Abstract Although the survival rate of intraocular retinoblastoma (RB) is nearly 100%, the outcome of central nervous system (CNS) involvement or Trilateral retinoblastoma (TRb: very rare RB which associated with brain tumor) is dismal. We retrospectively reviewed our six cases of these rare tumors. Their ages at diagnosis are 0y3m-1y10m (median 1y3m) (Male 4, Female 2). Only one had RB family history. Their affected eyes were bilateral 2, unilateral 3 and no 1. Their CNS diseases were suprasellar tumor 3, pineal tumor 1 and cerebrospinal fluid (CSF) cytology positive 2. Two of the suprasellar tumor patients had spinal metastasis. Three of the six patients were TRb. One TRb patient was treated with chemotherapy and high-dose chemotherapy without radiotherapy. Although he suffered with secondary osteosarcoma seven years later, he got complete remission and alive 5 years more without any tumor recurrence. The second TRb patient was treated with chemotherapy and local radiotherapy but relapsed 20 months later. The third TRb patient was chemotherapy resistant. Two CSF positive patients had optic nerve invasion. One patient with chiasm invasion died 11 months later because of treatment resistance. The other patient with optic nerve invasion before optic canal had no CNS tumor nor CSF involvement at diagnosis. Chemotherapy before enucleation was given to avoid dissemination. However, CSF cytology became positive after enucleation and remained even with intensified chemotherapy. Finally, he got remission with radiotherapy and high-dose chemotherapy, and alive without disease for 3.8 years. The last patient had suprasellar genetically classified retinoblastoma tumor and cerebrospinal metastasis. This patient showed good chemotherapy response and is still under treatment. Even with "so called° fatal RB cases, some case could survive with intensified therapy. Data accumulation is necessary for better survival of these tumors.
OBJECTIVE The prognosis of atypical teratoid/rhabdoid tumors (ATRTs) has improved in recent years with the use of multimodal therapy, mainly in cases not involving metastatic disease. The authors wanted to obtain historical control data and evaluate the suitable treatments in Japanese children with ATRTs that were proven negative for INI-1 immunostaining. METHODS The authors retrospectively collected clinical information on 38 pediatric patients with ATRTs treated from 2005 to 2016 and analyzed the data for this series. RESULTS The median age of the patient population was 1.3 years, and the male/female ratio was approximately 2:1. Twenty-three patients (60.5%) had metastases. The effects of treatment on prognosis were analyzed for 34 patients after exclusion of 4 patients who could not receive curative treatment. At a median follow-up of 40.9 months, the mean (± SD) progression-free survival (PFS) and overall survival (OS) were 66.6% ± 8.3% and 45.9% ± 8.7% at 2 years and 44.2% ± 9.9% and 34.2% ± 8.9% at 5 years, respectively. The metastasis stage at diagnosis (M0–1 vs M2–4) (HR 2.68, 95% CI 1.08–6.65; p = 0.0338) and gross tumor resection (yes vs no) (HR 3.49, 95% CI 1.01–12.1; p = 0.0481) were prognostic factors for PFS but not for OS. Postoperative chemotherapy was performed in all 34 cases. High-dose chemotherapy was performed in 19 (55.8%) of 34 patients and showed a positive impact on OS (HR 0.31, 95% CI 0.11–0.86; p = 0.0254); the most commonly used regimen was a double-conditioning regimen of thiotepa plus melphalan. Local radiotherapy had a positive impact on both PFS and OS; however, craniospinal irradiation (CSI) performed in 12 patients as the primary therapy was associated with a poor outcome. Disseminated recurrence within 12 months from diagnosis was the most common pattern of treatment failure regardless of CSI. CONCLUSIONS There has been an improvement in outcomes for pediatric ATRT patients since the introduction of multimodal therapy in Japan, mainly in patients without metastases. Even if selection bias is taken into consideration, CSI did not contribute to an improved prognosis. Novel treatment approaches are required for pediatric ATRT patients with metastases.
