A single-arm study of systemic and sub-Tenon chemotherapy for Groups C and D intraocular retinoblastoma: A Children's Oncology Group study (ARET 0231).

BACKGROUND: Eyes with Group D intraocular retinoblastoma have low salvage rates. A pilot study showed safety and efficacy of sub-Tenon's fascia carboplatin with systemic chemotherapy supporting further study. METHODS: Children with newly diagnosed bilateral intraocular retinoblastoma with at least one remaining Group C or D eye were treated with six courses of carboplatin/etoposide/vincristine (CEV) with sub-Tenon's fascia carboplatin for Group C/D eyes during courses 2-4. Local ophthalmic therapy started at course 3. The primary study objective was to determine the 1-year failure rate of Group D eyes. RESULTS: The study closed prematurely due to poor accrual and 22 of 30 patients were evaluable for failure rate, contributing 25 Group D and four Group C eyes. Among the 25 Group D eyes, there were 13 failures within the first year of study enrollment including eight needing external beam radiotherapy (EBR) and five needing enucleation, resulting in 1-year failure rate of 52%. The failure rate was significantly lower than the historical rate of 70% (P = .039). The 1-year eye preservation rate for Group D eyes was 80% (20/25). One-year failure rate for Group C eyes was 25% (1/4); 1-year preservation rate was 100% without need for EBR. Systemic toxicity included Grade 3 hearing loss in two subjects, infections, neutropenia, and thrombocytopenia. Ocular toxicities included periorbital fat atrophy (13/29 = 45% eyes), optic nerve atrophy (1/29 = 3% eyes), and restrictive fibrosis (1/29 = 3% eyes). CONCLUSIONS: Sub-Tenon's fascia carboplatin plus CEV was partially effective in Group D intraocular retinoblastoma but had unacceptable ocular toxicities.

Oxaliplatin and Doxorubicin for relapsed or refractory high-risk neuroblastoma.

Patients with relapsed or refractory neuroblastoma have poor long-term survival. New therapeutic regimens are needed. Doxorubicin and cisplatin are commonly used in the treatment of high-risk neuroblastoma. Oxaliplatin, a platinum compound with a 1,2-diaminocyclohexan carrier ligand, is more potent than cisplatin with less nephrotoxicity and ototoxicity. We treated seven relapsed/refractory neuroblastoma patients using oxaliplatin (105-130 mg/m(2)) and doxorubicin (60-75 mg/m(2)) together with dexrazoxane (10 mg/mg of doxorubicin) administered intravenously every three weeks. Prolonged thrombocytopenia causing treatment delay was observed when oxaliplatin was administered at 130 mg/m(2). A reduced dose of oxaliplatin 105 mg/m(2) on day 1 with doxorubicin at 20 mg/m(2)/dose on days 1-3 was well tolerated. Sensory neuropathies were mild and transient. No cardiotoxicity was noted despite all patients having a history of prior anthracycline exposure. Best responses included 1 complete response, 1 partial response, 1 mixed response, 3 stable diseases. In our cohort of heavily pretreated relapsed and refractory neuroblastoma patients, the combination of oxaliplatin and doxorubicin demonstrated anti-tumor activity and merits further investigation.

Outcomes of children younger than 24 months with langerhans cell histiocytosis and bone involvement: a report from a single institution.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disorder that ranges from single-system to disseminated multisystem disease. Patients younger than 24 months of age more commonly present with risk organ (liver, spleen, hematopoietic system, or lung) involvement at diagnosis and have a poor prognosis. Treatment approaches have changed over the last 25 years. Our goal was to describe the course and outcomes of patients younger than 24 months of age at diagnosis and identify the role of bone involvement in outcomes. METHODS: We conducted a retrospective chart review of patients diagnosed with LCH at Children's Hospital Los Angeles from 1984 to 2010, focusing on 71 patients younger than 24 months of age at diagnosis. RESULTS: Ten patients had single bone lesions at diagnosis and did well irrespective of therapy. The majority of patients (40/71 or 56%) had multiple bone lesions. Of the 37 patients with multisystem disease, 27 children (73%) had risk organ involvement. Fourteen patients with risk organ involvement received ≤ 6 months of initial chemotherapy with prednisone and vinblastine. Six of these patients had reactivation of the disease, and bone was the most frequent site of reactivation. Seven patients with risk organ involvement were treated with at least 12 months of chemotherapy. Only one of these patients had reactivation of the disease, and none died. The majority (7/10) of patients with risk organ involvement who progressed on therapy died despite multiple treatment regimens. CONCLUSIONS: Patients younger than 24 months of age at diagnosis are more likely to have multiple bone lesions than older patients, supporting that a radiographic skeletal survey at the time of LCH diagnosis is important to evaluate the extent of bone involvement. Bones were the most common site for reactivation for all patients. As expected, subjects with risk organ involvement had better outcomes when treated with systemic chemotherapy for at least 1 year. LEVEL OF EVIDENCE: As a retrospective review of all cases at our institution over a 26-year period, this article represents level IV evidence.

