Recurrent epithelial ovarian cancer: validation and improvement of an established prognostic index

OBJECTIVES: To validate and improve an established prognostic index in patients with recurrent ovarian cancer. METHODS: A Canadian three-covariate prognostic index (tumour grade at diagnosis, initial performance status, and time to relapse/primary progression (TRP)) was validated in a well-defined cohort of comparable Danish patients. Potential parameters to be included in an improved prognostic index were revealed by univariate and multivariate analyses in the Danish validation group. RESULTS: The Canadian index validated in the Danish patient population (n=189) found a statistical significant difference in survival between the prognostic groups good and intermediate (P<0.0001), whereas there was no significant difference in survival between the prognostic groups intermediate and poor (P=0.51). In order to improve the accuracy of the index, the candidate parameters, treatment free interval (TFI), CA125 level and performance status, at time of relapse/primary progression, were added, whereas the parameters, tumour grade, and initial performance status, from the Canadian index were excluded. As the correlation coefficient between TRP and TFI was very high (r=0.91), TRP was substituted with TFI in the improved prognostic model. The final model was: 0.8 (performance status)+0.33 log (CA125)-1.31 log (TFI). The improved model was a good predictor of one-year survival (AUC 0.85; logistic regression; P<0.0001). The median survival (with 95% CI) of the four prognostic groups (A-D) was 50.6 (34.0-not available), 25.0 (22.1-33.6), 11.3 (8.5-12.9), and 5.2 (3.5-6.3) months, respectively. CONCLUSIONS: A novel prognostic model (the Copenhagen index) for patients with recurrent ovarian cancer is presented.     

An activity-dependent increased role for L-type calcium channels in exocytosis is regulated by adrenergic signaling in chromaffin cells

Chromaffin cells of the adrenal medulla represent a primary output of the sympathetic nervous system. Their electrical stimulation evokes the fusion of large dense core granules with the cell membrane and the exocytic release of multiple transmitter molecules into the circulation. There the transmitters contribute to the regulation of basic metabolism of the organism. Under physiological activity, granule fusion and transmitter release are limited by activity-dependent Ca(2+) influx, entering through multiple isoforms of voltage-gated calcium channels. In this study we utilize perforated-patch voltage-clamp recordings and depolarize mouse chromaffin cells in situ with action potential-like waveforms to mimic physiological firing. We measure calcium influx through specific isoforms and measure cell capacitance as an index of granule fusion. Combining these approaches we calculate specific stimulus-secretion efficiencies for L-type, N-type, P/Q-type and R-type calcium channels under varied physiological activity levels. Current influx through all channel subtypes exhibited an activity-dependent depression. As expected P/Q-type channels, while responsible for modest Ca(2+) influx, are tightly coupled to catecholamine secretion under all conditions. We further find that stimulation designed to match sympathetic input under the acute stress response recruits L-type channels to a state of enhanced stimulus-secretion efficiency. N- and R-type channels do not undergo activity-dependent recruitment and remain loosely coupled to the secretion. Thus, only L-type channels exhibit activity-dependent changes in their stimulus-secretion function under physiological stimulation. Lastly, we show that treatment with the beta-adrenergic agonist, isoproterenol, specifically blocks the increase in the stimulus-secretion function of L-type channels. Thus, increased cell firing specifically enhances stimulus-secretion coupling of L-type Ca(2+) channels in chromaffin cells in situ. This mechanism is regulated by an adrenergic signaling pathway.     

