Gastrointestinale Stromatumoren (GIST) sind die häufigsten mesenchymalen Tumoren des Gastrointestinaltraktes. Diese Tumoren wurden früher meist als Leiomyome, Leiomyosarkome oder aggressive Neurinome klassifiziert. Die Entdeckung des c-kit Onkogens CD 117 auf der Oberfläche mesenchymaler Tumoren führte zu einer entscheidenden histologischen Differenzierung dieser Tumorgruppe. 1998 wurden gastrointestinale Stromatumoren – GIST als eigenständige Tumorentität neu definiert. Gastrointestinale Stromatumoren stammen aus den interstitiellen Zellen von Cajal. Diese sogenannten Schrittmacherzellen wurden erstmals 1893 von dem spanischen Neuroanatomen und Nobelpreisträger Santiago Ramon y Cajal (1852-1934) beschrieben. Obwohl die interstitiellen Cajal-Zellen (ICC) non-neuronale Zellen mesenchymalen Ursprungs sind, werden sie dennoch als intestinale Schrittmacherzellen bezeichnet, da sie offensichtlich in der Lage sind, neuronale Stimuli auf glatte Muskelzellen zu übertragen und sogenannte „slow waves“ zu generieren. Die Cajal-Zellen bilden dreidimensionale Netzwerke innerhalb der Tunica muscularis und sind sowohl untereinander als auch mit Muskel- und Nervenzellen durch Gap Junctions verbunden. Die Inzidenz der klinisch signifikanten gastrointestinalen Tumoren beträgt 10-20 pro Million pro Jahr . Diese Zahl zugrundegelegt sind dies in Deutschland etwa 1200 Erkrankungen pro Jahr. Das mediane Alter bei Erkrankungsbeginn liegt zwischen 55 und 65 Jahren. Eine familiäre Disposition für GIST wurde beschrieben. Gastrointestinale Stromatumoren können zudem in jedem Anteil des Gastrointestinaltraktes auftreten, bevorzugt im Magen sowie im Dündnarm, jedoch auch im Ösophagus, Anorektum sowie extraluminal im Bereich des Peritoneums. / Following the discovery of activating c-kit mutations and demonstration of c-kit (CD 117) immunoexpression on the surface of tumor cells in the majority of mesenchymal GI neoplasms formerly calssified as smooth muscle or neurogenic neoplasms, gastrointestinal stromal tumors (GISTs) were redefined as an independent tumor entity. The incidence of GISTs is estimated to be 14.5 cases per million people per year1. Accordingly, about 1200 new cases are diagnosed in Germany every year. Gain-of-function mutations in c-kit result in overexpression of the receptor tyrosine kinase on the cell surface with a consequent ligand-independent activation of the tyrosine kinases cascade. These novel findings represented the base for the targeted molecular therapy with the tyrosine kinase inhibitor imatinib (Glivec®), an agent that is easy-to-take orally and a highly effective systemic therapy that soon became available for patients with locally advanced and metastatic disease. However, the surgical R0 resection continues to be the treatment of choice for resectable tumors. A majority of GISTs could be resected by local excision. Multivisceral enbloc resection represents a relatively rare event and is necessary for huge GISTs that have involved neigbouring organs. Furthermore, surgical metastasectomy and ablative procedures are additional options for patients with solitary metastases or residual, metabolically active tumor masses and should be discussed individually. Taking in consideration that at least one half of patients with initial response to imatinib would ultimately develop drug resistance it is mandatory to be able to accurately predict the likelihood of tumor recurrence and/or metastases after R0 resection of GIST. Diverse prognostic factors that would predict the development of recurrence and/or metastases after R0 resection of GIST have been evaluated by several research groups worldwide, in particular for the category of high-risk tumors. The question whether adjuvant treatment with imatinib is indicated in patients with R0-resected high-risk GISTs has not yet been conclusively settled. However, results from current studies relating to this topic are anticipated in the near future. The objectives of this large monocentric trial were to evaluate the outcome after surgical resection and to determine prognostic factors for tumor relaps and tumor-related death.

