We have previously demonstrated safety of G207, a doubly mutated (deletion of both gamma(1)34.5 loci, insertional inactivation of U(L)39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score >or=70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 x 10(9) plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.

G207, a mutant herpes simplex virus (HSV) type 1, is safe when inoculated into recurrent malignant glioma. We conducted a phase 1 trial of G207 to demonstrate the safety of stereotactic intratumoral administration when given 24 hours prior to a single 5 Gy radiation dose in patients with recurrent malignant glioma. Nine patients with progressive, recurrent malignant glioma despite standard therapy were included. Patients received one dose of G207 stereotactically inoculated into the multiple sites of the enhancing tumor margin and were then treated focally with 5 Gy radiation. Treatment was well tolerated, and no patient developed HSV encephalitis. The median interval between initial diagnosis and G207 inoculation was 18 months (mean: 23 months; range: 11-51 months). Six of the nine patients had stable disease or partial response for at least one time point. Three instances of marked radiographic response to treatment occurred. The median survival time from G207 inoculation until death was 7.5 months (95% confidence interval: 3.0-12.7). In conclusion, this study showed the safety and the potential for clinical response of single-dose oncolytic HSV therapy augmented with radiation in the treatment of malignant glioma patients. Additional studies with oncolytic HSV such as G207 in the treatment of human glioma are recommended.

Etomoxir is an inhibitor of mitochondrial CPT1 (carnitine palmitoyltransferase 1) and thereby switches energy metabolism from fatty acids to glucose oxidation. Such a metabolic change may be beneficial in CHF (congestive heart failure). The ERGO (etomoxir for the recovery of glucose oxidation) study was designed in which etomoxir was tested at a dose of 80 and 40 mg compared with placebo for a period of 6 months in patients with CHF. As the principle measure of efficacy, a maximal exercise tolerance test and a submaximal 6-min corridor walk test were used. Secondary end points were echocardiographical dimensions and quality-of-life assessment scores. A total of 350 patients were planned to be screened, with the expectation that end point data would be available from approx. 260 patients. However, the study had to be stopped prematurely, because unacceptably high liver transaminase levels were detected in four patients taking etomoxir. At the termination of the study, 121 patients were randomized to placebo, 118 to 40 mg of etomoxir and 108 to 80 mg of etomoxir. At that time, 21 patients in the placebo group, 16 in the 40 mg of etomoxir group and 14 patients in the 80 mg of etomoxir group had completed the study. The mean increases in exercise time were 3.3, 10.2 and 19.4 s for the placebo, 40 mg of etomoxir and 80 mg of etomoxir groups respectively (P value was not significant). No changes were obvious in the 6-min corridor walk test or in echocardiographical parameters from baseline. The number of patients that completed the study was too small to demonstrate significant effects on exercise time, although there was a tendency towards an increase in exercise time. Therefore, before rejecting the hypothesis that inhibition of fatty acid oxidation might be beneficial in CHF, similar studies have to be performed using different inhibitors of fatty acid oxidation targeting CPT1 and other enzymes in this metabolic pathway.

Current regimens of systemic chemotherapy result in only modest lengthening of survival in patients with advanced stage, liver-dominant, metastatic colorectal cancer who have failed first-line chemotherapy. The objective of this study was to investigate the safety and tolerability of NV1020, a replication-competent, attenuated, genetically engineered herpes simplex virus type 1 (HSV-1), in patients with hepatic colorectal metastases refractory to first-line chemotherapy. A phase I, open-label, dose-escalating study of a single 10-min hepatic arterial infusion of NV1020 in four cohorts. Three patients in each cohort received doses of 3 x 10(6), 1 x 10(7), 3 x 10(7), and 1 x 10(8) plaque-forming units. Adverse events were either mild or moderate in severity, and self-limiting. Only three serious adverse events (one transient rise in serum y-glutamyltransferase, one diarrhea, and one leukocytosis) experienced by three patients were considered to be possibly or probably related to NV1020. There were no deaths during the study, and there was no evidence of disseminated herpes infection. Viral presence was detected in only one saliva sample and two serum samples from one asymptomatic patient in the highest dose cohort. In the first week after viral administration only rare and minor increases were noted for tumor necrosis factor-alpha (six samples; three patients; peak, 40 pg/ml), interleukin (IL)-1 (two samples; two patients; peak, 28 pg/ml), and interferon-y (four samples; two subjects; peak, 54 pg/ml). No IL-2 was detected. Mild liver enzyme elevations were self-limiting and not associated with clinical symptoms. We conclude that NV1020, a genetically engineered but replication-competent HSV-1 oncolytic virus, can be safely administered into the hepatic artery without significant effects on normal liver function.

ABVD8 and BEACOPP4+4 resulted in similar EFS and OS in patients with high-risk advanced-stage HL. Because BEACOPP4+4 did not demonstrate a favorable effectiveness or toxicity ratio compared with ABVD8, treatment burden, immediate and late toxicities, and associated costs must be considered before selecting one of these regimens on which to build future treatment strategies.

