- Cancer > Gynecologic Cancer
- Gynecologic Oncology
Director, Stanford Gynecologic Oncology Fellowship (2016 - Present)
Director, Stanford Clinical Research Group for Gynecologic Cancer Trials (2014 - Present)
Director, Stanford Gynecologic Oncology Clinical Care Program (2013 - Present)
Director, Mary Lake Polan Gynecologic Oncology Research Laboratory (2013 - Present)
Director, Stanford Obstetrics and Gynecology, Division of Gynecologic Oncology (2013 - Present)
Honors & Awards
American Association of Cancer Research Outstanding Poster Award, Toronto, Canada, American Association of Cancer Research, Toronto, Canada (1995)
Outstanding Podium Presentation Award, National Gynecologic Oncology Fellow’s Forum (2004)
Teaching Award, National Council on Resident Education in Obstetrics and Gynecology (2007)
STOP Cancer Career Development Award, STOP Cancer (2008)
OB/GYN Resident Teaching Award, University of California, Los Angeles (2008)
Boards, Advisory Committees, Professional Organizations
Member, Society of Pelvic Surgeons (2016 - Present)
Member, American Association of Cancer Research (1996 - Present)
Member, American Gynecological and Obstetrical Society (2016 - Present)
Member, Society of Gynecologic Investigations (2000 - Present)
Member, American Society of Gene Therapy (2000 - Present)
Member, Society of Gynecologic Oncology (2005 - Present)
Member, Gynecologic Oncology Group (2005 - Present)
Board Certification: Gynecologic Oncology, American Board of Obstetrics and Gynecology (2008)
Board Certification: Obstetrics and Gynecology, American Board of Obstetrics and Gynecology (2006)
Fellowship:UCLA School of Medicine (2005) CA
PhD, University of California, Los Angeles, Molecular Biology (2003)
Residency:UCLA School of Medicine (1999) CA
Residency:Ludwig Maximillians University (1992) Germany
Medical Education:University Heidelberg (1989) Germany
Cvac as Maintenance Treatment in Patients With Epithelial Ovarian Cancer in Complete Remission Following First-line Chemotherapy or Second-line Treatment
As < 10% of the necessary patients required by the protocol were recruited and the data were not intended to support a labeling claim, it was determined that the abbreviated clinical study report (CSR) was the appropriate reporting format. No efficacy analyses were performed as the trial was terminated early with incomplete enrollment of < 10%. The purpose of this study is to determine if an investigational cell therapy called Cvac can help epithelial ovarian cancer (EOC) from returning when administered to patients who are in complete remission after surgical removal of their tumor followed by standard first-line (Part A) or second-line (Part B) chemotherapy. Following remission, patients will undergo leukapheresis for the manufacture of the study agent. After completion of chemotherapy and confirmation of remission, patients will enter the treatment phase of the study.
Stanford is currently not accepting patients for this trial. For more information, please contact Kashif Naseem, 650-724-3155.
A Maintenance Study With Niraparib Versus Placebo in Patients With Platinum Sensitive Ovarian Cancer
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of niraparib as maintenance in platinum sensitive ovarian cancer patients who have either gBRCAmut or a tumor with high-grade serous histology and who have responded to their most recent chemotherapy containing a platinum agent. Niraparib is an orally active PARP inhibitor. Niraparib or placebo (in a 2:1 ratio) will be administered once daily continuously during a 28-day cycle. Health-related quality of life will be measured by the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI), European Quality of Life scale, 5-Dimensions (EQ-5D), and a neuropathy questionnaire. Safety and tolerability will be assessed by clinical review of adverse events (AEs), physical examinations, electrocardiograms (ECGs), and safety laboratory values. The primary objective of this study is to evaluate efficacy of niraparib as maintenance therapy in patients who have platinum sensitive ovarian cancer as assessed by the prolongation of progression free survival (PFS).
Stanford is currently not accepting patients for this trial. For more information, please contact Ashley Powell, 650-724-3308.
Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy.
Olaparib Monotherapy in Patients with BRCA Mutated Ovarian Cancer following First Line Platinum Based Chemotherapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Suzanne Friedrich, 650-725-0426.
Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer
This randomized phase II/III trial studies how well paclitaxel, carboplatin, and metformin hydrochloride works and compares it to paclitaxel, carboplatin, and placebo in treating patients with endometrial cancer that is stage III, IV, or has come back. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Metformin hydrochloride may help paclitaxel and carboplatin work better by making cancer cells more sensitive to the drugs. It is not yet known whether paclitaxel and carboplatin is more effective with or without metformin hydrochloride in treating endometrial cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Suzanne Friedrich, 650-725-0436.
Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer
This randomized phase II/III trial studies how well trametinib works and compares it to standard treatment with either letrozole, tamoxifen citrate, paclitaxel, pegylated liposomal doxorubicin hydrochloride, or topotecan hydrochloride in treating patients with low-grade ovarian cancer or peritoneal cavity cancer that has come back, become worse, or spread to other parts of the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective than standard therapy in treating patients with ovarian or peritoneal cavity cancer.
Clinical Trial of Lurbinectedin (PM01183) in Platinum Resistant Ovarian Cancer Patients
Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate the activity and safety of PM01183 versus PLD or topotecan as control arm in patients with platinum-resistant ovarian cancer. PM01183 will be explored as single agent in the experimental arm (Arm A) versus PLD or topotecan in the control arm (Arm B).
Stanford is currently not accepting patients for this trial. For more information, please contact Aarti Kale, 650-723-0622.
A Study of Niraparib in Patients With Ovarian Cancer Who Have Received Three or Four Previous Chemotherapy Regimens
This is a Phase 2, open-label, single arm study to evaluate the safety and efficacy of niraparib in ovarian cancer patients who have received three or four previous chemotherapy regimens. Niraparib is an orally active PARP inhibitor. Niraparib will be administered once daily continuously during a 28-day cycle. Health-related quality of life will be measured by Eastern Cooperative Oncology Group performance status (ECOG). Safety and tolerability will be assessed by clinical review of adverse events (AEs), physical examinations, electrocardiograms (ECGs), RECIST tumor assessments and safety laboratory values.
Safety, Tolerability & Potential Anti-cancer Activity of Increasing Doses of AZD5363 in Different Treatment Schedules
This study is designed to investigate the safety and tolerability of a new drug, AZD5363, in patients with advanced cancer - and to identify a dose and schedule that can be used in the future. This study will also investigate how the body handles AZD5363 (ie, how quickly the body absorbs and removes the drug). This study will also investigate anti-tumour activity of AZD5363 in patients with advanced / metastatic breast, gynaecological cancers or other solid cancers bearing either AKT1 / PIK3CA or PTEN mutation.
Stanford is currently not accepting patients for this trial. For more information, please contact Alma Gonzalez, 650-498-0624.
Acalabrutinib (ACP-196) Alone and in Combination With Pembrolizumab in Ovarian Cancer (KEYNOTE191)
To characterize the safety and efficacy of acalabrutinib (ACP-196) monotherapy and acalabrutinib plus pembrolizumab combination therapy in subjects with recurrent ovarian cancer
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
CT Antigen TCR-redirected T Cells for Ovarian Cancer.
This study, will take a subject's "T cells" and "teach" them to be able to recognize and attack the ovarian cancer cells. This is done by putting in a gene or genetic material that will change how a subject's T cells work and hopefully get them to attack and kill ovarian cancer cells. These new T cells are called "engineered T cells" because the new gene is causing them to become directed toward the ovarian cancer cells rather than their usual targets. These are also called "gene-modified T cells". For subjects who have the HLA A2 tissue-type marker, the T cells would be engineered to recognize a substance called "NY-ESO-1". After putting this new gene in T cells (a procedure called "gene therapy") the investigators will grow the cells in the laboratory and give these cells back to subjects.
