Reaching the target dose with one single 131I-mIBG administration in high-risk neuroblastoma: The determinant impact of the primary tumour

Background : ¹³¹I-metaiodobenzylguanidine (¹³¹I-mIBG) effectiveness in children with metastasised neuroblastoma (NB) is linked to the effective dose absorbed by the target; a target of 4 Gy whole-body dose threshold has been proposed. Achieving this dose often requires administering ¹³¹I-mIBG twice back-to-back, which may cause haematological toxicity. In this study, we tried identifying the factors predicting the achievement of 4 Gy whole-body dose with a single radiopharmaceutical administration. Materials and methods : Children affected by metastatic NB and treated with a high ¹³¹I-mIBG activity (>450 MBq (megabecquerel)/kg) were evaluated retrospectively. Kinetics measurements were carried out at multiple time points to estimate the whole-body dose, which was compared with clinical and activity-related parameters. Results : Seventeen children (12 females, median age 3 years, age range: 1.5–6.9 years) were included. Eleven of them still bore the primary tumour. The median whole-body dose was 2.88 Gy (range: 1.63–4.22 Gy). Children with a ‘bulky’ primary (>30 mL) received a higher whole-body dose than those with smaller or surgically removed primaries (3.42 ± 0.74 vs. 2.48 ± 0.65 Gy, respectively, p = .016). Conversely, the correlation between activity/kg and the whole-body dose was moderate (R: 0.42, p = .093). In the multivariate analysis, the volume of the primary tumour was the most relevant predictor of the whole-body dose (p = .002). Conclusions : These data suggest that the presence of a bulky primary tumour can significantly prolong the ¹³¹I-mIBG biological half-life, effectively increasing the absorbed whole-body dose. This information could be used to model the administered activity, allowing to attain the target dose without needing a two-step radiopharmaceutical administration.     

A phase II study of radioimmunotherapy with intraventricular 131I‐3F8 for medulloblastoma

1 Background

High‐risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell‐surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular ¹³¹I‐labeled 3F8 in patients with MB on a phase II clinical trial.

2 Methods

Patients with histopathologically confirmed high‐risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) ¹²⁴I‐3F8 or ¹³¹I‐3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) ¹³¹I‐3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region‐of‐interest analyses on serial imaging scans. Disease evaluation included pre‐ and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6–12 months thereafter.

3 Results

Forty‐three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment‐related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0–2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18–0.88, P = 0.024).

4 Conclusions

cRIT with ¹³¹I‐3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high‐risk or recurrent MB.     

Nothing but NET: A review of norepinephrine transporter expression and efficacy of 131I‐mIBG therapy

Neuroblastoma is unique amongst common pediatric cancers for its expression of the norepinephrine transporter (NET), enabling tumor‐selective imaging and therapy with radioactive analogues of norepinephrine. The majority of neuroblastoma tumors are avid for ¹²³I‐metaiodobenzaguanidine (mIBG) on imaging, yet the therapeutic response to ¹³¹I‐mIBG is only 30% in clinical trials, and off‐target effects cause short‐ and long‐term morbidity. We review the contemporary understanding of the tumor‐selective uptake, retention, and efflux of meta‐iodobenzylguanidine (mIBG) and strategies currently in development for improving its efficacy. Combination treatment strategies aimed at enhancing NET are likely necessary to reach the full potential of ¹³¹I‐mIBG therapy. Pediatr Blood Cancer 2015;62:5–11 © 2014 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals, Inc.

     

Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group

Background

Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy.

Objective

We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532.

Study design

A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index.

Results

For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002).

Conclusion

In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.     