Mesenchymal stem cells overexpressing interleukin-10 attenuate collagen-induced arthritis in mice

Mesenchymal stem cells (MSCs) have the inherent ability to migrate to multiple organs and to exert immunosuppressive activity. The aim of this study was to investigate the anti-arthritogenic effects of interleukin (IL)-10-transduced MSCs (IL-10-MSC) on the development of inflammatory arthritis. DBA/1 mice were immunized with type II collagen (CII) to induce inflammatory arthritis and then injected weekly three times with IL-10-MSCs 21 days after primary immunization. Control mice received vehicle or MSCs alone. Serum anti-CII antibody and T cell response to CII were determined. The results showed that cultured IL-10-MSCs were able to secrete high amounts of IL-10 in vitro. Injection of IL-10-MSCs decreased the severity of arthritis significantly. However, there was no difference in arthritis severity between mice treated with MSC and vehicle alone. Anti-CII antibody titres in the sera and T cell proliferative response to CII in lymph node cells were decreased significantly in mice treated with IL-10-MSCs compared with vehicle-treated mice. Serum IL-6 level was also decreased by the administration of IL-10-MSCs. In contrast, spleen cells of IL-10-MSC-treated mice produced higher amounts of IL-4 than those of control mice. Interestingly, although not as potent as IL-10-MSCs, injection of naive MSCs alone decreased serum levels of IL-6 and anti-CII antibody, while increasing IL-4 production from cultured splenic cells. Taken together, systemic administration of genetically modified MSCs overexpressing IL-10 inhibits experimental arthritis not only by suppressing autoimmune response to CII but also by regulating cytokine production, and thus would be a new strategy for treating rheumatoid arthritis.     

Results of reinduction therapy with paclitaxel and carboplatin in recurrent epithelial ovarian cancer

OBJECTIVE: The purpose of the study was to evaluate the treatment results and toxicity of a retreatment regimen of paclitaxel and carboplatin in patients with ovarian cancer relapse. METHODS: A retrospective analysis of 241 consecutive patients with primary epithelial ovarian cancer receiving paclitaxel and a platinum analogue as first-line treatment was performed. Relapse treatment of platinum-sensitive patients consisted of paclitaxel (175 mg/m(2)) over 3 h followed by carboplatin at an area under the concentration-time curve of 5, repeated every 3 weeks. RESULTS: Forty-three patients with relapse were treated with paclitaxel and carboplatin after a median progression-free interval from the end of first-line chemotherapy of 15.8 months (range 6.0-41.7 months). In patients with evaluable disease the overall response rate was 84% (95% CI: 68.0-93.8%). The progression-free survival and overall survival from start of relapse treatment were a median of 9.7 months (range 1.4-26.9 months) and 13.1 months (range 4.5-35.5 months), respectively. In a multivariate Cox analysis independent prognostic factors for progression-free survival after first relapse were response to relapse treatment (P = 0.002, hazard ratio = 13.9) and time to first recurrence (P = 0.016, hazard ratio = 0.167). The planned treatment was accomplished by 67% of patients. Grade 4 neutrocytopenia over 1 week was observed in 9.3% of patients. Grade 1-2 peripheral neuropathy was reported in 30% of patients. Only 1 patient had her paclitaxel dose attenuated because of grade 4 neuropathy. CONCLUSION: Retreatment with paclitaxel and carboplatin in patients with platinum-sensitive epithelial ovarian cancer relapse yielded a high response rate and encouraging progression-free survival and overall survival. Paclitaxel-carboplatin reinduction therapy is generally well tolerated and the toxicity is manageable.     

A phase II study of ifosfamide, carboplatin and cisplatin in advanced and recurrent squamous cell carcinoma of the uterine cervix

