Bilateral common carotid artery mycotic aneurysms in the setting of intravenous drug abuse.

Carotid mycotic aneurysms are rare, and fewer than five case reports have described carotid mycotic aneurysms due to intravenous drug abuse. Rare bilateral intracranial mycotic carotid aneurysms have been reported, although a review of literature revealed no cases of bilateral extracranial carotid aneurysms. We have reported the case of a 41-year-old man who had presented with intermittent fevers, headaches, and myalgias of 2 weeks' duration. He was found to have bilateral carotid artery mycotic aneurysms after intravenous drug abuse with neck injections. We used a management strategy entailing unilateral endovascular balloon control with open surgical resection followed by placement of a saphenous vein graft. The contralateral aneurysm was managed nonoperatively with antibiotics.

A real world analysis of payment per unit time in a Maryland Vascular Practice.

PURPOSE: In 1992, Centers for Medicare and Medicaid Services instituted the Resource Based Relative Value Scale (RBRVS) system to determine physician reimbursement. Relative value units (RVU) were assigned to each Current Procedure Terminology (CPT) code and intended to reflect the time and intensity of work. Little data exist correlating actual procedural and clinical time with respect to reimbursement within the RVU value system. The purpose of this study was to determine how well this system distributes payments per hour for hospital-based procedures in a single vascular practice in the state of Maryland between July 1, 2008 and June 30, 2009. METHODS: As part of an ongoing prospective outcomes program, procedural times for all vascular procedures (time into until time out of room) were recorded. Fifteen minutes were added for administrative functions on procedural day, each hospital day, and office visits during the global period. The combination of all times was reflected in the total care time (TCT) for each procedure. We recorded all physician fees collected for each procedure. This total fee collected for each procedure was then divided by the TCT to determine the procedure-specific payment per unit time. All similar procedures were grouped together and the average reimbursement per procedure was reported. RESULTS: Data was collected on all 1103 procedures performed during this period. Insurance carrier distribution was 75% Medicare and 25% private insurance. The average reimbursement was $316/hour for open procedures and $556/hour for endovascular. Higher reimbursing procedures included visceral endovascular procedures ($701/hour) and caval filters ($751/hour). Lower reimbursing procedures included lower extremity bypass ($292/hour), dialysis access ($268/hour) and lower extremity amputations ($223/hour). Striking was the difference between payment based on approach for similar conditions. Reimbursement for carotid stent vs carotid endarterectomy was $643/hour vs $383/hour, endovascular abdominal aortic aneurysm (AAA) repair vs open $593/hour vs $359/hour. CONCLUSION: This unique study demonstrates a "real world" experience of reimbursement per unit time and raises questions as to the validity of the RBRVS process. The disparity between payments for open and endovascular repair of similar conditions are typical of this inequality. These data do not reflect the intangible time of operative planning, administrative matters, or overhead, and these factors must be considered when interpreting this data. Regardless, this study suggests that capturing detailed financial data is possible and is a more accurate source for future discussions on reimbursement.

Angiographic lesion characteristics can predict adverse outcomes after carotid artery stenting.

BACKGROUND: Carotid artery angioplasty and stenting (CAS) is an evolving and increasingly common endovascular treatment for carotid artery stenosis. Risk factors associated with an increased incidence of adverse periprocedural neurologic outcomes are being recognized. The goal of this study was to determine if certain angiographic lesion characteristics were predictive of higher risks of adverse outcomes. METHODS: A total of 421 patients who underwent 429 carotid artery stenting procedures between June 1996 and June 2005 for symptomatic or asymptomatic carotid stenosis, and in whom preoperative carotid angiograms and follow-up records were available for review, were selected from a prospectively maintained database. Demographic data and procedural variables were recorded, including the presence or absence of the use of a cerebral protection device. Angiograms were reviewed for the following carotid lesion characteristics: length of lesion, percentage of stenosis, ostial involvement, lesion ulceration, calcification, and presence of contralateral carotid occlusion. Periprocedural stroke and 30-day adverse event rates (stroke, myocardial infarction, and death) were recorded for each patient. RESULTS: The periprocedural all-stroke rate was 3.7%. Octogenarians had a higher incidence of 30-day adverse events at 10.0% vs 3.8% (P = .029). The incidence of periprocedural stroke was increased in lesions > or =15 mm long, at 17.0% (8 of 47) vs 2.1% (8 of 382; P < .001), and in ostial centered lesions, 7.1% (11 of 154) vs 1.8% (5 of 275; P = .007). Multivariate regression also identified these two variables as independently associated with 30-day stroke rate: lesion length > or =15 mm (odds ratio [OR], 6.38; 95% confidence interval [CI], 35 to 17.29) or ostial involvement (OR, 3.12; 95% CI, 3.12 to 8.36). Other variables, including lesion calcification, ulceration, degree of stenosis, or presence of contralateral occlusion, were not associated with adverse outcomes. When studied separately, the use of cerebral protection devices in 241 patients (56%) did not change our observed correlations between angiographic characteristics and adverse procedural events. CONCLUSIONS: Certain lesion characteristics on angiography, such as length and ostial location, can predict adverse outcomes. The indication for CAS should be carefully evaluated in these cases.

