Transforming growth factor-alpha and epidermal growth factor receptor in colonic mucosa in active and inactive inflammatory bowel disease

Transforming growth factor-alpha (TGF-alpha) is overexpressed in colonic carcinomas and promotes mucosal wound healing. It may be implicated in chronic inflammatory bowel disease (IBD). We analyzed the expression of TGF-alpha and its receptor, epidermal growth factor receptor (EGF-r), in the colonic mucosa of patients with Crohn's disease (CD) or ulcerative colitis (UC), in active or inactive stages, as compared with controls. Proteins and mRNA were detected in biopsies from the right and left colon and in surgical colonic specimens. Immunoblot analysis revealed TGF-alpha protein as a 29 kDa band. This band was normally expressed in uninvolved colonic mucosa of patients with CD or UC whether in active or inactive stages, but decreased or absent in involved mucosa of active IBD, even when TGF-alpha mRNA and EGF-r protein were detected. In the unaffected mucosa of CD, the intensity of TGF-alpha immunoreactivity was similar to that of controls in the right colon but stronger (P = 0.05) in the left colon. There was no TGF-alpha overexpression in dysplastic regions. In conclusion, in active IBD disease, the decreased TGF-alpha protein amount seems not only related to epithelial cell loss but reflects a down-regulation at least at the protein level. We speculate that TGF-alpha does not play a role within the active stage but may be implicated later in the repair process.     

Somatostatin receptor scintigraphy in forty-eight patients with the Zollinger-Ellison syndrome

In patients with the Zollinger-Ellison syndrome, which is either sporadic or integrated into multiple endocrine neoplasia type 1, accurate localization of all the tumours is difficult and may have therapeutic implications. In an attempt to improve this localization, somatostatin receptor scintigraphy using [¹¹¹In-DTPA-D-Phe¹]-octreotide was performed prospectively in 48 consecutive patients with the Zollinger-Ellison syndrome. Thirty of them had the sporadic type of this disease. Scintigraphic data were compared with data obtained by conventional imaging methods, and also, in 32 selected patients, with those obtained by endoscopic ultrasonography. Somatostatin receptor scintigraphy showed abnormal tracer uptake in 39 patients (81%), in whom it correctly identified 50 of the 60 tumoral sites (83%) previously localized by the other imaging methods. In 17 patients (35%) somatostatin receptor scintigraphy disclosed abnormal tracer uptake at 18 different tumoral sites: 14 were located in the abdomen, including four in the liver and eight in the duodenopancreatic area, and four outside the abdomen, including two in the mediastinum. Six of the ten tumoral sites which were not correctly identified by somatostatin receptor scintigraphy were located in the duodeno-pancreatic area. However, in the 20 patients for whom conventional techniques failed to visualize any tumour in the duodenopancreatic area, somatostatin receptor scintigraphy was positive in ten (50%) whereas endoscopic ultrasonography was only positive in five (25%). In our patients with the Zollinger-Ellison syndrome, somatostatin receptor scintigraphy appeared to be a useful new addition to the battery of tests used for tumour detection.     

Current approach to the management of gastrinoma and insulinoma in adults with multiple endocrine neoplasia type I

The difficult and controversial diagnostic and therapeutic management of patients having gastrinoma or insulinoma with multiple endocrine neoplasia type I (MEN-I) has been discussed by reference to the literature and a personal series of 45 gastrinoma/MEN-I patients followed consecutively at Bichat Hospital. In both gastrinoma/ and insulinoma/MEN-I patients, anatomic distribution and morphology of tumoral process(es) are usually multiple, diffuse, of small size, and associated with endocrine cell hyperplasia and even nesidioblastosis. These features enhance the difficulty of tumor localization and eradication. Despite the dramatic development of modern medical imagery and surgical experience, the real possibility, on a long-term basis, of curing the patients from their disease remains limited, especially in the gastrinoma/MEN-I patients. In the latter group, according to our experience, persistence or recurrence of the disease after surgery is usual, and metachronous hepatic metastasis development is frequently observed when the follow-up is long enough. Patients with liver metastases, however, seem to undergo a more indolent course than sporadic gastrinoma cases. In insulinoma/MEN-I patients, removal of the functionally dominant islet cell area(s) is essential. Various preoperative and intraoperative localization techniques allow efficacious selective pancreatic surgery in many cases. The latter refinements and the promises of long-acting somatostatin analogs, if confirmed, might restrict to exceptional circumstances the indication of near-total or total pancreatectomy.