Independent Studies (5)
- Directed Reading in Obstetrics and Gynecology
OBGYN 299 (Win, Spr)
- Early Clinical Experience in Obstetrics and Gynecology
OBGYN 280 (Win, Spr)
- Graduate Research in Reproductive Biology
OBGYN 399 (Win, Spr)
- Medical Scholars Research
OBGYN 370 (Aut, Win, Spr, Sum)
- Undergraduate Research in Reproductive Biology
OBGYN 199 (Win, Spr)
- Directed Reading in Obstetrics and Gynecology
Ovarian Cancer, Version 1.2016
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK
2016; 14 (9): 1134-1163
View details for Web of Science ID 000382903900009
Hemophagocytic lymphohistiocytosis as a paraneoplastic syndrome associated with ovarian dysgerminoma.
Gynecologic oncology reports
2016; 17: 38-41
•Ovarian dysgerminoma associated with paraneoplastic fever, cytopenia and splenomegaly•Complete symptom resolution resulted from tumor resection and medical management•Non-hematolymphoid neoplasms are part of differential diagnosis in secondary HLH.
View details for DOI 10.1016/j.gore.2016.05.013
View details for PubMedID 27354999
Pilot prospective evaluation of F-18-FPPRGD(2) PET/CT in patients with cervical and ovarian cancer
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
2016; 43 (6): 1047-1055
We report the effect of antiangiogenic therapy on the biodistribution of (18)F-FPPRGD2 (a surrogate biomarker of integrin αvβ3 expression), and the potential of (18)F-FPPRGD2 to predict the prognosis in patients with cervical cancer and ovarian cancer in this clinical scenario.Data from six women, age range 30 - 59 years (mean ± SD 44.0 ± 12.5 years), who had undergone a (18)F-FPPRGD2 PET/CT scan and bevacizumab-containing therapy were prospectively collected and analyzed. We compared baseline (18)F-FPPRGD2 and (18)F-FDG uptake in the lesions and tumor-to-background (T/B) ratios. The maximum and mean (18)F-FPPRGD2 standardized uptake values (SUVmax and SUVmean) were recorded for 13 normal organs, as well as in all the identified malignant lesions on the pretreatment scan and the 1-week post-treatment scan. We also measured changes in (18)F-FPPRGD2 uptake from before to 1 week after treatment, and compared them to the changes in (18)F-FDG uptake from before to 6 weeks after treatment. Treatment outcomes were correlated with these changes.The uptake in lesions and T/B ratio of (18)F-FPPRGD2 were lower than those of (18)F-FDG (SUVmax 3.7 ± 1.3 vs. 6.0 ± 1.8, P < 0.001; SUVmean 2.6 ± 0.7 vs. 4.2 ± 1.3, P < 0.001; T/B ratio based on SUVmax 2.4 ± 1.0 vs. 2.6 ± 1.0, P < 0.04; T/B ratio based on SUVmean 1.9 ± 0.6 vs. 2.4 ± 1.0, P < 0.003). One patient did not return for the follow-up scan and in another patient no lesions were identified on the pretreatment scan. (18)F-FPPRGD2 uptake in lesions in the remaining four patients had significantly changed 1 week after treatment (SUVmean 3.3 ± 1.0 vs. 2.7 ± 1.0, P < 0.001), while uptake in all normal tissues analyzed was not affected by treatment. One patient with clinical disease progression had a decrease in lesional (18)F-FPPRGD2 SUVmean of 1.6 % and in (18)F-FDG SUVmean of 9.4 %. Two patients with a clinical complete response to treatment had decreases in lesional (18)F-FPPRGD2 SUVmean of 25.2 % and 25.0 % and in (18)F-FDG SUVmean of 6.1 % and 71.8 %. One patient with a clinical partial response had a decrease in lesional (18)F-FPPRGD2 SUVmean of 7.9 % and in (18)F-FDG SUVmean of 76.4 %.This pilot study showed that (18)F-FPPRGD2 and (18)F-FDG provide independent information about the biology of ovarian and cervical cancers. Bevacizumab-containing therapy does not affect (18)F-FPPRGD2 uptake in normal organs, but does result in statistically significant changes in lesions. In addition, (18)F-FPPRGD2 may have potential for early prediction of response to such treatments. These preliminary findings have to be confirmed in larger studies.
View details for DOI 10.1007/s00259-015-3263-7
View details for Web of Science ID 000374972900008
View details for PubMedID 26611425
- Screening cell mechanotype by parallel microfiltration SCIENTIFIC REPORTS 2015; 5
Uterine Sarcoma, Version 1.2016 Featured Updates to the NCCN Guidelines
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK
2015; 13 (11): 1321-1331
View details for Web of Science ID 000364277500005
Cervical Cancer, Version 2.2015 Featured Updates to the NCCN Guidelines
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK
2015; 13 (4): 395-404
View details for Web of Science ID 000352962200005
Cervical Cancer, Version 2.2015.
Journal of the National Comprehensive Cancer Network
2015; 13 (4): 395-404
The NCCN Guidelines for Cervical Cancer provide interdisciplinary recommendations for treating cervical cancer. These NCCN Guidelines Insights summarize the NCCN Cervical Cancer Panel's discussion and major guideline updates from 2014 and 2015. The recommended systemic therapy options for recurrent and metastatic cervical cancer were amended upon panel review of new survival data and the FDA's approval of bevacizumab for treating late-stage cervical cancer. This article outlines relevant data and provides insight into panel decisions regarding various combination regimens. Additionally, a new section was added to provide additional guidance on key principles of evaluation and surgical staging in cervical cancer. This article highlights 2 areas of active investigation and debate from this new section: sentinel lymph node mapping and fertility-sparing treatment approaches.
View details for PubMedID 25870376
Immunotherapeutic approaches to ovarian cancer treatment.
Journal for immunotherapy of cancer
2015; 3: 7-?
Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for ovarian cancer patients are inadequate. Immunotherapy offers a novel and promising therapeutic strategy for treating ovarian tumors. Following the demonstration of the immunogenicity of ovarian tumors, multiple immunotherapeutic modalities have been developed. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.
View details for DOI 10.1186/s40425-015-0051-7
View details for PubMedID 25806106
Screening cell mechanotype by parallel microfiltration.
2015; 5: 17595-?
Cell mechanical phenotype or 'mechanotype' is emerging as a valuable label-free biomarker. For example, marked changes in the viscoelastic characteristics of cells occur during malignant transformation and cancer progression. Here we describe a simple and scalable technique to measure cell mechanotype: this parallel microfiltration assay enables multiple samples to be simultaneously measured by driving cell suspensions through porous membranes. To validate the method, we compare the filtration of untransformed and HRas(V12)-transformed murine ovary cells and find significantly increased deformability of the transformed cells. Inducing epithelial-to-mesenchymal transition (EMT) in human ovarian cancer cells by overexpression of key transcription factors (Snail, Slug, Zeb1) or by acquiring drug resistance produces a similar increase in deformability. Mechanistically, we show that EMT-mediated changes in epithelial (loss of E-Cadherin) and mesenchymal markers (vimentin induction) correlate with altered mechanotype. Our results demonstrate a method to screen cell mechanotype that has potential for broader clinical application.