A Modified Protocol with Vincristine,Topotecan, and Cyclophosphamide for Recurrent/Progressive Ewing Sarcoma Family Tumors

Purpose: Topotecan has recently been used in the treatment of pediatric cancer. We evaluated our experience with the modified combination of vincristine, topotecan, and cyclophosphamide (VTC) given in 3 days, in children with recurrent Ewing sarcoma. Method: Children received vincristine (1.5 mg/m²/1st day), cyclophosphamide (600 mg/m²/day × 2 days) + mesna, and topotecan (1 mg/m²/day × 3 days) every 21 days. Result: A total of 118 courses of VTC were given to 13 patients. One patient received VTC both at first and at second relapse. Thus, 14 relapse episodes in 13 patients were evaluated. After three courses of VTC chemotherapy (CT), two achieved complete response (CR), five achieved partial response, thus an objective response was attained in 7/14 (50%) episodes. Two patients had stable disease and two patients progressed. In three episodes, CR was achieved by surgery before CT. One of them had a second relapse and attained CR with VTC. Median time from diagnosis to relapse was 23 months (5–45 months). Site of relapse was local in four patients, and metastatic in 10 episodes of nine patients. Seven patients are alive, three with no evidence of disease and four alive with disease; six have died of disease. Local treatment was used in 11 episodes. The toxicity of the VTC combination was limited mainly to the hematopoietic system. Conclusion: In conclusion, the modified VTC protocol in 3 days every 3 weeks seems to be effective and tolerable in children and adolescents with recurrent/progressive Ewing sarcoma.     

Evaluation of semi-quantitative scoring system for metaiodobenzylguanidine (mIBG) scans in patients with relapsed neuroblastoma

BACKGROUND: The purpose of this study was to determine the accuracy of two semi-quantitative scoring systems to assess response to (131)I-metaiodobenzylguanidine (mIBG) therapy in recurrent neuroblastoma. PROCEDURES: Diagnostic mIBG scan pairs (n = 57) were collected for patients who underwent (131)I-mIBG therapy for relapsed neuroblastoma. Two scoring systems were designated: Method 1, which divided the body into nine segments to view osteomedullary lesions with an additional tenth segment to assess soft tissue involvement; and Method 2, which divided the body into seven segments without a corresponding compartment for soft tissue involvement. Four nuclear medicine physicians independently assigned extension and intensity scores utilizing both methods, and separately recorded their impression of whether the post-therapy scan had improved, not changed, or worsened. Inter- and intra-observer concordance and correlation with overall response and progression-free survival (PFS) were performed. RESULTS: Method 1 produced the highest inter-observer concordance and was used to calculate the relative extension scores (post-therapy score divided by pre-therapy score), which correlated significantly with overall response. Patients who achieved complete response (CR) or partial response (PR) (n = 21) had lower relative extension scores, compared to those without response (P < 0.001). The readers' overall impression associated highly (P < 0.001) with the relative extension scores though results were less quantitative. Concordance was higher if initial scores were >5. Relative extension score did not predict PFS. CONCLUSION: Semi-quantitative scoring of mIBG scans provides a more reliable method of assessing response in patients with relapsed neuroblastoma than qualitative impression. The reproducibility and high inter-observer concordance makes mIBG score an important component of overall response criteria in patients with recurrent neuroblastoma.     

Treatment of Langerhans cell histiocytosis with a modified risk‐adapted protocol—experience from a tertiary cancer institute in India

Background

Involvement of risk‐organs (RO+) in Langerhans cell histiocytosis (LCH) and inadequate early response identifies patients at high risk for relapse and mortality requiring intensive salvage therapy including stem cell transplant, adding cost and toxicity. To mitigate this, we used a standard induction, augmented with metronomic etoposide, and prolonged maintenance—similarly augmented for RO+, and retrospectively analyzed its impact.

Procedure

LCH patients from 2009 through 2014 were included. Patients received standard vinblastine and prednisolone therapy weekly till week 25 for RO+. Single site (SS) and multisystem (MS) without risk organ involvement (RO?) received 3‐weekly pulses from week 13 till week 25. Maintenance was 3‐weekly vinblastine and 5‐day prednisolone pulses, daily 6‐mercaptopurine (60 mg/m²) and weekly methotrexate (15 mg/m²) for 18 and 9 months for RO+ and MSRO?, respectively. RO+ also received oral etoposide (50 mg/m²) for 21 of every 28‐day cycle for the first year.