---

Resumen El controvertido y difícil manejo diagnóstico y terapeútico de pacientes con gastrinoma o insulinoma y síindrome de neoplasia endocrina múltiple tipo I (NEM I) es discutido con referencia a la literatura y una serie personal de 45 pacientes con gastrinoma MEN I seguidos en forma consecutiva en el Hospital Bichat.Tanto en los pacientes con NEM I y gastrinoma o insulinoma, la distribución anatómica y morfológica de los procesos tumorales es usualmente múltiple, difusa y de tamaño pequeño, y asociada con hiperplasia celular endocrina y aún nesidioblastosis. Tales características incrementan la dificultad en la localización y erradicación del tumor. A pesar del dramático avance en la imagenología médica moderna y de la experiencia quirúrgica, la posibilidad real, a largo plazo, de curar al paciente permanece limitada, especialmente en los pacientes con NEM I. En este grupo, según la experiencia del Hospital Bichat, la persistencia o la recurrencia de la enfermedad luego de la cirugía es común y se desarrollan metástasis hepáticas metácronas cuando el seguimiento es lo suficientemente prolongado. Sin embargo, los pacientes con metástasis hepáticas parecen tener una evolución más indolente que los casos de gastrinoma esporádico.En los pacientes con insulinoma-NEM I es esencial la resección del área celular funcionalmente dominante. Diversas técnicas de localización preoperatoria e intraoperatoria permiten una eficaz cirugía pancreática. Los últimos refinamientos y los promisorios análogos sintéticos de la somatostatina, si se confirma su eficacia, podrian restringir a circunstancias realmente excepcionales la indicación para pancreatectomía casi total o total.

---

Résumé Les méthodes diagnostiques et thérapeutiques propres aux gastrinomes ou aux insulinomes faisant partie du syndrome des néoplasies endocrines de type I (MEN-I), difficiles et controversées, sont discutées en fonction des données de la littérature et ane série personnelle de 45 gastrinomes MEN-I suivis à l'Hôpital Bichat à Paris, France. Chez les patients ayant soit un gastrinome MEN-I, soit un insulinome MEN-I, les tumeurs se caractérisent anatomiquement et morphologiquement comme étant des formations généralement petites, multiples, diffuses, et associées à une hyperplasie cellulaire endocrine et parfois même une nésidoblastose. Ces caractéristiques augmentent les difficultés de la localisation et de l'exérèse. Malgré les progrès extraordinaires dans l'imagerie moderne et l'expérience chirurgicale, les possibilités réelles de cure durable restent maigres, surtout chez les patients ayant un gastrinome MEN-I. Selon notre expérience, la persistence ou la récidive de ces derniers après chirurgie sont la règle et on constate souvent des métastases hépatiques métachrones lorsque le suivi est suffisamment long. Lorsque ces métastases existent, cependant, il semble que l'évolution soit moins douleureuse qu'en cas de gastrinome sporadique. Chez le patient ayant un insulinome MEN-I, l'exérèse de la tumeur fonctionnelle est essentielle. Des techniques de localisation pré- et per-opératoires diverses permettent généralement une technique chirurgicale adaptée. L'espoir de disposer d'analogues de la somatostatine agissant à long terme pourrait restreindre à l'avenir les indications de la pancréatectomie totale ou presque totale.