18F-FDG PET scanning correlates with tissue markers of poor prognosis and predicts mortality for patients after liver resection for colorectal metastases.

UNLABELLED: (18)F-FDG PET has proven invaluable in the staging of patients with metastatic colorectal cancer. The aim of the current study was to determine whether this biologic scan would correlate with other cellular characteristics and the clinical behavior of tumors. METHODS: Ninety patients with resectable colorectal cancer metastatic to the liver underwent (18)F-FDG PET before hepatectomy. At surgery, tumors were harvested and prepared for assessment by histology and immunohistochemistry. Expression of Ki67 (a marker for cell proliferation), GLUT1 and GLUT3 (markers for glucose transportation), p53 and p27 (markers for cell cycle control), and BCL-2 (a marker for apoptosis) was assessed by a pathologist who was unaware of the PET results and the clinical outcome. Patients were followed to determine outcome. Survival analysis was performed comparing patient outcome in groups segregated according to standardized uptake values (SUVs) greater or less than 5, 7, or 10. RESULTS: Maximum SUV correlated with GLUT1 (P=0.03), Ki67 (P=0.026), and p53 (P=0.024) but did not correlate with p27, BCL-2, or GLUT3. Survival was significantly longer for patients with a low SUV than for patients with a high SUV, with P values of 0.014, 0.025, and 0.0095 for SUV cutoffs of 5, 7, and 10, respectively. CONCLUSION: (18)F-FDG PET is a biologic scan that predicts prognosis in patients with metastatic colorectal cancer. It is uncertain if this ability is due to cellular glucose metabolism or to a correlation with other cellular characteristics of aggressive tumors.

Predictors of diffuse renal microembolization following endovascular repair of abdominal aortic aneurysms.

We evaluated the incidence, risk factors, and clinical consequences of renal microembolic events following endovascular aneurysm repair using suprarenal or infrarenal fixation. Pre- and postoperative (1 month) computed tomographic angiograms were reviewed for new renal perfusion defects. Suprarenal aortic and infrarenal neck thrombus load was classified by circumference involved and thrombus thickness. Serum creatinine was measured preoperatively, on the first postoperative day, and 1 month postoperatively. Among 136 patients, 8 (5.9%) had bilateral microembolic cortical defects. Patients with moderate or severe suprarenal thrombus were more likely to have renal microemboli than those with no or mild suprarenal thrombus (17% vs 0%; p < .001). Similarly, patients with moderate or severe infrarenal neck thrombus were more likely to have renal microemboli than those with no or mild infrarenal thrombus (9.6% vs 1.5%; p = .08). Severe infrarenal thrombus was independently predictive of microembolization (odds ratio 15.0; 95% confidence interval 1.6-142; p = .018). There was no statistically significant difference in the incidence of renal microembolization when comparing suprarenal and infrarenal fixation (8.2% vs 4.0%; p = .47). Changes in creatinine from baseline were not different in those with or without renal microemboli. Renal microembolization is an uncommon but distinct radiographic finding that is more associated with significant neck thrombus than fixation level.

Endovascular management of isolated iliac artery aneurysms.