View details for DOI 10.1038/srep17595
View details for PubMedID 26626154
Increased risk and pattern of secondary malignancies in patients with invasive extramammary Paget disease
BRITISH JOURNAL OF DERMATOLOGY
2014; 170 (3): 661-671
Extramammary Paget disease (EMPD) is often associated with underlying or distant synchronous malignancies. The prognosis for affected patients is generally favourable; however, the risk of secondary malignancies is unknown.The goal of the study was to analyse the incidence, prognosis and pattern of secondary malignancies for patients with invasive EMPD using data from the Surveillance, Epidemiology and End Results (SEER) Program.We searched the SEER Program database for patients diagnosed with invasive EMPD between 1973 and 2008. Demographic data, outcome and secondary malignancies more than 1 year after the initial diagnosis of invasive EMPD were included in the analysis. We calculated the standardized incidence ratio (SIR) and estimated the excess absolute risk (EAR) per 10 000 person-years (PY).There were 1439 patients who were diagnosed with invasive EMPD. Most patients (80·4%) had localized disease, while 17·1% had locoregional spread and 2·5% presented with distant disease. The SIR for secondary malignancies in patients with invasive EMPD was significantly elevated with an EAR of 97·4 additional malignancies per 10 000 PY. The excess risk was mostly due to a significantly increased incidence of colorectal and anal malignancies. The initial site of disease predicted the site of the secondary malignancies, with patients with colorectal, anal, vulvar and scrotal disease showing an increased risk of colorectal, anal, vulvar and scrotal malignancies, respectively.Our study identified a long-term increased risk of developing secondary malignancies in patients with invasive EMPD that are mainly related to the site of origin of this disease. Patients with invasive EMPD require prolonged follow-up and screening for these malignancies.
View details for Web of Science ID 000332586100019
View details for PubMedID 24617434
Anti-N-Methyl-Aspartate Receptor Encephalitis in Identical Twin Sisters Role for Oophorectomy
OBSTETRICS AND GYNECOLOGY
2014; 123 (2): 433-435
Anti-N-methyl-aspartate receptor encephalitis is a potentially fatal form of encephalitis and frequently associated with ovarian teratomas. Surgical removal of ovarian teratomas improves clinical outcome, but it is unclear whether bilateral salpingo-oophorectomy for normal-appearing ovaries is of clinical benefit.Our report describes a unique clinical scenario of identical twin sisters with anti-N-methyl-aspartate receptor encephalitis. Neither patient responded to immunosuppressive therapy. Imaging studies showed normal-appearing ovaries. The first twin continued on medical therapy only and died of the disease. The second twin underwent a bilateral salpingo-oophorectomy followed by gradual recovery.Based on our experience in two genetically identical individuals, we suggest considering the removal of normal-appearing ovaries in patients with anti-N-methyl-aspartate receptor encephalitis who fail to respond to medical treatment.
View details for DOI 10.1097/AOG.0000000000000078
View details for Web of Science ID 000339069100007
View details for PubMedID 24413237
- The role of Rho GTPase in cell stiffness and cisplatin resistance in ovarian cancer cells INTEGRATIVE BIOLOGY 2014; 6 (6): 611-617
MMPs in Ovarian Cancer as Therapeutic Targets
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
2012; 12 (7): 764-772
In the United States, about 22,000 women will be diagnosed with ovarian cancer in 2011, and an estimated 14,000 patients will succumb to the disease. Surgery and chemotherapy present the main treatment modalities, but despite the development of novel therapies, the overall 5 years survival for ovarian cancer patients with advanced disease at diagnosis remains at only about 30%. Novel therapeutic strategies are needed to prolong survival and achieve greater cure rates. Matrix metalloproteinases (MMPs) are frequently expressed in ovarian cancer, and play an important role in the metastatic process. MMPs mediate degradation of the basement membrane as a crucial step in epithelial transformation, ovarian tumorigenesis and intraperitoneal metastasis. Various preclinical and clinical studies have demonstrated that MMPs might provide a suitable therapeutic target. This review summarizes important observations regarding the expression of MMPs in ovarian cancer, their biological role, and data from clinical trials targeting MMPs in ovarian cancer patients.
View details for Web of Science ID 000310052900009
View details for PubMedID 22292752
Solid pseudopapillary neoplasm, pancreas type, presenting as a primary ovarian neoplasm
2012; 43 (8): 1339-1343
Solid pseudopapillary neoplasm has historically been associated with the pancreas, categorized as a tumor of low malignancy. Recently, solid pseudopapillary neoplasm was reported to arise as a primary ovarian tumor in 3 women. We report a fourth case identified in a 48 year-old woman with an 8-cm left ovarian mass. A left salpingo-oophorectomy was performed. Microscopic examination demonstrated a predominately cystic neoplasm comprised of solid nests of cells with an epithelioid to plasmacytoid appearance, associated with blood vessels, hemorrhage, and degenerative changes, that is, pseudopapillary structures. The tumor cells stained focally for pancytokeratin, progesterone receptor, and CD57 with diffuse nuclear expression of β-catenin. Ki-67 was 5% to 10%. Synaptophysin, inhibin, and E-cadherin stains were negative. Clinical and radiologic follow-up of our patient demonstrated no pancreatic lesions. This is a rare report of a primary ovarian solid pseudopapillary neoplasm. Prolonged follow-up is needed to determine how this case will fare clinically.
View details for DOI 10.1016/j.humpath.2011.12.018
View details for Web of Science ID 000306979800025
View details for PubMedID 22534259
Expression of thyroid transcription factor-1 in normal endometrium is associated with risk of endometrial cancer development
2012; 25 (8): 1140-1148
Thyroid transcription factor-1 (TTF-1) is a DNA-binding protein that is mainly expressed in thyroid and lung tissue, but has also been found in gynecologic tissue. Recent studies have suggested that TTF-1 has tumor suppressor function in lung adenocarcinoma models. In the current study, we examined whether expression of TTF-1 in benign endometrium and endometrial hyperplasia might impact on the risk of developing endometrial cancer. Formalin-fixed paraffin-embedded endometrial tissues obtained from 535 cases were used to construct an endometrial tissue microarray. One hundred fifty of 207 patients had multiple serial endometrial specimens including 46 patients who progressed to endometrial cancer. The tissue microarray included a range of histopathologies including benign endometrium (n=231), simple hyperplasia (n=105), complex hyperplasia (n=36), simple atypical hyperplasia (n=10), complex atypical hyperplasia (n=44), and endometrial carcinoma (n=109). Expression of TTF-1 by immunohistochemistry in benign endometrium and endometrial hyperplasia was correlated with progression to cancer and clinical features known to be associated with increased risk of developing endometrial cancer. Carcinoma specimens showed a significantly greater expression of TTF-1 compared with benign endometrium and non-atypical hyperplasia (P=0.0007 and P=0.05). Presence of TTF-1 expression in benign endometrium was associated with a significantly decreased risk of cancer development (P=0.003, hazards ratio=0.104, 95% CI: 0.024-0.455). TTF-1 expression in hyperplasia did not significantly correlate with progression to cancer. The data from our study show that TTF-1 expression in normal endometrium is associated with a reduced risk of endometrial cancer development. This observation suggests that TTF-1 might function as a tumor suppressor in endometrial tissue. TTF-1 expression in normal endometrium could potentially provide clinically useful information as a biomarker for the risk of endometrial cancer.
View details for DOI 10.1038/modpathol.2012.64
View details for Web of Science ID 000307222200009
View details for PubMedID 22460811
Correlative nanomechanical profiling with super-resolution F-actin imaging reveals novel insights into mechanisms of cisplatin resistance in ovarian cancer cells
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
2012; 8 (5): 757-766
The exact molecular mechanisms of ovarian cancer platinum resistance are not well understood, and biomarkers to reliably predict ovarian cancer resistance to platinum and other chemotherapeutic agents are lacking. Biomechanics of cisplatin-treated ovarian cancer cells were measured quantitatively at nanoscale level using atomic force microscopy. We demonstrate that cisplatin modulates the cellular nanomechanics of ovarian cancer cells; sensitive cells show dose-dependent increase in cell stiffness, which is effected by disrupting the F-actin polymerization. In contrast, resistant cells show no significant changes in cell stiffness upon cisplatin treatment. Further, stimulated emission depletion, an emerging super-resolution microscopy, shows that at the molecular level, F-actin is indeed remodeled considerably in cisplatin-sensitive and cisplatin-resistant cells. These findings reveal a direct role of the actin remodeling mechanism in cisplatin resistance of ovarian cancer cells, suggesting potential future applications of nanomechanical profiling as a marker for cancer drug sensitivity.In this paper, nanomechanical profiling and an emerging super-resolution microscopy method was utilized to decipher the mechanisms of cisplatin resistance in ovarian cancer cells, paving the way to future studies of this and similar other problems with drug resistance in cancer biology.
