[Exertional dyspnea, myalgia, petechiae of the lower extremities and pronounced gingivitis in a 64-year-old female patient]. / Belastungsdyspnoe, Myalgien und Petechien der unteren Extremitäten sowie ausgeprägte Gingivitis bei einer 64-jährigen Patientin.

A female patient presented with exertional dyspnea, myalgia, a petechial rash of the lower extremities and pronounced gingivitis. The biochemical test results showed the presence of anemia. The patient had a known eating disorder and on questioning about eating habits admitted that she did not eat any fruit or vegetables. This led to the suspicion of a vitamin C deficiency, which was confirmed by high-pressure liquid chromatography. The patient was subsequently treated with 1000 mg ascorbic acid daily for 1 month whereby the clinical symptoms and anemia improved within a few weeks.

Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205.

BACKGROUND: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. METHODS: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m(-2) twice daily on days 1-14; oxaliplatin 100/130 mg m(-2) on day 1; bevacizumab 7.5 mg kg(-1) on day 1; imatinib 300 mg day(-1) on days 1-21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS). RESULTS: Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities. CONCLUSION: The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.

[A 31-year-old pregnant woman with refractory hypercalcemia]. / 31-jährige Schwangere mit refraktärer Hyperkalzämie.

A 31-year-old pregnant woman presented with refractory severe hypercalcemia due to an advanced neuroendocrine tumor masquerading as hyperemesis gravidarum. Octreotide therapy and extensive tumor debulking surgery resulted in symptom control. After a prolonged stay in the intensive care unit due to parapneumonic acute respiratory distress syndrome, the patient delivered a healthy child. Neuroendocrine tumors are a rare complication of pregnancy and a seldom cause of refractory hypercalcemia.

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation.

Recently, we identified the homeodomain transcription factor CUTL1 as important mediator of cell migration and tumor invasion downstream of transforming growth factor beta (TGFbeta). The molecular mechanisms and effectors mediating the pro-migratory and pro-invasive phenotype induced by CUTL1 have not been elucidated so far. Therefore, the aim of this study was to identify signaling pathways downstream of CUTL1 which are responsible for its effects on tumor cell migration. We found that the reduced motility seen after knock down of CUTL1 by RNA interference is accompanied by a delay in tumor cell spreading. This spreading defect is paralleled by a marked reduction of Src protein levels. We show that CUTL1 leads to Src protein stabilization and activation of Src-regulated downstream signaling molecules such as RhoA, Rac1, Cdc42 and ROCK. In addition, we demonstrate that CUTL1 decreases proteasome-mediated Src protein degradation, possibly via transcriptionally upregulating C-terminal Src kinase (Csk). Based on experiments using Src knockout cells (SYF), we present evidence that Src plays a crucial role in CUTL1-induced tumor cell migration. In conclusion, our findings linking the pro-invasive transcription factor CUTL1 and the Src pathway provide important new insights in the molecular effector pathways mediating CUTL-induced migration and invasion.

Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells.

Carcinoid tumors are predominantly found in the gastrointestinal tract and are characterized by hypersecretion of various substances, including bioamines and neuropeptides, leading to functional tumor disease. Here, we demonstrate that human BON carcinoid tumor cells express functionally active insulin-like growth factor-I (IGF-I) receptors and secrete IGF-I, suggesting an autocrine action of this growth factor. The IGF-I receptor was functionally active. IGF-I stimulated phosphatidylinositol 3-kinase (PI3-kinase), p70 S6 kinase (p70s6k), and extracellular signal-regulated kinase 2 activity in BON cells. Furthermore, immunoneutralization of endogenously released IGF-I markedly reduced the high basal activity of p70s6k and extracellular signal-regulated kinase 2 in serum-starved BON cells. Exogenously added IGF-I induced a marked increase in chromogranin A secretion, a marker protein for neuroendocrine secretion, by a process that was largely dependent on PI3-kinase activity. In addition, immunoneutralization of endogenously released IGF-I markedly reduced basal chromogranin A release by BON cells. Thus, the autocrine IGF-I loop regulates basal neuroendocrine secretion in BON cells. Next, we investigated the role of IGF-I as a growth promoting agent for BON cells. Our data demonstrate that IGF-I stimulates anchorage-dependent and anchorage-independent growth of BON cells by a pathway that involves PI3-kinase, mammalian target of rapamycin/p70s6k, and mitogen-activated protein kinase kinase 1 activity. Interestingly, mitogen-activated protein kinase kinase 1 activity was less important for anchorage-independent growth of BON cells. Endogenously released IGF-I was found to be largely responsible for autonomous growth of BON cells in serum-free medium and for the constitutive expression of cyclin D1 in these cells. In conclusion, IGF-I is a major autocrine regulator of neuroendocrine secretion and growth of human BON neuroendocrine tumor cells. Because our data also demonstrate that a significant proportion of neuroendocrine tumors express the IGF-I receptor and its ligand, interference with this pathway could be useful in the treatment of hypersecretion syndromes and growth of human neuroendocrine tumors.

