Search PubMed⌕ Search

Biomedical subjects

Yuman Fong

Publications and source records attributed to Yuman Fong.

At least 37 records · Page 2Linked to original sources
PubMed2006

Intraoperative localization of lymph node metastases with a replication-competent herpes simplex virus.

OBJECTIVES: Lymph node status is the most important prognostic factor determining recurrence and survival in patients with mesothelioma and other thoracic malignancies. Accurate localization of lymph node metastases is therefore necessary to improve selection of resectable and curable patients for surgical intervention. This study investigates the potential to identify lymph node metastases intraoperatively by using herpes-guided cancer cell-specific expression of green fluorescent protein. METHODS: After infection with NV1066, a herpes simplex virus carrying green fluorescent protein transgene, human mesothelioma cancer cell lines were assessed for cancer cell-specific infection, green fluorescent protein expression, viral replication, and cytotoxicity. Murine models of lymphatic metastasis were established by means of surgical implantation of cancer cells into the preauricular (drainage to cervical lymph nodes) and pleural (mediastinal and retroperitoneal lymph nodes) spaces of athymic mice. Fluorescent thoracoscopy, laparoscopy, and stereomicroscopy were used to localize lymph node metastases that were confirmed by means of immunohistochemistry. RESULTS: In vitro NV1066 infected, replicated (5- to 17,000-fold), and expressed green fluorescent protein in all cancer cells, even when infected at a low ratio of one viral plaque-forming unit per 100 tumor cells. In vivo NV1066 injected into primary tumors was able to locate and infect lymph node metastases producing green fluorescent protein that was visualized by means of fluorescent imaging. Histology confirmed lymphatic metastases, and immunohistochemistry confirmed viral presence in regions that expressed green fluorescent protein. CONCLUSIONS: Herpes virus-guided cancer cell-specific production of green fluorescent protein can facilitate accurate localization of lymph node metastases. Fluorescent filters that detect green fluorescent protein can be incorporated into operative scopes to precisely localize and biopsy lymph node metastases.

Animals↗
PubMed2006

Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver.

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.

Adult↗
PubMed2006

Perihepatic lymph node assessment in patients undergoing partial hepatectomy for malignancy.

OBJECTIVE: To assess the value of preoperative imaging studies and the intraoperative assessment of perihepatic lymph nodes in patients undergoing partial hepatectomy for malignancy. SUMMARY BACKGROUND DATA: Perihepatic lymph node status is an important prognostic factor for patients undergoing hepatic resection for 1(o) and metastatic cancer. The value of preoperative imaging studies and intraoperative assessment of perihepatic nodes is unknown. METHODS: Perihepatic lymph nodes were sampled in 100 patients undergoing resection for 1(o) and metastatic hepatic malignancy. At the time of sampling, participating surgeons assigned a clinical suspicion score (scale, 1-5: 1 = clinically negative, 5 = clinically positive). Preoperative CT scans and PET scans were reviewed in a blinded fashion by 2 radiologists. Clinical assessment, CT, and PET scan results were analyzed in the context of the pathologic status of the lymph nodes. RESULTS: A mean of 3.2 +/- 0.2 nodes were sampled per patient. Fifteen patients had metastatic disease in perihepatic lymph nodes; 13 had suggestive findings on preoperative CT or PET, and 2 were clinically positive at exploration. Clinical assessment had a high negative predictive value (NPV) = 99% but a low positive predictive value (PPV) = 39%. Similarly, CT scans had a high NPV = 95% and a low PPV = 30%. PET scans had a NPV = 88% and a PPV of 100%. Of the 48 patients with both negative preoperative CT and PET scans, only 1 (2.1%) had metastatic nodal disease, and this was suspected based on the clinical assessment. Of the patients with negative CT and PET scans and a negative clinical assessment (n = 39), none had involved perihepatic nodes. CONCLUSIONS: In patients with 1(o) and metastatic liver cancer, the incidence of truly occult metastatic disease to perihepatic lymph nodes is low. Routine sampling of perihepatic lymph nodes will therefore have a low yield in patients without some evidence of disease on preoperative CT or PET scans or at the time of exploration.

Bile Duct Neoplasms↗
PubMed2006

Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database.