View details for DOI 10.1016/j.nano.2011.09.015
View details for Web of Science ID 000305704800024
View details for PubMedID 22024198
Treatment outcomes in a large cohort of patients with invasive Extramammary Paget's disease
2012; 125 (2): 346-351
The outcome of patients with invasive Extramammary Paget's disease (EMPD) is poorly studied. The goal of the current study was to analyze the incidence, treatment approaches and outcome of patients with invasive EMPD.We searched the SEER program database for patients diagnosed with invasive EMPD between 1973 and 2007. Demographic data, outcome and therapeutic modalities were included in the analysis. Disease specific survival (DSS) was calculated from the time of original diagnosis.1439 patients were diagnosed with invasive EMPD. Most patients (80.4%) had localized disease, while 17.1% had locoregional spread, and 2.5% had distant disease. 1230 (86.4%) patients underwent site directed surgery, and 92 (6.4%) patients radiotherapy. 139 (9.7%) patients did not undergo any surgery or radiation therapy. The 5-year DSS was 94.9% for localized disease, 84.9% for regional disease and 52.5% for distant disease. Multivariate analysis showed a significantly shorter DSS associated with older age and advanced stage treatment modality (HR for death 1.07 and 2.5). Site directed surgery was associated with a significantly improved outcome when compared to patients who underwent no intervention (HR 0.44). Patients who received radiation, alone or in combination with site directed surgery, did not fare any better than patients who underwent surgery alone.The DSS of patients with invasive EMPD is generally favorable. A poor outcome was associated with older age, advanced stage and treatment modality. The association between a shortened DSS and the use of radiotherapy, alone or in combination with surgery, is surprising and warrants further investigation.
View details for DOI 10.1016/j.ygyno.2012.01.032
View details for Web of Science ID 000303227500014
View details for PubMedID 22293043
Predictors of resolution of complex atypical hyperplasia or grade 1 endometrial adenocarcinoma in premenopausal women treated with progestin therapy
2012; 124 (3): 542-548
To identify clinical and pathologic predictors of response to progestin treatment in premenopausal women with complex atypical hyperplasia (CAH) and Grade 1 endometrial adenocarcinoma (Grade 1 EA).Forty premenopausal patients with Grade 1 EA or CAH who underwent progestin therapy for a minimum of 8 weeks were retrospectively identified. Patient characteristics and histopathologic features of pretreatment and first follow-up endometrial specimens were evaluated as predictors of resolution, defined as absence of hyperplasia or carcinoma.Kaplan-Meier analysis indicated 63% resolution at 18 months of follow-up. Multivariate classification analysis showed that resolution rates were higher in individuals with a low pre-treatment qualitative abnormal architecture score and a BMI <35 (Standardized Resolution Ratio (SRR)=1.48, p=0.03). The diagnosis of benign endometrium or simple hyperplasia on the first follow-up specimen was highly predictive of resolution (SRR=2.25, p=0.002). Resolution rates were lower among subjects with a high pre-treatment qualitative abnormal architecture score (SRR=0.37, p<0.03) and lowest in subjects whose first follow-up specimen showed persistent complexity, atypia, or carcinoma with adjacent stromal decidualization (SRR=0.24, p=0.002).Clinical and pathologic parameters can predict response to progestin therapy in premenopausal women with CAH and Grade 1 EA. A low likelihood of resolution is predicted by an unfavorable pre-treatment architectural score and lack of pathological response in the first specimen, despite adjacent stromal decidualization.
View details for DOI 10.1016/j.ygyno.2011.11.004
View details for Web of Science ID 000300751900029
View details for PubMedID 22079678
Effect of PI3K/Akt Pathway Inhibition-Mediated G(1) Arrest on Chemosensitization in Ovarian Cancer Cells
2012; 32 (2): 445-452
Pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway prevents G(1) cell cycle progression into S, resulting in G(1) accumulation. The hypothesis that this arrest might negatively impact on chemotherapeutic agents primarily effective in S, G(2) or M-phase was investigated.Inhibition of PI3K/Akt pathway signaling via LY294002 and Akti-1/2 was demonstrated by immunoblotting. Cell cycle progression was determined by flow cytometric analysis. Cell proliferation was assayed using the XTT cell viability assay. The Chou and Talalay median effect principal was used to evaluate drug interaction.In SKOV3 and IGROV1 human ovarian cancer cells, LY294002 and Akti-1/2 increased the percentage of cells in G(1) and reversed the cell cycle effects of cisplatin, paclitaxel, gemcitabine and topotecan. Pathway blockade synergistically enhanced the cytotoxicity of cisplatin and paclitaxel, but antagonized gemcitabine and topotecan effects.Pharmacological PI3K/Akt inhibition antagonizes the efficacy of chemotherapeutic agents primarily effective in the S or G(2)-phase of the cell cycle.
View details for Web of Science ID 000299985800007
View details for PubMedID 22287731
Personalizing CA125 Levels for Ovarian Cancer Screening
CANCER PREVENTION RESEARCH
2011; 4 (9): 1356-1359
Screening trials for the early detection of ovarian cancer in the general population and in patients at a high risk for this disease have so far failed to show a reduction of ovarian cancer-specific mortality. Current screening modalities include pelvic examinations, transvaginal ultrasounds, and cancer antigen 125 (CA125) serum marker levels, which are associated with a high false-positive rate. The last decade has witnessed significant modifications in the interpretation of serum CA125 that extend beyond a static CA125 cutoff point. The Risk of Ovarian Cancer Algorithm (ROCA) incorporates changes of CA125 levels over time and an individual's age-specific risk. Ongoing screening trials have incorporated ROCA, but it is still unclear whether the algorithm will increase the sensitivity and specificity of early ovarian cancer diagnosis. A very recent study analyzed baseline CA125 serum marker levels from high-risk patients included in ovarian cancer screening trials conducted by the Cancer Genetics Network and the Gynecologic Oncology Group. The findings show that the distribution of CA125 serum marker levels in this population is significantly affected by various demographic and clinical factors, in particular menopausal status and oral contraceptive use in premenopausal patients. The data suggest that CA125 cutoff points might have to be stratified for subgroups of patients to reduce false-positive results. These intriguing observations will need to be validated in future screening trials for ovarian cancer.
