Biomedical subjects

A Hasenburg

Publications and source records attributed to A Hasenburg.

31 records · Page 2Linked to original sources

PubMedDate not supplied

Histologic and immunohistochemical analysis of tissue response to adenovirus-mediated herpes simplex thymidine kinase gene therapy of ovarian cancer.

Herpes simplex virus (HSV) thymidine kinase (tk) gene incorporated into adenovirus was delivered intraperitoneally (ip) followed by an antiherpetic prodrug and topotecan in patients with recurrent epithelial ovarian cancer. Tissue response was evaluated. Ten patients underwent secondary debulking with subsequent delivery of ADV-HSV-tk therapy. Two patients each were treated at dose level 1 (2 x 10(10) vector particles = VP), 2 (2 x 10(11) VP), and 3 (2 x 10(12) VP); four patients were treated at dose level 4 (2 x 10(13) VP). Five patients underwent second-look surgery about one month after gene therapy (GT). Treatment response, presence of vector DNA, protein expression of steroid hormone receptors, p53, c-erbB2 and Ki67 protein were analyzed. At second-look, two out of five patients were tumor-free and none of their peritoneal biopsies showed vector DNA. After GT, the vital tumor mass was smaller, desmoplastic reaction had increased, and tumors were less differentiated with an increase of Ki67 expression. There was no change in expression of hormone receptors, p53, or c-erbB2. ADV-HSV-tk GT appears to eliminate cells with higher differentiation first and might induce fibrosis. Dedifferentiation might render residual cells more sensitive to chemotherapy secondary to their subsequent higher mitotic activity.

Adenoviruses, Human↗

PubMedDate not supplied

The role of surgery in recurrent ovarian cancer.

The role of cytoreductive surgery (CS) in recurrent ovarian cancer (ROC) has not been clearly defined. We performed a retrospective study evaluating criteria for CS in ROC. Twenty-five institutions documented their patients with CS for invasive epithelial ROC performed 2000-2003. Two hundred sixty-seven patients were included. Complete tumor removal was achieved in 133 patients (50%). Complete resection was associated with prolonged survival compared to surgeries with residual tumor. Median survival of patients without residual tumor was 45.3 months and of patients with residual tumor, irrespective of its size, 19.0 months (HR 4.33; 95% CI 2.53-7.43; P < 0.0001). In a multivariate analysis, the following factors showed a significant influence on the probability to achieve a postoperative residual tumor of 0 mm: absence of ascites (<500 vs > or =500 mL: HR 4.63; 95% CI: 1.81-11.76; P= 0.0001), good performance status Eastern Cooperative Oncology Group (ECOG) 0 vs >0: HR: 2.41; 95% CI: 1.41-4.08; P= 0.001, and low FIGO stage at primary diagnosis (FIGO I/II vs III/IV: HR 1.87; 95% CI: 1.04-3.37; P= 0.036). Significant factors for survival after surgery for recurrence in a multivariate analysis were achievement of complete resection (residual tumor at surgery for recurrence 0 vs >0 mm: HR 2.86; 95% CI: 1.66-4.93; P < 0.001), absence of ascites (<500 vs > or =500 mL: HR 2.09; 95% CI: 1.18-3.71; P= 0.012), and application of a platinum-containing chemotherapy (platinum-containing chemotherapy vs others: HR 1.83; 95% CI: 1.16-2.88; P= 0.009). Only patients with complete resection seem to benefit from CS. This new panel of selection criteria will be evaluated in a prospective study.

Adult↗

PubMedDate not supplied

Thymidine kinase (TK) gene therapy of solid tumors: valacyclovir facilitates outpatient treatment.

BACKGROUND: In a Phase I study replication-deficient adenovirus containing the herpes simplex virus (HSV) thymidine kinase (TK) gene (AdV-HSV-TK) was instilled intraperitoneally in patients with recurrent ovarian cancer. Patients were treated with Acyclovir (ACV) or Valacyclovir (VCV) as enzymatic substrates. The purpose of this study was to compare serum levels of ACV and VCV. PATIENTS AND METHODS: The antiherpetic prodrug and Topotecan (1.0 mg/m2 over 30 minutes each day for 5 days) were started 24 hours after vector application. Eight patients received ACV (15 mg/kg i.v. over one hour every 8 hours for 42 doses), two patients were started on ACV for 5 days and then switched to oral VCV (2 g every 8 hours for a total of 42 doses). Blood samples were obtained 20 minutes prior to each drug. RESULTS: Serum levels of ACV and VCV (converted to ACV) were comparable. CONCLUSIONS: Suicide gene therapy with TK is under investigation in a variety of solid tumors. Replacing ACV by VCV will offer a cost-effective alternative and will significantly reduce duration of hospital stay improving quality of life and facilitating an outpatient gene therapy concept.