Results

Fifty consecutive patients were analyzed. Median age was 36 months (4–189 months). SS, MSRO?, and RO+ were 29 (58%), 12 (24%), and nine (18%), respectively. Four were lost to follow‐up and excluded from further evaluation. On response evaluation at week 6, 24 (52%) had no active disease (NAD), 17 (37%) had AD‐better (where AD is active disease), and one (2%) had AD‐worse. In RO+, eight (66.6%) had AD‐better and three (25%) had NAD. Forty‐five patients had NAD by week 12. Three patients relapsed. With median follow‐up of 39 months (8–84), 5‐year event free survival was 85.6% (RO? and SS), and 100% for RO+. One patient's death in remission from unrelated causes resulted in overall survival of 97%.

Conclusions

RO+LCH receiving oral etoposide augmented induction and maintenance had early and durable responses. Prolonging maintenance lowered reactivation rates in RO+ and RO?LCH, resulting in excellent survival.

     

Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: A Pediatric Oncology Group study: A Report from the Children's Oncology Group

Background

The Pediatric Oncology Group performed a pilot study to assess the feasibility of tandem high dose chemotherapy (HDC) with stem cell rescue (HDC/SCR). We report here the results of this single arm trial of induction chemotherapy, local control measures (surgery and local radiation), and tandem HDC/SCR.

Procedure

Patients with high risk neuroblastoma (NBL) underwent five cycles of induction chemotherapy and resection of primary tumors. Peripheral blood stem cells (PBSC) were collected after Course 3 without exvivo manipulation. Myeloablative chemotherapy was performed in rapid sequence after induction chemotherapy and surgery. The ability of patients to complete both cycles of HDC/SCR was a primary endpoint. Transplant‐related toxicity, progression‐free survival (PFS) and overall survival (OS) were recorded.

Results

A total of 33 patients were enrolled. Twenty‐two patients completed at least one HDC/SCR procedure and 17 patients completed both. Only one patient had insufficient stem cells collected for both transplants. There was one transplant‐related death; engraftment was rapid and toxicity was as expected. The PFS of the 33 patients treated on this study is 24.2% ± 7.5% and OS is 36.4% ± 8.4% at 5 years. For patients who received at least one transplant PFS is 36.4% ± 11.0% and OS is 45.5% ± 11.2% at 5 years.

Conclusions

The treatment of high risk NBL with tandem HDC/SCR is feasible in terms of transplant‐related mortality and the ability to collect adequate PBSC for two transplants. The outcomes from this intensified treatment have been used to design a Children's Oncology Group Phase III study testing the efficacy of tandem HDC/SCR. Pediatr Blood Cancer 2012; 59: 902–907. © 2012 Wiley Periodicals, Inc.     

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.     

Clinical outcomes and toxicity following palliative radiotherapy for childhood cancers

1 Background

Few reports of palliative radiotherapy (RT) for pedialltric malignancies have been published. We described clinical indications, outcomes, and toxicities for children who received palliative RT.

2 Procedure

Pediatric patients (age ≤18 years) treated with palliative RT for incurable cancer from January 1 2008 to February 26, 2014 were included. Diagnosis, details of RT, treatment response, toxicity, and survival were retrospectively reviewed.

3 Results

Forty‐six patients received 76 RT courses. Fifteen patients (33%) had ≥2 courses. Median age at palliative RT was 10.3 years; 54% were male. The most common diagnoses were neuroblastoma (20%) and diffuse intrinsic pontine glioma (17%). The most common indications for RT were oligometastatic disease in asymptomatic patients (39%) and pain (25%). The most common treatment sites were brain (32%) and bone (29%). Median RT dose was 30 Gy. Median number of RT fractions was 12. Sixty‐five treatment courses (86%) were delivered with fraction sizes ≥2.5 Gy. Twenty‐seven treatment courses (36%) were given under general anesthesia. Median follow‐up was 3.9 months. Grade 1–2 RT‐related toxicity occurred in 21% of treatment courses and 4–8% up to 12 months after RT. Two patients had Grade 3 toxicity during RT (esophagitis). Of symptomatic patients, 91%, 73%, 58%, and 43% had improved or stable symptoms during RT and 0–3, 3–6, and 6–12 months afterwards, respectively. Median survival after palliative RT was 4.2 months. Four of 21 surviving patients (19%) had hospice care at last follow‐up.