OBJECTIVE: We reviewed our experience with endovascular treatment of isolated iliac artery aneurysms (IAAs). METHODS: Medical records for consecutive patients undergoing endovascular IAA repair from 1995 to 2004 were reviewed. Computed tomography (CT) angiograms were used to assess IAA location, size, and presence of endoleaks after endovascular repair. Rates of primary patency and freedom from secondary interventions were estimated using the Kaplan-Meier life-table method. RESULTS: From July 1995 to November 2004, 45 patients (42 men), with a mean age of 75 years, underwent endovascular repair of 61 isolated IAAs: 41 common iliac, 19 internal iliac, and one external iliac. Five patients (11%) were symptomatic, although none presented with acute rupture. The mean preoperative IAA diameter was 4.2 +/- 1.7 cm. Fifteen patients (33%) had prior open abdominal aortic aneurysm repair. Local or regional anesthesia was used in 28 cases (62%). Thirty-four patients (75%) were treated with unilateral iliac stent-grafts, eight (18%) with bifurcated aortic stent-grafts, and three (7%) with coil embolization alone. Perioperative major complications included one early graft thrombosis that eventually required conversion to open repair and one groin hematoma that required operative evacuation. On follow-up, late complications included one additional graft thrombosis and one late death after amputation. No late ruptures occurred after endovascular repair, with a mean follow-up of 22 months (range, 0 to 60 months). The mean postoperative length of stay was 1.3 +/- 1.0 days. On postoperative CT scans obtained at 1, 6, 12, 24, and 36 months, aneurysm shrinkage was noted in 18%, 29%, 57%, 67%, and 83% of IAAs, respectively, compared with the baseline diameter. One hypogastric aneurysm enlarged in the presence of a later identified type II endoleak. Five endoleaks were noted (4 type II, 1 indeterminate) at 1 month, with four other endoleaks (1 type II, 1 type III, 2 indeterminate) identified on later CT scans. At 2 years, primary patency was 95%, and freedom from secondary interventions was 88%. CONCLUSIONS: Endovascular repair of isolated IAAs appears safe and effective, with initial results similar to those after endovascular abdominal aortic aneurysm repair.

Estrogen enhances the efficacy of an oncolytic HSV-1 mutant in the treatment of estrogen receptor-positive breast cancer.

Oncolytic herpes simplex virus-1 (HSV-1) mutants selectively replicate in and lyse tumor cells. Viral replication is dependent on the cellular proliferative mechanism. Estrogen increases cellular proliferation and decreases apoptosis in estrogen receptor-positive (ER+) human breast cancer cells. We hypothesize that the cellular changes produced by estrogen may enhance oncolytic viral replication and improve the treatment of ER+ breast cancer cells. Estrogen increased proliferation and replication of the HSV-1 mutant, NV1066, in ER+ breast cancer cells. Additionally, cells grown with estrogen had lower rates of apoptosis and higher bcl-2 levels at baseline and after infection. Estrogen enhanced the oncolytic effect of NV1066, with cell kills of 95% and 97% at MOIs of 0.1 and 0.5, compared to 53 and 87% respectively without estrogen (p<0.001). Therapy of ER+ human breast cancer cells with a replication-competent HSV-1 mutant is improved in the presence of estrogen, in contrast to more standard therapies, such as chemotherapy and radiation, which demonstrate decreased efficacy in similar conditions. These data provide the mechanistic basis for the use of oncolytic HSV-1 in patients with hormone receptor-positive breast cancer, particularly if the disease progresses with conventional therapies.

Real-time diagnostic imaging of tumors and metastases by use of a replication-competent herpes vector to facilitate minimally invasive oncological surgery.

Current efforts on expanding minimally invasive techniques into the realm of oncological surgery are hindered by lack of accurate visualization of tumor margins and failure to detect micro metastases in real time. We used a systemic delivery of a herpes viral vector with cancer-selective infection and replication to precisely differentiate between normal and malignant tissue. NV1066 is a genetically modified, replication-competent herpes simplex virus carrying a transgene for enhanced green fluorescent protein (GFP). We tested the potential of NV1066 in delineating tumor tissue in vitro and in vivo in a wide range of cancers and whether NV1066-induced GFP expression can detect small foci of tumors and metastases in in vivo models using an operating endoscope with fluorescent filters. Our findings indicate that NV1066 can be used for real-time intraoperative imaging and enhanced detection of early cancers and metastases. We demonstrate that a single dose of NV1066, administered either locally (intratumoral or intracavitary) or systemically, will detect loco-regional and distant disease throughout the body. Such cancer selectivity is confirmed in 110 types of cancer cells from 16 different primary organs. Fluorescence-aided minimally invasive endoscopy revealed microscopic tumor deposits unrecognized by conventional laparoscopy/thoracoscopy. Furthermore, NV1066 ability to transit and infect tumor and metastases is proven in syngenic and transplanted tumors in different animal models, both immunocompetent and immunodeficient. Cancer-selective GFP expression is confirmed by histology, immunohistochemistry, and qRT-PCR. These studies form the basis for real-time, intraoperative diagnostic imaging of tumor and metastases by minimally invasive endoscopic technology.

