Development of randomized trials in adults with medulloblastoma - the example of EORTC 1634-BTG/NOA-23

Simple Summary Medulloblastoma is rare after puberty. Among several molecular subgroups that have been described, the sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal population and can be targeted with smoothened (SMO) inhibitors. However, no practice-changing prospective clinical trials have been published in adults to date. Tumors often recur, and treatment toxicity is relevant. Thus, the EORTC 1634-BTG/NOA-23 trial for post-pubertal patients with standard risk medulloblastoma will aim to increase treatment efficacy and to decrease treatment toxicity. Patients will be randomized between standard-dose vs. reduced-dosed radiotherapy, and SHH-subgroup patients will also be randomized between the SMO inhibitor sonidegib (Odomzo(TM,), Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone. In ancillary studies, we will investigate tumor tissue, blood and cerebrospinal fluid samples, magnetic resonance images, and radiotherapy plans to gain information that may improve future treatment. Patients will also be monitored long-term for late side effects of therapy, health-related quality of life, cognitive function, social and professional live outcomes, and reproduction and fertility. In summary, EORTC 1634-BTG/NOA-23 is a unique multi-national effort that will help to council patients and clinical scientists for the appropriate design of treatments and future clinical trials for post-pubertal patients with medulloblastoma. Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (Odomzo(TM), Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.Neurolog

The stability of facial advancement surgery (in the management of combined mid and lower dento-facial deficiency)

The short-term (6 weeks postoperative) and long-term (12 months postoperative) skeletal stability of combined maxillary and mandibular advancement was evaluated by cephalometric analysis in 15 patients. The mean horizontal advancement of the maxilla was 5.84 mm. 6 weeks later a mean relapse of 0.03 mm (0.5%) was identified. The mean relapse at long-term follow-up was 0.59 mm (10.1%). The mean horizontal advancement of the mandible was 12.35 mm at menton and 12.65 mm at pogonion. At 6 weeks, mean horizontal relapse, respectively at the above landmarks, was 0.11 mm and 0.21 mm (1.3%). The mean relapse at long-term follow-up was respectively 2.19 mm and 1.98 mm (16.9%). Subjectively and objectively improvements were seen in facial aesthetics and dental occlusion. The results indicate that rigid fixation of osteotomies undertaken to correct 'horizontal facial deficiency' is a surgically predictable and relatively stable procedure when reviewed up to 12 months after surgery

Custom cranioplasty using stereolithography and acrylic

Numerous methods of cranioplasty have been described. Customisation and prefabrication have been reported to reduce operating time and improve cosmesis. An original technique for the manufacture of customised cranioplastic implants has been developed and tested in 30 patients. Thirty patients requiring cranioplasties were selected. Data acquired from computed tomography (CT) were used to manufacture exact plastic replicas (biomodels) of craniotomy defects and master cranioplastic implants using the rapid prototyping technology of stereolithography (SL). The three-dimensional (3D) imaging techniques of mirroring and interpolation were used to extrapolate on existing anatomy to design the master implants. The master implants were hand finished to fit the defect in the corresponding cranial biomodel exactly and were then used to create a cavity mould. The mould was used to cast thermally polymerised custom acrylic implants. The surgeons reported that the customised implants reduced operating time, afforded excellent cosmesis and were cost effective. The patients reported that the opportunity to see the biomodel and implant preoperatively improved their understanding of the procedure. Two complications were noted, one infection and one implant required significant trimming. The simultaneous manufacture of the master implant (male) and biomodel (female) components from SL allowed custom accurate implants to be manufactured. Disadvantages identified were the time required for computer manipulations of the CT data (up to 2 h), difficulty in assessing the accuracy of the computer generated master as a 3D rendering, the potential for SL parts to warp, manufacturing time (minimum 2 days) and the cost of approximately $1300 US per case ($1000 for the SL biomodel and $300 for the acrylic casting). (C) 2000 The British Association of Plastic Surgeons

Biomodelling of skull base tumours

Stereolithographic (SL) biomodelling is a new technology that allows three-dimensional computed tomography magnetic resuance data to be used to generate solid plastic replicas of anatomical structures (biomodels). A prospective trial of 11 patients to assess the utility of SL biomodelling in skull base tumour surgery has been performed. Biomodels were manufactured and used for patient education, diagnosis and operative planning. The results suggest that biomodelling has significant utility in skull base tumour surgery and is a cost-effective technology. Biomodels were found to be particularly effective for surgical simulation and the production of customised cranioplastic implants for reconstruction after tumour resection

Stereolithographic (SL) biomodelling in craniofacial surgery

Background: Stereolithographic (SL) biomodelling allows 3D CT to be used to generate solid plastic replicas of anatomical structures (biomodels). Case reports in the literature suggest that such biomodels may have a use in craniofacial surgery but no large series or assessment of utility has been reported. A prospective trial to assess the utility of biomodelling in craniofacial surgery has been performed. Methods: Forty patients with complex craniofacial abnormalities were selected and 3D CT scanning performed. The data of interest was used to guide a laser to selectively polymerise photosensitive resin to manufacture SL biomodels. The biomodels were used for patient education, diagnosis and operative planning. An assessment protocol was designed to test the hypothesis that biomodels in addition to standard imaging had greater utility in the surgery performed than the standard imaging alone. Results: Anecdotally surgeons found biomodelling useful in 40 complex craniofacial operations. The formal assessment of the first 10 cases suggested biomodels improved operative planning (image 76%, image with biomodel 97%, P < 0.01) and diagnosis (image 82.5%, image with biomodel 99.25%, P < 0.01). Surgeons estimated that the use of biomodels had reduced operating time by a mean of 16% and were cost effective at a mean price of $1100 AUS. Conclusion: Biomodelling was reported as an intuitive, user-friendly technology that facilitated diagnosis, operative planning and communication between colleagues and patients. Limitations of the technology were manufacturing time and cost

Spinal biomodelling

A prospective trial of stereolithographic biomodeling in complex spinal surgery.To investigate the use of stereolithographic biomodeling as an aid to complex spinal surgery.Of the array of imaging methods available to assist the spinal surgeon, no single method provides a complete overview of the anatomy, although three-dimensional imaging has been shown to have advantages.Stereolithographic biomodeling is a new technology that allows data from three-dimensional computed tomographic scans to be used to generate exact plastic replicas of anatomic structures. Five patients with complex deformities were selected: two children with congenital deformities, a patient with an osteoblastoma, a patient with basilar invagination caused by osteogenesis imperfecta, and a patient with a failed lumbar fusion. Computed tomographic scanning was performed and stereolithographic biomodels generated. The stereolithographic biomodels were used for patient education, operative planning, and surgical navigation.The surgeons reported that biomodeling was useful in complex spinal surgery and was an effective technology. Stereolithographic biomodels were found to be particularly useful in morphologic assessment, in the planning and rehearsal of surgery, for intraoperative navigation, and for informing patients about surgical procedures.Stereolithographic biomodeling allows imaging data to be displayed in a physical form. This intuitive medium may improve data display and allows surgical simulation on a proxy of the surgical site. Draw-backs of the technology were a minimum 24 hours' manufacturing time and the cost