View details for DOI 10.1158/1940-6207.CAPR-11-0378
View details for Web of Science ID 000294490100005
View details for PubMedID 21893498
Cisplatin and PI3kinase Inhibition Decrease Invasion and Migration of Human Ovarian Carcinoma Cells and Regulate Matrix-Metalloproteinase Expression
2010; 67 (8): 535-544
Targeting of the PI3K (phosphoinositide3-kinase)/Akt/mTOR pathway in human ovarian cancer cells is a promising novel therapeutic strategy. We investigated the effects of cisplatin and the PI3K inhibitor LY294002 on invasion, migration and the expression of essential matrix metalloproteinases (MMPs) in ovarian cancer cells. SKOV3, OVCAR5 and IGROV1 human ovarian cancer cell lines were treated with cisplatin, LY294002 and a combination of both drugs. Invasion and migration of treated cells was assessed using Matrigel and uncoated PET membrane assays. Expression levels of pro-MMP2, MMP2, TIMP1, TIMP2 and MT1-MMP were determined using Western Blotting. Gel zymography was used to quantitate the functional levels of active MMP2. All three cell lines showed significantly reduced invasion and migration after treatment with cisplatin, LY294002, and the combination of both drugs compared to untreated controls. In SKOV3 cells, cisplatin alone and in combination with LY294002 resulted in a 6.3 and 7.1-fold reduction in the total amount of activated MMP2. TIMP1 expression decreased by 5.0, 6.6 and 28.4-fold with cisplatin, LY294002 and the combination respectively (P < 0.05). In contrast, only cisplatin and the combination of both drugs resulted in a significant, 3.7 and 5.1-fold reduction in the level of TIMP2. Expression levels of MT1-MMP remained unchanged. These observations were corroborated in IGROV1 cell lines that showed similar changes of activated MMP2 and TIMP2 expression, but no significant decrease in TIMP1 levels. Our data suggests that inhibition of ovarian cancer cell motility is mediated via down-regulation of activated MMP2, TIMP1 and TIMP2 expression under these treatment conditions.
View details for DOI 10.1002/cm.20465
View details for Web of Science ID 000280543100006
View details for PubMedID 20607860
Robust In Vivo Transduction of a Genetically Stable Epstein-Barr Virus Episome to Hepatocytes in Mice by a Hybrid Viral Vector
JOURNAL OF VIROLOGY
2009; 83 (7): 3249-3257
To make a safe, long-lasting gene delivery vehicle, we developed a hybrid vector that leverages the relative strengths of adenovirus and Epstein-Barr virus (EBV). A fully gene-deleted helper-dependent adenovirus (HDAd) is used as the delivery vehicle for its scalability and high transduction efficiency. Upon delivery, a portion of the HDAd vector is recombined to form a circular plasmid. This episome includes two elements from EBV: an EBV nuclear antigen 1 (EBNA1) expression cassette and an EBNA1 binding region. Along with a human replication origin, these elements provide considerable genetic stability to the episome in replicating cells while avoiding insertional mutagenesis. Here, we demonstrate that this hybrid approach is highly efficient at delivering EBV episomes to target cells in vivo. We achieved nearly 100% transduction of hepatocytes after a single intravenous injection in mice. This is a substantial improvement over the transduction efficiency of previously available physical and viral methods. Bioluminescent imaging of vector-transduced mice demonstrated that luciferase transgene expression from the hybrid was robust and compared well to a traditional HDAd vector. Quantitative PCR analysis confirmed that the EBV episome was stable at approximately 30 copies per cell for up to 50 weeks and that it remained circular and extrachromosomal. Approaches for adapting the HDAd-EBV hybrid to a variety of disease targets and the potential benefits of this approach are discussed.
View details for DOI 10.1128/JVI.01721-08
View details for Web of Science ID 000264046000041
View details for PubMedID 19158239
Dual targeting of mammalian target of rapamycin and phosphoinositide 3-kinase using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma
2009; 112 (2): S9-S10
View details for Web of Science ID 000264230200018
Death from Metastatic Donor-Derived Ovarian Cancer in a Male Kidney Transplant Recipient
AMERICAN JOURNAL OF TRANSPLANTATION
2009; 9 (2): 428-432
Posttransplant malignancy developing in an allograft is an uncommon complication of organ transplantation. The tumor may represent malignant transformation of donor or recipient cells that were previously normal, metastatic malignancy of recipient origin or malignancy transmitted from organ donor to recipient. Establishing the origin of the malignancy is critical to treatment algorithms. It is generally believed allograft removal and immunosuppression withdrawal will lead to resolution of transmitted malignancies in cases where the renal allograft is the origin. We report a male patient who developed metastatic ovarian malignancy secondary to donor transmission.
View details for DOI 10.1111/j.1600-6143.2008.02507.x
View details for Web of Science ID 000262781400027
View details for PubMedID 19178417
HER-2/neu targeting for recurrent vulvar Paget's disease A case report and literature review
2008; 111 (3): 568-571
The treatment of Paget's disease of the vulva particularly for recurrences can be challenging. Overexpression of the HER-2/neu protein has been found in about 30% of vulvar Paget's cases therefore presenting a potential therapeutic target.We report the case of a 52-year-old patient with persistent Paget's disease of the vulva despite eight surgical excisions over a 15-year period. Immunohistochemistry demonstrated overexpression of the HER-2/neu protein in the vulva resection specimen. Treatment with Trastuzumab resulted in a significant regression of her disease and resolution of symptoms.Based on our case report, therapeutic targeting of HER-2/neu for patients with Paget's disease of the vulva using for example Trastuzumab is a potentially effective, alternative approach, and warrants further investigation.
View details for DOI 10.1016/j.ygyno.2007.12.014
View details for Web of Science ID 000261758000037
View details for PubMedID 18252264
- CA125: Megadaltons of novel opportunities GYNECOLOGIC ONCOLOGY 2007; 104 (3): 505-507
- Enhanced Expression of L9'S Mutant nAChR in Adult Mice Increases the Loss of Midbrain Dopaminergic Neurons The Journal of the Federation of American Societies for Experimental Biology 2006: 935-946
Development of a novel helper-dependent adenovirus-Epstein-Barr virus hybrid system for the stable transformation of mammalian cells
JOURNAL OF VIROLOGY
2004; 78 (12): 6556-6566
Epstein-Barr virus (EBV) episomes are stably maintained in permissive proliferating cell lines due to EBV nuclear antigen 1 (EBNA-1) protein-mediated replication and segregation. Previous studies showed the ability of EBV episomes to confer long-term transgene expression and correct genetic defects in deficient cells. To achieve quantitative delivery of EBV episomes in vitro and in vivo, we developed a binary helper-dependent adenovirus (HDA)-EBV hybrid system that consists of one HDA vector for the expression of Cre recombinase and a second HDA vector that contains all of the sequences for the EBV episome flanked by loxP sites. Upon coinfection of cells, Cre expressed from the first vector recombined loxP sites on the second vector. The resulting circular EBV episomes expressed a transgene and contained the EBV-derived family of repeats, an EBNA-1 expression cassette, and 19 kb of human DNA that functions as a replication origin in mammalian cells. This HDA-EBV hybrid system transformed 40% of cultured cells. Transgene expression in proliferating cells was observed for over 20 weeks under conditions that selected for the expression of the transgene. In the absence of selection, EBV episomes were lost at a rate of 8 to 10% per cell division. Successful delivery of EBV episomes in vivo was demonstrated in the liver of transgenic mice expressing Cre from the albumin promoter. This novel gene transfer system has the potential to confer long-term episomal transgene expression and therefore to correct genetic defects with reduced vector-related toxicity and without insertional mutagenesis.