Proefschrift Universiteit van Amsterdam. / Auteursnaam op omslag: Gertien J. Smits. Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Gastrointestinės stromos tumorai (GIST) – dažniausi mezenchiminės kilmės virškinamojo trakto navikai, kurie pradėti identifikuoti ir diagnozuoti tik per pastaruosius 25 m. GIST, pagal ligos progresavimo reliatyvią riziką, klasifikuojami į rizikos kategorijas, kurių nustatymas 2002 m. Nacionalinių sveikatos institutų sutarimu (NSI) paremtas dviem kintamaisiais: naviko dydžiu ir navikinių ląstelių mitozių skaičiumi 50 DPRL, kurių apimamas plotas įvairių studijų ir rekomendacijų duomenimis varijuoja nuo 5 mm² iki 11,9 mm². Neaišku, kaip netikslus mitozių skaičius įtakoja rizikos kategorijos nustatymą bei jų sąsajas su ligos progresavimu. Nors atliktose didžiausiose GIST studijose teigiama, kad, esant identiškiems morfologiniams požymiams, skrandžio GIST prognozė geresnė, kiti tyrėjai nustatė morfologinius požymius lemiančius geresnę šių navikų prognozę. Esant prieštaringoms nuomonėms, tyrimo metu nustatėme ir palyginome skirtingų lokalizacijų GIST morfologinius požymius ir prognozę. NSI klasifikacijoje buvo pastebėta, kad ligos prognozę įtakoja ir GIST histologinis fenotipas, tačiau tuomet nebuvo pakankamai atliktų studijų, paneigiančių ar patvirtinančių šiuos teiginius, todėl detaliai nagrinėjome skirtingų histologinių fenotipų GIST morfologinius požymius ir jų įtaką ligos prognozei bei kitų morfologinių požymių: naviko dydžio, mitozių skaičiaus, ląstelingumo, branduolių polimorfizmo ir nekrozės sąsajas su ligos prognoze. / Gastrointestinal stromal tumours (GIST) – the most common mesenchymal tumours of the gastrointestinal tract which have been identified and diagnosed in the past 25 years. GIST, according to relative risk of disease progression, are classified in risk categories which under the agreement of the National Institutes of Health (2002) were based on two variables: tumour size and mitotic count in 50 HPF, which total area varies from 5 mm² to 11.9 mm². There is no consensus what area is sufficient for the counting of mitoses. Thus, we compare number of GIST tumor cell mitoses in different sized areas and evaluated the impact of mitotic rate changes in determination of risk categories and their relation to the progression of the disease. According to the data of largest GIST study, disease prognosis is also influenced by tumour localization, other researchers found morphological features of these tumours leading to a better prognosis. Thus, we identified and compared the different localizations of GIST morphological features and prognosis. It was observed that disease prognosis is also determined by the tumour histological phenotype, but up till now the controversial results of histological phenotypes relationship to disease prognosis are published. We set morphological features of different GIST histological phenotypes and evaluate their relation to disease progression, evaluate the impact of GIST morphological features to disease prognosis.

Thesis (Doctoral)--Universiteit van Amsterdam, 1982.

Introduction: Gastrointestinal stromal tumours (GIST) are the commonest tumour of mesenchymal origin; favour the stomach, and account for a very small percentage of gastrointestinal tract tumours. Methods: In this retrospective audit of GISTs presenting to the Groote Schuur Hospital surgical and oncological multidisciplinary team (MDT) between 2004 – 2019, gastric GISTs were evaluated as regards presentation, gastric anatomical position, histological subtype with risk stratification, management and outcomes. Results: Of 126 GIST tumours presenting to this MDT, 82 originated in the stomach. Complete histopathological records could be obtained for 64. With an average of 59 years (50 male: 32 female), 18 (28%) presented with a herald bleed. Other common presentations included anaemia, epigastric mass and pain. The tumours were predominantly found in the body and fundus (64%), with a spindle cell subtype predominance (41%). The association between cancer cell subtype and gastric position was not significantly different (p=0.728). Cystic degeneration was found on 11 (17%) analyzed and cell necrosis on 12 (18%). These findings were not related to larger tumor size or prognosis. Five required downstaging with Imatinib prior to surgery. Thirty-seven patients underwent a surgical procedure: 24 wedge resections and 12 anatomical resections. Risk stratification was performed with the modified National Institutes of Health (NIH/Fletcher) score. Twenty-eight cases had inaccurate mitotic counts and couldn't be scored, 17 scored high risk, 9 intermediate risk, 9 low risk and 1 very low risk. Ten patients died of metastatic disease, 34 were discharged with no disease progression after 3 years, 1 patient with disease progression currently remains on Imatinib, and 19 were lost to follow up. Conclusion: Gastric GISTs appear to have a predilection for the proximal stomach; it is unsure whether this is purely due the greater surface area. The spindle cell subtype dominated in the proximal gastric GISTs. Cystic degeneration and cell necrosis did not seem to be related to larger tumours or outcomes.