Acyclovir↗

PubMedDate not supplied

Breast size as risk factor for tumor size at diagnosis.

BACKGROUND: A prospective study was conducted to determine whether patients with larger breasts show larger tumors. MATERIALS AND METHODS: 123 patients with primary breast cancer were evaluated (median follow-up 36 months). Breast size was determined as a reflection of cup size. RESULTS: Cup size correlated with tumor diameter at diagnosis (p = 0.0038). On average, cup sizes were larger in postmenopausal than in premenopausal women (p = 0.0011), however, postmenopausal women did not show larger tumors than premenopausal. There was a significant positive correlation between body mass index, body weight and breast size (p < 0.0001). The mode of tumor detection (self vs. not self) was independent of breast size. No correlation was found between breast size and the patient's height, duration of breast feeding, smoking behavior or amount of alcohol consumption, hormone replacement therapy or use of oral contraceptives, number of involved lymph nodes or DFS and OS. CONCLUSION: Patients with larger breasts showed larger tumors. The mode of tumor detection is independent of breast size.

Adult↗

PubMedDate not supplied

Four-channel tocography in uneventful pregnancies: a prospective study in primigravidas and multigravidas.

OBJECTIVE: The simultaneous recording of external uterine pressure in four locations on the abdominal wall with four-channel-tocography provides new ways to describe the dynamics of uterine activity. METHODS: Fifty-eight healthy primigravidas and 25 healthy multigravidas were studied prospectively with four-channel tocography during the course of pregnancy. Starting at 21 weeks' gestation, the following five intervals were defined: 21-24, 25-28, 29-32, 33-36 and more than 37 completed weeks. Eligibility criteria included informed consent, no history of malformations of the uterus, and no previous preterm deliveries. Patients were excluded for the following reasons: medication for preterm labor, cerclage, placenta previa, delivery before 37 weeks' gestation, less than three measurements completed, and patient's withdrawal of consent. RESULTS: The median contraction frequency per hour was six for primigravidas and five for multigravidas, without significant correlation with gestational age. At all time periods studied, the median rate of global contractions developing simultaneously in at least three uterine segments was less than 15%; however, it was significantly higher in primigravidas than in multigravidas (14% versus 4%, P <.001). Both groups had more activity in the right upper quadrant of the uterus shortly before delivery. CONCLUSION: Four-channel tocography provided insight into uterine activity patterns and might enable obstetricians to select clinically relevant contractions for further treatment.

Adolescent↗

PubMedDate not supplied

Adenovirus-mediated thymidine kinase gene therapy for recurrent ovarian cancer: expression of coxsackie-adenovirus receptor and integrins alphavbeta3 and alphavbeta5.

OBJECTIVE: Ten patients with recurrent ovarian cancer received a combined treatment of optimal tumor debulking, adenovirus-mediated herpes simplex virus thymidine kinase gene therapy (GT), and systemic application of acyclovir or valacyclovir and topotecan. Biopsies were taken at the time of secondary debulking about 1 month after the application of GT and chemotherapy and were analyzed for expression of coxsackie-adenovirus receptor (CAR) and integrins alphavbeta3 and alphavbeta5 with respect to treatment response. METHODS: Treatment modalities and study design have been described recently. Immunohistochemistry was used to visualize expression of CAR and integrins alphavbeta3 and alphavbeta5 in tumor samples taken before and after application of GT. RESULTS: Before GT six of ten patients presented with CAR-positive and four with CAR-negative tumors. After GT all tumors showed CAR expression. Integrin alphavbeta3 was found in all tumors before and after GT. Expression of integrin alphavbeta5 was seen in eight of ten tumor samples before GT and in all samples after GT. CONCLUSION: Despite the importance of CAR and integrin expression for successful adenovirus internalization, other cell surface receptors might be involved in this process. It is too early to decide whether expressions of CAR and integrin alphavbeta3/alphavbeta5 on tumor cells are appropriate additional inclusion criteria for the enrollment of patients in GT trials. Further research is necessary to evaluate the effect of GT plus chemotherapy on CAR and integrin expression.