View details for DOI 10.1128/JVI.78.12.6556-6566.2004
View details for Web of Science ID 000221772000048
View details for PubMedID 15163748
Enhanced expression of L9'S mutant alpha 4 nAChR in adult mice increases the loss of midbrain dopaminergic neurons
2004; 19: S42-S42
View details for Web of Science ID 000221639600126
- Specific keynote: Immunological therapy for ovarian cancer GYNECOLOGIC ONCOLOGY 2003; 88 (1): S105-S109
Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
2002; 129 (1): 99-106
We report the immunological characterization of three colon carcinoma cell lines, COLO 205, SW620 and SW403, which we selected to combine with cytokine-secreting fibroblasts for the development of an allogeneic tumour cell vaccine. The cell lines expressed HLA-A2 as well as shared tumour-associated antigens (TAAs) representative of colon carcinomas: CEA, Ep-CAM, MUC1, HER2/neu and MAGE antigens. They did not secrete high levels of the immunosuppressive factors TGF-beta, IL-10 or prostaglandins. The lines presented TAAs in a manner recognized by immune effector cells, which was demonstrated by the lysis of SW620 by HLA-A2-restricted anti-p53 cytotoxic T lymphocytes (CTL). COLO 205 and SW620 were genetically modified to express the co-stimulatory molecule CD80 (B7.1), which increased the ability of the cells to stimulate CTL in vitro. CTL clones derived from HLA-A2+ peripheral blood mononuclear cells stimulated with the CD80-expressing lines lysed the stimulator cell and an HLA-A2+ colon cancer cell line, but did not lyse an isogeneic fibroblast line or an HLA-A2- colon cancer cell line. CTL clones derived from colon carcinoma patients immunized with an allogeneic vaccine containing these lines demonstrated killing of autologous tumour cells, the vaccine cell lines and other HLA-A2+ colon cancer cell lines, but not fibroblasts isogeneic to certain of the target cell lines. Our studies demonstrate that these colon carcinoma cell lines express shared TAAs that can induce CTLs which recognize and lyse other colon carcinoma cells, and support the continued clinical evaluation of the CD80 gene modified allogeneic colon cell/cytokine-secreting fibroblast carcinoma vaccine.
View details for Web of Science ID 000176518200014
View details for PubMedID 12100028
- A radical debulking of leiomyomatosis peritonealis disseminata from a colonic obstruction: A case report and review of the literature JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 2000; 191 (2): 212-215
IL-2 plasmid therapy of murine ovarian carcinoma inhibits the growth of tumor ascites and alters its cytokine profile
JOURNAL OF IMMUNOLOGY
1999; 163 (12): 6378-6385
We have evaluated whether i.p. murine ovarian tumors could be treated with an IL-2 plasmid DNA complexed with the cationic lipid, (+/-)-N-(2-hydroxyethyl)-N,N-dimethyl-2, 3-bis(tetradecyloxy)-1-propanaminium bromide/dioleoylphosphatidylethanolamine (DMRIE/DOPE). Reporter gene studies were initially conducted in which mice bearing i.p. murine ovarian teratocarcinoma (MOT) were injected i.p. with reporter gene plasmid DNA (pDNA):DMRIE/DOPE. Histochemical analyses revealed that transfection occurred primarily in the tumor cells of the ascites, with only a minority of other ascitic cells or surrounding tissues transfected. IL-2 levels in the MOT ascites were determined after i. p. injection of either IL-2 pDNA:DMRIE/DOPE or recombinant IL-2 protein. IL-2 was detected in tumor ascites for up to 10 days after a single i.p. injection of IL-2 pDNA:DMRIE/DOPE, but was undetectable 24 h after a single i.p. injection of IL-2 protein. In an antitumor efficacy study, MOT tumor-bearing mice injected i.p. with IL-2 pDNA:DMRIE/DOPE on days 5, 8, and 11 after tumor cell implant had a significant inhibition of tumor ascites (p = 0.001) as well as a significant increase in survival (p = 0.008). A cytokine profile of the MOT tumor ascites revealed that mice treated with IL-2 pDNA:DMRIE/DOPE had an IL-2-specific increase in the levels of IFN-gamma and GM-CSF. Taken together, these findings indicate that i. p. treatment of ovarian tumors with IL-2 pDNA:DMRIE/DOPE can lead to an increase in local IL-2 levels, a change in the cytokine profile of the tumor ascites, and a significant antitumor effect.
View details for Web of Science ID 000084134200005
View details for PubMedID 10586027
Sensitization of rat glioblastoma multiforme to cisplatin in vivo following restoration of wild-type p53 function
JOURNAL OF NEUROSURGERY
1998; 88 (3): 535-540
To study the combined potential of wild-type p53 gene transfer and administration of cisplatin for the treatment of glioblastoma multiforme, the authors used the 9L rat glioblastoma cell line, which expresses a mutant p53.Stable expression of wild-type p53 in 9L cells was achieved by transfection of the cells with a wild-type p53-expressing plasmid (pCEP4p53). The resultant cell line, 9LpCEP4p53, was found to be more sensitive to cisplatin treatment in vitro than control (9LpCEP4) cells. The in vitro growth rates of control cells and wild-type p53-modified cells were similar in the absence of cisplatin. Fischer 344 rats were implanted intracerebrally with 9LpCEP4p53 cells and intraperitoneally administered 4 mg/kg cisplatin weekly for 7 weeks. These animals survived significantly longer than animals that were implanted with 9LpCEP4p53 cells but were given no cisplatin treatment. In contrast, concurrent cisplatin treatment provided no benefit for animals implanted with 9LpCEP4 cells. Tumors that developed in animals that had been implanted with 9LpCEP4p53 cells and treated with cisplatin had lost expression of wild-type p53, indicating a correlation between expression of wild-type p53 and cisplatin sensitivity in vivo.The findings of this study suggest that p53-based gene therapy in combination with cisplatin-based chemotherapy may be superior to single-modality treatment in dealing with glioblastoma multiforme.
View details for Web of Science ID 000072133800016
View details for PubMedID 9488309
- Gene therapy for ovarian cancer – Molecular scissors of the new millenium? Journal of Gynecologic Techniques 1998; 4: 149-162
- Synergy of transforming growth factor beta (TGF-beta) antisense and IL-2 gene therapy in the murine ovarian teratoma model Gynecologic Oncology 1998: 204-210
Progress and prospects in vaccine therapy for gynecologic cancers.
Oncology (Williston Park, N.Y.)
1997; 11 (11): 1727-?
Therapeutic and prophylactic vaccines that harness the potential of the immune system against a number of gynecologic cancers are now being developed. The therapeutic vaccines coerce the cellular components of the immune system to attack malignant tissue. The prophylactic vaccines induce the production of antibodies capable of neutralizing viral antigens before they infect host cells. However, malignant tumors are usually a heterogeneous mixture of different malignant cells, and it is likely that variant tumor clones within a tumor may not express the target antigen or may possess defects in their antigen-presenting mechanism. Ultimately, therapeutic vaccines may be better suited for the treatment of preinvasive disease or for use as an adjuvant following primary therapy. The prospects for developing efficacious vaccines to treat or prevent cervical, ovarian, uterine, and other gynecologic cancers are promising, however. This article describes the methodology of and rationale for these vaccines.
View details for PubMedID 9394368
Construction and characterization of retroviral vectors for interleukin-2 gene therapy
JOURNAL OF IMMUNOTHERAPY
1997; 20 (6): 437-448
Several investigators have employed interleukin-2 (IL-2) gene transfer to enhance the immunogenicity of tumor cell vaccines. We describe in this report the construction and characterization of retroviral vectors for IL-2 gene therapy. Human IL-2 cDNA with a chimeric rat preproinsulin/IL-2 DNA leader sequence was subcloned into the pLXSN (long terminal repeat promoter) and pLNCX (cytomegalovirus [CMV] promoter) vectors to generate the plasmids pLXSN-iIL2 and pLNCX-iIL2, respectively. Human IL-2 cDNA with a chimeric human tissue factor/IL-2 DNA leader sequence was utilized to construct the vector pLXSN-tIL2. The levels of IL-2 secreted by transduced tumor cells and fibroblasts were evaluated by enzyme-linked immunosorbent assay (ELISA) of culture supernatants and compared with those of normal peripheral blood mononuclear cells (PBMC) activated in vitro with calcium ionophore and phorbol 12-myristate 13-acetate. The highest levels of IL-2 secreted by transduced tumor cells (760 units/10(6) cells/24 h), adult fibroblasts (625 units/10(6) cells/24 h), and embryonic fibroblasts (3,975 units/10(6) cells/24 h) were 150- to 1,000-fold higher than than secreted by the activated PBMC (4 units/10(6) cells/24 h). Similar levels of IL-2 were expressed by human fibroblasts transduced with pLXSN vectors employing the preproinsulin (pLXSN-iIL2) or tissue factor (pLXSN-tIL2) leader sequences (range in IL-2 units/10(6) cells/24 h pLXSN-iIL2 = 375-625 vs. pLXSN-tIL2 = 90-440). Because IL-2-transduced cells for clinical applications are generally irradiated to prevent cellular proliferation, we evaluated the effects of radiation on IL-2 production. Radiation doses between 1,500 and 10,000 cGy resulted in gradual decreases in IL-2 secretion by transduced cells. The range of the decrease in IL-2 secretion was 7-11% by day 7, 0-29% by day 14, and 25-50% by day 35. For clinical applications, stable production of the vector in high concentrations is an important consideration. The retroviral vector pLXSN-tIL2 produced the highest viral titer and was chosen for further characterization. Southern blot analysis of SacI-digested genomic DNA from the LXSN-tIL2 producer cell line and SacI-digested pLXSN-tIL2 plasmid DNA revealed the expected 3.2-kbp fragment, suggesting the absence of transgene rearrangement and the suitability of this vector as a candidate for clinical applications.
