Three-dimensional power Doppler ultrasound in cervical carcinoma: monitoring treatment response to radiotherapy.

OBJECTIVES: To investigate, using three-dimensional power Doppler ultrasound (3D-PDU), alterations in cervical intratumoral vascularization during and after radiotherapy. METHODS: Between 2004 and 2009 we enrolled into the study 37 patients with FIGO Stages IB1-IIB cervical carcinoma who were undergoing radiotherapy. Serial 3D-PDU scans were performed during treatment, providing ultrasonographic measurement of tumor size, vascularization index, flow index and vascularization flow index, as well as monthly for 3 months post-treatment and tri-monthly thereafter, until vascularity was undetectable on two consecutive occasions. Physical examination, cervical cytology and serum marker evaluation were performed every 3-6 months for the first 5 years following treatment. Patients evaluated after a 2-year tumor-free interval and those with clinically assessed positive findings at follow-up underwent 3D-PDU to detect possible local disease. RESULTS: A total of 329 3D-PDU scans were performed in the 37 women. Cervical tumors and intratumoral vascularization disappeared within 3 months following radiotherapy, except in one patient with persistent disease. Nine patients had disease relapse, in four of whom the recurrence was local. In three of these four, there was recurrence of tumor and vascularization after a complete response. At follow-up, 3D-PDU detected local disease with 75.0% sensitivity and 98.5% specificity, while serum markers detected local disease among 34 patients with squamous cell carcinoma with 20.0% sensitivity and 77.3% specificity. CONCLUSIONS: Compared with serum markers in cervical squamous cell carcinoma, 3D-PDU has higher sensitivity and specificity for detecting local recurrence or persistence in cervical carcinoma. Thus, 3D-PDU combined with clinical assessment may be a new and safe method for monitoring radiotherapy treatment response and detecting local recurrence.

Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion.

Malignant pleural effusion (MPE) is a poor prognostic sign for patients with non-small-cell lung cancer (NSCLC). The generation of MPE is largely regulated by vascular endothelial growth factor (VEGF), and upregulation of VEGF by Stat3 has been observed in several types of tumor cells. In this study, we demonstrate constitutively activated Stat3 in several human lung cancer cell lines and in tumor cells infiltrated in the pleurae of patients with adenocarcinoma cell lung cancer (ADCLC) and MPE. The observations suggest that activated Stat3 plays a role in the pathogenesis of ADCLC. In PC14PE6/AS2 cells, a Stat3-positive human ADCLC cell line, autocrine IL-6 activated Stat3 via JAKs, not via Src kinase. PC14PE6/AS2 cells express higher VEGF mRNA and protein than do Stat3-negative PC14PE6/AS2/dnStat3 cells. In an animal model, PC14P6/AS2/dnStat3 cells produced no MPE and less lung metastasis than did PC14P6/AS2 cells. PC14PE6/AS2 cells also expressed higher VEGF protein, microvessel density, and vascular permeability in tumors than did PC14P6/AS2/dnStat3 cells. Therefore, we hypothesize that autocrine IL-6 activation of Stat3 in ADCLC may be involved in the formation of malignant pleural effusion by upregulating VEGF. Higher levels of IL-6 and VEGF were also found in the pleural fluids of patients with ADCLC than in patients with congestive heart failure. The autocrine IL-6/Stat3/VEGF signaling pathway may also be activated in patients with ADCLC and MPE. These findings provide novel targets for the management of MPE.

Clinical significance and outcome of one or two rib lesions on bone scans in breast cancer patients without known metastases.

The presence of one or two rib lesions on bone scans of post-treatment breast cancer patients without known metastases often makes clinical decision making problematic. The aim of this study was to identify skeletal metastasis predictors that might help the management of these patients. We recruited post-treatment breast cancer patients without overt metastases whose bone scans showed (1) one or two rib hot spots, or (2) one rib lesion and a concurrent bone abnormality. Their clinical and serial scintigraphic data were collected, reviewed and evaluated for correlations. After their first abnormal bone scans, 23 patients (11 of the 77 patients initially with one rib lesion (incidence, 14.3%), three of the 27 patients with two rib lesions (incidence, 11.1%), and nine of the 11 patients with one rib lesion plus a concurrent bone abnormality (incidence, 81.8%)) developed multiple bone metastases within 2 years of the initial rib lesions in all but one case. Univariate analyses revealed that a concurrent bone lesion other than the rib, direct tumour invasion to the chest wall or skin, and 10 or more lymph nodes involved were associated with increased risks of bone metastases whereas longer persistence of the rib lesions was associated with a lower risk. Multivariate proportional hazard analyses indicated that patients with a concurrent bone lesion other than the rib (relative risk (RR)=39.65; 95% confidence interval (CI)=8.13-193.28), 10 or more lymph nodes involved (RR=13.49; 95% CI=2.09-86.91), and no radiotherapy (RR=7.59; 95% CI=2.11-27.39) were more likely to have bone metastases, while those with longer persistence of the rib lesions (RR=0.92; 95% CI=0.84-0.98) and longer time interval between surgery and the rib lesion detection (RR=0.96; 95% CI=0.94-0.99) were less likely. We have identified clinical features applicable to risk stratification. High incidence of bone metastases was noted in patients with one rib lesion and a concurrent bone abnormality. Regular follow-up for 2 years after detection of rib lesions is recommended, especially for those with risk factors.

Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder.

Recepteur d'Origine Nantais (RON) is a distinct receptor tyrosine kinase in the c-met proto-oncogene family. We examined the mutational and expression patterns of RON in eight human uroepithelial cell lines. Biological effects of RON overexpression on cancer cells were investigated in vitro, and the prognostic significance of RON and/or c-met protein (MET) expression was analysed in a bladder cancer cohort (n=183). There was no evidence of mutation in the kinase domain of RON. Overexpression of RON using an inducible Tet-off system induced increased cell proliferation, motility, and antiapoptosis. Immunohistochemical analysis showed that RON was overexpressed in 60 cases (32.8%) of primary tumours, with 14 (23.3%) showing a high level of expression. Recepteur d'Origine Nantais expression was positively associated with histological grading, larger size, nonpapillary contour, and tumour stage (all P<0.01). In addition, MET was overexpressed in 82 cases (44.8%). Co-expressed RON and MET was significantly associated with decreased overall survival (P=0.005) or metastasis-free survival (P=0.01) in 35 cases (19.1%). Recepteur d'Origine Nantais-associated signalling may play an important role in the progression of human bladder cancer. Evaluation of RON and MET expression status may identify a subset of bladder-cancer patients who require more intensive treatment.