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ABSTRACT: The origin and pathogenesis of malignant pleural mesothelioma (MPM) are closely aligned with inflammation. MPM tumors express interleukin-4 receptor α (IL-4Rα), the principal subunit of the IL-4 receptor. We set out to determine the biologic function and clinical relevance of IL-4Rα in human MPM.
Expression of IL-4Rα by human MPM tumors was determined by quantitative real-time PCR (n = 37) and immunohistochemistry (n = 52). Intracellular cytokine analysis of T-cell-derived IL-4 was carried out on matched tumor and blood samples from eight patients with MPM. Four human MPM cell lines were used to determine the direct effects of IL-4 on MPM tumor cells.
High tumor mRNA expression of IL-4Rα was an independent predictor of poor survival in patients with epithelial MPM [HR, 3.13, 95% confidence interval (CI), 1.68-7.15; P = <0.0001]. Ninety-seven percent of epithelial MPM tumors and 95% of nonepithelial MPM tumors expressed IL-4Rα protein by immunohistochemistry, and strong IL-4Rα staining correlated with worse survival in patients with epithelial histology (P = 0.04). A greater percentage of tumor-infiltrating T cells produced IL-4 compared with matched blood T cells (21% ± 7% vs. 4% ± 2%, P = 0.0002). In response to IL-4, human MPM cells showed increased STAT-6 phosphorylation and increased production of IL-6, IL-8, and VEGF, without effect on proliferation or apoptosis.
Tumor expression of IL-4Rα is inversely correlated with survival in patients undergoing surgical resection for epithelial MPM. Tumor-infiltrating T cells in MPMs are polarized to produce IL-4 and may provide endogenous activation signals to MPM tumor cells in situ. The IL-4/IL-4 receptor axis is a potential therapeutic target in human MPM.
Clinical Cancer Research 03/2012; 18(6):1568-77. · 7.74 Impact Factor
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ABSTRACT: Sarcoma frequently metastasizes to the lungs, and pulmonary metastasectomy is the only treatment modality that can provide a cure for these patients. We attempted to determine the clinicopathologic features and survival determinants of a common subset of patients who undergo pulmonary metastasectomy for leiomyosarcoma.
All patients undergoing pulmonary metastasectomy at The Brigham and Women's Hospital from 1989 to 2004 were reviewed retrospectively. Analyzed variables included number, size, pathology, and location of metastases, age, gender, location of primary tumor, disease-free interval (DFI), surgical approach, margin status, adjuvant therapy, recurrence, number of metastasectomies, and disease-free and overall survival.
Eighty-two patients underwent pulmonary metastasectomy for metastases from sarcoma. Leiomyosarcoma was the most common histologic finding (n = 31; 38%). Fifteen patients with leiomyosarcoma (48%) underwent repeated pulmonary metastasectomy. Patients with leiomyosarcoma were more commonly female (77% versus 43%; p = 0.031), less frequently received chemotherapy for their primary tumor (48% versus 71%, p = 0.041), and presented with fewer number of pulmonary metastases than did patients with nonleiomyosarcoma metastases (1.9 ± 1.5 standard deviation [SD] versus 3.6 ± 4.4; p = 0.033). Although there was no difference in disease-free survival, patients with leiomyosarcoma demonstrated improved overall survival compared with those with nonleiomyosarcoma metastases (70 versus 24 months; p = 0.049). In multivariate analyses, the DFI from primary tumor resection to pulmonary metastases and the DFI from pulmonary metastasectomy to second pulmonary recurrence were identified as independent predictors of survival.
Leiomyosarcoma is a common subset of sarcomatous pulmonary metastases that behave more indolently compared with other pulmonary metastases from sarcoma. Long-term survival is achievable with an aggressive approach toward pulmonary metastasectomy and repeated pulmonary metastasectomy.
The Annals of thoracic surgery 08/2011; 92(4):1202-7. · 3.74 Impact Factor
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ABSTRACT: Malignant pleural mesothelioma (MPM) tumor cells produce copious amounts of myeloid cell-stimulating factors. The current study examined the prognostic significance of circulating monocytes and tumor-infiltrating macrophages on overall survival in patients with MPM.