View details for Web of Science ID A1997YJ86800003
View details for PubMedID 9409449
Gene therapy for ovarian cancer: Development of novel treatment strategies
INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
1997; 7 (1): 1-13
In the last decade, advances in molecular biology have lead to the development of techniques that permit the manipulation of mammalian cell DNA for diagnostic and therapeutic purposes. Gene therapy has subsequently evolved as a treatment option in patients with malignancies. In this article, we have summarized current strategies in gene therapy for ovarian cancer.
View details for Web of Science ID A1997VZ43800001
View details for PubMedID 12795798
- Interleukin-2 (IL-2) gene therapy with allogenic fibroblasts in the CT-26 model of murine colorectal carcinoma Oncology Reports 1997; 4 (N1): 135-138
Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
1996; 93 (7): 2909-2914
Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor beta (TGF-beta). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-beta expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-beta expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-beta antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-beta expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-beta antisense gene therapy for TGF-beta-expressing tumors.
View details for Web of Science ID A1996UD37500054
View details for PubMedID 8610141
- Immuno-gene therapy of colon carcinoma and central nervous tumors In: Gene Therapy and Cancer 1996
COMPARISON OF GENE-THERAPY WITH INTERLEUKIN-2 GENE MODIFIED FIBROBLASTS AND TUMOR-CELLS IN THE MURINE CT-26 MODEL OF COLORECTAL-CARCINOMA
JOURNAL OF IMMUNOTHERAPY
1995; 17 (4): 201-208
We compared the efficacy of gene therapy mediated by interleukin-2 (IL-2) gene-modified tumor cells to gene therapy mediated by IL-2 transduced fibroblasts in the CT-26 model of murine colorectal carcinoma. We transduced CT-26 tumor cells and BALB/c 3T3 fibroblasts with three different retroviral vectors using three different promoters for the human IL-2 gene: DC/TKIL-2 (thymidine kinase promoter), LXSN-iIL2 (long terminal repeat promoter), and LNCX-iIL2 (cytomegalovirus promoter). These transductions resulted in CT-26 and 3T3 subclones that secreted different amounts of IL-2. Immunization of animals with either CT-26/IL-2 cells or with fibroblast/IL-2 cells mixed with CT-26 induced similar levels of immunity that protected 62-82% of animals against a subsequent tumor challenge with parental CT-26. However, mice developed tumors at the site of inoculation in 46% of the animals immunized with CT-26/IL-2 cells. In a separate experiment, CT-26/IL-2 cells were exposed to 6,000 cGy of gamma irradiation to prevent tumor growth at the site of inoculation. Although the CT-26/IL-2 cells continued to secrete IL-2 after irradiation, they were no longer effective at inducing antitumor immunity. In contrast, both irradiated and nonirradiated fibroblast/IL-2 cells, mixed with irradiated CT-26, were equally effective at inducing antitumor immunity. These data suggest that in the CT-26 model, fibroblast-mediated IL-2 gene therapy has advantages for the induction of antitumor immunity and abrogation of tumorigenic potential at the site of inoculation compared with tumor cell-mediated IL-2 gene therapy.
View details for Web of Science ID A1995RN34600002
View details for PubMedID 7582256
INTERLEUKIN-2 GENE-THERAPY IN A PATIENT WITH GLIOBLASTOMA
1995; 2 (2): 164-167
A patient with glioblastoma multiforme (GBM) who had failed conventional therapy was treated with IL-2 gene therapy. The patient received 10 subcutaneous immunizations with autologous tumor cells and fibroblasts genetically modified to secrete IL-2 by retroviral gene transfer. An antitumor immune response mediated in part by CD8+ cytotoxic T cells was demonstrated with the patient's peripheral blood mononuclear cells. A magnetic resonance imaging (MRI) scan performed 4 weeks after the highest treatment dose revealed marked tumor necrosis. These results support the evaluation of this form of IL-2 gene therapy in additional patients with glioblastoma.
View details for Web of Science ID A1995QK78200012
View details for PubMedID 7719933
CHARACTERIZATION OF A NEW HUMAN GLIOBLASTOMA CELL-LINE THAT EXPRESSES MUTANT P53 AND LACKS ACTIVATION OF THE PDGF PATHWAY
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
1995; 31 (3): 207-214
We have established and characterized a new glioblastoma cell line, termed GT9, from a biopsy sample of a female adult patient with glioblastoma multiforme. The line has now undergone over 60 passages and has been successfully cultured after cryopreservation. Immunofluorescence analyses with a panel of monoclonal antibodies were positive for glial fibrillary acidic protein and vimentin, and negative for neurofilament, galactocerebroside, and fibronectin, a pattern typical of glial cells. Based on a tetraploid, the composite karyotype of GT9 cells included the loss of chromosome 10, gain of chromosome 7, and the presence of double minute chromosomes, three of the most common karyotypic abnormalities in glioblastoma. Sequence analysis of p53 cDNA revealed a homozygous double mutation at codon 249 (commonly mutated in aflatoxin-associated hepatocellular carcinoma) and codon 250. Moreover, there was a complete absence of wild-type p53. However, unlike the majority of human glioblastomas previously described, the expression of platelet-derived growth factor-B (PDGF-B), a potent mitogenic autocrine factor, was low in GT9 cells. The expression and phosphorylation of c-Jun and Jun-B, downstream mediators of the PDGF pathway, were also low. Thus, deregulation of the PDGF pathway does not appear to be involved in the pathogenesis of the GT9 glioblastoma. Conversely, Jun-D, a negative regulator of cell growth, was also low. In addition, Phosphorylated Egr-1, a recently reported suppressor of PDGF-B/v-sis-transformed cells, was also low, suggesting that the lack of activation of the PDGF pathway was not due to these suppressive mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1995QL75600010
View details for PubMedID 7757303
- INJECTION OF COLON-CARCINOMA PATIENTS WITH AUTOLOGOUS IRRADIATED TUMOR-CELLS AND FIBROBLASTS GENETICALLY-MODIFIED TO SECRETE INTERLEUKIN-2 (IL-2) - A PHASE-I STUDY HUMAN GENE THERAPY 1995; 6 (2): 195-204
- Apoptosis of CD4+ and CD8+ cells from HIV-1 infected individuals: role of anti-idiotypic antibodies Vaccine Research 1995; Vol 4 (No 4): 229-238
VALUE OF BOWEL RESECTION AND PREOPERATIVE COLOSCOPY IN OVARIAN-CANCER
ARCHIVES OF GYNECOLOGY AND OBSTETRICS
1993; 254 (1-4): 966-968
View details for Web of Science ID A1993MP00300368
LYMPHOCYTE SUBPOPULATIONS IN WOMEN WITH MALIGNANT-TUMORS IN CORRELATION WITH KNOWN PROGNOSTIC FACTORS AND AS DISEASE PARAMETERS DURING CYTOKINE THERAPY
ARCHIVES OF GYNECOLOGY AND OBSTETRICS
1993; 254 (1-4): 1091-1093
View details for Web of Science ID A1993MP00300429
ACTIVATION OF NEUTROPHILS IN THE MICROVASCULATURE OF THE ISCHEMIC AND REPERFUSED MYOCARDIUM
EUROPEAN HEART JOURNAL
1993; 14: 82-86
In 11 rats, the microcirculation of the repeatedly ischaemic (stunned) left ventricular myocardium was studied using in vivo fluorescence microscopy. Stunning was provoked by six subsequent 10 min ligations of the left anterior descending coronary artery, each of them followed by a 20 min reperfusion period. In the stunned myocardium showing hypokinetic wall motion, myocardial blood flow dropped by 55%; in this region, leukocytes often appeared in slow-flow capillaries plugging capillary branches. Closely linking to leukocyte adherence, a rise of microvascular permeability was documented by extravascular clouds of fluorescent dextran. After nifedipine treatment, in ischaemic regions marked dilatation of larger A1 and A2 arterioles was noted, in addition to the ischaemia-induced dilatation of smaller A3 and A4 arterioles. Furthermore nifedipine and nisoldipine reduced the number of adherent leukocytes in post-capillary venules and capillaries of the repeatedly ischaemic myocardium. In 12 patients with coronary one-vessel disease and without previous transmural myocardial infarction, elective coronary angioplasty (PTCA) was performed (balloon inflation for 2 min). After elective PTCA of the LAD, a significant rise in the proportion of activated neutrophils was noted. After elective 2 min PTCA of the LAD, coronary sinus blood samples showed a marked rise of FMLC stimulated superoxide anion production, whereas passive deformability decreased considerably. Furthermore, an increase in chemotactic activity in coronary sinus blood samples was observed.