BACKGROUND: A recent revision of the American Joint Committee on Cancer (AJCC) staging for gallbladder cancer (6th Edition) involved some major changes. Most notably, T2N0M0 tumors were moved from stage II to stage IB; T3N1M0 disease was moved from stage III to stage IIB; and T4NxM0 (x = any) tumors were moved from stage IVA to stage III. METHODS: In order to determine if these changes were justified by data, an analysis of the 10,705 cases of gallbladder cancer collected between 1989 and 1996 in the NCDB was performed. All patients had >5 year follow-up. RESULTS: The staging according to the 6th Edition provided no discrimination between stage III and IV. Five-year survivals for stage IIA, IIB, III, and IV (6th Edition) were 7%, 9%, 3%, 2% respectively. The data from the National Cancer Database (NCDB) were used to derive a proposed new staging system that builds upon Edition 5 and had improved discrimination of stage groups over previous editions. CONCLUSIONS: Changes in staging systems should be justified by data. Multicenter databases, including the NCDB, represent important resources for verification of evidence-based staging systems.

Databases as Topic↗
PubMed2006

Real-time intraoperative detection of breast cancer axillary lymph node metastases using a green fluorescent protein-expressing herpes virus.

OBJECTIVE: To investigate the use of a green fluorescent protein (GFP)-expressing oncolytic herpes virus to enable real-time intraoperative detection of breast cancer lymph node metastases. SUMMARY BACKGROUND DATA: Axillary lymph node status is the most important factor determining treatment, recurrence, and overall survival for women with breast cancer. The current methods of determining nodal status, however, have limitations. NV1066 is a novel oncolytic herpes viral strain that specifically infects cancer cells and expresses GFP. METHODS: Seven human breast cancer cell lines were infected in vitro with NV1066 and assessed for GFP expression, viral replication, and cytotoxicity. An in vivo model of breast cancer lymphatic metastasis was established in mice. Tumor-bearing mice were treated with NV1066 via injection into the primary tumor. Axillary lymph nodes were analyzed using an in vivo fluorescent imaging system. Histologic and molecular assessment of lymph nodes were performed using immunohistochemistry and reverse transcriptase PCR and operating characteristics were determined. RESULTS: NV1066 infected, expressed GFP, replicated within, and killed all human breast cancer cell lines in vitro. Injection of NV1066 into primary breast tumors resulted in viral transit to axillary lymph nodes, infection of lymphatic metastases, and GFP expression that was visualized with in vivo fluorescent imaging. Histologic and molecular confirmation demonstrated favorable operating characteristics of this method (sensitivity 80%; specificity 96%). CONCLUSIONS: We introduce a novel, sensitive, and specific method of lymphatic mapping that utilizes NV1066-guided cancer cell-specific viral production of GFP to enable real-time intraoperative detection of lymphatic metastases.

Animals↗
PubMed2006

A selective approach to the resection of cystic lesions of the pancreas: results from 539 consecutive patients.

OBJECTIVE: To define a group of patients with pancreatic cysts who do not require resection. SUMMARY BACKGROUND DATA: The increased use of cross-sectional imaging has resulted in an increased identification of small, asymptomatic pancreatic cysts. Data have not been available to determine which lesions should be resected. METHODS: All patients evaluated at our institution between January 1995 and January 2005 for the ICD-9 diagnosis of pancreatic cyst were reviewed. Analysis was performed to identify associations between patient and cyst characteristics, and selection of operative or nonoperative management. RESULTS: Pancreatic cysts were evaluated in 539 patients. Initial management was operative in 170 patients (32%), and nonoperative (radiographic follow-up) in 369 patients (68%). Factors associated with initial operative management included presence of a solid component (45% vs. 6%, P < 0.001), larger size of the lesion (mean 4.8 cm vs. 2.4 cm, P = 0.001), and presence of symptoms (44% vs. 16%, P = 0.001). Malignancy was present in 18% (32 of 170) of patients initially resected. Mucinous tumors (n = 18) were the most common malignant histologic subtype. None of the invasive cancers arising from mucinous cysts was <3 cm. Median radiographic follow-up in patients initially managed nonoperatively was 24 months (range, 1-172 months). In 29 patients (8%), changes developed within the cyst that resulted in resection; malignancy was present in 11 of 39 (38%), representing 3% (11 of 369) of all patients being followed radiographically. CONCLUSIONS: Selected patients with cystic lesions <3 cm in diameter and without a solid component may be followed radiographically with a malignancy risk (3% this study) that approximates the risk of mortality from resection. Malignancy within mucinous tumors is associated with size, and small mucinous tumors are very unlikely to be malignant.

