EpCAM expression varies significantly and is differentially associated with prognosis in the luminal B HER2(+), basal-like, and HER2 intrinsic subtypes of breast cancer.

BACKGROUND: Epithelial cell adhesion molecule (EpCAM) is frequently expressed in breast cancer, and its expression has been associated with poor prognosis. Breast cancer can be subdivided into intrinsic subtypes, differing in prognosis and response to therapy. METHODS: To investigate the association between EpCAM expression and prognosis in the intrinsic subtypes of breast cancer, we performed immunohistochemical studies on a tissue microarray encompassing a total of 1365 breast cancers with detailed clinicopathological annotation and outcomes data. RESULTS: We observed EpCAM expression in 660 out of 1365 (48%) cases. EpCAM expression varied significantly in the different intrinsic subtypes. In univariate analyses of all cases, EpCAM expression was associated with a significantly worse overall survival. In the intrinsic subtypes, EpCAM expression was associated with an unfavourable prognosis in the basal-like and luminal B HER2(+) subtypes but associated with a favourable prognosis in the HER2 subtype. Consistently, specific ablation of EpCAM resulted in increased cell viability in the breast cancer cell line SKBR3 (ER(-), PR(-), and HER2(+)) but decreased viability in the breast cancer cell line MDA-MB-231 (ER(-), PR(-), and HER2(-) ). CONCLUSION: The differential association of EpCAM expression with prognosis in intrinsic subtypes has important implications for the development of EpCAM-targeted therapies in breast cancer.

Feasibility of a multdisciplinary lung cancer videoconference between a peripheral hospital and a comprehensive cancer centre.

OBJECTIVE: Treatment of lung cancer patients is changing rapidly and new treatment options have emerged in recent years. In 2007, to guarantee the best treatment procedure for lung cancer patients being treated in our peripheral hospital, we decided to introduce an interdisciplinary tumour videoconference between the Haemato-Oncological Day Hospital in Merano and the Comprehensive Cancer Centre Innsbruck. This retrospective analysis aims to describe the feasibility of such a conference. PATIENTS AND METHODS: Two hundred and three patients with lung cancer treated at the peripheral hospital of Merano between May 2003 until May 2011 were retrospectively analysed. After introduction of the tumour videoconference in 2007, 54% (n = 110) of the patients in this cohort were discussed in the conference. RESULTS: One hundred and four videoconferences were performed. Videoconference was feasible for 110 patients. Radiotherapeutic treatments were prescribed more frequently in patients from the conference group. Overall, major and minor treatment changes were undertaken in 7% (n = 8) and 18% (n = 20), respectively. CONCLUSION: Interdisciplinary tumour videoconference is feasible between a peripheral hospital and a comprehensive cancer centre. Radiotherapeutic treatment was prescribed more frequently, suggesting that such a conference facilitates the access to cancer-centre-specific treatment modalities. Accordingly, tumour videoconference between a peripheral hospital and a cancer centre is to be recommend.

Preoperative chemotherapy with cisplatin and docetaxel followed by surgery and clip-oriented postoperative chemoradiation in patients with localized gastric or gastroesophageal junction adenocarcinoma: results from a phase II feasibility study.

BACKGROUND: We conducted a phase II feasibility study using preoperative chemotherapy with cisplatin and docetaxel followed by surgical resection and postoperative chemoradiation in patients with gastric or gastroesophageal cancer. METHODS: Preoperative chemotherapy (two or three cycles) consisted of 50 mg/m(2) docetaxel and 50 mg/m(2) cisplatin. Surgical resection was planned 4 weeks after the last chemotherapy cycle. Patients underwent postsurgical chemoradiation, receiving a total dose of 39.6 Gy and 5-fluorouracil (5-FU) continuous infusion (350 mg/m(2)/day). The primary end-points were feasibility, overall response rate and R0 resectability rate after preoperative chemotherapy. The secondary end-points were tolerability, treatment-associated complications, disease-free survival and overall survival. RESULTS: Between 2002 and 2004, 15 patients were enrolled in this study. After neoadjuvant treatment, two patients (13%) experienced progressive disease, four patients (27%) showed partial remission and nine patients (60%) showed stable disease. In 11 patients (73%) R0 resectability could be achieved. Six of these patients (54%) were able to undergo postoperative chemoradiation. Notably, five (83%) of these patients were disease free and alive at median follow-up of 72 months. Chemotherapy-associated neutropaenia and neutropaenic fever, anastomotic dehiscence, pulmonary embolism and acute pancreatitis were observed. CONCLUSIONS: The combination of preoperative chemotherapy and postoperative chemoradiation is feasible in a significant subset of gastric cancer patients.