4 Conclusions

Palliative RT was well tolerated in children with incurable malignancies, with most cases associated with acceptable toxicity, and improved or stable symptoms.     

Central nervous system relapse of rhabdomyosarcoma

1 Purpose

The optimal management of central nervous system (CNS) relapse of rhabdomyosarcoma (RMS) is unclear. We examined diagnosis, management, and outcomes of patients with RMS developing CNS relapse.

2 Methods

Records of 23 patients diagnosed with CNS relapse between 1999 and 2016 were reviewed. Median age at presentation of CNS relapse was 15 years (range, 1–34 years). High‐risk features at initial presentation were as follows: 16 alveolar patients, 13 Stage IV, and 13 with primary tumor in parameningeal locations.

3 Results

CNS relapse occurred at a median 12 months (range, 1–23 months) from diagnosis and most common presenting symptoms were headache (n = 9), nausea/vomiting (n = 8), visual difficulty (n = 5), and none (n = 5). Leptomeningeal metastases were detected in 21 patients while only 2 developed parenchymal metastases without leptomeningeal involvement. Fifteen patients received CNS‐directed radiation therapy (RT), including craniospinal irradiation to a median 36 Gy (range, 18–36 Gy) and/or whole brain radiotherapy to a median 30 Gy (range, 6–41.4 Gy). Three patients received concurrent chemotherapy. Follow‐up magnetic resonance imaging was conducted in 13 patients after RT initiation with 8 demonstrating improvement, 2 with stable disease, and 3 with progression. Twelve patients were tested for reactivity to I‐131‐labeled monoclonal antibody 8H9, and three tested positive and received at least one intra‐Ommaya dose; all three lived >12 months post‐CNS relapse. Twenty‐one patients died of CNS disease and two of metastatic disease at other sites. Median survival post‐CNS relapse was 5 months (range, 0.1–49 months).

4 Conclusions

The prognosis for patients with RMS developing CNS relapse remains poor. Treatment including CNS‐directed RT should be considered and investigation into preventative therapies is warranted.     

The prognostic value of IKZF1plus in B-cell progenitor acute lymphoblastic leukemia: Results from the EORTC 58951 trial

Background

IKZF1 gene deletion is an indicator of poor prognosis in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The AEIOP/BFM group proposed that the prognostic strength of IKZF1 deletion could be remarkably improved by taking into account additional genetic deletions and reported that among patients with an IKZF1 deletion those with deletions in CDKN2A/2B, PAX5, or PAR1 in the absence of ERG deletion, grouped as IKZF1^plus, had the worst outcome.

Procedure

Between 1998 and 2008, 1636 patients under 18 years of age with previously untreated BCP-ALL were registered in the EORTC 58951 trial. Those with multiplex ligation-dependent probe amplification data were included in this analysis. Unadjusted and adjusted Cox model was used to investigate the additional prognostic value of IKZF1^plus.

Results

Among 1200 patients included in the analysis, 1039 (87%) had no IKZF1 deletion (IKZF1^WT), 87 (7%) had an IKZF1 deletion but not IKZF1^plus (IKZF1^del) and 74 (6%) had IKZF1^plus. In the unadjusted analysis, both patients with IKZF1^del (hazard ratio [HR] = 2.10, 95% confidence interval [CI]: 1.34–3.31) and IKZF1^plus (HR = 3.07, 95% CI: 2.01–4.67) had a shorter event-free survival compared with IKZF1^WT. However, although the IKZF1^plus status was associated with patients’ characteristics indicating poor prognosis, the difference between IKZF1^plus and IKZF1^del was not statistically significant (HR = 1.46, 95% CI: 0.83–2.57, p = .19). The results of the adjusted analysis were similar to the unadjusted analysis.