Abstract The multidisciplinary standard of care for medulloblastoma, a typical pediatric malignant brain tumor of cerebellar primary origin, has been established by large RCTs in the United States. The results of the Phase III RCTs sponsored by Children's Oncology Group's for newly-diagnosed medulloblastoma in children 3 years of age and older, ACNS0331, which attempted radiotherapy reduction for the average-risk group, and ACNS0332, which attempted intensified treatment with carboplatin as a radiosensitizer and isotretinoin as an apoptosis inducer for high-risk group are discussed.It has recently been reported that some infantile glioma cells have activating fusion genes with tyrosine kinase receptor genes, including NTRK, and that TRK inhibitors are effective against these tumors, and two TRK inhibitors have been used with cancer genome panel tests as companion diagnostics, Two TRK inhibitors can now be available for glioma treatment in Japanese practice. The results of clinical trials on the efficacy of these targeting agents in brain tumors with NTRK mutations will be presented.CAR-T cell therapy was developed for GD2 following HER2, which had attracted attention as an immunotherapeutic target for pediatric glioma, and its efficacy was demonstrated in clinical trials. We will examine the results of clinical trials of this immunotherapy, a promising treatment for DMS/DIPG, the disease with absolutely poor prognosis with no effective drug therapy, although it is used in a small number of cases.
Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200-2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 106/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 109/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.
We report a 56-year-old woman with progressive gait disturbance. Her mother had Parkinson's disease with onset at age 70. She died at age 74 and the post-mortem examination confirmed the diagnosis of Lewy body positive Parkinson's disease. The patient was well until the age of 50(1995) when she noted an onset of resting tremor and difficulty of gait. She also developed delusional ideation and was admitted to a psychiatric service of another hospital, where a major tranquilizer was given. The delusion disappeared but she developed marked rigidity. The major tranquilizer was discontinued and an anticholinergic and amantadine HCl were given. She showed marked improvement to Hoehn and Yahr stage II and was discharged. In 1995, when she was 52 years of the age, she developed delusion again and a major tranquilizer was given. She developed marked parkinsonism again and became Hoehn and Yahr stage V. The major tranquilizer was discontinued and she was treated with levodopa/carbidopa, trihexyphenidyl, bromocriptine, and dops. She improved remarkably to stage II. She was admitted to our service on October 8, 1996 for drug adjustment. She was alert and not demented. She was anxious but delusion or hallucination was noted. Higher cerebral functions were intact. Cranial nerve functions were also intact except for masked face and small voice. Her posture was stooped and steps were small. She showed retropulsion and moderate bradykinesia. Resting tremor was noted in her left hand. Rigidity was noted in both legs. No cerebellar ataxia or weakness was noted. Deep tendon reflexes were within normal range and sensation was intact. Her cranial MRI revealed some atrophic changes in the putamen, in which a T 2-high signal linear lesion was seen along the lateral border of the putamen bilaterally. In addition, posterior part of the putamen showed T 2-low signal intensity change. She was treated with 1.6 mg of talipexole, 6 mg of trihexyphenidyl, and 100 mg of L-dops. She was in stage III of Hoehn and Yahr. She developed neurogenic bladder with a large amount of residual urine for which she required catheterization. She was transferred to another hospital. Despite drug adjustment, she lost response to levodopa and her parkinsonism deteriorated gradually. She also developed syncope orthostatic hypotension. In April of 1998, she developed intracerebral hemorrhage and was admitted again on April 19, 1998. She was unable to stand and showed marked akinesia and rigidity. She was in stage V of Hoehn and Yahr. Her cranial CT scan revealed bilateral high-density lesions in the posterior parietal lobes. She developed dysphagia for which she required gastrostomy. She was transferred to another hospital but her clinical condition deteriorated further. On December 22, 1999, she developed fever and dyspnea and was admitted to our service again. She developed cardial arrest at the emergency room from hypoxia. She was resuscitated; however, she was comatose with loss of brain stem reflexes. Later on she developed generalized myoclonus. She developed cardiac arrest and pronounced dead on December 28, 1999. The patient was discussed in a neurological CPC. The chief discussant arrived at the conclusion that the patient had striatonigral degeneration because of poor response to levodopa in the later course, autonomic failures, and MRI changes. Some other participants thought that the patient had a form of familial Parkinson's disease. Opinions were divided into these two possibilities. Post-mortem examination revealed that the substantia nigra showed intense neuronal loss and gliosis, however, no Lewy bodies were seen. In addition, intracytoplasmic inclusions were seen in oligodendrocytes. The putamen was markedly atrophic in its posterior part with marked gliosis and neuronal loss. The ventromedial part of the pontine nucleus also showed neuronal loss and intracytoplasmic glial inclusions. Pathologic diagnosis was multiple system atrophy. In the parietal lobe, an arteriovenous malformation with bleeding was noted. This is very unique case. Although her mother had Lewy body-positive Parkinson's disease, the patient had Lewy body-negative multiple system atrophy with a-synuclein-positive glial inclusions. Whether this is just a coincidental occurrence or the presence of a genetic load for Parkinson's disease might triggered her multiple system atrophy is an interesting question to be answered in future.