Overexpression of p150, a part of the large subunit of the eukaryotic translation initiation factor 3, in colon cancer.

BACKGROUND: P150, a 150 kDa protein, was isolated from virally and oncogene-transformed mouse cell lines, partially purified and cloned. P150 is part of the large subunit of the eukaryotic translation initiation factor 3 with sequence homology to centrosomin A. A significant correlation between p150 expression and malignancy in breast, cervical and esophageal cancer have recently been demonstrated. MATERIALS AND METHODS: Here, 110 colorectal carcinomas of different grades and stages, including lymph node and liver metastases were compared to adjacent normal mucosa by immunohistochemistry of P150. Western blot analysis of selected cases confirmed the expression levels determined by immunohistochemistry. Additionally, immuno-electron and laser scanning microscopy (LSM) was performed. RESULTS: All investigated carcinomas revealed high levels of p150 protein compared to normal adjacent mucosa. The staining intensity was slightly heterogeneous, and positivity was correlated to the tumor grade with statistically significant differences of p150 expression between normal and neoplastic mucosa (p<0.0001, Kruskal-Wallis test). Western blots confirmed higher expression levels of p150 in the tumor. Immunogold labelling and LSM investigation showed high expression levels of p150 on the rough endoplasmic reticulum and polyribosomes, indicating that p150 is translationally active in these tumors. CONCLUSION: Thus, we propose that p150 plays an important role in development and growth of colorectal carcinomas. Furthermore, p150 expression might provide us with reliable information on the biological behaviour of tumors and the clinical course of the disease.

Neoclassical transport in the helical reversed-field pinch.

Test particle evaluation of the diffusion coefficient in a fusion plasma in the reversed-field pinch (RFP) configuration shows distinct similarities with stellarators when the plasma spontaneously evolves towards a helical shape. The almost total absence of superbanana particles at the levels of helical deformation seen in experiment (Bh/B=10%) causes transport to be proportional to collision frequency (at low collisions). This fact excludes the possibility that the minimum conceivable transport could be inversely proportional to collision frequency, which is typical of unoptimized stellarators. This result strengthens the perspectives of the helical RFP as a fusion configuration.

TROP2 expression as prognostic marker for gastric carcinoma.

BACKGROUND: In gastric cancer the recurrence rate is unacceptably high, even after R0 resection and (neo)adjuvant chemotherapy. Therefore, there is an urgent need for identification of predictive and/or prognostic biomarkers to select high-risk patients who might benefit from additional therapies. Expression of TROP2 has been shown to be associated with tumour aggressiveness and poor prognosis in patients with various epithelial cancers. AIMS: To investigate TROP2 expression in gastric cancer and its correlation with clinicopathological features and disease outcome. METHODS: Expression of TROP2 was investigated by immunohistochemistry of tumour specimens from 104 patients who underwent resection for gastric cancer. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. RESULTS: TROP2 was found to be overexpressed in 58 (56%) tumour samples. Significantly higher expression of TROP2 could be detected in intestinal-type carcinomas (p = 0.03). In intestinal-type gastric cancer, TROP2 overexpression was significantly correlated with shorter disease-free survival (DFS) (p = 0.03). Among the total group, TROP2 overexpression was predictive for poor disease-free (p<0.01) and overall (p = 0.03) survival in lymph node positive patients. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent prognostic marker for poor DFS in the subgroup of patients with intestinal-type gastric cancer irrespective of lymph node involvement. CONCLUSION: Results show that TROP2 is an independent prognostic marker for disease recurrence in intestinal type gastric cancer. Due to its wide distribution TROP2 may become an attractive therapeutic target in a subgroup of patients with gastric cancer.

High expression of TROP2 correlates with poor prognosis in pancreatic cancer.

Pancreatic cancer is one of the most devastating human malignancies. Despite considerable research efforts, it remains resistant to almost all available treatment regimens. The human trophoblast cell-surface antigen, TROP2, was found to be strongly expressed in a variety of human epithelial cancers, correlating with aggressiveness and poor prognosis. TROP2 antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumour tissue samples from a series (n=197) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated using Kaplan-Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 109 (55%) of 197 pancreatic cancer patients and was significantly associated with decreased overall survival (P<0.01). By univariate analysis, TROP2 overexpression was found to correlate with the presence of lymph node metastasis (P=0.04) and tumour grade (P=0.01). Furthermore, in the subgroup of patients treated surgically with curative intent, TROP2 overexpression significantly correlated with poor progression-free survival (P<0.01). Multivariate analyses revealed TROP2 to be an independent prognosticator. These findings suggest for the first time that TROP2 could be a novel prognostic biomarker for pancreatic cancer. Targeting TROP2 might be a useful treatment approach for patients with pancreatic cancer overexpressing this cell-surface marker.