Adult↗

PubMedDate not supplied

[Significance of the site of uterine contraction for labor progress and duration of pregnancy].

A four-channel topographic technique was developed in order to improve information about spatial uterine motility. 54 women were monitored during delivery. Four pressure transducers were attached in a square around the umbilicus. Most frequently the origin of labour could be determined in the upper right segment of the uterus. The rate of operative deliveries was decreased in case of predominant upper right origin of labour. The majority of contractions with clear propagation patterns originated at the upper right site, continued to the left and then to the lower right part of the uterus. The highest relative intensity was also measured at the upper right site. Predominant upper right origin of labour may be important for undisturbed delivery. The probability of a preterm delivery is increased in case of an upper right origin of labour.

Adult↗

PubMedDate not supplied

Human epithelial ovarian cancer xenotransplants into nude mice can be cured by adenovirus-mediated thymidine kinase gene therapy.

BACKGROUND: Adenovirus-mediated suicide gene therapy of ovarian cancer has effective anti-tumor effects in vitro and in vivo. By transduction of ovarian adenocarcinoma with the Herpes Simplex Thymidine Kinase gene and subsequent treatment with the antiviral agent ganciclovir, prolongation of survival has been described in nude mice. So far, however, in animal models of solid tumors no cures have been reported after gene therapy. METHODS: In a prospective randomized experimental design 76 mice with xenotransplanted serous ovarian carcinoma were treated with three different doses of ADV/RSV-TK at three different time points followed by intraperitoneal ganciclovir administration. The experiment was designed to show significance of survival differences upon doubling of the number of survived days at a p-value of 0.05 with a power of 80%. The endpoint of the trial was survival. RESULTS: Treatment response was seen in all treated animals evident by significant prolongation of survival. Treatment response was dependent on the therapeutic viral dose and the tumor burden of the animal at the time of treatment. Two out of eight mice with early disease have now survived ten months without evidence of disease with untreated animals dying after nineteen days. Subcutaneous tumor development at the injection site was the reason of death in the remaining six mice of this group. CONCLUSIONS: Intraperitoneal ADV/RSV-TK suicide gene therapy of epithelial ovarian cancer in combination with ganciclovir administration can cure nude mice with early disease. This treatment modality may lend itself to incorporation into the current treatment concept of human ovarian malignancy. Clinical trials are warranted.

Adenoviridae↗

PubMedDate not supplied

Improvement of gene therapy for ovarian cancer by using acyclovir instead of ganciclovir in adenovirus mediated thymidine kinase gene therapy.

Adenovirus(ADV) mediated thymidine kinase(TK) gene therapy followed by ganciclovir(GCV) administration is widely used in different types of cancer. ACV shares the same mechanism of selective cell killing in ADV/TK positive cells as GCV and can be used at 4.5 times higher doses in patients without significant side effects. An increased dose of TK substrate is associated with improved bystander effect and more efficient cell killing. Toxicity and cell killing efficacy were assessed using a 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide(MTT) based assay in three ovarian cancer cell lines with different proliferation patterns. At the same concentration, equal or higher cell killing efficacy and bystander effect were observed using ACV rather than GCV. 2.5 and 5 times (25 micrograms/ml and 50 micrograms/ml) higher concentrations of ACV always resulted in more effective cell killing than GCV (10 micrograms/ml, P < 0.01). Our data indicate that replacing GCV with ACV in the ADV-TK gene therapy may increase the treatment effect without increasing toxicity.

Acyclovir↗

PubMedDate not supplied

The efficacy of adenovirus-mediated gene therapy of ovarian cancer is enhanced by using the cytomegalovirus promoter.

The cytomegalovirus(CMV) promoter is considered one of the strongest positive regulators. In this study toxicity, cell killing efficacy and bystander effect of Rous Sarcoma Virus(RSV) driven herpes simplex thymidine kinase(TK) gene therapy was compared with CMV driven TK gene therapy in three ovarian cancer cell lines with different growth patterns using a 3-(4,5-dimethylthiazol)-2,5-diphenyl tetra-zolium bromide (MTT) based assay. ADV/CMV-TK was shown to be 2 to 10 times more effective in tumor cell killing than ADV/RSV-TK. The difference in cell killing efficacy between ADV/CMV-TK and ADV/RSV-TK was dependent on the individual cell line. A CMV promoter dependent eight to ten fold improvement in cell killing efficacy was observed in the relatively slow growing SKOV3 cell line which is not easily transducible, while only a 2 to 4 fold difference was observed in the easily transducible OV-CA-2774 and OV-CA-1225 cell lines. ADV/CMV-TK also showed a stronger bystander effect than ADV/RSV-TK in all three ovarian cancer cell lines. Our data demonstrated that the efficacy of adenovirus-mediated gene therapy of ovarian cancer can be enhanced by using the CMV promoter without increasing toxicity.

