Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5

BackgroundHigh-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5–19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5.MethodsAll children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m²) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1–3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy).ResultsFifty-one patients (median age, 8 y; range, 5–19) were enrolled. The median follow-up was 7.1 years (range: 3.4–9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65–88) and 76% (63–86), and the 3 and 5-year OS were 84% (72–92) and 76% (63–86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated.ConclusionsThis treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.     

Restoration of thoracic kyphosis by simultaneous translation on two rods for adolescent idiopathic scoliosis

Introduction

Sagittal and axial corrections of the three-dimensional deformity characteristic of scoliosis remain challenging.

Materials and Method

The author developed a new technique for scoliosis correction consisting of the translation of vertebrae simultaneously towards two rods, which are pre-bent to the correct sagittal profile. Using two rods ensures both reduction and stabilization of the curve. The system includes stable anchorages with polyaxial-threaded extensions that connect to the rods. Deformity reduction is done by tightening nuts simultaneously and progressively on the two rods. Results demonstrate the efficiency of this technique to achieve normal thoracic kyphosis (>20°) in all 99 patients, with a mean gain of 19° of thoracic kyphosis in hypokyphotic cases. Coronal correction was 70−80 % with a vertebral rotation gain of 40 % where derotation connectors were used.

Conclusions

In a large consecutive series of patients, this new technique allows to achieve a good 3D correction of the scoliosis.

     

PET imaging of fatty acid amide hydrolase in the brain: synthesis and biological evaluation of an 11C-labelled URB597 analogue

IntroductionFatty acid amide hydrolase (FAAH) is part of the endocannabinoid system (ECS) and has been linked to the aetiology of several neurological and neuropsychiatric disorders. So far no useful PET or SPECT tracer for in vivo visualisation of FAAH has been reported. We synthesized and evaluated a carbon-11-labeled URB597 analogue, biphenyl-3-yl [¹¹C]-4-methoxyphenylcarbamate or [¹¹C]-1, as potential FAAH imaging agent.MethodsThe inhibitory activity of 1 was determined in vitro using recombinant FAAH. Radiosynthesis of [¹¹C]-1 was performed by methylation using [¹¹C]-CH₃I, followed by HPLC purification. Biological evaluation was done by biodistribution studies in wild-type and FAAH knock-out mice, and by ex vivo and in vivo metabolite analysis. The influence of URB597 pretreatment on the metabolisation profile was assessed.Results[¹¹C]-1 was obtained in good yields and high radiochemical purity. Biodistribution studies revealed high brain uptake in wild-type and FAAH knock-out mice, but no retention of radioactivity could be demonstrated. Metabolite analysis and URB597 pretreatment confirmed the non-FAAH-mediated metabolisation of [¹¹C]-1. The inhibition mechanism was determined to be reversible. In addition, the inhibition of URB597 appeared slowly reversible.ConclusionsAlthough [¹¹C]-1 inhibits FAAH in vitro and displays high brain uptake, the inhibition mechanism seems to deviate from the proposed carbamylation mechanism. Consequently, it does not covalently bind to FAAH and will not be useful for mapping the enzyme in vivo. However, it represents a potential starting point for the development of in vivo FAAH imaging tools.     

Combined treatment of cancer of the posterior oral cavity and oropharynx

Ninety composite resections were carried out as primary treatment for a squamous carcinoma of the tonsillar region between 1970 and 1978. All patients have been followed-up for at least 3 years, except for 5 who have been lost to follow-up. All patients received postoperative radiotherapy (between 50 Gy and 65 Gy depending on the tumour resection status). Sixty-one patients received preoperative chemotherapy and 42% had clinical reduction of tumour size. The overall survival was 45.5% at 3 years and 43% at 5 years. Local recurrences were the most frequent oncological failure (25%). Tumours classed T3, insufficient tumour resection and lymph node invasion had poor prognostic value. We emphasize the necessity for primary surgery with preoperative chemotherapy and postoperative radiotherapy for squamous carcinoma of the posterior oral cavity and oropharynx.     

Prolonged disease-free survival in pediatric non-Hodgkin's lymphoma using ifosfamide-containing combination chemotherapy.