Simultaneous colonic adenocarcinoma and medulloblastoma in a 12-year-old with biallelic deletions in PMS2.

We describe a 12-year-old girl, simultaneously presenting with colonic adenocarcinoma and medulloblastoma from bialleic deletions in the mismatch repair gene PMS2. Her distinctive physical and clinical findings are characteristic of constitutional mismatch repair deficiency syndrome. Earlier recognition of such findings may permit better screening and more effective treatment.

Graduate medical education changes: yes we can or enough already?

The Accreditation Council for Graduate Medical Education (ACGME) established new duty hour recommendations for pediatric subspecialty trainees in July 2011. Short-term and long-term implications to Pediatric Hematology/Oncology (PHO) are reviewed. Other modifications have been introduced by the ACGME and the American Board of Pediatrics (ABP) in the last decade, including the introduction of the six core competencies and an expansion in the definition of scholarship for fellows. The effect of these on fellows are discussed with suggested strategies for PHO to prepare for further change likely to result from a new ABP initiative to evaluate subspecialty training and certification over the next 3 years. Pediatr Blood Cancer 2012; 59: 1168-1172. © 2012 Wiley Periodicals, Inc.

Intensive Multimodality Therapy for Extraocular Retinoblastoma: A Children's Oncology Group Trial (ARET0321).

PURPOSE: Metastatic retinoblastoma has a poor prognosis when treated with conventional chemotherapy and radiation therapy (RT). Intensified therapy may improve the outcome. METHODS: A prospective, international trial enrolled patients with extraocular retinoblastoma. Patients with stage II or III (locoregional) retinoblastoma received four cycles of chemotherapy, followed by involved field RT (45 Gy). Patients with stage IVa or IVb (metastatic or trilateral) retinoblastoma also received four cycles of chemotherapy and those with ≥ partial response then received one cycle of high-dose carboplatin, thiotepa, and etoposide with autologous hematopoietic stem-cell support. Patients with stage IVa or IVb with residual tumor postchemotherapy received RT. The proportion of patients who achieved event-free survival would be reported and compared with historical controls separately for each of the three groups of patients. RESULTS: Fifty-seven eligible patients were included in the analyses. Event-free survival at 1 year was 88.1% (90% CI, 66.6 to 96.2) for stage II-III, 82.6% (90% CI, 61.0 to 92.9) for stage IVa, and 28.3% (90% CI, 12.7 to 46.2) for stage IVb/trilateral. Toxicity was significant as expected and included two therapy-related deaths. CONCLUSION: Intensive multimodality therapy is highly effective for patients with regional extraocular retinoblastoma and stage IVa metastatic retinoblastoma. Although the study met its aim for stage IVb, more effective therapy is still required for patients with CNS involvement (ClinicalTrials.gov identifier: NCT00554788).

Trilateral retinoblastoma: potentially curable with intensive chemotherapy.