This thesis explores the role of gist memory and gist representation in the formation of false recognition, specifically in the Deese, Roediger and McDermott Paradigm. We found that normal individuals displayed a range of susceptibility to false recognition and true recognition and this was related to their scores on both the Autism Spectrum Quotient and the Toronto-Alexithymia Scale. More ‘male-brained’ participants exhibited less susceptibility to false recognition but also less veridical recognition. The reverse was true for more ‘female-brained’ participants. The idea of false recognition and gist memory lying along a continuum was further emphasised by work on individuals with Autism Spectrum Disorder. We found they were less susceptible to false recognition but also produced less veridical recognition. We also found differences in performance between two groups of autism individuals who also differed in age. The results of further manipulations using both picture and word paradigms suggested that gist memory could be improved in younger individuals with autism. We also examined a patient group with Functional Memory Disorder using the DRM paradigm and a confabulation task and found them less able to produce true recognition in the DRM compared with a control group. Their memory impairments could not be attributed to depression since none were clinically depressed, so we suggested that they represent the tale end of impairment to gist memory. We also explored gist memory in a patient with dense anterograde amnesia who showed reduced true recognition and a tendency to reduced false recognition, but through manipulation of the stimuli using word and pictorial material she could perform like controls due to improved item-specific discrimination. A new face recognition paradigm was also tested in which she showed a tendency towards increased false recognition in comparison with controls. Finally, we suggest the use of the DRM paradigm as a test for memory malingering since we found participants could not replicate the performance of amnesia patients without a cost in their response latencies. This is discussed through the case study of GC a man suspected of exaggerating his memory symptoms.

Depuis la formulation de la théorie de l’immuno-surveillance en 1957 par Burnet et Thomas, le monde scientifique s’est efforcé d’identifier les cellules immunitaires impliquées dans ce processus. Les lymphocytes Natural Killer (NK) constituent une composant majeure de l’immuno-surveillance innée dans plusieurs cancers hématologiques et solides. L’activité des lymphocytes NK passe principalement par une grande variété de récepteurs avec un rôle activateur ou inhibiteur. Parmi les récepteurs activateurs présents à la surface des lymphocytes NK, le récepteur NCR3/NKp30 a un rôle majeur dans la toxicité directe contre la cellule cible et dans l’activation des cellules dendritiques.Les tumeurs stromales gastrointestinales (GIST) et le Neuroblastome (NB) sont deux tumeurs sensibles à l’immuno-surveillance par les lymphocytes NK. Dans une étude récente notre équipe a démontré que l’épissage alternatif du gène NCR3/NKp30 peut être déterminant dans la fonction NK et dans la survie des patients atteints de GIST.Afin de caractériser les lymphocytes infiltrant le GIST, nous avons effectué une recherche visant à analyser l’infiltrat des lymphocytes CD3+, des lymphocytes T régulateurs (Treg) et des lymphocytes NK dans des tumeurs GIST localisés, et corréler ces résultats à la survie des patients. Nous avons mis en évidence que, avant traitement, les lymphocytes NK sont surtout localisés au niveau des fibres trabéculaires qui entourent la tumeur, alors que les lymphocytes T sont localisé à l’intérieur de la tumeur en contact avec les cellules tumorales qui expriment HLA-I.Nous avons aussi observé que les cellules NK ont un phénotype plutôt CD56bright et migrent à l’intérieur de la tumeur après traitement par Imatinib. L’analyse de survie a mis en évidence que les lymphocytes NK et T peuvent prédire la survie sans progression (PFS). Ces résultats mettent en évidence l’importance de l’infiltrat immunitaire dans la prédiction du risque de rechute dans le GIST et surlignent l’importance de viser une réponse immunitaire dans les protocoles thérapeutiques.Nous avons ensuite déterminé la proportion de lymphocytes NK dans le sang