John A. Fort

High-risk ewing's sarcoma: end-intensification using autologous bone marrow transplantation

Because of retrospective analysis showing survival to be related to primary tumor size, in February 1982 a study to test this hypothesis prospectively was begun at the University of Florida. Patients with primary tumors 8 cm or less in maximum diameter and no metastases received adjuvant chemotherapy consisting of vincristine, cyclophosphamide, doxorubicin, and dactinomycin plus radiotherapy or surgery (standard-risk protocol). All others received a similar regimen followed by end-intensification with high-dose melphalan and autologous bone marrow transplantation (Protocol HR-2). Because of poor results of HR-2, another high-risk protocol (HR-3) was initiated in January 1985. Patients on HR-3 received 2 cycles of chemotherapy containing vincristine, cyclophosphamide, and doxorubicin followed by local radiation therapy and maintenance chemotherapy. At the end of this therapy, autologous bone marrow transplantation (ABMT) was performed, using a preparatory regimen of total body irradiation and intensive chemotherapy. The 2-year disease-free survival rate was 70% for the standard-risk protocol, 20% for HR-2, and 80% for HR-3. The follow-up on HR-3 is still short, but the results are promising enough to warrant further clinical trials.

Late toxicity following craniospinal radiation for early-stage medulloblastoma

Abstract Background. The purpose of this study is to review late toxicity following craniospinal radiation for early-stage medulloblastoma. Material and methods. Between 1963 and 2008, 53 children with stage M0 (n = 50) or M1 (n = 3) medulloblastoma were treated at our institution. The median age at diagnosis was 7.1 years (range 1.2–18.5). The median craniospinal irradiation (CSI) dose was 28.8 Gy (range 21.8–38.4). The median total dose, including boost, was 54 Gy (range 42.4–64.8 Gy). Since 1963, the CSI dose has been incrementally lowered and the high-risk boost volume reduced. Twenty-one patients (40%) received chemotherapy in their initial management, including 12 who received concurrent chemotherapy. Late sequelae were evaluated by analyzing medical records and conducting phone interviews with surviving patients and/or care-takers. Complications were graded using the NCI Common Terminology Criteria for Adverse Events, version 4.0. Results. The median follow-up for all patients was 15.4 years (range 0.4–44.4) and for living patients it was 24 years (range 5.6–44.4). The overall survival, cause-specific survival, and progression-free survival rates at 10 years were 67%, 67%, and 71%, respectively. Sixteen patients (41% of patients who survived five years or more) developed grade 3 + toxicity; 15 of these 16 patients received a CSI dose > 23.4 Gy. The most common grade 3 + toxicities for long-term survivors are hearing impairment requiring intervention (20.5%) and cognitive impairment (18%) prohibiting independent living. Four patients developed secondary (non-skin) malignancies, including three meningiomas, one rhabdomyosarcoma, and one glioblastoma multiforme. Three patients (5.6%) died from treatment complications, including radionecrosis, severe cerebral edema, and fatal secondary malignancy. Conclusion. Ongoing institutional and cooperative group efforts to minimize radiation exposure are justified given the high rate of serious toxicity observed in our long-term survivors. Follow-up through long-term multidisciplinary clinics is important and warranted for all patients exposed to radiotherapy in childhood.

FGFR1 N546K and H3F3A K27M mutations in a diffuse leptomeningeal tumour with glial and neuronal markers

1. Lee W, Teckie S, Wiesner T et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 2014; 46; 1227–1232. 2. De Raedt T, Beert E, Pasmant E et al. PRC2 loss amplifies Rasdriven transcription and confers sensitivity to BRD4-based therapies. Nature 2014; 514; 247–251. 3. Zhang M, Wang Y, Jones S et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat. Genet. 2014; 46; 1170–1172. 4. Schaefer IM, Fletcher CD, Hornick JL. Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod. Pathol. 2016; 29; 4–13. 5. Prieto-Granada CN, Wiesner T, Messina JL et al. Loss of H3K27me3 expression is a highly sensitive marker for sporadic and radiationinduced MPNST. Am. J. Surg. Pathol. 2016; 40; 479–489. 6. Plath K, Fang J, Mlynarczyk-Evans SK et al. Role of histone H3 lysine 27 methylation in X inactivation. Science 2003; 300; 131–135.

Local control in non-metastatic medulloblastoma.