The authors retrospectively reviewed 667 patients with MPM who underwent cytoreductive surgery at the Brigham and Women's Hospital in Boston, Massachusetts between 1989 and 2009. Kaplan-Meier and Cox proportional hazards models were used to determine the impact of preoperative circulating monocytes on overall survival. Immunohistochemical staining for CD68 was performed on a tissue microarray of MPM tumors from 52 patients undergoing cytoreductive surgery. The phenotype of circulating monocytes and tumor-infiltrating macrophages in 7 additional patients was determined by flow cytometry.
The median survival for all patients was 13.4 months, and 35% of patients had tumors of nonepithelial histology. For patients with nonepithelial compared with epithelial tumors, survival was significantly worse (9.3 months vs 16.6 months; P < .0001), the number of monocytes was significantly higher (580 ± 20 cells/μL vs 520 ± 10 cells/μL; P = .002), and higher monocyte counts were associated with higher tumor stage. Increasing monocyte counts were correlated with poor survival for all patients with MPM. Within MPM tumors, macrophages comprised 27% ± 9% of the tumor area and demonstrated an immunosuppressive phenotype with high expression of CD163, CD206, and interleukin-4 receptor α. The degree of macrophage infiltration was found to be negatively correlated with survival in patients with nonepithelial (P = .008) but not those with epithelial (P = .7) MPM, independent of disease stage.
Higher numbers of circulating monocytes are associated with poor survival in all patients with MPM and higher densities of tumor-infiltrating macrophages are associated with poor survival in patients with nonepithelial MPM. Both may enable a novel target for immunotherapy.
Cancer 04/2011; 117(22):5234-44. · 4.77 Impact Factor
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ABSTRACT: A type II obturator hernia is a rare clinical entity that may be found on imaging and at surgery, as seen in this case of a 91-year-old woman who presented to our emergency department. Images are presented with treatment choices and a brief discussion on different types of obturator hernias.
American journal of surgery 03/2010; 199(6):e75-6. · 2.36 Impact Factor
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ABSTRACT: The human liver is enriched in NK cells which are potent effectors of the innate immune system. We have determined that liver NK cells freshly isolated from surgical specimens from patients with hepatic malignancy have less cytolytic activity than autologous blood NK cells. This difference was due to a higher proportion of CD16(-) NK cells in the liver and reduced cytotoxicity by CD16(+) liver NK cells compared with their blood counterparts. CD16(+) liver NK cells had similar expression of activating NK receptors and had similar intracellular granzyme B and perforin content compared with CD16(+) blood NK cells. CD16(+) liver NK cells contained a reduced fraction of cells with inhibitory killer Ig-like receptors specific for self-MHC class I (self-killer Ig-related receptor (KIR)) and an increased fraction of self-KIR(neg)NKG2A(pos) and self-KIR(neg)NKG2A(neg) cells. Using single-cell analysis of intracellular IFN-gamma production and cytotoxicity assays, we determined that CD16(+) liver NK cells expressing self-KIR were more responsive to target cells than those cells that did not express self-KIR molecules. CD16(+) liver NK cells gained cytolytic function when stimulated with IL-2 or cultured with LPS or poly(I:C)-activated autologous liver Kupffer cells. Thus, the human liver contains NK cell subsets which have reduced effector function, but under appropriate inflammatory conditions become potent killers.
The Journal of Immunology 09/2009; 183(3):1789-96. · 5.79 Impact Factor
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ABSTRACT: The liver is believed to promote tolerance, which may be beneficial due to its constant exposure to foreign Ags from the portal circulation. Although dendritic cells (DCs) are critical mediators of immune responses, little is known about human liver DCs. We compared freshly purified liver DCs from surgical specimens with autologous blood DCs. Liver and blood DCs were equally immature, but had distinct subset compositions. BDCA-1(+) DCs represented the most prevalent liver DC subset, whereas the majority of peripheral blood DCs were CD16(+). Upon TLR4 ligation, blood DCs secreted multiple proinflammatory cytokines, whereas liver DCs produced substantial amounts of IL-10. Liver DCs induced less proliferation of allogeneic T cells both in a primary MLR and after restimulation. Similarly, Ag-specific CD4(+) T cells were less responsive to restimulation when initially stimulated by autologous liver DCs rather than blood DCs. In addition, liver DCs generated more suppressive CD4(+)CD25(+)FoxP3(+) T regulatory cells and IL-4-producing Th2 cells via an IL-10-dependent mechanism. Our findings are critical to understanding hepatic immunity and demonstrate that human liver DCs promote immunologic hyporesponsiveness that may contribute to hepatic tolerance.