Carotid artery stenting in octogenarians is associated with increased adverse outcomes.

BACKGROUND: Carotid artery stenting is an increasingly common endovascular treatment of carotid artery stenosis advocated in high-risk patients despite reports of increased adverse periprocedural outcomes in patients aged >80 years. We sought to evaluate our single institution experience with octogenarians and whether they have an increased incidence of major complications with carotid artery stenting. METHODS: Three hundred eighty-six patients, including 260 patients from 10 regulatory trials, who underwent carotid artery stenting between June 1996 and March 2004 for symptomatic or asymptomatic carotid stenosis were reviewed from a prospectively maintained database. Periprocedural (< or =30 days after carotid artery stenting) cerebrovascular accident, transient ischemic attack, myocardial infarction, and death outcomes were compared between 87 octogenarians and 295 nonoctogenarians. Univariate and multivariate analysis was performed for confounding factors. Kaplan-Meier analysis of stroke and death outcomes was performed for a 1-year follow-up. RESULTS: All adverse outcomes were significantly higher in octogenarians compared with younger patients: 30-day stroke rate, 8.0% vs 2.7% (P = .02); 30-day stroke, myocardial infarction, or death, 9.2% vs 3.4% (P = .02). Cohorts were similar in terms of gender, comorbidities, antiplatelet medications, symptomatic status, and use of cerebral protection. Octogenarians had a greater incidence of contralateral internal carotid artery occlusion (26% vs 12%, P = .001), atrial fibrillation (21% vs 8%, P = .001), and congestive heart failure (28% vs 15%, P = .007), but a lower incidence of hypercholesterolemia (53% vs 72%, P = .001) and active smoking (8% vs 24%, P = .001). Multivariate analysis of 30-day major adverse outcomes demonstrated an association between age > or =80 and adverse outcome (odds ratio, 2.85; P = .043) as well as a protective effect of the preprocedural use of aspirin (odds ratio, 0.30, P = .027). At 1-year follow-up, only 75% of octogenarians and 87% of nonoctogenarians were free from stroke, myocardial infarction, or death (P = 005, Kaplan-Meier analysis). CONCLUSIONS: Octogenarians undergoing carotid artery stenting are at higher risk than nonoctogenarians for periprocedural complications, including neurologic events and death. Major event-free survival at 1 year is also significantly better in nonoctogenarians. These risks should be weighed when considering carotid stenting in elderly patients.

Can computed tomography scan findings predict "impending'' aneurysm rupture?

Several findings on computed tomography (CT) scans of intact aneurysms have been taken to suggest "imminent'' or "impending'' aneurysm rupture. Often these are identified incidentally in asymptomatic patients when an urgent operation was not planned and may even be ill advised. The authors evaluated whether these signs can truly predict short-term aneurysm rupture. A computerized medical archival system was reviewed from August 1994 to August 2004. Patients with aortic aneurysms and official CT scan reports of "impending rupture'' were reviewed. CT films and reports were reviewed for aneurysm characteristics, while computerized medical records were reviewed for patient demographics, comorbidities, symptoms, documented subsequent rupture, and operative findings. Signs of "impending rupture'' included the crescent sign, discontinuous circumaortic calcification, aortic bulges or blebs, aortic draping, and aortic wall irregularity. Rupture occurring within 2 weeks of the index CT was defined as supporting the "imminent'' label. Forty-five patients with aortic aneurysms and CT stigmata of "impending rupture'' were identified. Five patients with additional signs of suspicious leak and 1 with an infected previously repaired aneurysm were excluded. Of 39 intact aneurysms, 26 (67%) were infrarenal, 2 (5%) were suprarenal, and the remaining 11 (28%) were thoracoabdominal. The patient group had more women than expected (19/39, 49%) and larger aneurysms (mean diameter, 6.8 +/- 1.4 cm). Mean age was 74 years. Ten patients underwent elective repair within the first 2 weeks after the index CT scan (mean, 4 days), precluding adequate observation for early rupture. None had intraoperative signs of rupture. Early rupture: 2 of the 29 remaining patients ruptured within 72 hours of the CT scan, for a positive predictive value of 6.9%. One additional patient ruptured 7 months later after declining an early intervention. No Rupture: 26 patients were observed an average of 246 days (range, 14 days to 3 years) without evidence of rupture. Fourteen were repaired electively 2 weeks to 3 years after the index CT scan, and 12 never underwent repair, mostly because of severe associated comorbidities, and were observed a mean of 394 days without rupture. Although they should be taken seriously, CT signs of "impending rupture'' alone are poor predictors of short-term aortic aneurysm rupture, and alternative terminology is needed until better predictors can be identified.

