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Joanna Nicholls

Publications and source records attributed to Joanna Nicholls.

6 recordsLinked to original sources
PubMed2004

A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene.

PURPOSE: HER-2/neu oncogene is overexpressed in 10-30% of epithelial ovarian cancers and is associated with a poor prognosis. The E1A gene product of adenovirus type 5 down-regulates HER-2/neu and causes tumor regression in animal models. In the current study, we sought to determine the toxicity and biological activity of E1A-lipid complex in ovarian cancer patients. EXPERIMENTAL DESIGN: A Phase I trial involving intraperitoneal (i.p.) administration of E1A-lipid complex was initiated in ovarian cancer patients to assess biological activity (E1A gene transfer/transcription/translation and HER-2/neu expression) and to determine the maximum tolerated dose. Successive cohorts received E1A-lipid complex at doses of 1.8, 3.6, and 7.2 mg DNA/m(2), given as weekly i.p. infusions for 3 of 4 weeks (each cycle) up to a maximum of six cycles. Peritoneal fluid was sampled at baseline and twice monthly for cellularity, cytology, CA-125, and biological activity RESULTS: Fifteen patients, with a median age of 57 years (range, 43-81) were recruited. Three (1.8 mg DNA/m(2)), 4 (3.6 mg DNA/m(2)), and 8 patients (7.2 mg DNA/m(2)) received i.p. E1A. A total of 91 infusions (range, 1-18) was administered. Abdominal pain was the dose-limiting toxicity, and the maximum-tolerated dose was 3.6 mg DNA/m(2). E1A gene transfer and expression was observed in all of the patients and at all of the dose levels. HER-2/neu down-regulation could be demonstrated in the tumor cells of 2 patients (18%). There was no correlation between dose and biological activity. CONCLUSIONS: I.P. EIA-lipid complex gene therapy is feasible and safe. Future studies, either alone or in combination with chemotherapy, particularly in patients with minimal residual disease, should be evaluated.

Abdominal Pain↗
PubMed2003

How we do a bloodless partial splenectomy.

Partial splenectomy and Tru-cut biopsy are not routinely practiced because of the lack of vascular control to arrest bleeding. Using radiofrequency energy to coagulate the resection margin and biopsy tract, a 74-year-old woman with a tumor in the lower pole of the spleen underwent partial splenectomy and Tru-Cut biopsy of the spleen. Hemostasis was excellent. Blood loss was minimal and the patient was discharged with a functioning spleen. This new technique may allow safe and bloodless partial splenic resection and Tru-cut biopsy of the spleen, which might reduce the number of splenectomies performed and the consequent difficulties for the patient that can arise.

Aged↗
PubMed2002

Clinical trial of E1B-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The prognosis of HCC is poor and current therapies are largely ineffective. Genetic abnormalities are commonly seen in HCC tumors particularly with inactivation of the p53 tumor suppressor. Gene therapy with E1B-deleted (dl1520) adenovirus could be of therapeutic value as it offers the potential of tumor growth control in patients with p53 mutation. Ten patients with posthepatitis cirrhosis and histologically proven HCC were enrolled into an open label, randomized prospective study. Randomization was to receive either percutaneous ethanol injection (control group) or dl1520. Toxicity and complications in the ethanol group were pain and fever, whereas in the gene therapy group complications were minimal. Grade I-II toxicity fever, stable performance status, and no significant rise in liver enzymes were observed in patients treated with dl1520. Analysis of patients' response to treatment in the gene therapy group showed one patient with a partial response and four patients with progressive disease. In the ethanol-treated group two patients had stable disease and three patients showed disease progression. In conclusion, this study showed that the adenovirus was well tolerated, but did not seem to offer significant tumor control. Although only a small number of patients were treated here it appears that more effective vectors are needed to achieve a useful clinical impact.

Adenoviridae↗
PubMed2002

Assessment of growth inhibition and morphological changes in in vitro and in vivo hepatocellular carcinoma models post treatment with dl1520 adenovirus.

BACKGROUND AND AIMS: E1B-deleted virus dl1520 (ONYX-015) has been previously used in clinical trials mainly for treatment of head and neck tumors, and has been shown to have beneficial effects independent of p53 status. The main aim of this investigation was to carry out a preclinical study for assessment of the use of dl1520 in in vitro and in vivo hepatocellular carcinoma (HCC) models with various p53 status (deleted, mutant, and wild type), and study the ultrastructural changes in the carcinoma cells during and following treatment with dl1520. METHODS: dl1520 (ONYX-015) virus was used for treatment of three HCC cell lines in culture, then for treatment of developed xenografts in SCID mice. The effects of dl1520 on HCC cell growth and accompanied morphological changes were assessed by various techniques including transmission electron microscopy. dl1520 infection was confirmed using polymerase chain reaction and immunolabeling at transmission electron microscopy level. RESULTS: dl1520 was effective in killing cells and inhibiting HCC cell growth both in vitro and in vivo. The cell killing was at higher levels in cells possessing abnormal p53. Survival rates in SCID mice treated with dl1520 were statistically significantly higher in HCC tumors with deleted and mutant p53, than in tumors with wild-type p53. CONCLUSIONS: The findings in this study suggest that dl1520 could be safely and effectively used for treatment of HCC dependent on the p53 status of the cells in vivo. Characteristic morphological changes that took place in the dl1520-treated HCC cells/tumors were distinct at transmission electron microscopy level and are the first of their kind to be reported.

Adenoviridae↗
PubMed2002

Gene therapy for liver metastases.

Although resection is currently the only curative approach for metastatic liver cancer, only a small number of cases are suitable for this procedure. In the past few years, gene therapy has emerged as an appealing treatment option for liver cancer. Phase I and II clinical trials have been conducted in patients with either primary or secondary liver cancer using a variety of genes including tumor-suppressor gene p53, suicide genes, immune genes, and replication-competent oncolytic adenoviruses. The results have shown that, although gene therapy has been well tolerated and toxicity has been low, the clinical benefit has so far been marginal. Gene therapy as a definitive treatment for liver metastases remains limited, at least for the time being, but it may be useful as an adjuvant treatment in combination with radiotherapy, chemotherapy, and/or surgery to achieve disease-free survival.

Apoptosis↗