BACKGROUND: Trilateral retinoblastoma has been lethal in virtually all cases previously reported. We describe a series of 13 patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. PROCEDURE: Induction chemotherapy generally included vincristine, cisplatin or carboplatin, cyclophosphamide, and etoposide. Hematopoietic stem cells typically were harvested after the first or second cycle of induction chemotherapy, usually from peripheral blood. High-dose chemotherapy regimens were thiotepa-based (n = 7) or melphalan and cyclophosphamide (n = 3). RESULTS: Trilateral sites were pineal (n = 11) and suprasellar (n = 2); 7 patients had localized (M-0) disease and six had leptomeningeal dissemination (M-1+). Five patients had trilateral retinoblastoma at original diagnosis of intra-ocular retinoblastoma; eight later developed trilateral disease at a median of 35 months (range 3-60 months) following diagnosis of intra-ocular retinoblastoma. One patient died of toxicity (septicemia and multi-organ system failure) during induction and three developed disease progression prior to high-dose chemotherapy. Nine patients received high-dose chemotherapy at a median of 5 months (range 4-9) post-diagnosis of trilateral disease. Five patients survive event-free at a median of 77 months (range 36-104 months) and never received external beam radiation therapy. Four of seven patients with M-0 disease survive event-free versus only one of six patients with M-1+ disease. CONCLUSIONS: Intensive chemotherapy is potentially curative for some patients with trilateral retinoblastoma, especially those with M-0 disease.

Management of retinoblastoma with proximal optic nerve enhancement on MRI at diagnosis.

BACKGROUND: In North America, retinoblastoma rarely presents with gross clinical evidence of tumor involving the optic nerve. Extent of microscopic tumor infiltration into the postlaminar optic nerve is a significant risk factor for metastasis, especially if there is tumor at the cut end. Due to poor outcomes in patients with metastatic disease, historical treatment for patients with clinical evidence of extraocular optic nerve involvement has included upfront enucleation followed by aggressive adjuvant chemotherapy. Additional orbital irradiation is advocated for individuals with optic nerve involvement at the surgical margin. Little is known about the role of neoadjuvant therapy in the setting of orbital optic nerve enhancement on magnetic resonance imaging (MRI) at diagnosis. METHODS: A retrospective review of consecutive retinoblastoma cases at Childrens Hospital Los Angeles over a 3-year period (2004-2006) found to have gadolinium contrast enhancement in the proximal portion of optic nerve on MRI at diagnosis. RESULTS: Nine patients fit the inclusion criteria. Two had secondary glaucoma of a sufficient degree to cause an enlarged eye (buphthalmos). Median age at presentation was 17 months (2-36 months). All patients received neoadjuvant chemotherapy prior to enucleation. Only two received external beam radiation. All are disease-free with a median follow-up of 22 months (12-41 months). CONCLUSIONS: Neoadjuvant chemotherapy is well tolerated prior to enucleation of retinoblastoma-containing eyes associated with contrast enhancement of the proximal optic nerve on MRI at diagnosis. Such an approach may be used to decrease intensity or duration of chemotherapy and need for external beam radiation.

Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue.

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.

Three presentations of CNS disease in patients with intraocular retinoblastoma at a tertiary medical center in the United States.

BACKGROUND: Patients with intraocular retinoblastoma who present with central nervous (CNS) disease at diagnosis is very rare in developed countries. METHODS: Herein, we report a review of patients with intraocular retinoblastoma diagnosed with concurrent CNS disease in the United States between January 2011 and June 2013. RESULTS: Three patients were identified in this review. The first case is a 2-year old male who presented with unilateral Group E retinoblastoma, optic nerve infiltration to the orbital apex, and a suprasellar mass. The second case is a 5-month old female with bilateral retinoblastoma, who had no optic nerve invasion, but demonstrated a temporal lobe lesion that was biopsy-proven to be metastatic retinoblastoma. The third case is a 10-month old girl with bilateral retinoblastoma who presented with a sellar mass and no evidence of optic nerve invasion in the enucleated Group E eye. CONCLUSIONS: Although rare in developed countries, patients with intraocular retinoblastoma can present with a spectrum of CNS findings at the time of diagnosis. Magnetic resonance imaging of the brain and orbits is a critical component of the staging evaluation.

Treatment Outcomes of Focal Laser Consolidation during Chemoreduction for Group B Retinoblastoma.