Adenoviridae↗

PubMedDate not supplied

Telomere length in human white blood cells remains constant with age and is shorter in breast cancer patients.

BACKGROUND: Telomeres, which are TTAGGG repeats at the end of the eukaryotic chromosome, are essential for complete DNA replication. Telomere length has been reported to decrease in peripheral WBC, unlike the telomerase activity found in these cells. The purpose of this study was to investigate whether telomere length in WBC is indeed age dependent and could serve as a genetic marker in breast or ovarian cancer. METHODS: Five age groups: 20-29; 30-39; 4049; 50-59 and > or = 60 years were examined. The cancer patients were 18 women with ovarian cancer and 18 women with breast cancer. Southern blot analysis of the DNA from peripheral white blood cells (WBC) was performed using 32P-labeled (TTAGGG)3 probe. Blots were scanned in a phosphoimager and analyzed by computer-assisted image analysis. RESULTS: No statistically significant correlation was observed between telomere length and age in either healthy females or cancer patients. However, significantly shorter median telomere length was found in WBC obtained from breast cancer patients as compared to healthy individuals and ovarian cancer patients. CONCLUSIONS: It is concluded that telomere length in WBC is not age dependent, but is significantly shorter in breast cancer patients.

Adult↗

PubMedDate not supplied

[Fetal movements in 4-channel tocography].

INTRODUCTION: The four-channel-tocography was developed to register the spatial and temporal pattern of uterine contractions and to evaluate their clinical relevance. In this study it should be assessed whether the four-channel-tocography can also register fetal movements. MATERIAL AND METHODS: The study included 38 women with a gestational age between 28 and 43 weeks and singleton pregnancy. Four pressure transducers were attached in a square around the umbilicus. Parallel to the continuous registration of four-channel-tocography fetal movements were observed by conventional ultrasound. RESULTS: In a total of 23 hours and 11 minutes 403 fetal movements were registered by ultrasound and 405 by four-channel-tocography. 17% of the ultrasonically observed fetal movements were documented by the four-channel-tocography and 70% of the tocographically registered movements could be verified by ultrasound. CONCLUSION: Fetal movements can be registered by four-channel-tocography with good sensitivity and reliability. Essential for its clinical use is an automatic analysis, which is being developed.

Female↗

PubMedDate not supplied

Adenovirus mediated thymidine kinase gene therapy may enhance sensitivity of ovarian cancer cells to chemotherapeutic agents.

The current treatment concept of ovarian cancer consists of radical surgery with subsequent chemotherapy. We have shown that adenovirus (ADV) mediated thymidine kinase (TK) gene transduction of cisplatin-resistant human ovarian cancer xenotransplanted into nude mice followed by ganciclovir (GCV) administration leads to prolongation of survival or cure. In this study the interaction of ADV-TK gene therapy and selected chemotherapeutic agents commonly used for the treatment of ovarian cancer was investigated in three ovarian cancer cell lines with different growth patterns. Toxicity and cell killing efficacy of gene therapy, chemotherapy and their combinations with different concentrations and time intervals were measured by a 3-(4,5- dimethylthiazol)-2,5-diphenyl tetrazolium bromide (MTT) based assay. A slightly increased resistance to gene therapy was observed in cells pretreated with chemotherapy. Removal of the drugs restored the previous susceptibility of the cells to gene therapy. No antagonism was observed with gene therapy followed by chemotherapy. The concomitant application of gene therapy and chemotherapy resulted in a higher rate of cell death than the interval therapy. A dose dependent synergistic interaction was observed only for the combination of gene therapy and the topoisomerase 1 inhibitor topotecan. This synergistic effect was still seen even if the chemotherapeutic agent was added 72 hours later. Our data demonstrate that in addition to its own therapeutic efficacy, ADV-TK based gene therapy may enhance the effect of subsequent chemotherapy while up-front chemotherapy was disadvantageous.

Adenoviridae↗