BACKGROUND:: Discouraging response durations and long-time survivals haveso far been the result of cisplatin-containing combination chemotherapyagainst advanced or recurrent squamous cell carcinoma of theuterine cervix. In order to increase the platinum-based effectupon this tumor without an increase in the specific toxicityof cisplatin, we combined it with carboplatin, added ifosfamide,which has been shown to possess a comparable degree of single-agentactivity. PATIENTS AND METHODS:: Thirty-six patients with advanced or recurrent squamous cellcarcinoma of the uterine cervix not curable by radiation orsurgery were treated with a combination of ifosfamide 1.5 gr/m²i.v. days 1–3, carboplatin 200 mg/m² i.v. day 1, and cisplatin50 mg/ml² Thirty-one patients were evaluable for response and34 patients for toxicity. RESULTS:: Twenty-three patients responded (64%), 11 (31%) of them completely,and 12 (33%) partially. Median response duration was 23 weeks(range 8–107 weeks), reaching 27 weeks and 21 weeks patientswith and without disease in previously irradiated areas, respectively.Median survival is 40 weeks (range 1–114 weeks). Toxicityconsisted mainly of moderate to severe myelosuppression, resultingin 2 toxic deaths. CONCLUSION:: The response rate, also for earlier irradiated areas, comparesfavorably with other known cisplatin-containing regimens. Thecombination deserves investigation in a randomized setting. Uterine cervical cancer, advanced, recurrent, chemotherapy     

Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer

Background:

Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance.

Methods:

We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab.

Results:

Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting.

Conclusions:

Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.     

FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study

Background:

In preclinical gastric cancer (GC) models, FGFR2 amplification was associated with increased tumour cell proliferation and survival, and drugs targeting this pathway are now in clinical trials.

Methods:

FGFR2 FISH was performed on 961 GCs from the United Kingdom, China and Korea, and the relationship with clinicopathological data and overlap with HER2 amplification were analysed.

Results:

The prevalence of FGFR2 amplification was similar between the three cohorts (UK 7.4%, China 4.6% and Korea 4.2%), and intratumoral heterogeneity was observed in 24% of FGFR2 amplified cases. FGFR2 amplification was associated with lymph node metastases (P<0.0001). FGFR2 amplification and polysomy were associated with poor overall survival (OS) in the Korean (OS: 1.83 vs 6.17 years, P=0.0073) and UK (OS: 0.45 vs 1.9 years, P<0.0001) cohorts, and FGFR2 amplification was an independent marker of poor survival in the UK cohort (P=0.0002). Co-amplification of FGFR2 and HER2 was rare, and when high-level amplifications did co-occur these were detected in distinct areas of the tumour.

Conclusion:

A similar incidence of FGFR2 amplification was found in Asian and UK GCs and was associated with lymphatic invasion and poor prognosis. This study also shows that HER2 and FGFR2 amplifications are mostly exclusive.     

Urokinase receptor-associated protein (uPARAP) is expressed in connection with malignant as well as benign lesions of the human breast and occurs in specific populations of stromal cells

The urokinase-type plasminogen activator (uPA) and the uPA receptor (uPAR) are key components in the plasminogen activation system, serving to promote specific events of extracellular matrix degradation in connection with tissue remodeling and cancer invasion. We recently described a new uPAR-associated protein (uPARAP), an internalization receptor that interacts with the pro-uPA:uPAR complex. In our study, we generated a specific polyclonal peptide antibody against human uPARAP and used it for the localization of uPARAP in different breast lesions. The affinity-purified antibodies specifically recognized uPARAP in Western blotting and gave a strong signal in immunohistochemistry. The immunohistochemic localization pattern was found to be identical to that of uPARAP mRNA as determined in parallel by in situ hybridization. uPARAP expression was then studied in both benign and malignant breast lesions. Whereas the normal breast tissue was uPARAP-negative, all benign lesions and ductal carcinoma in situ lesions showed immunoreactivity in fibroblast-like cells and myoepithelial cells associated with the lesion. In invasive carcinoma, uPARAP immunoreactivity was limited to tumor-associated mesenchymal cells. Double immunofluorescence analysis of invasive ductal carcinoma using antibodies against specific cell markers showed that uPARAP was localized in myofibroblasts and macrophages. No malignant cells, no endothelial cells and no vascular smooth muscle cells showed uPARAP immunoreactivity. We conclude that expression of uPARAP is associated with the abnormal breast and that expression appears in myofibroblasts, macrophages and myoepithelium. We suggest that uPARAP is involved in the clearance of the uPA:uPAR complex as well as other possible ligands during benign and malignant tissue remodeling.