Adult↗
PubMed2006

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.

Breast Neoplasms↗
PubMed2006

Advances in oncolytic viral therapy.

Viral oncolytic therapy is under intense investigation as a novel anticancer strategy. Both alone and in combination with other conventional treatment modalities, viral oncolytics exploit the natural cytotoxicity of viruses to directly kill tumor cells. Results from preclinical studies demonstrating the intricate interaction between oncolytic viruses, the targeted tumors and their hosts, has resulted in new strategies being developed to overcome the challenges of maximizing oncolytic viral efficacy while ensuring safety. Advances in genetic engineering and the understanding of tumor biology targeting every step of the inherent host-virus interaction have allowed the design of novel viruses that selectively target, preferentially replicate in, and destroy cancer cells. A number of these oncolytic viruses have the potential to become powerful anticancer agents, especially against advanced solid tumors. The theory behind their design, the accomplishments to date and the most promising areas of research for this class of novel antineoplastic therapies are summarized in this review, with a particular focus on completed or ongoing clinical trials.

Adenoviridae↗
PubMed2005

Recent chemotherapy reduces the sensitivity of [18F]fluorodeoxyglucose positron emission tomography in the detection of colorectal metastases.

PURPOSE: [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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗
PubMed2005

Outcome of partial hepatectomy for large (> 10 cm) hepatocellular carcinoma.

BACKGROUND: Surgical resection for large (> 10 cm) hepatocellular carcinoma (HCC) is believed by many to be ineffective. The objective of the current study was to review the outcome of partial hepatectomy in patients with large HCC. METHODS: Between 1985 and 2002, 193 consecutive patients who underwent partial hepatectomy for HCC were identified from a prospective database. The 82 patients with tumors > 10 cm were compared with the remaining 111 patients with < or = 10 cm tumors. Clinicopathologic features were analyzed and prognostic factors were evaluated by univariate and multivariate analysis. RESULTS: The 5-year overall survival for patients with large HCC was 33% with a median of 32 months. Patients with < or = 10 cm tumors had similar survival. Furthermore, there was no significant difference between the groups in operative mortality (2% in large HCC vs. 6%) or recurrence rate. In patients with large HCC, vascular invasion by tumor and intraoperative blood loss > 2 liters predicted overall survival on multivariate analysis. CONCLUSIONS: Partial hepatectomy is safe for patients with large HCC. In selected patients with large tumors, resection achieves similar overall survival and recurrence-free survival to that of patients with smaller tumors. Minimizing intraoperative blood loss appears to be critical for favorable long-term outcome in patients with large HCC.

Aged↗
PubMed2005

Herpes simplex virus amplicon delivery of a hypoxia-inducible soluble vascular endothelial growth factor receptor (sFlk-1) inhibits angiogenesis and tumor growth in pancreatic adenocarcinoma.

BACKGROUND: Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates angiogenesis and tumor proliferation. The VEGF signaling pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase 1; sFlk-1), which bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV) amplicons are replication-incompetent viruses used for gene delivery. We attempted to attenuate angiogenesis and inhibit pancreatic tumor growth through HSV amplicon-mediated expression of sFlk-1 under hypoxic control. METHODS: A multimerized hypoxia-responsive enhancer (10 x HRE) was cloned upstream of the sFlk-1 gene (10 x HRE/sFlk-1). A novel HSV amplicon expressing 10 x HRE/sFlk-1 was genetically engineered (HSV10 x HRE/sFlk-1).Human pancreatic adenocarcinoma cells (AsPC1) were transduced with HSV10 x HRE/sFlk-1 and incubated in normoxia (21% oxygen) or hypoxia (1% oxygen). Capillary inhibition was evaluated by human umbilical vein endothelial cell assay. Western blot assessed sFlk-1 expression. AsPC1 flank tumor xenografts (n = 24) were transduced with HSV10 x HRE/sFlk-1. RESULTS: Media from normoxic AsPC1 transduced with HSV10 x HRE/sFlk-1 yielded a 36% reduction in capillary formation versus controls (P < .05), whereas hypoxic AsPC1 yielded a 76% reduction (P < .005). Western blot of AsPC1 transduced with HSV10 x HRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia versus normoxia. AsPC1 flank tumors treated with HSV10 x HRE/sFlk-1 exhibited a 59% reduction in volume versus controls (P < .000001). CONCLUSIONS: HSV amplicon delivery of a hypoxia-inducible soluble VEGF receptor significantly reduces new vessel formation and tumor growth. Tumor hypoxia can thus be used to direct antiangiogenic therapy to pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed2005

Clinical and pathologic features of proximal biliary strictures masquerading as hilar cholangiocarcinoma.