The Journal of Immunology 03/2009; 182(4):1901-11. · 5.79 Impact Factor
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ABSTRACT: Whether a freshly isolated immune cell can be equipped with both natural killing and antigen-presenting cell (APC) function has recently become controversial in mice. We sought to probe the existence of a candidate human cell with these properties by searching for cells in healthy subjects that co-express APC surface molecules and NK cell receptors. We have found that CD3(-)CD14(-)CD19(-) mononuclear cells of human blood, spleen, liver, and lymph nodes contain two distinct populations of cells that co-express HLA-DR (DR) and CD56. Circulating CD56(+) cells expressing high levels of DR were phenotypically and functionally similar to conventional CD56(-)dendritic cells (DC). Furthermore, we demonstrate here that a separate cohort of CD56(+) cells that express low levels of DR are NK cells that possess dual function as potent killers endowed with weak APC function.
Human Immunology 08/2008; 69(8):469-74. · 2.84 Impact Factor
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ABSTRACT: The liver contains a unique repertoire of immune cells and a particular abundance of NK cells. We have found that CD11c defines a distinct subset of NK cells (NK1.1(+)CD3(-)) in the murine liver whose function was currently unknown. In naïve animals, CD11c(+) liver NK cells displayed an activated phenotype and possessed enhanced effector functions when compared with CD11c(-) liver NK cells. During the innate response to adenovirus infection, CD11c(+) NK cells were the more common IFN-gamma-producing NK cells in the liver, demonstrated enhanced lytic capability, and gained a modest degree of APC function. The mechanism of IFN-gamma production in vivo depended on TLR9 ligation as well as IL-12 and -18. Taken together, our findings demonstrate that CD11c(+) NK cells are a unique subset of NK cells in the murine liver that contribute to the defense against adenoviral hepatitis.
Journal of Leukocyte Biology 08/2008; 84(4):1039-46. · 4.99 Impact Factor
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ABSTRACT: The high rate of mortality in patients with sepsis results from an inappropriately amplified systemic inflammatory response to infection. Toll-like receptors (TLRs) are important for the activation of innate immunity against microbial pathogens. We demonstrate a critical role of TLR9 in the dysregulated immune response and death associated with sepsis. Compared with wild-type (WT) mice, TLR9(-/-) mice exhibited lower serum inflammatory cytokine levels, higher bacterial clearance, and greater survival after experimental peritonitis induced by cecal ligation and puncture (CLP). Protection of TLR9(-/-) mice after CLP was associated with a greater number of peritoneal dendritic cells (DCs) and granulocytes than in WT controls. Adoptive transfer of TLR9(-/-) DCs was sufficient to protect WT mice from CLP and increased the influx of peritoneal granulocytes. Subsequent experiments with a depleting antibody revealed that granulocytes were required for survival in TLR9(-/-) mice. Remarkably, a single injection of an inhibitory CpG sequence that blocks TLR9 protected WT mice, even when administered as late as 12 h after CLP. Our findings demonstrate that the detrimental immune response to bacterial sepsis occurs via TLR9 stimulation. TLR9 blockade is a potential strategy for the treatment of human sepsis.
Journal of Experimental Medicine 07/2008; 205(6):1277-83. · 13.85 Impact Factor
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ABSTRACT: The liver harbors a diversity of cell types that have been reported to stimulate T cells. Although most hepatic dendritic cells are immature, a small population of CD11c(high) conventional dendritic cells (cDCs) exists that expresses high levels of costimulatory molecules. We sought to determine the relative contribution of cDCs to cross-presentation by the liver. In vitro, liver nonparenchymal cells (NPCs) depleted of cDCs induced only minimal proliferation and activation of antigen-specific CD8(+) T cells when loaded with soluble protein antigen. Using a transgenic mouse with the CD11c promoter driving expression of the human diphtheria toxin receptor, we found that selective depletion of cDCs in vivo reduced the number and activation of antigen-specific CD8(+) T cells in the liver after intravenous administration of soluble protein antigen. Adoptive transfer of DCs, but not CD40 stimulation, restored the hepatic T-cell response. Conclusion: Our findings indicate that the ability of the liver to effectively cross-present soluble protein to antigen-specific CD8(+) T cells depends primarily on cDCs. Despite costimulation, other resident liver antigen-presenting cells cannot compensate for the absence of cDCs.