Abstract Background Second malignant neoplasms (SMNs) are one of the most severe late complications after pediatric cancer treatment. However, the effect of genetic variation on SMNs remains unclear. In this study, we revealed germline genetic factors that contribute to the development of SMNs after treatment of pediatric solid tumors. Methods We performed whole‐exome sequencing in 14 pediatric patients with SMNs, including three brain tumors. Results Our analysis revealed that five of 14 (35.7%) patients had pathogenic germline variants in cancer‐predisposing genes (CPGs), which was significantly higher than in the control cohort ( p < 0.01). The identified genes with variants were TP53 ( n = 2), DICER1 ( n = 1), PMS2 ( n = 1), and PTCH1 ( n = 1). In terms of the type of subsequent cancer, leukemia and multiple episodes of SMN had an exceptionally high rate of CPG pathogenic variants. None of the patients with germline variants had a family history of SMN development. Mutational signature analysis showed that platinum drugs contributed to the development of SMN in three cases, which suggests the role of platinum agents in SMN development. Conclusions We highlight that overlapping effects of genetic background and primary cancer treatment contribute to the development of second cancers after treatment of pediatric solid tumors. A comprehensive analysis of germline and tumor samples may be useful to predict the risk of secondary cancers.
Abstract BACKGROUND pLGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. pHGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. The result of a phase II global clinical trial (NCT02684058) of D+T vs carboplatin + vincristine (C+V) in first-line BRAF V600-mutant pLGG and single arm D+T in relapsed/refractory (r/r) BRAF V600-mutant pHGG has already been described. Briefly, the primary endpoint was the independently assessed overall response rate, ORR (CR+PR) using RANO criteria. The ORR was 47% (95% CI, 35%-59%) with D+T vs 11% (95% CI, 3%-25%) with C+V (P<.001; odds ratio, 7.2 [95% CI, 2.3-22.4]) in pLGG and 56.1% (95% CI, 39.7%-71.5%) in pHGG. Safety was consistent with the established profile of D+T in other indications. We report results for the Japanese subgroup. RESULTS A total of 6 Japanese pts were included in pLGG (D+T; n=4, C+V; n=2). And a total of 11 Japanese pts with diverse WHO Grade III/IV gliomas were included in r/r pHGG. The best overall response assessed by independent reviewer were as followed; D+T; SD 75% (n=3), PD 25% (n=1), C+V; CR 50% (n=1), PD 50% (n=1) in pLGG and CR 9.1% (n=1), PR 27.3% (n=3), SD 9.1% (n=1), PD 36.4% (n=4) in r/r pHGG. Treatment-related grade ≧3 adverse events were D+T; 25% (n=1) and C+V; 100% (n=2) in pLGG and 27.3% (n=3) in r/r pHGG. DISCUSSION AND CONCLUSIONS Treatment with D+T showed encouraging efficacy in Japanese pLGG and r/r pHGG. Profile of AEs was similar or consistent which is reported in other adult cohorts. Thus, these results suggest that D+T may represent a critical treatment advance for pLGG and r/r pHGG Japanese pts with BRAF V600-mutant.
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