Unicoronal craniosynostosis correction with fronto-orbital advancement and cranial vault remodeling has traditionally been the gold standard. Distraction osteogenesis has the advantage of increased size of movement without constriction of the scalp and decreased morbidity. Although fronto-orbital advancement and cranial vault remodeling are usually performed at 6 months of age or later, distraction osteogenesis is performed at a younger age, between 3 and 6 months, to take advantage of the infant bony physiology. Herein, the authors demonstrate a case of distraction osteogenesis for unicoronal craniosynostosis in a 3-month-old female with significant improvement of her orbital, nasal, and frontal symmetry. The video can be found here: https://vimeo.com/519047922.
Angiocentric glioma, a rare brain neoplasm with features of ependymal differentiation, has only recently been recognized as a distinct clinicopathological entity. To date, all reported cases have involved tumors in the cerebral hemispheres, and the majority have presented with seizures. The authors report the case of a 5-year-old girl who presented with several cranial neuropathies and mild gait disturbance. An exophytic neoplasm arising from the posterior midbrain and causing obstructive hydrocephalus was identified, and surgical resection revealed a neoplasm with features of angiocentric glioma.
Abstract DNA mismatch repair machinery is an integral part of the human genome and its defect has been involved in tumorigenesis and treatment resistance. Heterozygous monoallelic germline loss of function in MLH-1, MSH-2, MSH-6 or PMS-2 is involved in Lynch syndrome, whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) which is associated with hematologic malignancies and glioblastoma. We report here the clinical characterization and molecular analyses of 7 patients who presented with gliomas and MMR machinery aberrations. Two patients had a clinical diagnosis of NF-1 with dermatologic stigmata, of whom one patient has CMMRD and the other has Lynch syndrome. Two patients had a known family history of Lynch syndrome upon their diagnosis of glioma. Three patients with high-grade glioma and negative family history, 2 had germline mutations in MMR genes, and one had numerous mutations including MMR genes with microsatellite instability. Patients were initially treated with chemotherapy and radiation for high-grade gliomas (HGG); 5/7 had progression. Median time to progression was 12 months (range: 5–52), and median time from progression to death was 7 months (range: 2–25). One patient had low-grade glioma initially but progressed to HGG and is currently on therapy. Another patient treated with temozolomide and radiation is currently receiving maintenance therapy without any disease recurrence. Although the literature data on brain tumors with MMR deficiency is limited, these consistently show that MMRD-associated gliomas are treatment-resistant and have a dismal outcome. Collaborative efforts are needed to better understand this subgroup of pediatric HGG and to define optimal treatment strategy.
Prognosis of recurrent/refractory medulloblastoma, ependymoma and atypical teratoid/rhabdoid neoplasms (AT/RT) remains dismal. Preclinical data showing efficacy of activated/propagated NK cells to lyse and kill these tumor cells in culture and in mice have been demonstrated, along with feasibility and safety of infusions of biologic agents into the ventricles. The ongoing phase I trial evaluates for the first time in humans, safety of infusions of autologous NK cells directly into the ventricles of patients with these tumors. Assessment of antitumor activity, and correlative biologic studies are being evaluated to define the immunophenotype and function of expanded NK cells. Patients receive three cycles of NK-cell infusions over 12 weeks through an Ommaya reservoir. To date, 9 patients have been enrolled, 8 patients achieved successful expansion of their NK cells, and 7 patients received up to 27 infusions each of NK cells at doses up to 3x10e7/m2/infusion. Currently this study is enrolling patients in the last cohort. This phase I study has so far demonstrated safety with no dose-limiting toxicity attributable to the infused NK cells. Significant CSF pleocytosis is seen in patients receiving NK cells with the increased dosage, with no evidence of infection. Influx of CD4+ and CD8+ T cells into the CSF in noted. This could suggest a proinflammatory environment induced by higher doses of NK cell infusion. This study also intends to evaluate the migration and persistence of NK cells with novel neuroimaging techniques to correlate efficacy outcome and the pharmacokinetics of NK cells.