PURPOSE: To evaluate the ocular treatment outcomes of focal laser consolidation during systemic chemoreduction for Group B tumors in the posterior fundus. DESIGN: Single-institution retrospective chart review from 1995 to 2016. PARTICIPANTS: Patients with Group B retinoblastoma with at least 1 tumor in the posterior fundus. METHODS: Evaluation of tumor response to chemotherapy and laser consolidation. OUTCOME MEASURES: Change in the tumor size with treatment, and the association of timing of laser consolidation to the horizontal and vertical diameter of the final chorioretinal scar. RESULTS: Forty Group B eyes (22 right eyes and 18 left eyes) were included in the analysis. Mean age at diagnosis was 6.4 months (range 0-24 months). Of the 40 eyes, 35 were treated with both systemic chemotherapy and laser, 4 with chemotherapy only, and 1 eye with laser without chemotherapy. Mean age at initial laser treatment was 7.7 months (standard deviation 5.9 months) and mean number of laser sessions was 6 (standard deviation 5 sessions). The overall globe salvage rate was 95% (38/40 eyes). Mean horizontal and vertical diameters of the tumors in this group showed statistically significant decreases from diagnosis to all subsequent visits (P = 0.0024). The median percent reductions in the horizontal and vertical diameters of the tumors treated with both chemotherapy and laser from diagnosis to the final visit were 13% and 14%, respectively; the overall scar area showed a 13% decrease. For tumors receiving chemotherapy prior to laser therapy, the median reduction in tumor area was 18% from diagnosis to the final examination. Small tumors were found to have a 52% increase in final scar size from diagnosis, whereas larger tumors demonstrated a 37% decrease. CONCLUSIONS: The overall success in treating Group B tumors with chemotherapy and laser was very favorable when considering scar size and globe salvage rates. The size of the chorioretinal scar at the end of treatment was on average 13% smaller than the original tumor size, with greater reductions being noted when chemotherapy preceded laser treatment and when the tumor size at diagnosis was greater than 4.5 mm. A small subset of perifoveal lesions was treated successfully with chemotherapy, alone without laser consolidation.

Disordered respiratory control in children with partial cerebellar resections.

While the cerebellum is not traditionally thought of as having an important role in respiratory control, breathing involves cyclic motor acts that require cerebellar coordination. We postulate that children with partial cerebellar resections have disordered respiratory control due to altered synchronization of ventilatory muscles. We reviewed the records of 36 children following partial cerebellar resections due to neoplasms confined to the cerebellum. P aCO2 values were elevated in 19% of patients. Six patients had apneic or bradypneic events documented within the first month after resection. Two patients required intubation with assisted ventilation, and one needed assisted ventilation for 7.3 weeks. Those with apnea had lower oxygen saturations, and a longer need for supplemental oxygen. Patients with apnea were older than those without apnea. Swallowing, which uses many of the same muscles as those needed to maintain upper airway patency, was dysfunctional in 50% of those with apneas. We conclude that children with cerebellar resections have an increased incidence of apnea, hypoventilation, and hypoxemia not otherwise explained by pulmonary disease, and some require prolonged assisted ventilation. We speculate that these abnormalities are manifestations of altered respiratory control caused by dysfunctional cerebellar coordination of ventilatory muscles.

Central nervous system germ cell tumors: controversies in diagnosis and treatment.

The variability and complexity of central nervous system germ cell tumors have led to controversy in both diagnosis and management. If a germ cell tumor is suspected, the measurement of cerebrospinal fluid and serum alpha-fetoprotein and beta-human chorionic gonadotropin is essential. A histologic specimen is not necessary if the patient has elevated levels; however, if the tumor markers are negative, a biopsy is needed to confirm the diagnosis of a germinoma. Germinomas are extremely radiosensitive, enabling 5-year survival rates that exceed 90%. Treatment has traditionally included focal and craniospinal axis irradiation; however, multiple ongoing studies are being conducted to examine the efficacy of reduction or elimination of radiation therapy with the addition of chemotherapy. Nongerminomatous germ cell tumors, on the other hand, are relatively radioresistant with a poorer outcome. The combination of chemotherapy and irradiation is associated with overall survival rates of up to 60%. This article provides a review of the controversies in diagnosis and treatment of central nervous system germ cell tumors.

Clinical outcomes of radiation therapy in the management of Langerhans cell histiocytosis.