Pediatric non-Hodgkin's lymphoma (NHL) constitutes 16 per cent of pediatric malignancies reported to the National Cancer Institute (NCI) in Cairo. The adopted treatment for these cases was, from 1982 to July 1985, a modified St Jude's regimen consisting of: vincristine, cyclophosphamide, adriamycin, prednisone and intrathecal methotrexate for the first 6 weeks for induction, followed by cranial irradiation for cranial prophylaxis. Patients in remission received maintenance therapy for 18 months. Of 32 patients complete remission (CR) was achieved in 24 patients (75 per cent); partial remission (PR) in one patient (3 per cent); five patients showed no response (15 per cent) while two patients died during the induction phase. At 60+ months follow-up, 60 per cent of cases are still alive, disease-free, and overall survival is 66 per cent. A new protocol was adopted in 1985, consisting of alternating cycles: A and B, for 4-8 cycles. Cycle A: cyclophosphamide, high dose ara-C, adriamycin, and vincristine. Cycle B: ifosfamide, methotrexate, VP 16, with intrathecal methotrexate. The response in 39 cases is: CR in 31 cases (82 per cent); PR in four cases (10 per cent); no response in three cases (8 per cent). At 60+ months, the disease-free survival is 60 per cent, and overall survival 80 per cent. This new protocol has the advantage of: short duration of therapy and so better patient compliance, no maintenance therapy or cranial irradiation with its sequelae in the future. Moreover, it has a better overall survival.     

Ifosfamide in the treatment of high-grade recurrent non-Hodgkin's lymphomas.

We report the results of two phase II trials of ifosfamide in very high risk patients with either partially responsive or recurrent non-Hodgkin's lymphomas. In the first study, in which patients were extremely heavily pretreated (50 per cent had received a very intensive salvage regimen containing very high dose cyclophosphamide), there were two complete responses, two partial responses and one objective (minimal) response among 14 patients treated. Toxicity was acceptable even in this end-stage patient group. We concluded that ifosfamide is an active agent even in patients with tumours resistant to cyclophosphamide. The second trial was a pilot study in 13 patients of a regimen incorporating VP16, ifosfamide/mesna, and high dose ara-C (VIPA). There were four complete responses, five partial responses and two objective responses. Two patients died in complete remission from toxic complications, while a third, with a stably regressed mediastinal mass died after completion of the protocol. While very toxic, we considered that this regimen was highly effective, and have since incorporated a slightly less intensive combination of the same drugs into the primary therapy of high risk patients. Since the primary toxicity of the VIPA combination was myelosuppression, the use of a modified protocol incorporating colony stimulating factors to ameliorate the side-effects and possibly increase dose rate is worthy of further exploration in patients with recurrent B cell tumours.     

Occurrence of an Ascending Aorta Aneurysm 25 Years After Cure of a Tetrology of Fallot

Abstract   The patient, who had undergone a complete cure of a tetralogy of Fallot 25 years previously, was discovered to have an ascending aorta aneurysm on echography. Bentall's procedure was carried-out, using a modified indirect coronary artery transplantation based on the Cabrol technique. As reported in the literature complications are mainly right sided and less frequently occur on the left side in this disease. Including the hypothesis of the overload volume which may provoke aortic root dilation, there is also an intrinsic pathology of the media which could often be related to embryogenesis abnormalities, i.e., abnormal migration of cardiac neural crest cells which may explain this condition.     

The isolated pulmonary nodule. Biopsy guided by x-ray computed tomography

Transparietal CT-guided biopsy location can be successfully performed for isolate pulmonary nodules, defined as lesions with a maximal diameter of 3 cm, without any other parenchymal or mediastinal abnormality. A 21 G needle has been used according to an identical protocole in 64 cases (10 benign, 54 malignant). The biopsy was successful in 77.7% of the malignant cases. In relation to the diameter of the nodules, biopsy was successful in 66.7% of the nodules smaller than 2 cm and in 76% of the nodules ranging from 2 to 3 cm. The complications observed were rare (1 case of pneumothorax requiring drainage, 9 cases of pneumothorax without clinical signs and simply followed up, 4 cases of minor hemoptysis requiring no treatment and 5 cases of hematomas smaller than 5 cm on CT).