Fallopian tube cancer associated with paraneoplastic dermatomyositis -- asymptomatic multivisceral exacerbated dermatomyositis mimicking recurrent widespread malignant disease: case report.

OBJECTIVE: To report an uncommon case of a recurrent episode of primarily paraneoplastic dermatomyositis which was completely disconnected from the initially triggering malignancy and manifested as a silent pure multivisceral exacerbation. CASE: A 70-year-old woman presented with a pure multivisceral episode of dermatomyositis without characteristic musculo-cutaneous symptoms one year after successful treatment of fallopian tube carcinoma with complete resolvement of a concomittant paraneoplastic dermatomyositis. The uncommon manifestation of recurrent dermatomyositis involving the lungs, spleen and liver, both adrenal glands and abdominal lymph nodes, mimicked a highly disseminated recurrence of the fallopian tube cancer. Physicians participating in the interdisciplinary tumor board were misled to opt for reinductive chemotherapy. Only histologic diagnosis obtained from multiple biopsies uncovered the inflammatory nature of the disease and spared the patient unneeded chemotherapy. CONCLUSION: Asymptomatic multivisceral dermatomyositis may mimic metastatic spread of the initially underlying malignancy and may misdirect therapeutic strategies towards inadequate antineoplastic treatment.

Ep-CAM expression in pancreatic and ampullary carcinomas: frequency and prognostic relevance.

AIMS: Pancreatic adenocarcinoma is an aggressive gastrointestinal malignancy with only a few long-term survivors even after radical surgery. Patients with ampullary cancer have a better prognosis but adjuvant therapy needs further improvement. Epithelial cell adhesion molecule (Ep-CAM) is strongly expressed in a variety of epithelial cancers and represents a promising target for immunological tumour therapy. Thus, the aim of this study was to investigate Ep-CAM expression and its potential prognostic impact in pancreatic and ampullary carcinomas. METHODS: Ep-CAM expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumour tissue samples from a series of consecutive patients with pancreatic (n = 153) and ampullary cancer (n = 34). RESULTS: Ep-CAM overexpression was observed in 85 of 153 pancreatic cancer specimens (56%) and in 29 of 34 ampullary cancer samples (85%). Overall, Ep-CAM failed to be an independent prognostic marker. However, subgroup analyses showed that Ep-CAM overexpression correlated with shorter overall survival among patients with ampullary cancer and advanced stage pancreatic cancer. In the latter subgroup, survival gradually worsened with increasing Ep-CAM scores. Furthermore, in ampullary cancer, Ep-CAM overexpression was found to correlate with tumour stage. CONCLUSIONS: Ep-CAM overexpression was detectable in the majority of cases with pancreatic and ampullary cancer. Therefore, Ep-CAM represents an attractive target for immune-based therapeutic interventions in these tumour entities. However, the prognostic value of Ep-CAM overexpression remains undetermined.

STAT-1 expression in human glioblastoma and peritumoral tissue.

BACKGROUND: Glioblastoma is a very aggressive brain tumour with poor prognosis despite radical surgery or radiotherapy. Signal transducers and activators of transcription (STAT) proteins are important elements in intracellular signalling and part of the JAK-STAT pathway. They are activated by growth factors and cytokines and translocate into the nucleus upon activation to exert their function as transcription factors. STAT-1 can be induced by interferons and has also been found to be important in sensitizing tumours to chemotherapeutic drugs. MATERIALS AND METHODS: Forty-six glioblastoma samples have been analysed for the expression of STAT-1 by immunohistochemistry. RESULTS: In our study performed by immunohistochemistry, 22 out of 46 glioblastomas (48%) were strongly positive for staining with a STAT-1 antibody, 9 (20%) showed an intermediate reactivity, 8 (17%) low immunoreactivity, and 7 (15%) were completely negative. In the tumour tissue, STAT-1 expression was mostly localized in the cytoplasm. This location of STAT-1 suggests the predominant presence of an inactive form of STAT-1. Tumour giant cells were frequently strongly stained. Part of the peritumoral brain tissue showed strongly positively reactive glial cells. Interestingly, within the infiltration area strong STAT-1 expression was found in reactive astrocytes, glia, and particularly in microglial components. CONCLUSION: The expression of STAT-1 in the majority of glioblastomas, together with its documented role in apoptosis and in the action of chemotherapeutic drugs on tumour cell lines point to a possible function of this protein in the response of glioblastomas to chemotherapy.