Determining in-stent stenosis of carotid arteries by duplex ultrasound criteria.

PURPOSE: To develop customized duplex ultrasound criteria for assessment of in-stent restenosis in the carotid arteries. METHODS: A retrospective review was conducted of 605 patients who underwent carotid artery stenting (CAS) from July 1996 to August 2004 at a single institution. Data on the stented carotid artery were accumulated from patients who had carotid angiography and duplex ultrasound (US) within 30 days of each other. Preliminary review found 118 pairs of ultrasound scans and angiograms in stented carotid arteries. Peak systolic velocity (PSV), end-diastolic velocity (EDV), and internal carotid artery to common carotid artery ratio (ICA/CCA) were examined. Angiographic stenosis was graded by NASCET criteria and compared to velocity parameters at clinically relevant levels of stenosis. The Student t test was used to compare similarly obtained data from 41 nonstented carotid arteries. RESULTS: PSV, ICA/CCA ratio, and EDV increased to a greater degree in stented arteries with stenosis. In 50% to 69% stenotic arteries, mean ICA/CCA ratio was 4.74+/-0.61 in stented versus 3.68+/-0.24 in nonstented carotid arteries (p = 0.043). In arteries with > or = 70% stenosis, there were increases in PSV (475+/-22 versus 337+/-26 cm/s, p = 0.001), EDV (172+/-23 versus 122+/-8 cm/s, p = 0.043), and the ICA/CCA ratio (8.18+/-2.19 versus 5.11+/-0.66, p = 0.063) in stented versus nonstented arteries, respectively. To detect > or = 70% angiographic stenosis, PSV > or = 350 cm/s had 100% sensitivity, 96% specificity, 55% positive predictive value (PPV), and 100% negative predictive value (NPV); an ICA/CCA ratio > or = 4.75 had 100% sensitivity, 95% specificity, 50% PPV, and 100% NPV. To predict > 50% stenosis, combining PSV > or = 225 cm/s and ICA/PCA ratio > or = 2.5 increased sensitivity (95%), specificity (99%), PPV (95%), NPV (99%), and accuracy (98%). CONCLUSIONS: PSV and ICA/CCA increase with stenosis to a greater extent in stented carotid arteries, necessitating revision of existing US criteria to follow CAS patients. To determine > or = 70% in-stent stenosis, PSV > or = 350 cm/s and ICA/CCA ratio > or = 4.75 are sensitive criteria. To determine > or = 50% stenosis, combining PSV > or = 225 cm/s and ICA/PCA ratio > or = 2.5 is optimal.

Oncolytic herpes simplex virus-1 mutant expressing green fluorescent protein can detect and treat peritoneal cancer.

NV1066 is a herpes simplex virus-1 (HSV-1) oncolytic mutant that contains the gene for enhanced green fluorescent protein (EGFP). We sought to determine (1) whether NV1066 is effective against human peritoneal cancer, (2) whether EGFP is detectable in an animal model of gastric cancer, and (3) whether EGFP expression can be used to assess oncolytic therapy in a minimally invasive, laparoscopic system. The current study demonstrates that NV1066 is cytotoxic to OCUM human gastric cancer cells in vitro and in an in vivo model of disseminated peritoneal gastric cancer. In vitro this human gastric cancer cell line is sensitive to NV1066. Lysis occurs in a dose-dependent fashion, achieving near-complete lysis even at multiplicities of infection (MOIs) as low as 0.01 by 7 days. NV1066 also replicates within OCUM cells and induces expression of GFP in a dose-dependent manner. At MOIs of 0.01 to 1, EGFP expression is seen by flow cytometry in 100% of OCUM cells within 5 days after infection. NV1066 effectively treats OCUM carcinomatosis in an in vivo model. After intraperitoneal administration of NV1066, macroscopic tumor foci express EGFP by direct laparoscopy with the appropriate fluorescent filtering. Noncancerous organs are not infected and do not express EGFP. We conclude that NV1066 has significant oncolytic activity in vitro and in vivo and reliably induces EGFP expression in infected tumor cells. Furthermore, EGFP expression in intraperitoneal tumors can be visualized laparoscopically, allowing detection and localization of viral gene therapy.

