Owing to their clinical success, there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia ...(AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform that consists of a universal effector module (EM) and individual target modules (TMs). Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (for example, the extracellular CD137 ligand domain) to the TM, the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector-to-target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.
Phosphorylation of serine, threonine and tyrosine residues by cellular protein kinases plays an important role in the regulation of various cellular processes. The serine/threonine specific casein ...kinase 1 and 2 protein kinase families — (CK1 and CK2) — were among the first protein kinases that had been described. In recent years our knowledge of the regulation and function of mammalian CK1 kinase family members has rapidly increased. Extracellular stimuli, the subcellular localization of CK1 isoforms, their interaction with various cellular structures and proteins, as well as autophosphorylation and proteolytic cleavage of their C-terminal regulatory domains influence CK1 kinase activity. Mammalian CK1 isoforms phosphorylate many different substrates among them key regulatory proteins involved in the control of cell differentiation, proliferation, chromosome segregation and circadian rhythms. Deregulation and/or the incidence of mutations in the coding sequence of CK1 isoforms have been linked to neurodegenerative diseases and cancer. This review will summarize our current knowledge about the function and regulation of mammalian CK1 isoforms.
Heterotopic pancreas is usually a silent gastrointestinal malformation, but it may become clinically evident when complicated by chronic inflammation or by growth.
We report on eleven cases of ...heterotopic pancreatic tissue. The cases were selected from the records of our Surgical Department and Institute of Pathology. The literature about heterotopic pancreas is reviewed.
Nausea and vomiting (27%), epigastric pain (27%), ulceration (27%) and weight loss (18%) were the three most frequent symptoms and signs. The lesions were diagnosed as gastrointestinal tumor or ulcer by gastroduodenoscopy (36%). The other patients were diagnosed during surgery (64%). Definitive diagnosis was only achievable by pathology. Heterotopic pancreas was the reason for surgery in 36% of the cases, in another 45% diagnosis was incidental during surgery and in 18% the diagnosis was established endoscopically and surgery was not necessary.
The diagnosis of heterotopic pancreas is rarely established, most cases remain clinically silent. In symptomatic patients diagnosis should to be secured histologically to exclude malignant disease.
Expression of gangliosides is affected in various ways by malignant cell transformation. In the present study, we investigated the expression of CDw60, a constituent of O-acetylated ...disialogangliosides, in benign and atypical proliferative breast diseases, and preinvasive and invasive carcinomas by immunohistochemistry and thin-layer chromatography (TLC). In normal ducts, antibodies to CDw60 (mAb M-T21) reacted to membranes of the Golgi apparatus in the juxtaluminal cell compartment. A similar polarized distribution of Golgi cisterns in epithelial cells was observed in several benign lesions, i.e., fibroadenomas, intraductal papillomas, and gynecomastia. In contrast, blunt duct adenosis and duct hyperplasia exhibited an abnormal cytosolic and cell surface staining, whereas atypical duct hyperplasia showed randomly dispersed immunoreactive Golgi cisterns, indicating loss of epithelial polarity. In mammary carcinomas and in two breast carcinoma cell lines (MCF-7 and EFM-19) the neoplastic cells contained CDw60-immunolabelled Golgi complexes, which were distributed in a disorderly fashion throughout the cytoplasm, thus reflecting a loss of epithelial polarity. Additionally, only well differentiated ductal carcinomas in situ or invasive ductal carcinomas disclosed a strong cell surface labelling, which was absent in lower differentiated carcinomas of the same types. In all carcinomas, the intensity of CDw60 immunostaining decreased with progressing loss of differentiation (grade of dedifferentiation), as demonstrated by staining intensity in paraffin sections and by evaluation of the relative amounts of extracted 9-O-acetyl GD3 by TLC. Our results indicate that abnormal CDw60 expression is already detectable in benign proliferative breast lesions with different risk rates to develop into malignant lesions. Downregulation of CDw60 expression in poorly differentiated invasive carcinomas may be the consequence of loss of cell functions usually associated with poor prognosis.
This report describes the clinico-pathological features of myofibroblastic tumors of the breast in six patients. Four women and one man presented with a benign myofibroblastoma. The sixth patient was ...a woman with myofibrosarcoma. All myofibroblastomas were composed of a fascicular arrangement of spindle cells embedded in dense bundles of collagen. Tumors differed with respect to their proportion of neoplastic cells and collagenous stroma as well as cellular pleomorphism. Based on this variation, the tumors could be subclassified as classic, collagenized, epithelioid and cellular myofibroblastoma. Immunohistological staining confirmed myofibroblastic differentiation by strong expression of either desmin or smooth muscle actin with coexpression of vimentin. In addition, numerous cells reacted with antibodies to CD68. Proliferative activity was rather low in the myofibroblastoma with an average of 0-2 mitotic figures per 10 HPF. DNA cytometric analysis was performed in two cases and showed diploid stem lines with minor S-phase fractions (1% and 3%). In the myofibrosarcoma, cells contained pleomorphic nuclei with some giant cells and numerous mitotic figures (6-7/10 HPF) and had infiltrating margins that were apparent even grossly. Immunohistochemically, tumor cells strongly expressed vimentin, smooth muscle actin and fibronectin. Ultrastructurally, neoplastic cells met the criteria of myofibroblasts, i.e. contained abundant intermediate filaments and myofilament bundles with focal densities as well as fibronexus junctions. DNA cytometric analysis exhibited again a diploid stemline but marked proliferative activity was present as indicated by an S-phase fraction of 20%. In conclusion, in benign myofibroblastoma there may be some cellular pleomorphism but mitotic activity is always low. The malignant counterpart, myofibrosarcoma, is characterized by marked cellular pleomorphism, infiltrating margins and high mitotic rate.
The more frequent use of endoscopic ultrasonography (EUS) leads to an increased number of diagnosed gastric submucosal tumors (G-SMT). Since until now rather little therapeutical success in respect ...of these tumors has been achieved, we evaluated our concept of watchful waiting and selective treatment of patients with G-SMT in an analysis of prospectively collected data.
Forty-seven consecutive patients with G-SMT treated at our institution between 1994 and 2000, were included. All patients underwent abdominal ultrasound and EUS, and in case of suspicious findings or a tumor size > 2 cm EUS fine needle aspiration (EUS-FNA) was performed. Patients were operated on if a malignant tumor was suspected (tumor size > 2 cm; detection of metastases) or if complications occurred (e.g. bleeding, ulceration).
All 47 patients were included in this study. Typical symptoms were nausea (64%), bleeding (11%) and pain (9%). EUS showed a G-SMT averaging 6.4 (0.8 - 30) cm in size. EUS-FNA was performed in 24 patients revealing PAP III (n = 1), PAP II (n = 21) and PAP I (n = 2) scores. Surgery was performed in 33 patients, revealing gastrointestinal stromal tumors (GISTs) in 18 patients as well as several other malignant and non-malignant lesions. During follow-up (median 37 months), none of the conservatively treated patients (n = 14) developed a malignant tumor.
In one third of our patients surgery could be avoided with this strategy. No delayed diagnosis of a malignant tumor during follow-up was established. Small G-GMT's should be monitored conservatively if diagnostic procedures and follow-up was performed by EUS and eventually EUS-FNA.
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