Improved particle confinement in transition from multiple-helicity to quasi-single-helicity regimes of a reversed-field pinch.

The quasi-single-helicity (QSH) state of a reversed-field pinch (RFP) plasma is a regime in which the RFP configuration can be sustained by a dynamo produced mainly by a single tearing mode and in which a helical structure with well-defined magnetic flux surfaces arises. In this Letter, we show that spontaneous transitions to the QSH regime enhance the particle confinement. This improvement is originated by the simultaneous and cooperative action of the increase of the magnetic island and the reduction of the magnetic stochasticity.

Active-feedback control of the magnetic boundary for magnetohydrodynamic stabilization of a fusion plasma.

Stable operation with control on magnetohydrodynamic modes has been obtained in the modified reversed field experiment employing a set of 192 feedback controlled saddle coils. Improvements of plasma temperature, confinement (twofold), and pulse length (threefold) and, as a consequence of the magnetic fluctuation reduction, strong mitigation of plasma-wall interaction and mode locking are reported.

Transport barrier inside the reversal surface in the chaotic regime of the reversed-field pinch.

Magnetic field lines and the corresponding particle orbits are computed for a typical chaotic magnetic field provided by a magnetohydrodynamics numerical simulation of the reversed-field pinch. The m = 1 modes are phase locked and produce a toroidally localized bulging of the plasma which increases particle transport. The m = 0 and m = 1 modes produce magnetic chaos implying poor confinement. However, they also allow for the formation of magnetic islands which induce transport barriers inside the reversal surface.

Feedback stabilization of multiple resistive wall modes.

Active feedback stabilization of multiple independent resistive wall modes is experimentally demonstrated in a reversed-field pinch plasma. A reproducible simultaneous suppression of several nonresonant resistive wall modes is achieved. Coupling of different modes due to the limited number of the feedback coils is observed in agreement with theory. The feedback stabilization of nonresonant RWMs also has an effect on tearing modes that are resonant in the central plasma, leading to a significant prolongation of the discharge pulse.

Low-dose thalidomide for multiple myeloma: interim analysis of a compassionate use program.

BACKGROUND: Despite recent advances in systemic and supportive therapies, multiple myeloma remains an incurable plasma cell malignancy. Novel therapeutic approaches are thus needed. Thalidomide has recently been recognized as an effective new agent for previously untreated, refractory or relapsed myeloma. PATIENTS AND METHODS: To evaluate the efficacy and tolerability of thalidomide in myeloma, we performed a retrospective analysis of 21 consecutive patients receiving thalidomide alone or in combination with dexamethasone and/or intermittent cyclophosphamide as first-line, maintenance or salvage therapy within a compassionate use program. RESULTS: Of the 21 patients, 16 (76.2%) had refractory or relapsed disease, including 7 (33.3%) patients relapsing after autologous stem cell transplantation. Three patients received thalidomide as maintenance therapy after having achieved a partial remission following autologous stem cell transplantation or conventional chemotherapy. Two patients were given thalidomide as first-line treatment for indolent disease. During long-term treatment (median 12 months, range 1-27 months), patients tolerated only low doses of thalidomide (50-150 mg/day) due to cumulative neurotoxicity. At a median follow-up of 16 months (range 1.5-28 months), we observed an overall response rate of 61.9% (50% for the subgroup receiving thalidomide alone; 77.8% for combination therapy) consisting of 1 complete response, 2 near-complete responses, 8 partial responses and 2 minor responses. Median progression-free survival was 20 months. CONCLUSIONS: We conclude that low-dose thalidomide (50-100 mg/day) alone or in combination is a safe, well-tolerated and effective form of therapy for patients with myeloma at various stages of disease.

Observations of multiple magnetic islands in the core of a reversed field pinch.