Infection with oncolytic herpes simplex virus-1 induces apoptosis in neighboring human cancer cells: a potential target to increase anticancer activity.

PURPOSE: The antitumor efficacy of a herpes simplex virus (HSV)-1 oncolytic virus depends on the cytotoxic effect of the virus, but also on viral replication and spread within the tumor. Apoptosis is considered a defense mechanism of infected cells that minimizes the spread of viral progeny by limiting cellular production of virus. We sought to determine whether oncolytic HSV-1 infection induces apoptosis in neighboring, uninfected cells and whether manipulation of apoptosis can increase viral replication and cytotoxicity. EXPERIMENTAL DESIGN: NV1066 is an oncolytic HSV-1 mutant that contains the marker gene for enhanced green fluorescent protein. OCUM human gastric cancer cells were infected with NV1066 in vitro and inspected for apoptosis by Hoechst and terminal deoxynucleotidyltransferase-mediated nick end labeling staining and for infection by expression of green fluorescence. RESULTS: A significant increase in apoptosis was seen in cells infected by NV1066. More interestingly, a significant percentage (10%) of uninfected cells also proceeded to apoptosis. After NV1066 infection, cells were also treated with N-acetylcysteine (NAC), an inhibitor of apoptosis. By day 4 after infection, 2.7x more NV1066 was produced in cells exposed to NAC than in those not exposed to NV1066 (P = 0.04). NAC also increased tumor kill when administered with virus. CONCLUSIONS: These data suggest that NV1066 induces apoptosis in uninfected cocultured cells, potentially hindering propagation of viral progeny and concomitant tumor kill. Inhibition of apoptosis may improve the efficacy of oncolytic HSV-1 therapy.

The replication-competent oncolytic herpes simplex mutant virus NV1066 is effective in the treatment of esophageal cancer.

BACKGROUND: The oncolytic herpes simplex-1 virus, NV1066, is a replication-competent virus that has been engineered to infect and lyse tumor cells selectively and to carry a transgene for enhanced green fluorescent protein (EGFP). The purpose of this study was to determine viral cytotoxicity in an esophageal cancer cell line and to determine whether EGFP expression could be used as a marker of viral infection. METHODS: BE3 esophageal adenocarcinoma cells were infected with NV1066 in vitro to determine cell kill and viral replication. EGFP expression was assessed by flow cytometry. The in vivo anti-tumor activity of NV1066 was tested in subcutaneous and intraperitoneal xenograft models. EGFP expression was localized in vivo by fluorescent microscopy and fluorescent laparoscopy. RESULTS: NV1066 effectively replicated within and killed BE3 cells in vitro and in vivo. EGFP expression identified infected tumor cells. After NV1066 treatment in vivo, EGFP expression localized to the tumor. In an intraperitoneal tumor model, EGFP could be visualized endoscopically using a laparoscope with a fluorescent filter. CONCLUSIONS: NV1066 has oncolytic activity against the BE3 cell line and may be a useful therapy against esophageal cancer. EGFP expression localizes the virus and may help to identify tumor deposits in vivo. Oncolytic activity with NV1066 against gastrointestinal cancers may potentially be tracked by endoscopy.

Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase.

BACKGROUND: Replication-competent herpes simplex virus-1 (HSV-1) mutants have an oncolytic effect on human and animal cancers. The aim of this study was to determine whether G207, an HSV-1 mutant, can be combined with ionizing radiation (IR) to increase antitumor activity while decreasing treatment-associated toxicity. METHODS: This study was performed by using G207, a replication-competent HSV-1 mutant deficient in viral ribonucleotide reductase (RR) and the gamma(1)34.5 neurovirulence protein. The antitumor activity of G207 or IR was tested against HCT-8 human colorectal cancer cells in vitro and in an in vivo mouse subcutaneous tumor model. RESULTS: We demonstrated that G207 has significant oncolytic effect on HCT-8 cells in vitro in a cytotoxicity assay and in vivo in a mouse flank tumor model and that these effects are improved with low-dose IR. We further illustrated that the increased tumoricidal effect is dependent on the up-regulation of cellular RR by IR measured by a functional bioassay for RR activity. Chemical inhibition of RR by hydroxyurea abrogates the enhanced effect. In contrast to G207, R3616, the parent virus of G207 that expresses functional RR, does not exhibit enhanced oncolysis when combined with IR. CONCLUSIONS: These data encourage clinical investigation of combination radiation therapy and HSV oncolytic therapy.