Persistent infection with human papillomaviruses (HPV) is a prerequisite for the development of cervical cancer. Vaccination with virus-like particles (VLP) has demonstrated efficacy in prophylaxis but lacks therapeutic potential. HPV16 L1E7 chimeric viruslike particles (CVLP) consist of a carboxy-terminally truncated HPV16L1 protein fused to the amino-terminal part of the HPV16 E7 protein and self-assemble by recombinant expression of the fusion protein. The CVLP are able to induce L1-and E7-specific cytotoxic T lymphocytes. We have performed a first clinical trial to gain information about the safety and to generate preliminary data on the therapeutic potential of the CVLP in humans. A randomized, double blind, placebo-controlled clinical trial has been conducted in 39 HPV16 mono-infected high grade cervical intraepithelial neoplasia (CIN) patients (CIN 2/3). Two doses (75 lg or 250 lg) of CVLP were applied. The duration of the study was 24 weeks with 2 optional visits after another 12 and 24 weeks. The vaccine showed a very good safety profile with only minor adverse events attributable to the immunization. Antibodies with high titers against HPV16 L1 and low titers against HPV16 E7 as well as cellular immune responses against both proteins were induced. Responses were equivalent for both vaccine concentrations. A trend for histological improvement to CIN 1 or normal was seen in 39% of the patients receiving the vaccine and only 25% of the placebo recipients. Fifty-six percent of the responders were also HPV16 DNA-negative by the end of the study. Therefore, we demonstrated evidence for safety and a nonsignificant trend for the clinical efficacy of the HPV16 L1E7 CVLP vaccine. ' 2007 Wiley-Liss, Inc.Key words: cervical cancer; clinical trial; immunization; antibody; T cell Genital infection with human papillomavirus (HPV) is one of the most common sexually transmitted diseases. Various molecular and epidemiological studies have documented a correlation between infection with ''high risk'' HPV types and premalignant or malignant tumors of the anogenital tract. 1,2 It is widely acknowledged that a causal relationship exists between persistent HPV infection and development of cervical intraepithelial neoplasia (CIN) and cervical cancer. 3,4 There are over 100 known papillomavirus types that are stratified into low and high risk, based on their association with malignant and invasive lesions. More than 95% of invasive cervical cancers are positive for HPV-DNA, mainly from HPV types 16 (50%) and 18 (20%). Moreover, HPV16 can be detected in 30270% of all HPV-positive high grade CIN patients. 5,6 The prevalence of HPV16 in other intraepithelial neoplasias is even higher, e.g., 70280% in high grade vulvar intraepithelial neoplasia. 7 Whereas for low grade CIN a high spontaneous recovery rate is observed 6,8 high grade CIN regress less often particular at higher age when lesions are more persistent. 9 Because of the potential progression of high grade CIN to invasive cancer, 10 a thorough evaluation consisting of colp...

Genetically engineered herpes simplex viruses (HSVs) can selectively infect and replicate in cancer cells, and are candidates for use as oncolytic therapy. This long-term report of a phase I trial examines vascular administration of HSV as therapy for cancer. Twelve subjects with metastatic colorectal cancer within the liver failing first-line chemotherapy were treated in four cohorts with a single dose (3 x 10(6) to 1 x 10(8) particles) of NV1020, a multimutated, replication-competent HSV. After hepatic arterial administration, subjects were observed for 4 weeks before starting intra-arterial chemotherapy. All patients exhibited progression of disease before HSV injection. During observation, levels of the tumor marker carcinoembryonic antigen (CEA) decreased (median % drop = 24%; range 13-74%; P < 0.02). One of three individuals at the 10(8) level showed a 39% radiologic decrease in tumor size by cross-section and 75% by volume. HSV infection was documented from liver tumor biopsies. After beginning regional chemotherapy, all patients demonstrated a further decrease in CEA (median 96%; range 50-98%; P < 0.008) and a radiologic partial response. Median survival for this group was 25 months. During follow-up, no signs of virus reactivation were found. Multimutated HSV can be delivered safely into the human bloodstream to produce selective infection of tumor tissues and biologic effects.

Summary Background  Psoralen plus ultraviolet A (PUVA) is the standard treatment for early stages of mycosis fungoides. There have been no adequate randomized controlled trials with sufficient power comparing this modality with other therapies. Objective  To assess disease response and to compare the response rates of patients treated with PUVA alone or PUVA and bexarotene. Methods  EORTC 21011 (NCT 00056056) was a randomized phase III study comparing combined bexarotene (Targretin®) and PUVA vs. PUVA alone in patients with stage IB and IIA mycosis fungoides (MF). The primary endpoint was the overall response rate [complete clinical response (CCR) plus partial response (PR)]. Results  The study was prematurely closed due to low accrual after 93 of 145 required patients (65%) were randomized. Of the 93 randomized patients, 87 started treatment, 41 received PUVA and 46 received PUVA + bexarotene. Total UVA doses received were 107 J cm−2 (range 1·4–489·9) in the PUVA arm vs. 101·7 J cm−2 (0·2–529·9) in the combination arm. The safety profile was acceptable with few grade 3–4 toxicities observed in either arm. More drop‐outs due to toxicity were observed in the combination arm compared with the PUVA‐alone arm. The best overall response (CCR + PR) rate was 71% for PUVA alone and 77% for the combination arm (P = 0·57). The median duration of response was 9·7 months for PUVA vs. 5·8 months for the combination arm (P = 0·33). CCR was seen in 25 patients of whom 10 received PUVA alone (CCR 22%) and 15 received combination therapy (CCR 31%) (P = 0·45). CCR was sustained in 25% of patients regardless of therapy. There was a trend towards fewer PUVA sessions needed to achieve CCR in the combination arm (median 22) compared with the PUVA arm (median 27·5) (P = 0·11). Similarly, a trend towards lower UVA dose required to achieve CCR in the combination arm (median 55·8 J cm−2) compared with the PUVA arm alone (median 117·5 J cm−2) (P = 0·5) was observed. Conclusions  No significant difference in response rate or response duration was observed in this study. However, there was a trend towards fewer PUVA sessions and lower UVA dose required to achieve CCR in the combination arm (PUVA + bexarotene) but this did not achieve statistical significance due to insufficient power.