Abstract Background. A single-institution review of long-term outcomes and factors affecting local control (LC) following radiotherapy for non-metastatic medulloblastoma. Material and methods. From 1963 to 2008, 50 children (median age, 7.3 years; range 1.2–18.5) with stage M0 medulloblastoma were treated with radiotherapy; half underwent a gross total resection (no visible residual tumor) or near-total resection (< 1.5 cm3 of gross disease remaining after resection). Median craniospinal dose was 28.8 Gy (range 21.8–38.4 Gy). Median total dose to the posterior fossa was 54.3 Gy (range 42.4–64.8 Gy). Eighteen patients (36%) received chemotherapy as part of multimodality management, including 11 who received concurrent chemotherapy. Results. Median follow-up was 15.7 years (range 0.3–44.4 years) for all patients and 26.6 years (range 7.3–44.4 years) for living patients. The 10-year overall survival, cancer-specific survival, and progression-free survival rates were 65%, 65%, and 69%. The 10-year LC rate was 84% and did not significantly change across eras. Four percent of patients experienced local progression five years after treatment. On univariate analysis, chemotherapy and overall duration of radiotherapy ≤ 45 days were associated with improved LC. Patients receiving chemotherapy had a 10-year 100% LC rate versus 76% in patients not receiving chemotherapy (p = 0.0454). When overall radiotherapy treatment lasted ≤ 45 days, patients experienced a superior 95% 10-year LC rate (vs. 73% in patients treated > 45 days; p = 0.0419). Three patients (6%) died from treatment complications, including radionecrosis/cerebellar degeneration, severe cerebral edema leading to herniation, and secondary malignancy. Conclusions. While we cannot draw definitive conclusions given the retrospective nature of our study, our long-term data suggest that reductions in craniospinal dose and boost target volume to reduce toxicity have not compromised disease control in the modern era. Our data also support analyses that implicate duration of radiotherapy, rather than interval between surgery and radiotherapy, as a factor in LC. Chemotherapy in multimodality management of medulloblastoma may have an underappreciated role in improving LC rates.

Late Effects After Radiotherapy for Childhood Low-grade Glioma.

Objectives: This single-institution report describes long-term disease control and late effects in pediatric patients with low-grade glioma (LGG) following radiotherapy (RT). Materials and Methods: Twenty-nine pediatric patients with LGG were treated with photon-based RT from 1970 to 2004 (mean age at time of RT, 9.8 y; range, 0.6 to 19 y). One patient underwent gross total resection, 25 underwent subtotal resection or biopsy, and 3 were treated based on radiographic characteristics alone. Three patients underwent chemotherapy before RT. The median RT dose was 54 Gy (range, 40 to 55 Gy). Results: The median follow-up was 17.8 years (range, 1.6 to 36.8 y) for all patients and 19.9 years (range, 1.6 to 36.8 y) for all living patients. The 5-, 10-, and 20-year local control and progression-free survival rates were equivalent at 82%, 74%, and 63%, respectively. The 5-, 10-, and 20-year cause-specific survival and overall survival rates were equivalent at 89%, 85%, and 58%, respectively. On univariate analysis, age below 4 years during treatment was associated with significantly inferior local control (P=0.0067), cause-specific survival (P=0.0021), and overall survival (P=0.0021). Of the 23 survivors analyzed for late toxicity, 15 (65%) developed grade 3+ toxicity. The most common Common Terminology Criteria for Adverse Events grade 3 toxicity (30% of survivors) was serious cognitive disability. Four patients (14%) died secondary to treatment complications, all occurring over a decade after completing RT. Conclusions: Over half of children diagnosed with LGG survive >20 years after RT; this report reveals the chronicity of toxicity beyond the typically reported follow-up. Our findings inform the therapeutic ratio of RT in this disease and may help guide late-effect screening recommendations.

Optic nerve pilomyxoid astrocytoma in a patient with Noonan syndrome

Noonan syndrome (NS; MIM 163950) is an autosomal dominant syndrome which is clinically diagnosed by the distinct facial features, short stature, cardiac anomalies and developmental delay. About 50% of cases are associated with gain of function mutations in PTPN11 gene which leads to activation of the RAS/mitogen‐activated protein kinase signaling pathway. This is known to have a role in tumorigenesis. Despite this, only limited reports of solid tumors (Fryssira H, Leventopoulos G, Psoni S, et al. Tumor development in three patients with Noonan syndrome. Eur J Pediatr 2008;167:1025–1031; Schuettpelz LG, McDonald S, Whitesell K et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer 2009;53:1147–1149; Sherman CB, Ali‐Nazir A, Gonzales‐Gomez I, et al. Primary mixed glioneuronal tumor of the central nervous system in a patient with Noonan syndrome. J Pediatr Hematol Oncol 2009;31:61–64; Sanford RA, Bowman R, Tomita T, et al. A 16 year old male with Noonans syndrome develops progressive scoliosis and deteriorating gait. Pediatr Neurosurg 1999;30:47–52) and no prior reports of optic gliomas have been described in patients with NS. We present here a patient with NS with a PTPN11 mutation and an optic pathway pilomyxoid astrocytoma. Pediatr Blood Cancer 2015;62:1084–1086.

A Case Presentation: Rare Occurrence of an Adolescent Male Presenting With an ATRT and Simultaneous Low-grade Glioneuronal Tumor

Atypical rhabdoid/teratoid tumor (ATRT) is an uncommon and highly malignant tumor of the central nervous system. The majority of ATRT tumors occur in infancy and young children located in the posterior fossa. The ideal treatment for cure remains controversial and prognosis is typically unfavorable. We present a case of an atypical presentation of ATRT, presenting in adolescence with an additional low-grade glioneuronal tumor discovered at diagnosis.

Vasoocclusion with homozygous hemoglobin-C disease.

Hemoglobin-CC is a relatively uncommon hemoglobinopathy, seen primarily in the black population. These patients usually have a mild clinical course, without significant risk of vasoocclusive crises. There are no routine recommendations for preparation prior to surgery. We present a patient who developed a clinical picture suggestive of major vasoocclusion after cardiac by-pass surgery. In retrospect, these signs appear to be the result of hemodynamic instability and cardiogenic shock instead of vasoocclusion.