EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand

Background: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.Methods: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.Results: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.Conclusions: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.</p

Frequent occurrence of the triphasic response (diabetes insipidus/hyponatremia/diabetes insipidus) after surgery for craniopharyngioma in childhood

It is not exactly known how many children develop the triphasic response (diabetes insipidus (DI)/hyponatremia/DI) immediately after surgery for childhood craniopharyngioma; neither is it known which factors predict this. We studied the occurrence of the triphasic response after primary surgery for craniopharyngioma in children, and aimed to identify possible predictors. Patients <18 years old who had undergone a primary craniopharyngioma resection between January 1990 and February 2010 in either of the 2 academic centers in Amsterdam were studied retrospectively. Twenty-one patients (5 males) fulfilled the inclusion criteria. Median age at surgery was 9.1 (range: 4.0-15.1) years. Six patients developed a triphasic response (29%). Of all factors, only the duration of surgery was found to be a predictor of a triphasic response: 8.5 (6.0-11.0) versus 4.6 (3.5-11.5) h in patients who did not develop a triphasic response (p = 0.03). After primary surgery for a craniopharyngioma, a considerable number of patients develop a triphasic response in the regulation of the sodium and water balance. This is predicted by (factors associated with) a longer duration of surgery. Other predictors could not be identified, which may be due to the small sample siz

Children Born Small for Gestational Age: Differential Diagnosis, Molecular Genetic Evaluation, and Implications

Children born small for gestational age (SGA), defined as a birth weight and/or length below -2 SD score (SDS), comprise a heterogeneous group. The causes of SGA are multifactorial and include maternal lifestyle and obstetric factors, placental dysfunction, and numerous fetal (epi)genetic abnormalities. Short-term consequences of SGA include increased risks of hypothermia, polycythemia, and hypoglycemia. Although most SGA infants show catch-up growth by 2 years of age, ∼10% remain short. Short children born SGA are amenable to GH treatment, which increases their adult height by on average 1.25 SD. Add-on treatment with a gonadotropin-releasing hormone agonist may be considered in early pubertal children with an expected adult height below -2.5 SDS. A small birth size increases the risk of later neurodevelopmental problems and cardiometabolic diseases. GH treatment does not pose an additional risk

Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification

Context: Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature. The incidence of submicroscopic deletions is unknown, as is the effect of GH therapy in this condition. Objective: The objective of the study was to describe the use of a novel genetic technique [multiplex ligation probe amplification (MLPA)] to detect haploinsufficiency of the IGF1R gene in a patient suspected of an IGF1R gene defect and evaluate the effect of long-term GH therapy. Patient: A 15-yr-old adolescent, born small for gestational age, showed persistent postnatal growth retardation, microcephaly, and elevated IGF-I levels. She had been treated with GH since the age of 5 yr. Methods: MLPA and array comparative genomic hybridization (aCGH) were performed to examine gene copy number changes. Dermal fibroblast cultures were used for functional analysis. Results: With MLPA, a deletion of one copy of the IGF1R gene was detected, defined by aCGH as a loss of 15q26.2->qter. IGF1R mRNA expression was decreased in fibroblasts. IGF-I binding and type 1 IGF receptor protein expression as well as activation of type 1 IGF receptor autophosphorylation and protein kinase B/Akt by IGF-I tended to be lower, but this did not reach statistical significance. GH treatment resulted in a good growth response and a normal adult height. Conclusions: MLPA and aCGH are useful tools to detect submicroscopic deletions of the IGF1R gene in patients born small for gestational age with persistent growth failure. The phenotype resembles that of a heterozygous inactivating IGF1R mutation. Long-term GH therapy causes growth acceleration in childhood and a normal adult height. Copyrigh

Phenotypic Features and Response to GH Treatment of Patients with a Molecular Defect of the IGF-1 Receptor

Context The phenotype and response to GH treatment of children with an IGF1R defect is insufficiently known. Objective To develop a clinical score for selecting children with short stature for genetic testing and evaluate the efficacy of treatment. Design and Setting Case series with an IGF1R defect identified in a university genetic laboratory. Patients and Interventions Of all patients with sufficient clinical data, 18 had (likely) pathogenic mutations (group 1) and 7 had 15q deletions including IGF1R (group 2); 19 patients were treated with GH. Main Outcome Measures Phenotype and response to GH treatment. Results In groups 1 and 2, mean (range) birth weight, length, and head circumference (HC) SD scores (SDSs) were -2.1 (-3.7 to -0.4), -2.7 (-5.0 to -1.0), and -1.6 (-3.0 to 0.0), respectively. At presentation, height, HC, and serum IGF-1 SDSs were -3.0 (-5.5 to -1.7), -2.5 (-4.2 to -0.5), and +1.2 (-1.3 to 3.2), respectively. Feeding problems were reported in 15 of 19 patients. A clinical score with 76% sensitivity is proposed. After 3 years of GH treatment [1.1 (0.2) mg/m 2 /d] height gain in groups 1 (n = 12) and 2 (n = 7) was 0.9 SDS and 1.3 SDS (at a mean IGF-1 of 3.5 SDS), less than reported for small for gestational age (1.8 SDS). Conclusion A clinical score encompassing birth weight and/or length, short stature, microcephaly, and IGF-1 is useful for selecting patients for IGF1R analysis. Feeding problems are common and the growth response to GH treatment is moderate

Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation

GH insensitivity can be caused by defects in the GH receptor (GHR) or in the postreceptor signaling pathway. Recently, two female patients with severe growth retardation and pulmonary and immunological problems were described with a defect in STAT5b, a critical intermediary of downstream GHR signaling. The objective was to determine the functional characteristics of a novel STAT5b mutation and describe the phenotype. Patient: We describe an adult male patient with short stature [-5.9 sd score (SDS)], delayed puberty, and no history of pulmonary or immunological problems. GH-binding protein level as well as GH secretion characteristics were normal. Plasma prolactin level was elevated. Extremely low levels of IGF-I (-6.9 SDS), IGF-binding protein-3 (-12 SDS), and acid-labile subunit (-7.5 SDS) were found. We found a homozygous frameshift mutation in the STAT5b gene (nucleotide 1102-3insC, Q368fsX376), resulting in an inactive truncated protein, lacking most of the DNA binding domain and the SH2-domain. This report confirms the essential role of STAT5b in GH signaling in the human. We show for the first time that immunological or pulmonary problems or elevated GH secretion are not obligatory signs of STAT5b deficiency, whereas hyperprolactinemia appears to be part of the syndrome. Therefore, in patients with severe short stature, signs of GH insensitivity, and a normal GHR, analysis of the STAT5b gene is recommende