Conclusions

In patients with BCP-ALL from the EORTC 58951 trial, the improvement of the prognostic importance of IKZF1 by considering IKZF1^plus was not statistically significant.     

Isolated late testicular relapse of B‐cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response‐based testicular radiation: A Children's Oncology Group study

1 Background

The incidence of isolated testicular relapse (ITR) of acute lymphoblastic leukemia (ALL) has decreased with contemporary treatment strategies, but outcomes are suboptimal with a 58% 5‐year overall survival (OS). This study aimed to improve outcome in patients with ITR of B‐cell ALL (B‐ALL) occurring after 18 months of first clinical remission using intensive systemic chemotherapy and to decrease long‐term sequelae by limiting use of testicular radiation.

2 Procedure

Forty patients in first ITR of B‐ALL were enrolled. Induction (dexamethasone, vincristine, daunorubicin, and intrathecal triple therapy) was preceded by one dose of high‐dose methotrexate (MTX, 5 g/m²). Following induction, 25 of 26 patients who had persistent testicular enlargement underwent testicular biopsy. Eleven had biopsy‐proven disease and received bilateral testicular radiation (24 Gy), whereas twenty‐nine did not.

3 Results

Overall 5‐year event‐free survival (EFS)/OS was 65.0 ± 8.8%/73.1 ± 8.3%, with 5‐year EFS 62.1 ± 11.0% vs. 72.7 ± 14.4% for patients who did not receive radiation therapy (XRT) (n = 29) compared with those who did (n = 11), respectively (P = 0.64). There were six second bone marrow relapses and six second ITRs. The proportion of second relapses was similar in the patients that received testicular radiation and those who did not. However, the 5‐year OS was similar for patients who did not receive XRT (72.6 ± 10.2%) compared with those who did (72.7 ± 14.4%) (P = 0.85).

4 Conclusions

A 5‐year OS rate of 73.1 ± 8.3% was obtained in children with first ITR of B‐ALL occurring after 18 months of CR1 (length of first clinical remission) using intensive chemotherapy and limiting testicular radiation.     

Management of Neuroblastoma: ICMR Consensus Document

Neuroblastoma (NBL) is the most common extra-cranial solid tumor in childhood. High-risk NBL is considered challenging and has one of the least favourable outcomes amongst pediatric cancers. Primary tumor can arise anywhere along the sympathetic chain. Advanced disease at presentation is common. Diagnosis is established by tumor biopsy and elevated urinary catecholamines. Staging is performed using bone marrow and mIBG scan (FDG-PET/bone scan if mIBG unavailable or non-avid). Age, stage, histopathological grading, MYCN amplification and 11q aberration are important prognostic factors utilized in risk stratification. Low-risk disease including Stage 1 and asymptomatic Stage 2 disease has an excellent prognosis with non-mutilating surgery alone. Perinatal adrenal neuroblastoma may be managed with close observation alone. Intermediate-risk disease consisting largely of unresectable/symptomatic Stage 2/3 disease and infants with Stage 4 disease has good outcome with few cycles of chemotherapy followed by surgical resection. Paraspinal neuroblastomas with cord compression are treated emergently, typically with upfront chemotherapy. Asymptomatic Stage 4S disease may be followed closely without treatment. Organ dysfunction and age below 3 mo would warrant chemotherapy in 4S. High-risk disease includes older children with Stage 4 disease and MYCN amplified tumors. High-risk disease has a suboptimal outcome, though the survival is improving with multimodality therapy including autologous stem cell transplant and immunotherapy. Relapse after multimodality therapy is difficult to salvage. Late presentation, lack of transplant facility, malnutrition and treatment abandonment are additional hurdles for survival in India. The review provides a consensus document on management of NBL for developing countries, including India.     