OBJECTIVES: Langerhans cell histiocytosis (LCH) is a rare disease with variable clinical presentation. In the present study, we report on the effectiveness and clinical complications of radiation therapy in children with LCH. MATERIALS AND METHODS: We retrospectively reviewed all patients with LCH treated with radiation therapy over a 6-decade period at a single institution. Radiotherapy data, clinical features, radiographic data, and vital status were analyzed. RESULTS: The mean age at diagnosis for 69 patients was 5.3 years (3 mo to 37 y) and the median duration of follow-up was 6 years (7 d to 32 y). Radiation therapy was performed for 169 sites, primarily bone lesions. The median radiotherapy dose was 10 Gy (2.5 to 45 Gy). Radiographic follow-up data were available for 139 of the sites treated and clinical follow-up was available for 156 of sites treated. The radiographic local control was 91.4%, and 13% of lesions showed complete sclerosis or reconstitution of bone. A total of 90.4% of patients reported stabilization or improvement in lesion-related symptoms, most often pain. Twelve patients had diabetes insipidus at diagnosis or during follow-up. Eight of these patients received radiation treatment to the pituitary and none experienced a reduction in desmopressin dosage posttreatment. Radiation complications were few, including femoral neck fracture in 1 patient and facial asymmetry in 3 patients. No secondary malignancies were observed. CONCLUSIONS: Radiotherapy for LCH has high rates of local control and symptomatic improvement. Importantly, however, there is evidence of short-term and long-term morbidity when children are treated with low-dose irradiation.

A case of composite neuroblastoma composed of histologically and biologically distinct clones.

We report a case of a 12-month-old girl with stage 3 neuroblastoma composed of 2 distinct clones in the adrenal primary tumor. One clone showed neuroblastoma, poorly differentiated subtype with a low mitosis-karyorrhexis index (favorable histology), and the other was neuroblastoma, poorly differentiated subtype with a high mitosis-karyorrhexis index (unfavorable histology), according to the International Neuroblastoma Pathology Classification. Fluorescent-labeled in-situ hybridization using the formalin-fixed, paraffin-embedded material showed that the MYCN oncogene was amplified in the latter clone but not in the former clone. Lymph nodes from ipsilateral and contralateral sides contained metastatic neuroblastoma of the latter clone. It is well documented that tumors in the Ganglioneuroblastoma, nodular (composite, Schwannian stroma-rich/stroma-dominant and stroma-poor) category are composite and composed of multiple clones. To our knowledge, however, this is the 1st case report of composite tumor with biologically favorable and unfavorable clones in the Neuroblastoma (Schwannian stroma-poor) category.

Predictors of outcome in children with Langerhans cell histiocytosis.

BACKGROUND: Our goal was to examine the clinical course of patients with Langerhans cell histiocytosis (LCH), with a special emphasis on bone disease and to attempt to identify and examine the factors that may predict reactivation and overall prognosis. PROCEDURE: We conducted a retrospective chart review of 132 consecutive pediatric patients treated at Children's Hospital Los Angeles for LCH from 1984 to 2001. RESULTS: The risk for reactivation after initial management is significantly higher for patients with multiple bone and those with multiple organ involvement as compared with patients who had a single bone lesion (hazard ratios are 7.1 and 11.6). Patients younger than 1 year in the multiple organ group have an increased risk of death at 2 years when compared with the older patients in that group (hazard ration = 6.2, P = 0.022). Endocrine abnormalities were seen in 20% and 7.5% of patients with or without skull lesions respectively. CONCLUSIONS: Patients with LCH involving only the bones have a significantly better outcome than those with other organ involvement. Patients with multiple organ involvement who are less than 1 year of age are at high risk of death and should be approached more aggressively upfront.

Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience.

Extraocular retinoblastoma is associated with a very poor outcome. At Children's Hospital Los Angeles, 10 of 207 patients with retinoblastoma had extraocular disease. Four patients with no histopathologic risk factors developed extraocular disease. All patients with direct extension into the central nervous system or with distant metastatic disease died. One of three patients with trilateral retinoblastoma and one patient with regional recurrence are alive after autologous bone marrow transplant. Patients with extraocular retinoblastoma who achieve remission may benefit from consolidation of their therapy with autologous bone marrow transplant.