View details for Web of Science ID A1993MK92600014
View details for PubMedID 8293784
A NON-LYMPHOMA IDIOTYPE IS INDICATIVE AND PREDICTIVE FOR B-CELL MALIGNANCIES IN AIDS
1993; 12 (5): 529-537
The 1F7 idiotype previously defined (J Immunol 147:933;1991 and Eur J Immunol 22:1749;1992) is expressed on antibodies reactive to different proteins of HIV (gp41, p24, gp120). Since serum levels of 1F7 (IgM or IgG) are significantly higher in patients with HIV lymphoma as opposed to HIV-infected individuals, normal controls and non-HIV lymphoma patients, we hypothesized the B-cell neoplasms were the source of the idiotype. However, immunohistochemistry on cryostat sections revealed no 1F7 idiotype signal on neoplastic B-cells nor tumor infiltrative T-cells (n = 8). Interestingly, reactive lymphocytosis adjacent to tumor masses and reactive follicular hyperplastic controls (n = 5) exhibited significant 1F7 reactivity. The reactivity appeared in paracortical and perifollicular lymphoid regions, predominantly regions of B, T and antigen presenting cells in lymph nodes or tonsils. A survey of electrophoretically defined paraproteins with anti-HIV specificities derived from HIV-infected patients showed no Western blot reactivity with the 1F7 anti-idiotypic antibody. Therefore, the idiotype does not appear to be a direct product of B-cell neoplasia or abnormal B-cell proliferation, but is produced by B cell clones responding to HIV infection. This high level of serum 1F7 reactivity could be an important clue in the pathogenesis of HIV lymphomas and confers a highly predictive serological test for HIV lymphoma.
View details for Web of Science ID A1993MG99100007
View details for PubMedID 8300126
A MONOCLONAL-ANTIBODY (IF7) SPECIFIC FOR HUMAN ANTI-HIV IG INDUCES APOPTOSIS AND INHIBITS CTL ACTIVITY IN CD8+ LYMPHOCYTES FROM HIV-1 INFECTED INDIVIDUALS
JOURNAL OF CELLULAR BIOCHEMISTRY
View details for Web of Science ID A1993KX96500252
NEW TECHNIQUES FOR THE STUDY OF THE CORONARY MICROCIRCULATION - IMPORTANCE OF MEASUREMENTS OF CORONARY FLOW RESERVE IN THE CLINICAL SETTING
CORONARY ARTERY DISEASE
1992; 3 (7): 586-592
View details for Web of Science ID A1992JJ14500007
SHORT-TERM OUTCOME IN INFANTS WITH BIRTH WEIGHTS LESS-THAN 1750-G BORN TO MOTHERS WITH HELLP SYNDROME
JOURNAL OF PERINATAL MEDICINE
1992; 20 (1): 25-28
Premature infants born to mothers with HELLP syndrome were reported to have a less favourable outcome compared to infants with uncomplicated maternal history. We investigated the short term outcome in 21 premature infants with birth weights less than 1750 g born to mothers with HELLP syndrome. Median birth weight was 1050 g (range 420 g-1750 g), corresponding gestational age 29 weeks (range 26-35 weeks). Mechanical ventilation for RDS was necessary in 15 infants. Intracranial hemorrhage was diagnosed in 2 infants, 1 of the surviving infants developed bronchopulmonary dysplasia. Acute renal failure was observed in 3 infants immediately after birth. Mortality was attributed to progressive respiratory failure in 2 patients (b.w. 420 g and 490 g) and persisting acute renal failure in 1 patient (b.w. 520 g) Leucocytopenia (less than 9000/mm3) was observed in 13 infants and thrombocytopenia (less than 115000/mm3) was noted in 4 infants during the first day. Eighteen infants survived. We conclude, that the short term outcome in infants born to mothers with HELLP syndrome is not as poor, as previously reported.
View details for Web of Science ID A1992HT93600004
View details for PubMedID 1608020
- PHARMACOLOGICAL EFFECTS ON CORONARY MICROVESSELS DURING MYOCARDIAL-ISCHEMIA EUROPEAN HEART JOURNAL 1990; 11: 10-15
MICROCIRCULATION IN THE HYPERTROPHIC AND ISCHEMIC HEART
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
1990; 39: S9-S12
1. Myocardial hypertrophy, for instance in patients with hypertensive heart disease, is characterized by a reduction of coronary vascular reserve, even in the presence of normal coronary arteries. In hypertensive animals, on the microcirculatory level functional changes can be observed before the onset of any structural rarefications. In 10 rats with renal hypertension and pressure-induced left ventricular hypertrophy (LVH), the microcirculation of the left ventricular myocardium was studied using in vivo fluorescence microscopy and morphometric analysis. Renal hypertension was provoked by clipping of the left renal artery. After 8 weeks, systolic blood pressure in LVH rats averaged 172 +/- 8 mm Hg, compared to 91 +/- 2 mm Hg in 10 normotensive (NT) rats. In LVH rats, distances of plasma-perfused capillaries were significantly increased (NT = 17.7; LVH = 20 microns; p less than 0.001). Volume density, surface density, and length density of capillaries in LVH rats were reduced by 20% compared to NT rats. Capillary red cell content as measured by the ratio of capillaries filled with red cells to those containing plasma alone (Q) in LVH animals exceeded that in NT rats (LVH: Q = 0.83 +/- 0.04; NT: Q = 0.77 +/- 0.04; p less than 0.025). During hypoxia (H, 5% O2) capillary red cell recruitment in LVH rats (Q: control c = 0.83; H = 0.95) was diminished by 33% as compared to NT rats (Q: c = 0.77; H = 0.95). Thus, in addition to the decreased capillary density, the reduction of capillary red cell recruitment may be responsible for chest pain in patients with LVH and normal coronary arteries.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1990EF89800002
View details for PubMedID 2148154