Infant robot-assisted laparoscopic upper urinary tract reconstructive surgery

ObjectiveOur aim was to assess the outcomes of infant robot-assisted laparoscopic (RAL) upper urinary tract reconstruction.Materials and methodsThe medical records of all infants who underwent RAL upper urinary tract reconstruction were reviewed. Patients less than 1 year of age at surgery were included. Patient demographics, intraoperative details, narcotic usage, and complications were reviewed.ResultsTen infants met the study criteria. There were five right and five left-sided procedures. Eight pyeloplasties (4 right, 4 left) and two ureteroureterostomies (1 right single system, 1 left duplex system) were performed. The median age was 8 months (range 3–12 months). Median weight was 7.7 kg (range 5.8–10.9 kg). Median operative time was 128 min (range 95–205 min). There was no significant blood loss or intraoperative complications. One (10%) patient received a regional block. Eight (80%) patients did not receive postoperative narcotics. Median hospital stay was 1 day (range 1–2). Median follow-up was 10 months (range 3–18 months). Complications included one urinary leak, one ileus, and one urinary tract infection. Hydronephrosis improved in all patients.ConclusionsInfant RAL upper urinary tract reconstruction is technically feasible, safe, and effective. It can be applied for duplication anomalies and single system obstructions in infants.     

Determining the prevalence of vestibular screening failures in pediatric cancer patients whose therapies include radiation to the head/neck and platin‐based therapies: A pilot study

1 Background

Sensorineural hearing loss due to ototoxic cancer therapy is well established; effects on the vestibular system are unknown. We examined the feasibility of implementing vestibular screens for pediatric cancer survivors exposed to ototoxic agents. The prevalence of screening failures is reported.

2 Methods

Cancer survivors who were 6–17 years, at least 1‐month posttreatment, and received ototoxic therapy (radiation to the head/neck, cisplatin, carboplatin) were eligible. Screening measures included (1) Pediatric Vestibular Symptom Questionnaire, (2) Modified Clinical Test of Sensory Interaction on Balance, and (3) Dynamic Visual Acuity.

3 Results

Vestibular screening failures were observed in 30 participants (60%). Patients with a brain tumor diagnosis were at increased risk for failures compared to nonbrain tumor patients (74.2% vs. 36.8%, P = 0.009). Patients who underwent brain surgery were at increased risk for failures compared to patients without brain surgery (71% vs. 42%, P = 0.043). Patients with a longer duration between end of treatment and vestibular screening had a reduced risk of failures, with an almost 20% decrease for each year between the time points (odds ratio = 0.812; 95% confidence interval: 0.683–0.964, P = 0.018). Receiving carboplatin correlated with a decreased risk of failure (P = 0.016), due to a negative correlation with other clinical risk factors (diagnosis of a brain tumor, major brain surgery) that are associated with vestibular screening failure.

4 Conclusion

Vestibular screening failures are highly prevalent in childhood cancer survivors who received ototoxic therapy. Broad screening of this population and further characterization of these patients are warranted.     

A pooled subgroup analysis of glucarpidase treatment in 86 pediatric,adolescent, and young adult patients receiving high-dose methotrexate therapy in open-label trials

Background

Delayed methotrexate elimination can occur in patients undergoing high-dose methotrexate cancer treatment. Effectiveness of glucarpidase for rapidly reducing methotrexate concentrations was shown in compassionate-use trials in patients aged 0–84 years.

Methods

We performed post hoc analyses of infants (≥28 days to <2 years), children (≥2 to <12 years), adolescents (≥12 to <15 years), and young adults (≥15 to <25 years) from four multicenter, open-label, single-arm, glucarpidase compassionate-use trials. Patients had toxic methotrexate levels due to delayed methotrexate elimination and/or renal dysfunction, and received glucarpidase (50 U/kg). The primary endpoint was clinically important reduction (CIR) in plasma methotrexate (methotrexate ≤1 μmol/L at all post-glucarpidase measurements) based on high-performance liquid chromatography.