périphérique et dans la moelle dans une cohorte de Neuroblastome (NB) localisé et métastatique : une infiltration plus important par les NK CD56bright a été observé chez les patients présentant une maladie métastatique et chez les patients avec une réponse mineure au traitement d’induction. De plus, les NK présents dans les échantillons de moelle osseuse infiltrés par les neuroblastes, présentaient une expression plus basse du récepteur NKp30. L’expression du ligand de NKp30, B7-H6, a été mise en évidence sur les neuroblastes infiltrant la moelle osseuse, et sa forme soluble, sB7-H6, a été retrouvée être positivement corrélée à l’extension de maladie et inversement à la réponse au traitement d’induction. L’analyse de l’épissage alternatif du gène NCR3/NKp30 a permis de mettre en évidence l’impact des isoformes NKp30 sur la survie sans progression chez les patients atteints de NB de haut risque en maladie minimale résiduelle après chimiothérapie d’induction. En particulier, les patients présentant un taux élevé de l’isoforme pro-inflammatoire (NKp30b) par rapport à l’isoforme immunosuppressive (NKp30c), présentent une meilleure survie sans évènement. Nous avons aussi démontré le rôle des monocytes dans l’amplification de la réponse NKp30 dépendant. Les résultats de notre recherche dans le GIST et dans le NB, deux maladies différentes mais toutes les deux sensibles aux lymphocytes NK, surlignent l’importance d’intégrer de nouvelles options thérapeutiques aptes à cibler le système immunitaire. / Since Burnet and Thomas formulated in 1957 the cancer immunosurveillance theory, the scientific world has made tremendous progress to identify the immune cells involved in this process. Natural Killer (NK) cells have emerged as a major component of the innate immunosurveillance of several hematological and solid malignancies. The activity of NK-cells is mainly mediated through their wide variety of receptors with activating and inhibitory functions. Among the versatile receptors present on NK cells, the activating receptor NCR3/NKp30 is a major receptor involved in both direct killing of target cells and mutual NK and dendritic cell activation.Gastrointestinal stromal tumors (GIST) and Neuroblastoma (NB) are known to be tumors sensitive to NK immunosurveillance. In a recent study we showed that alternative splicing of NCR3/NKp30 gene can affect NK cell function and GIST patient’s outcome.In order to better characterize the GIST tumor-infiltrating lymphocytes, we analyzed the CD3+, T regulatory (Treg) and NK lymphocytes infiltration within primary localized GIST tumors and we determined their prognostic value. We described that, before treatment, NK cells are mainly localized in fibrous trabeculae while T lymphocytes are in the tumor nests in HLA-I positive tumor cells contact. Moreover infiltrating NK cells displayed a secreting CD56bright phenotype, and accumulate in tumor nests after Imatinib (IM) treatment. Importantly CD3+ and NK lymphocytes independently predicted progression free survival (PFS). These results highlight the importance of the immune infiltrate in re-define the GIST risk stratification and allow enhancing the immune response in the therapeutic decisions.We next investigated the proportions of NK cells in blood and bone marrow (BM) in a cohort of localized and metastatic NB; a high proportion of CD56bright NK cells was associated with metastatic NB and with poor response to induction treatment within the metastatic NB. Moreover, infiltrated BM presented NKp30 down regulation. The expression of the NKp30 ligand, B7-H6, was found on BM neuroblasts, while the soluble protein, sB7-H6 correlated with resistance to treatment. Furthermore the transcriptional status of NKp30/NCR3 dictated the event-free survival rates of HR-NBs with minimal residual disease post-induction chemotherapy: in particular patients presenting a high proportion of the immunosuppressive isoform (NKp30c) compared to the pro-inflammatory isoform (NKp30b), presented a worse outcome. We further demonstrated the significant role of monocytes to amplify the NKp30 activation response.These researches in GIST and NB, two different but at the meantime NK-sensitive diseases support the effort to define new immunological therapeutic approaches and to determine their optimal use.

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