Hepatology 05/2008; 47(4):1343-51. · 11.66 Impact Factor
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ABSTRACT: NK dendritic cells (NKDC) are a novel subtype of DC with NK cell properties. IL-15 is a pleiotropic cytokine that plays an obligate role in the proliferation and survival of NK cells. We hypothesized that IL-15 is also essential for NKDC development. NKDC were nearly absent in IL-15(-/-) mice, but restored by administration of exogenous IL-15. Treatment of wild-type mice with IL-15 caused a 2- to 3-fold expansion of both NK cells and NKDC. After 7 days of culture with IL-15, sorted splenic NKDC expanded 10-fold while NK cells increased 5-fold. NKDC expanded in IL-15 retained their cytolytic capacity but lost the ability to stimulate naive T cells. Meanwhile, NKDC expanded in IL-15 produced 10 times more IFN-gamma as fresh NKDC and conferred protection in a tumor prevention model. Thus, IL-15 is essential to the proliferation and survival of NKDC and IL-15 expanded NKDC possess antitumor properties.
The Journal of Immunology 11/2007; 179(7):4654-60. · 5.79 Impact Factor
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ABSTRACT: Described here is a rare case of intraperitoneal hemorrhage caused by diverticulitis of a non-perforated, non-ectopic tissue containing Meckel's diverticulum. Literature review and pathophysiology are discussed.
Digestive Diseases and Sciences 10/2006; 51(9):1546-8. · 2.12 Impact Factor
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ABSTRACT: [18F]2-fluoro-2-deoxyglucose (FDG) -positron emission tomography (PET) has become a useful tool in the assessment of patients with colorectal cancer. Patients often undergo chemotherapy as treatment for primary or metastatic colorectal malignancy. Because cytotoxic chemotherapy may decrease the cellular metabolic activity of tumor, we assessed the effects of chemotherapy on PET imaging.
This is a prospective study examining detection of hepatic colorectal metastases by FDG-PET as related to use of chemotherapy. Pathologic analysis of the liver resection specimens was used as gold standard.
There was significantly decreased tumor FDG uptake (as measured by the maximal standardized uptake value) in patients treated preoperatively with chemotherapy, resulting in less efficient detection of cancerous lesions. One biologic basis of this change in accuracy of PET was a significant decrease in the activity of the key glycolytic enzyme hexokinase in tumors from patients treated with chemotherapy.
These results indicate that FDG-PET scanning should be interpreted in the context of concurrent cytotoxic therapy. FDG-PET scanning results may also be useful in assessment of response to such cytotoxic therapies.
Journal of Clinical Oncology 01/2006; 23(34):8713-6. · 18.37 Impact Factor
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Digestive Diseases and Sciences 12/2005; 50(11):2163-4. · 2.12 Impact Factor
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ABSTRACT: To determine the effect of tumor diameter on the long-term survival of patients with stage I non-small cell lung cancer (NSCLC) within a large multi-institutional database, and to assess the accuracy of the T-descriptor threshold of 3 cm.
A total of 9,191 patients > or = 20 years old with surgically treated stage I NSCLC < or = 6 cm registered in the Surveillance, Epidemiology, and End Results database from 1992 to 1997 were included. The size of the nodule was grouped into six categories: < 1 cm (n = 191, 2%), 1 to 1.9 cm (n = 2,130, 23%), 2 to 2.9 cm (n = 2,851, 31%), 3 to 3.9 cm (n = 1,984, 22%), 4 to 4.9 cm (n = 1,161, 13%), and 5 to 6 cm (n = 874, 9%). Due to its limited sample size, subcentimeter nodules were not included in the survival analysis. Survival analyses were performed with Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards models.