Results

Among 86 patients included in efficacy analyses, CIR was achieved by zero of one infant (0.0%), five of 16 children (31.3%), seven of 24 adolescents (29.2%), and 26/45 young adults (57.8%). Median methotrexate reduction was 98.7% or higher in each group 15 minutes post-glucarpidase. Patients with pre-glucarpidase methotrexate less than 50 μmol/L (35/42, 83.3%) were more likely to achieve CIR than those with methotrexate 50 μmol/L or higher (1/37, 2.7%). The most common treatment-related adverse event was paresthesia, occurring in three adolescents (4.5%) and six young adults (5.2%). No other treatment-related adverse event occurred in 5% or higher of any age group.

Conclusion

After accounting for pre-glucarpidase methotrexate levels, glucarpidase efficacy at inducing CIR in pediatric/young adult patients was consistent, with efficacy observed in the overall study population (i.e., patients aged 0–84), and no unexpected safety findings were observed. These findings demonstrate glucarpidase (50 U/kg) is an effective and well-tolerated dose for pediatric, adolescent, and young adult patients.     

Clinical evaluation of late outcomes in Dutch childhood cancer survivors: Methodology of the DCCSS LATER 2 study

Background

Childhood cancer survivors face late health problems; despite advances in research, details on risk remain unclear. We describe the methodological aspects of the Dutch Childhood Cancer Survivor Study (DCCSS) cross-sectional clinical study (LATER 2 study).

Procedure

From the multi-center DCCSS LATER cohort of 6165 five-year survivors diagnosed during 1963–2001, we invited 4735 eligible survivors in 2016, as well as siblings and parents of survivors. Gaps in evidence identified during development of surveillance guidelines were translated into clinical research questions for 16 outcome-specific subprojects. The regular care visit to the LATER outpatient clinic forms the backbone of outcome assessment complemented with research-defined measurements (physical examination, clinical tests, questionnaires). Furthermore, blood/saliva samples were taken for deoxyribonucleic acid (DNA) extraction.

Results

In total, 2519 (53.2%) survivors participated in the LATER 2 study. When comparing participants with nonparticipants, we observed that males, CNS survivors, and those treated with surgery only were less likely to participate. Of the participating survivors, 49.3% were female. Median time since childhood cancer diagnosis was 26.9 years (range 14.8–54.7 years) and median attained age was 34.4 years (range 15.4–66.6 years).

Conclusions

The high-quality data generated in the LATER 2 study will provide valuable insights into risks of and risk factors for clinical and physical and psychosocial health outcomes and factors for early recognition of those health outcomes in long-term childhood cancer survivors. This will contribute to fill in important gaps in knowledge and improve the quality of life and care for childhood cancer survivors.     

Epidemiology of Hirschsprung disease in California from 1995 to 2013

Purpose

This study seeks to update current epidemiology of Hirschsprung disease (HD) in California.

Methods

Using data from the California Office of Statewide Health Planning and Development Linked Birth (1995–2012) and Patient Discharge Databases (1995–2013), patients from either dataset with an ICD-9 diagnosis code of HD (751.3) or procedure code of Soave (48.41), Duhamel (48.65), or Swenson/other pull-through (48.49) were included. Patients?>?age 18 during their first admission were excluded.

Results

Of 9.3 million births, 2,464 patients were identified. Incidence was 2.2 cases/10,000 live births, with rates peaking at 2.9/10,000 births in 2002. Incidence was highest among African American (4.1/10,000) and Asian/Pacific Islander (2.5/10,000) births. Most were male (n?=?1652, 67.1%). Sixty patients (2.4%) had Down syndrome. The median gestational age at birth was 38 weeks 6 days (interquartile range [IQR] 37 weeks 1 day–40 weeks 1 day). Mortality during the first year of life was 1.7%. Median age at death was 14.5 days (IQR 0–113 days).

Conclusion

This is one of the largest population-based studies of HD. In California, the incidence of HD is stable, risk is highest among African American children, and the mortality rate is <?2%.