We describe in this Letter the first measurement of multiple islands in the core of a reversed field pinch (RFP). These islands appear with current profile modification leading to magnetic fluctuation reduction in the Madison symmetric torus RFP. Magnetic island widths decrease to an unprecedented level, reducing the overlap of adjacent islands and allowing distinct islands to appear. The structures are observed in multichord measurements of soft-x-ray emissivity. The soft-x-ray data is validated with Poincaré reconstructions of the magnetic field structure in the core.

Aberrant tetranectin expression in human breast carcinomas as a predictor of survival.

AIMS: Tetranectin (TN), a plasminogen kringle 4 binding protein, is thought to play a prominent role in the regulation of proteolytic processes via binding to plasminogen. The aim of this study was to evaluate the expression of TN in human breast cancer and adjacent normal breast tissue and to determine the impact of this expression on survival. METHODS: A retrospective analysis was performed on 189 patients with breast cancer, with a median follow up time of 10.6 years. The expression of TN was assessed in tumour tissue and adjacent normal breast tissue by immunohistochemistry, and the prognostic relevance of its expression in tumour cells was evaluated. RESULTS: TN was highly expressed in connective tissue fibres surrounding normal breast epithelium, but not in normal epithelial cells. High expression of TN in tumour cells was found in 131 (69%) of the tumour samples. By western blot analysis, no significant difference in the amount and molecular weight of TN was seen between tumour tissue and normal tissue. Strong TN immunoreactivity in tumour tissue was predictive of poor disease free and tumour specific overall survival. By multivariate analysis, high TN expression in cancer cells was an independent prognostic factor for disease free and tumour specific overall survival. CONCLUSIONS: Our results demonstrate differential TN expression in normal and malignant breast tissue and a prognostic impact of TN protein expression in breast carcinoma tissue. These data suggest a possible role of TN in invasiveness and the metastatic spread of human breast cancer.

Epidermal growth factor receptor as a novel therapeutic target in anaplastic thyroid carcinomas.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies, with a median survival of up to 6 months. Such a bad prognosis under the present treatment procedures suggests the need for novel approaches in the management of this disease. Since some epidermal growth factor receptor (EGFR) inhibitors are now in clinical trials and few data are available concerning EGFR expression in anaplastic thyroid carcinomas, we tried to estimate a possible overexpression of this receptor in a larger tumor series. Twenty-five ATCs, including 3 ATCs with poorly differentiated thyroid carcinoma (PDTC) parts, were immunohistochemically investigated with a mouse monoclonal antibody directed against EGFR (EGFR pharmDX kit). The tumors revealed primarily a distinct membranous staining pattern, and in several tumor cells an additional cytoplasmic reactivity could be observed. The anaplastic carcinomas presented with 5 of 25 (20%) without EGFR reaction, 10 of 25 (40%) with reactivity, and 10 of 25 (40%) with overexpression of the receptor. All ATCs with PDTC parts (100%) showed EGFR overexpression. Cytoplasmic reactivity was observed in 56% of all ATCs. A significant correlation was calculated for EGFR overexpression and cytoplasmic staining (P = 0.036). Concerning receptor overexpression, ATCs were significantly different from ATCs with PDTC parts (P = 0.023). For the first time, we present EGFR overexpression in ATC in a larger tumor series, demonstrating that EGFR overexpression is a common finding in ATC. For at least one-third of all anaplastic thyroid carcinomas, EGFR seems to be a promising agent for the targeted molecular therapy of these extraordinarily aggressive tumors.

Her2/neu overexpression in differentiated thyroid carcinomas predicts metastatic disease.

To investigate the prognostic value of Her2/neu expression in differentiated thyroid carcinomas 103 patients were retrospectively investigated. All of them received surgical and an identical follow-up treatment. The patients with papillary and follicular thyroid cancer were further separated into two groups concerning their clinical development, including one group without distant metastasis (follow-up of minimum 8 years). The second group presented with distant metastases as a sign of an aggressive behaviour. Her2/neu was immunohistochemically detected on sections from formalin-fixed, paraffin-embedded tissues using c-erbB-2/Her-2/neu oncoprotein Ab-17 monoclonal antibody (mAb). In statistical analysis using the Mann-Whitney U-test and chi(2) test, Her2/neu protein overexpression was significantly correlated with prognosis. Both tumour entities without distant metastases showed significantly less cytoplasmic immunostaining than patients with development of metastases. Concerning the clinical outcome, Her2/neu overexpression may be regarded as a prognostic factor in differentiated thyroid carcinomas. Moreover, in addition to standard radio-iodine elimination therapy, application of Herceptin could lead to new successful therapeutic concepts for a number of patients with progressive thyroid cancer.