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Camperdown, Australia

Sunderland N.S.,The Heart Research Institute | Sunderland N.S.,University of Sydney | Thomson S.E.,Royal Prince Alfred Hospital | Heffernan S.J.,Royal Prince Alfred Hospital | And 8 more authors.
Cytokine | Year: 2011

Preeclampsia is a common disease of pregnancy characterised by maternal hypertension and proteinuria. Abnormal placentation in early pregnancy and abnormal cytokine and anti-angiogenic factor expression are thought to contribute to the clinical syndrome of endothelial dysfunction evident in the second half of gestation. The mechanisms underlying both the placental pathology and its translation to the maternal clinical syndrome are not fully understood. A model of preeclampsia manifest by clinically evident endothelial dysfunction (increased blood pressure and proteinuria) was induced by administration of low-dose TNF-α for 2. weeks at mid-gestation in pregnant baboons (Papio hamadryas). Blood pressure was monitored continuously and remotely by intra-arterial radiotelemetry. Following TNF-α infusion, there was an increase in systolic and diastolic blood pressure and development of proteinuria in pregnant treated animals, but not in pregnant saline controls nor in non-pregnant TNF-α treated animals. The treated pregnant animals also developed elevated plasma soluble FMS-like tyrosine kinase-1 (sFLT-1) and increased placental mRNA expression of sFLT-1 and soluble endoglin (sEng). These results clearly demonstrate that the cytokine TNF-α can induce the clinical and biochemical features of human preeclampsia. The results identify a link between cytokines, placental dysfunction and endothelial dysfunction resulting in a loss of maternal blood pressure control. © 2011 Elsevier Ltd.


Faries M.B.,John Wayne Cancer Institute | Thompson J.F.,Sydney Melanoma Unit | Cochran A.,University of California at Los Angeles | Elashoff R.,Veterans Affairs Greater Los Angeles Healthcare System | And 10 more authors.
Annals of Surgical Oncology | Year: 2010

Background: Complete lymph node dissection, the current standard treatment for nodal metastasis in melanoma, carries the risk of significant morbidity. Clinically apparent nodal tumor is likely to impact both preoperative lymphatic function and extent of soft tissue dissection required to clear the basin. We hypothesized that early dissection would be associated with less morbidity than delayed dissection at the time of clinical recurrence. Materials and Methods: The Multicenter Selective Lymphadenectomy Trial I randomized patients to wide excision of a primary melanoma with or without sentinel lymph node biopsy. Immediate completion lymph node dissection (early CLND) was performed when indicated in the SLN arm, while therapeutic dissection (delayed CLND) was performed at the time of clinical recurrence in the wide excision-alone arm. Acute and chronic morbidities were prospectively monitored. Results: Early CLND was performed in 225 patients, and in the wide excision-alone arm 132 have undergone delayed CLND. The 2 groups were similar for primary tumor features, body mass index, basin location, and demographics except age, which were higher for delayed CLND. The number of nodes evaluated and the number of positive nodes was greater for delayed CLND. There was no significant difference in acute morbidity, but lymphedema was significantly higher in the delayed CLND group (20.4% vs. 12.4%, P = .04). Length of inpatient hospitalization was also longer for delayed CLND. Conclusion: Immediate nodal treatment provides critical prognostic information and a likely therapeutic effect for those patients with nodal involvement. These data show that early CLND is also less likely to result in lymphedema. © 2010 Society of Surgical Oncology.


Hoshimoto S.,John Wayne Cancer Institute | Faries M.B.,The Surgical Center | Morton D.L.,The Surgical Center | Shingai T.,John Wayne Cancer Institute | And 8 more authors.
Annals of Surgery | Year: 2012

Objective: To verify circulating tumor cell (CTC) prognostic utility in stage IV resected melanoma patients in a prospective international phase III clinical trial. Background: Our studies of melanoma patients in phase II clinical trials demonstrated prognostic significance for CTCs in patients with AJCC stage IV melanoma. CTCs were assessed to determine prognostic utility in follow-up of disease-free stage IV patients pre-and during treatment. Methods: After complete metastasectomy, patients were prospectively enrolled in a randomized trial of adjuvant therapy with a whole-cell melanoma vaccine, Canvaxin, plus Bacille Calmette-Guerin (BCG) versus placebo plus BCG. Blood specimens obtained pretreatment (n = 244) and during treatment (n = 214) were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction (qPCR) for expression of MART-1, MAGE-A3, and PAX3 mRNA biomarkers. Univariate and multivariate Cox analyses examined CTC biomarker expression with respect to clinicopathological variables. Results: CTC biomarker(s) (1) was detected in 54% of patients pretreatment and in 86% of patients over the first 3 months. With a median follow-up of 21.9 months, 71% of patients recurred and 48% expired. CTC levels were not associated with known prognostic factors or treatment arm. In multivariate analysis, pretreatment CTC (> 0 vs. 0 biomarker) status was significantly associated with disease-free survival (DFS; HR 1.64, P = 0.002) and overall survival (OS; HR 1.53, P = 0.028). Serial CTC (>0 vs. 0 biomarker) status was also significantly associated with DFS (HR 1.91, P = 0.02) and OS (HR 2.57, P = 0.012). Conclusion: CTC assessment can provide prognostic discrimination before and during adjuvant treatment for resected stage IV melanoma patients. Study registration ID# NCT00052156. © 2012 by Lippincott Williams & Wilkins.