A total of 4,904 (53%) men and 4,287 women (mean +/- SD age, 66.6 +/- 9.4 years) with stage I NSCLC were analyzed. The use of lobectomies and pneumonectomies as surgical treatment instead of limited resections increased with the size of the tumor, from 62% in subcentimeter nodules to 96% in 5- to 6-cm tumors (p < 0.0001). Survival decreased with increasing size of the tumor (p < 0.0001). There was a significant survival difference when size groups were compared to tumors 1.0 to 1.9 cm: 2.0 to 2.9 cm (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.16 to 1.47), 3.0 to 3.9 cm (HR, 1.49; 95% CI, 1.32 to 1.69), 4.0 to 4.9 cm (HR, 1.82; 95% CI, 1.59 to 2.08), and 5.0 to 6.0 cm (HR, 2.04; 95% CI, 1.77 to 2.36). Survival was similar in tumors between 2.0 to 2.9 cm and 3.0 to 3.9 cm, and in tumors between 4.0 to 4.9 cm and 5.0 to 6.0 cm.
The T descriptor should be changed so that T1 is reserved for tumors < 2 cm. Further refinement of larger tumors into T2a (2 to 3.9 cm) and T2b (> or = 4 cm) should be considered.
Chest 11/2005; 128(5):3255-60. · 5.25 Impact Factor
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ABSTRACT: Acute lumbar hernia secondary to blunt trauma is an uncommon injury of the abdominal wall and, when encountered, is a difficult challenge for the trauma surgeon.
Three cases of lumbar hernia secondary to blunt trauma are described and a review of the literature was conducted for other such cases. Clinical, anatomic, and demographic data were extracted from these reports and analyzed.
Sixty-three cases of lumbar hernia secondary to blunt trauma were found in the English literature and three cases are described here. Hernias occurred most commonly in the inferior lumbar triangle (70%) and were most frequently a result of a motor vehicle collision (71%). Physical examination findings were variable and reported in only a minority of cases (palpable hernia, 33%; flank hematoma, 27%) and associated intra-abdominal injuries were common (61%). Most traumatic lumbar hernias were diagnosed immediately, and computed tomography was 98% sensitive for diagnosis. Fifty-eight percent of patients were managed initially with exploratory laparotomy. Timing of hernia repair was variable.
Traumatic lumbar hernias are associated with a high incidence of intra-abdominal injury and should be considered in all cases of severe blunt abdominal trauma. Computed tomography should be implemented when the diagnosis is suspected in a hemodynamically stable patient. Repair should be performed by mesh patching techniques at a time based on clinical correlation.
The Journal of trauma 01/2005; 57(6):1361-70. · 2.48 Impact Factor
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ABSTRACT: Oncolytic viruses used for gene therapy have been genetically modified to selectively target tumor cells while sparing normal host tissue. The multimutant virus G207 has been attenuated by inactivation of viral ribonucleotide reductase and by deletion of both viral gamma134.5 genes. Deletion of gamma134.5 greatly decreases the neurovirulence of this mutant virus but also reduces its antitumor efficacy. The mammalian homologue to the gamma134.5 gene product is the GADD34 protein. This protein can functionally substitute for the gamma134.5 gene and is also up-regulated during DNA damage. We postulated that combining use of the chemotherapy agent mitomycin C (MMC) with G207 will selectively up-regulate GADD34 in tumor that may complement the gamma134.5 gene deletion and augment viral antitumor efficacy. This hypothesis was tested in human gastric cells in vitro and in vivo. Using both the isobologram method and combination-index method of Chou-Talalay, significant synergism was demonstrated between MMC and G207. As a result of such synergism, a dose-reduction for each agent can be accomplished over a wide range of drug-effect levels without sacrificing tumor cell kill. Northern blot analysis confirmed that expression of GADD34 mRNA was increased by MMC treatment. SiRNA directed at GADD34 decreased MMC-associated enhancement of viral proliferation and resulted in decreased viral synergy with MMC. These data indicate that induction of GADD34 selectively restores the virulent phenotype of the deleted gene in G207 and thus provides a cellular basis for the combined use of DNA-damaging agents and gamma134.5 HSV mutants in the treatment of cancer.
