart transplantation and children with congenital heart disease

Siahi‐Benlarbi R, Nies SM, Sziegoleit A, Bauer J, Schranz D, Wetzel W‐E. Caries‐, Candida‐ and Candida antigen/antibody frequency in children after heart transplantation and children with congenital heart disease.
Pediatr Transplantation 2010: 14:715–721. © 2008 Wiley Periodicals, Inc. Abstract: The aim of this study was to determine the incidence of oral/intestinal Candida colonization and Candida‐antigen/antibody in immunosuppressed children after HTx (group III, n = 31), in children with CHD (group II, n = 24) and in children with healthy hearts (comparison group, group I, n = 23) aged 2–16 yr according to their dental status between 2004 and 2007. Candida species in saliva, dental plaque, carious lesions and stool were detected with Sabouraud‐/CHROMagar and Auxacolor system. Candida‐specific‐antigen/antibody assays were used for serological diagnosis. Dental status was determined on the basis of the DMF/dmf(T/t)‐index. We found significant group differences in fecal Candida colonization (p = 0.027). In relation to dental status, oral Candida colonization increased within group III from 28.5% [DMF/dmf(T/t) = 0] to 66.7% [DMF/dmf(T/t) ≥ 1] up to 100.0% [D/d(T/t) ≥ 1], similar in groups I and II. Candida‐mannan‐antigen was determined to be positive in 16.1% (HTx), 5.5% (CHD) and 13.0% (comparison group). We show correlation between oral Candida colonization and (carious) dental status. We assume that high oral Candida and their descending/resorption through the gastrointestinal tract may lead to serologic Candida accumulation or rather candidiasis. Therefore, healthy oral cavity (especially before/after HTx) is an important precondition to prevent Candida infections.     

Syndrome of inappropriate anti‐diuretic hormone in Kawasaki disease

Background: The pathogenesis of hyponatremia in acute Kawasaki disease (KD) remains unclear. A recent case report of KD complicated by syndrome of inappropriate anti‐diuretic hormone (SIADH) led us to determine the prevalence of SIADH in acute KD patients. Methods: Subjects were 39 Japanese KD patients (2–84 months of age, 25 males and 14 females) treated with intravenous immunoglobulin (IVIG), 2 g/kg/day and oral aspirin. SIADH was defined when hyponatremic patients (serum sodium concentration <135 mEq/L) had decreased serum osmolality <280 mOsm/kg H₂O, elevated urine sodium concentration >20 mEq/L and elevated urine osmolality >100 mOsm/kg H₂O without dysfunctions of renal, thyroid or adrenal gland. We also studied the relation between clinical course of SIADH and the amount of infused fluid during IVIG. Results: Before IVIG, 27 patients (69%) had hyponatremia and 11 (28% of total; 41% of hyponatremic patients) had SIADH while after IVIG, 13 (33%) hyponatremia and four (10%; 31% of hyponatremic patients) SIADH. Among 11 patients with SIADH before IVIG, SIADH improved in 10 after IVIG, but hyponatremia persisted in five. Significant correlation was observed between serum sodium concentration after IVIG and infusion amount in SIADH patients (r=?0.64, P= 0.03), but not in non‐SIADH patients. Conclusions: This is the first report to show that SIADH is common as a cause of hyponatremia in acute KD and hence careful management of water and sodium is warranted.