Nelson's syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene.

Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for Cushing's disease. Extremely high plasma ACTH levels and aggressive neoplastic growth might be explained by the lack of appropriate glucocorticoid negative feedback due to defective glucocorticoid signal transduction. To study the glucocorticoid receptor (GR) gene in Nelson's syndrome, DNA was extracted from pituitary adenomas and leukocytes of four patients with this condition and amplified by PCR for direct sequence analysis. In one of the tumors, a heterozygous mutation, consisting of an insertion of a thymine between complementary DNA nucleotides 1188 and 1189, was found in exon 2. This frame-shift mutation led to premature termination at amino acid residue 366 of the wild-type coding sequence, excluding the expression of a functioning receptor protein from the defective allele. The mutation was not detected in the sequence of the GR gene in the patient's leukocyte DNA, indicating a somatic origin. By lowering the receptor number in tumorous cells, this defect might have caused local resistance to negative glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistance syndrome. P53 protein accumulation, previously reported in 60% of corticotropinomas, could not be detected in any of the four pituitary tumors examined by immunohistochemistry. We suggest that a somatic GR defect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation.

Substrate stiffness and the receptor-type tyrosine-protein phosphatase alpha regulate spreading of colon cancer cells through cytoskeletal contractility.

Microenvironmental clues are critical to cell behavior. One of the key elements of migration is the generation and response to forces. Up to now, there is no definitive concept on how the generation and responses to cellular forces influence cancer-cell behavior. Here, we show that expression of receptor-type tyrosine-protein phosphatase alpha (RPTPalpha) in human SW480 colon cancer cells sets a threshold for the response to matrix forces by changing cellular contractility. This can be explained as an RPTPalpha-mediated increase in contractility with a consecutive increase in number and size of adhesion sites and stress fibers. These effects are mediated through myosin light chain kinase and largely independent of Rho/Rho-kinase (ROCK) signaling. In addition, we report that RPTPalpha influences spreading on low-rigidity surfaces, binding of collagen-coated beads and expression of RPTPalpha is required for invasion into the chorioallantoic membrane. These data suggest that force-responsive proteins such as RPTPalpha can influence cancer-cell behavior and identify potential targets for cancer therapy.

[Adjuvant chemotherapy of solid tumors of the gastrointestinal tract: where is the progress?]. / Adjuvante Chemotherapie bei soliden Tumoren des Gastrointestinaltrakts : Sind Fortschritte zu erkennen?

Surgical therapy of any malignancy always attempts the complete removal of a cancer from the organism. An adjuvant chemotherapy has the goal to remove remaining tumor-cells, to prevent recurrence of the disease and to improve long term survival. Within the last years there has been a substantial improvement in prognosis due to multi-modal therapeutic regimens including combination-chemo-therapy and innovative radiation-protocols. This review aims to present and to critically review current concepts in the treatment of selected tumors of the gastrointestinal tract.

Mechanisms of disease: the biophysical interpretation of the ECM affects physiological and pathophysiological cellular behavior.

Physiological and pathophysiological migration during the development and systemic spread of tumor cells requires a highly regulated interaction with the extracellular matrix. Sensing of the physical properties of the matrix as well as of forces exerted by the cell or acting on a cell is a prerequisite for productive migration. This review focuses on current concepts of the transmission of a physical stimulus into a biochemical signal in non-neuronal cells. Moreover, we summarize the current concepts on the regulation of affinity-modulation and regulation of protein-turnover for the formation and functionality of adhesion sites with special emphasis on the role of oncogenic signal transduction pathways such as Src family kinases and focal adhesion kinase.