The FASEB Journal 07/2004; 18(9):1001-3. · 5.71 Impact Factor
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ABSTRACT: This study examined the clinical and pathologic features of regional spread of nonneurogenic neoplastic disease to the intratemporal segments of the facial nerve.
Retrospective review.SETTING Three tertiary referral centers.
Six patients with neoplastic disease of nonneurogenic origin involving segments of the facial nerve within the temporal bone.
All patients underwent surgery with curative intent. Five patients received adjuvant radiation, and two received adjuvant radiation and chemotherapy.
Histopathology, site of primary tumor, intratemporal location of regional spread along the facial nerve, degree of facial paralysis, and presence of residual disease.
Five cases of malignancy were reported: one case of parotid adenoid cystic carcinoma, one case of parotid mucoepidermoid carcinoma, two cases of squamous cell carcinoma of the skin, and one case of an unidentified carcinoma. Perineural spread was histologically found in all cases of malignant disease. In addition, one case of benign pleomorphic adenoma of the parotid gland that circumferentially involved an intratemporal segment of the facial nerve was reported. Facial paralysis was present in five of six (83%) of cases. Four patients had unresectable malignant disease, and two died despite multimodality therapy.
The facial nerve provides a route for the spread of neoplastic disease into the temporal bone, and perineural invasion is an important mechanism of invasion and motility of malignant disease. Nonneurogenic intratemporal tumors of the facial nerve are a rare but significant cause of facial paralysis.
Ontology & Neurotology 04/2003; 24(2):326-33. · 1.90 Impact Factor
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ABSTRACT: It was hypothesized that routine operative drainage is unnecessary for elective hepatic resection.
A review was made of the clinical records of patients undergoing liver resection at a tertiary referral hepatobiliary surgery center since the conclusion in April of 1994 of our previous randomized drainage trial. The main outcome measures were operative drainage versus no operative drainage assessed for possible association with diagnoses, extent of hepatectomy, hospital course, and postoperative radiologic percutaneous drainage procedures.
Of 1,165 patients, 184 were operatively drained with closed drains according to specific practice criteria and 981 were not subject to operative drainage. Patients who were not operatively drained had length of stay (10.1 days), mortality (2%), and complication rate (34%) comparable with the nondrained patients in the previous randomized trial. Ten percent of these patients required postoperative percutaneous drainage. Patients who were operatively drained were a group who were at higher risk for biliary leakage or infections and consequently had a significantly longer hospital stay, greater mortality, higher complication rate, and required a greater number of percutaneous abdominal drainages.
The 84% of patients not operatively drained had no greater adverse outcome. After hepatic resection, routine drainage of the abdomen is unnecessary.
The American Journal of Surgery 12/2002; 184(5):441-5. · 2.78 Impact Factor
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ABSTRACT: G207 and NV1020 are two replication-competent, multimutant oncolytic herpes simplex viruses evaluated in the current studies for their anticancer effects in the treatment of gastric cancer. Deletion of both gamma(1)34.5 genes and inactivation of ICP6 (ribonucleotide reductase) allows G207 to selectively replicate within tumor cells. NV1020 is another attenuated recombinant herpes virus with deletions of the HSV joint region, with deletion of only one copy of the gamma(1)34.5 gene, and with the ICP6 gene intact. In vitro, both G207 and NV1020 effectively infected, replicated, and killed human gastric cancer cells, with NV1020 being more effective at lower concentrations of virus. In a murine xenograft model of peritoneally disseminated gastric cancer, both NV1020 and G207 reduced tumor burden when given intraperitoneally (i.p.) at higher doses. When viral doses were lowered or when advanced tumor was treated, i.p. NV1020 was superior to i.p. G207. In vitro viral replication and cytotoxicity predicted the in vivo antitumor response. Intravenous delivery of either G207 or NV1020 failed to reduce tumor burden, demonstrating the importance of regional therapy as treatment for compartmentalized malignancy. Both agents were safe for use in animals, and immunohistochemistry performed on mouse tissue revealed selective viral targeting of tumor. Oncolytic therapy using genetically engineered HSVs represents a promising strategy for peritoneal malignancies.
Cancer Gene Therapy 12/2002; 9(11):935-45. · 2.80 Impact Factor