Howard J.H.,The Surgical Center | Thompson J.F.,Sydney Melanoma Unit | Mozzillo N.,Istituto Nazionale Dei Tumori de Naples | Nieweg O.E.,Netherlands Cancer Institute | And 14 more authors.
Annals of Surgical Oncology | Year: 2012

Background: For stage IV melanoma, systemic medical therapy (SMT) is used most frequently; surgery is considered an adjunct in selected patients. We retrospectively compared survival after surgery with or without SMT versus SMT alone for melanoma patients developing distant metastases while enrolled in the first Multicenter Selective Lymphadenectomy Trial. Methods: Patients were randomized to wide excision and sentinel node biopsy, or wide excision and nodal observation. We evaluated recurrence site, therapy (selected by treating clinician), and survival after stage IV diagnosis. Results: Of 291 patients with complete data for stage IV recurrence, 161 (55 %) underwent surgery with or without SMT. Median survival was 15.8 versus 6.9 months, and 4-year survival was 20.8 versus 7.0 % for patients receiving surgery with or without SMT versus SMT alone (p < 0.0001; hazard ratio 0.406). Surgery with or without SMT conferred a survival advantage for patients with M1a (median > 60 months vs. 12.4 months; 4-year survival 69.3 % vs. 0; p = 0.0106), M1b (median 17.9 vs. 9.1 months; 4-year survival 24.1 vs. 14.3 %; p = 0.1143), and M1c (median 15.0 vs. 6.3 months; 4-year survival 10.5 vs. 4.6 %; p = 0.0001) disease. Patients with multiple metastases treated surgically had a survival advantage, and number of operations did not reduce survival in the 67 patients (42 %) who had multiple surgeries for distant melanoma. Conclusions: Our findings suggest that over half of stage IV patients are candidates for resection and exhibit improved survival over patients receiving SMT alone, regardless of site and number of metastases. We have begun a multicenter randomized phase III trial comparing surgery versus SMT as initial treatment for resectable distant melanoma. © 2012 Society of Surgical Oncology.


Soong S.-J.,University of Birmingham | Ding S.,University of Birmingham | Coit D.,Sloan Kettering Cancer Center | Balch C.M.,Johns Hopkins Medical Institution | And 3 more authors.
Annals of Surgical Oncology | Year: 2010

Background: We sought to develop a reliable and reproducible statistical model to predict the survival outcome of patients with localized melanoma. Methods: A total of 25,734 patients with localized melanoma from the 2008 American Joint Committee on Cancer (AJCC) Melanoma Database were used for the model development and validation. The predictive model was developed from the model development data set (n = 14,760) contributed by nine major institutions and study groups and was validated on an independent model validation data set (n = 10,974) consisting of patients from a separate melanoma center. Multivariate analyses based on the Cox model were performed for the model development, and the concordance correlation coefficients were calculated to assess the adequacy of the predictive model. Results: Patient characteristics in both data sets were virtually identical, and tumor thickness was the single most important prognostic factor. Other key prognostic factors identified by stratified analyses included ulceration, lesion site, and patient age. Direct comparisons of the predicted 5-and 10-year survival rates calculated from the predictive model and the observed Kaplan-Meier 5-and 10-year survival rates estimated from the validation data set yielded high concordance correlation coefficients of 0.90 and 0.93, respectively. A Web-based electronic prediction tool was also developed (http://www.melanomaprognosis.org/). Conclusions: This is the first predictive model for localized melanoma that was developed based on a very large data set and was successfully validated on an independent data set. The high concordance correlation coefficients demonstrated the accuracy of the predicted model. This predictive model provides a clinically useful tool for making treatment decisions, for assessing patient risk, and for planning and analyzing clinical trials. © Society of Surgical Oncology 2010.

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