This study shows that high keratin 18 (K18) expression in tumor cells is associated with reduced invasiveness in vitro and lack of tumorigenicity in nude mice. We previously showed that high K18 expression correlated with a good prognosis and that reducing K18 expression increased the aggressiveness of established breast cancer cell lines. To confirm these observations, we transfected the human K18 gene into the human breast cancer cell line MDA-MB-231 and isolated a stable overexpressing clone. The forced K18 expression was associated with a complete loss of the previously strong vimentin expression in the parent cell line, induction of the K18 dimerization partner K8, and up-regulation of adhesion proteins. These changes were accompanied by a dramatic reduction in the aggressiveness of the K18 transfectants in vitro and in vivo. We conclude that forced reexpression of K18 causes at least partial redifferentiation of the tumor cell, followed by a corresponding regression of malignant phenotype. (Mol Cancer Res 2005;3(7):365 -71)

This in vitro study on MCF-7 and ZR-75-1 breast cancer cells showed that the antiproliferative action of glucocorticosteroids (GCS) on breast cancer cells is weakened by a high oxidative activity of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD; EC 1.1.1.146): both endogenic as well as synthetic GCS (dexamethasone, prednisolone) were metabolised to hormonally inactive 11-dehydro metabolites. This enzymatic shield protected the breast cancer cells from the antiproliferative action of GCS. Continuous exposure of breast cancer cells to GCS resulted in enhanced 11 beta-HSD activity. The intracellular GCS concentration was further reduced by this feedback and thus the antiproliferative effect was additionally weakened. These mechanisms of GCS deactivation could be influenced by inhibiting 11 beta-HSD with the liquorice compound glycyrrhetinic acid (GLY). In MCF-7 and ZR-75-1 cultures the antiproliferative effect of GCS was significantly increased by GLY.

Purpose: The aim of this study was to assess the 6-months dysphagia-free survival, improvement in swallowing function, complication rate, and overall survival in patients with incurable esophageal cancer treated with palliative radiotherapy.Methods: We retrospectively reviewed data from 139 patients (median age 72 years) with advanced/recurrent incurable esophageal cancer, who were referred to 3 German radiation oncology centers for palliative radiotherapy between 1994 and 2014. Radiotherapy consisted of external beam radiotherapy (EBRT) with 30 - 40.5 Gy/2.5 - 3 Gy per fraction, brachytherapy alone (BT) with 15 - 25 Gy/5 - 7Gy per fraction/weekly and EBRT + BT (30 - 40.5 Gy plus 10 - 14 Gy with BT) in 65, 46, and 28 patients, respectively. Dysphagia-free survival (Dy-PFS) was defined as the time to worsening of dysphagia for at least one point, a new loco-regional failure or death of any cause.Results: Median follow-up time was 6 months (range 1-6 months). Subjective symptom relief was achieved in 72 % of patients with median response duration of 5 months. The 1-year survival rate was 30%. The 6-months Dy-PFS time for the whole group was 73 ± 4%. The 6-months Dy-PFS was 90 ± 4% after EBRT, 92 ± 5% after EBRT + BT and 37 ± 7% after BT, respectively (p<0.001). Five patients lived for more than 2 years, all of them were treated with EBRT ± BT. Ulceration, fistula and stricture developed in 3, 6 and 7 patients, respectively.Conclusions: Radiotherapy leads to symptom improvement in the majority of patients with advanced incurable esophageal cancer. The present results favor EBRT ± BT over BT alone. Due to the retrospective nature of this study, imbalances in baseline characteristics might have contributed to this finding, and further trials appear necessary.

To the Editor: We read with interest the article by Seidman et al 1 describing the risks of adverse cardiac events associated with trastuzumab therapy for metastatic breast cancer, published in the March 1, 2002, issue of the Journal of Clinical Oncology. In that retrospective review of records from 1,219 patients enrolled onto one of seven phase II or III clinical trials, the risk of adverse cardiac events was low (3% to 7%) when trastuzumab was prescribed alone. In contrast, the risk was higher when trastuzumab was combined with paclitaxel (13%) and inordinately high when it was combined with anthracyclines and cyclophosphamide (26%).From pathophysiologic and clinical perspectives, several aspects of this cardiotoxicity remain unclear. 2,3 For instance, data from clinical studies do not clarify whether cardiotoxicity develops early or whether it is related to a cumulative dose of treatment, as has been observed with anthracyclines. Likewise, the clinical course of the cardiomyopathic disorder after discontinuation of treatment has not been described.Since March 2001, we have followed prospectively 28 consecutive patients treated for metastatic breast cancer with trastuzumab, administered in an initial dose of 4 mg/m 2 followed by 2 mg/m 2 weekly, and paclitaxel, in a dose of 80 mg/m 2 , 6 out of 8 weeks. Surveillance of the cardiac status was by way of echocardiography, systematically performed at weekly intervals during the first month and then every 2 months by the same techniques and same operator, to ensure reproducibility of the measurements. The criterion threshold for detection of cardiotoxicity was a more than 10% decrease in left ventricular ejection fraction between two consecutive examinations. The 28 patients (mean age, 54 years; range, 40 to 70 years) had received an anthracycline, including doxorubicin in five patients, epirubicin in 11 patients, or mitoxantrone in 12 patients, as adjunctive therapy before being placed on the trastuzumab-paclitaxel combination. A more than 10% decrease in left ventricular ejection fraction was observed in four patients (14%), similar to the 13% incidence of adverse cardiac effects reported by Seidman et al. 1 In all cases, this decrease in left ventricular function appeared unexpectedly early. It was observed immediately after the first inductive course of therapy in two patients, after 2 weeks of treatment in one patient, and after 4 weeks in one patient. No progression of ventricular dysfunction was observed after withdrawal of therapy. Echocardiographic measurements have remained unchanged in two patients and have normalized within 4 months in the others. During long-term follow-up of the other 24 patients, including a mean number of courses of therapy of 20 (range, 12 to 54 courses), no evidence of cardiotoxicity was observed.This observation of very early, non-dose-dependent cardiotoxicity suggests the development of an acute inflammatory reaction resembling acute myocarditis. Like myocarditis, the disorder may resolve without sequelae, or evolve toward chron...