Surgery is an important therapeutic modality for pediatric patients with intractable epilepsy. However, existing imaging and diagnostic technologies such as MR imaging and electrocochleography (ECoG) do not always effectively delineate the true resection margin of an epileptic cortical lesion because of limitations in their sensitivity. Optical spectroscopic techniques such as fluorescence and diffuse reflectance spectroscopy provide a nondestructive means of gauging the physiological features of the brain in vivo, including hemodynamics and metabolism. In this study, the authors investigate the feasibility of using combined fluorescence and diffuse reflectance spectroscopy to assist epilepsy surgery in children.In vivo static fluorescence and diffuse reflectance spectra were acquired from the brain in children undergoing epilepsy surgery. Spectral measurements were obtained using a portable spectroscopic system in conjunction with a fiber optic probe. The optical investigations were conducted at the normal and abnormal cortex as defined by intraoperative ECoG and preoperative imaging studies. Biopsy samples were taken from the investigated sites located within the zone of resection. The optical spectra were classified into multiple subsets in accordance with the ECoG and histological study results. The authors used statistical comparisons between 2 given data subsets to identify unique spectral features. Empirical discrimination algorithms were developed using the identified spectral features to determine if the objective of the study was achieved.Fifteen pediatric patients were enrolled in this pilot study. Elevated diffuse reflectance signals between 500 and 600 nm and/or between 650 and 850 nm were observed commonly in the investigated sites with abnormal ECoG and/or histological features in 10 patients. The appearance of a fluorescent peak at 400 nm was observed in both normal and abnormal cortex of 5 patients. These spectral alterations were attributed to changes in morphological and/or biochemical characteristics of the epileptic cortex. The sensitivities and specificities of the empirical discrimination algorithms, which were constructed using the identified spectral features, were all > 90%.The results of this study demonstrate the feasibility of using static fluorescence and diffuse reflectance spectroscopy to differentiate normal from abnormal cortex on the basis of intraoperative assessment of ECoG and histological features. It is therefore possible to use fluorescence and diffuse reflectance spectroscopy as an aid in epilepsy surgery.
Abstract Background/rationale: Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival, making it imperative to profile novel therapeutic combinations. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. At the gene level high PDGFR amplification (most commonly seen) and overexpression of the PI3K-Akt-mTOR pathway were noted in these tumors. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositol 3-kinase signaling pathway were found in 47% of DIPG. Thus targeting this pathways with mTOR inhibitors could hold therapeutic promise. Elevated expression of DNA repair proteins in the NHEJ and HRR pathway are known to induce resistance to radiation. Preclinical data shows inhibition of these pathways potentiates the sensitivity of these tumors to radiation. SAHA a pan HDAC inhibitor, has been associated with decreased expression of key DNA repair proteins in both the NHEJ and HRR pathways. Both temsirolimus (an mTOR inhibitor) and SAHA are well described in pediatric clinical trials with an established maximum tolerated dose (MTD). The efficacy of the combination of temsirolimus and SAHA has been well-established in other malignancies including prostate cancer, mantle lymphoma, and renal carcinoma. This is the first multi-targeted therapeutic trial in pediatric DIPG, using SAHA and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules along with enhancing the radiation sensitivity. Correlative study: Stratum I (chemoradiotherapy phase): Histone acetylation will be quantified from peripheral blood mononuclear cell (PBMC) collected prior to the first dose of vorinostat and radiation and at the end of radiation. Stratum I and II (maintenance phase): Evaluation of histone acetylation, phosphorylated 70S6K and Akt on day 1 and 8 (prior to chemotherapy with temsirolimus) during cycle 1 and cycle 2. Methods Patients with a performance score of 50 or greater with newly diagnosed (Stratum 1) or progressive DIPG (stratum II) as confirmed by gadolinium enhanced MRI are eligible. Biopsy is not mandatory. Stratum I: Patients will receive radiation therapy concurrently with vorinostat on the days of radiation at a dose of 230mg/m2/dose, followed by adjuvant therapy with vorinostat and temsirolimus for 10 cycles if patients do not have progressive disease. Stratum II: Patients will receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if patient does not have progressive disease. SAHA will be given once daily at 230 mg/m2 orally from day 1 to day 8, along with temsirolimus at 25mg/m2 intravenously on day 1 and day 8. This will be the dose level 1 and 2 dose escalations and 1 dose de-escalation will be allowed. A standard 3+3 design will be used and a minimum of 9 patients and a maximum of 18 patients will be enrolled. Trial is ongoing (30% of planned patients enrolled), with patients now in the second dose level (enrollment of this cohort started on September 2018). No dose limiting toxicity (DLT) were noted at the first dose level. Trial: NCT02420613 (currently recruiting). Note: This abstract was not presented at the meeting. Citation Format: Soumen Khatua, Joya Chandra, Miriam M. Morrell, Heather B. Meador, David I. Sandberg, Jeffrey Weinberg, Greg Fuller, Leena Ketonen, Jason M. Johnson, Kenneth R. Hess, Wafik Zaky. A Phase I study of Suberoylanilide Hydroxamic Acid (SAHA) with Temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT113.
125 patients suffering from hiatal hernia were seen at the Surgical Clinic of Bonn-University between 1963 and 1977. 76 patients underwent surgery and could be followed-up. Our treatment of choice is gastropexy.
