Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor a (PDGFRa) gene. Both PDGFRa and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale—Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale—Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2–6 and 9–15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2–6 months and 25.7% at 9–15 months. At 9–15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months; this failed to reach significance at 9–15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Most gastrointestinal stromal tumors (GISTs) carry activating mutations of the KIT gene encoding the receptor tyrosine kinase KIT. In a previous study we were able to show an association between the lack of KIT mutations (wild-type GISTs) and the presence of a significant epithelioid tumor component. A very recent study described the occurrence of PDGFRalpha mutations in KIT wt GISTS. Therefore, we studied a panel of 87 GISTs for mutations in the hot spot regions of the PDGFRalpha gene with single strand conformation polymorphism analysis and sequencing and correlated the PDGFRalpha status with pathomorphological data. We detected 20 cases with exon 18 mutations but none with exon 12 mutations. The mutations were located in the second kinase domain of PDGFRalpha with 16 point mutations, and four larger deletions of 9 to 12 bp. All cases with mutations in the PDGFRalpha gene revealed wild-type KIT in common regions of mutation, ie, exons 9 and 11. Most interestingly, the occurrence of PDGFRalpha mutations was significantly associated with a higher frequency of epithelioid or mixed morphology (18 of 20 cases, P < 0.0001) and gastric location (all cases, P = 0.0008). Our data indicate that GISTs represent distinctive entities, differing in genetic, biological, and morphological features.

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Features of PDGFRalpha-mutated GISTs are multinuclear giant cells and dot-like staining for PDGFRalpha. In contrast, c-kit-mutated GISTs display a spindle cell phenotype and Kit-dots on immunohistochemistry. Our findings not only help to distinguish distinctive entities of GISTs using histological and immunhistochemical features, but also indicate that Kit and PDGFRalpha are differentially regulated in a subset of GISTs.

Secondary dystonia encompasses a heterogeneous group with different etiologies. Cerebral palsy is the most common cause. Pharmacological treatment is often unsatisfactory. There are only limited data on the therapeutic outcomes of deep brain stimulation in dyskinetic cerebral palsy. The published literature regarding deep brain stimulation and secondary dystonia was reviewed in a meta-analysis to reevaluate the effect on cerebral palsy. The Burke-Fahn-Marsden Dystonia Rating Scale movement score was chosen as the primary outcome measure. Outcome over time was evaluated and summarized by mixed-model repeated-measures analysis, paired Student t test, and Pearson's correlation coefficient. Twenty articles comprising 68 patients with cerebral palsy undergoing deep brain stimulation assessed by the Burke-Fahn-Marsden Dystonia Rating Scale were identified. Most articles were case reports reflecting great variability in the score and duration of follow-up. The mean Burke-Fahn-Marsden Dystonia Rating Scale movement score was 64.94 ± 25.40 preoperatively and dropped to 50.5 ± 26.77 postoperatively, with a mean improvement of 23.6% (P < .001) at a median follow-up of 12 months. The mean Burke-Fahn-Marsden Dystonia Rating Scale disability score was 18.54 ± 6.15 preoperatively and 16.83 ± 6.42 postoperatively, with a mean improvement of 9.2% (P < .001). There was a significant negative correlation between severity of dystonia and clinical outcome (P < .05). Deep brain stimulation can be an effective treatment option for dyskinetic cerebral palsy. In view of the heterogeneous data, a prospective study with a large cohort of patients in a standardized setting with a multidisciplinary approach would be helpful in further evaluating the role of deep brain stimulation in cerebral palsy. © 2013 Movement Disorder Society.

Fetal male germ cells are comprised of two major groups with distinct immunohistochemical phenotypes. Germ cells that are predominantly found before week 25 of gestation co-express oncofetal proteins OCT3/4, c-KIT, M2A and AP-2gamma. After week 25, most germ cells have lost their pluripotent potential and acquire a spermatogonial phenotype defined by expression of MAGE-A4.

Most germ cell tumors (GCTs) arise from intratubular germ cell neoplasias (IGCNUs, also referred to as carcinoma in situ), which are thought to originate from a transformed fetal germ cell, the gonocyte. However, the nature of the molecular pathways involved in IGCNU formation remains elusive. Therefore, identification of novel oncofetal markers is an important prerequisite to further our understanding of the etiology of this tumor entity. In the present study, we show that in humans AP-2g is expressed in gonocytes at weeks 12-37 of gestation, indicating a role of this transcription factor in fetal germ cell development. AP-2g and c-KIT, a known target of AP-2 transcription factors, were coexpressed in gonocytes, making a direct regulation possible. With increasing differentiation of fetal testis, gradual downregulation of AP-2g from the 12th to 37th week of gestation was observed. Furthermore, AP-2g was expressed abundantly in 25/25 IGCNUs, 52/53 testicular seminomas, 10/10 metastatic seminomas, 9/9 extragonadal seminomas and 5/5 dysgerminomas. In embryonal carcinomas and choriocarcinomas, focal staining only was observed. Spermatocytic seminomas, teratomas and yolk sac tumors as well as normal adult testis and various control tissues were negative for AP-2g. The expression pattern of AP-2g, like that of other oncofetal markers, supports the model of a gonocytal origin of IGCNUs and germ cell tumors. Finally, our results provide the basis for applying AP-2g immunohistochemistry to the detection of GCT, a tumor entity with a steadily growing incidence in the male population worldwide. ' 2005 Wiley-Liss, Inc.Key words: AP-2g; gonocyte; neoplastic; seminoma; germ cell tumor The most abundant malignancies among men aged 17-45 are GCTs. 1 They comprise a heterogeneous group of neoplasms in terms of their histology, marker expression and age at manifestation. First described by Skakkebaek in 1972, the common precursor lesion of all GCTs, IGCNU (CIS, TIN, IGCN), arises from transformation of a gonocyte. 2,3 Markers commonly used for immunohistology, such as OCT3/4, PLAP and c-KIT, are expressed in gonocytes as well as IGCNUs and some stages of GCT, further supporting this model. TFAP2C belongs to a family of 5 closely related genes that are involved in the morphogenesis of craniofacial, urogenital, neural crest and placental tissues. 4 AP-2 transcription factors are believed to regulate the expression of several genes involved in cell growth and differentiation during development. 5 AP-2g is essential for mammalian embryonic development because embryonic trophectodermal cells fail to proliferate in AP-2g knockout mice. 6,7 In transgenic studies, overexpression of AP-2g impaired differentiation of epithelial cells of the mammary gland and the seminal vesicle. 8 Besides trophoblastic and neuroectodermal lineage, AP-2g can be detected in lung, testis and ovary. 9,10 In human tumors, AP-2g is upregulated in certain stages of melanoma 11 and breast cancer. 12,13 In the present study, we investigated the expression of AP-2...