BACKGROUND: Nontraumatic inflammatory hilar strictures are uncommon, but are known to mimic malignancy. This study examines the clinical and pathologic features of benign idiopathic strictures. STUDY DESIGN: Patients without a history of trauma or earlier biliary operation treated for benign strictures were identified. Clinical information was obtained from the medical record and all resected specimens were reexamined. RESULTS: From January 1992 to July 2003, 275 patients with proximal biliary strictures were referred. Among these, 22 patients had a final histologic diagnosis of benign stricture, despite a suspected preoperative diagnosis of malignancy. All 22 patients underwent resection of the extrahepatic biliary tree, which in 10 patients was combined with en bloc partial hepatectomy. Histologic reexamination identified five different benign processes: lymphoplasmacytic sclerosing pancreatitis and cholangitis, primary sclerosing cholangitis, granulomatous disease, nonspecific fibrosis/inflammation, and stone disease. Major postoperative morbidity occurred in 6 (26%) patients but none died. No preoperative clinical or radiographic features were identified that could reliably distinguish patients with benign strictures from those with cancer. CONCLUSIONS: "Malignant masquerade" of the proximal bile duct results from several different underlying conditions, and differentiating benign strictures from cancer remains problematic. The treatment approach should continue to be resection for presumed malignancy.

Adolescent↗
PubMed2005

Citation characteristics of basic science research publications in general surgical journals.

BACKGROUND: Basic science research (BSR) publications in general surgical (GS) journals are an important "translational bridge" for practicing surgeons and surgical trainees. The purpose of this study is to characterize the BSR publications in GS journals and to analyze their citation frequencies. METHODS: In 1996, all (224) BSR publications in the five highest rated U.S. GS journals (by impact factor) were reviewed, characterized, and their citation frequencies were compared to BSR publications in non-GS journals. RESULTS: On average, a BSR publication from these journals is cited 32 times (range 1-141, median 11). Half of the publications were cited more than 10 times in 6 years and 22% were cited twice, or more, within 1 year of publication. One in four publications were cited twice or more in journals with an impact factor greater than five. Citation frequencies of BSR publications in GS journals were related to the journal impact factor (P = 0.07), and to having a basic scientist (i.e., Ph.D.) as one of the authors (P < 0.01). Citation characteristics of BSR publications in GS journals were similar to those of BSR publications in non-GS journals with similar impact factors. CONCLUSIONS: We found that BSR publications in the U.S. GS journals studied had significant citation frequencies.

Biomedical Research↗
PubMed2005

Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days. RESULTS: The MTD for patients in group A was Oxal 100 mg/m(2), CPT-11 150 mg/m(2), and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m(2), LV 400 mg/m(2), and FU 1,400 mg/m(2) by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection. CONCLUSION: Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.

Adult↗
PubMed2005

Enhanced nectin-1 expression and herpes oncolytic sensitivity in highly migratory and invasive carcinoma.

PURPOSE: Although a variety of malignant tumors are susceptible to therapy with oncolytic herpes simplex viruses, the determinants of tumor sensitivity to these viruses are poorly understood. Nectin-1 is a cell surface adhesion molecule that is a component of intercellular adherens junctions and also functions as a herpes viral receptor. Because highly invasive cells may have decreased intercellular adhesion, we sought to determine if such cells might also have altered availability of cell surface nectin-1 to act as a herpes receptor. EXPERIMENTAL DESIGN AND RESULTS: A series of squamous cell carcinoma lines of increasing migratory and invasive potential, termed MG1-MG14, were selected by serial passages of murine SCC7 through Matrigel invasion chambers. Available cell surface nectin-1 was enhanced on the MG11 and MG14 cell lines in comparison to SCC7 as measured by cellular ELISA and immunofluorescence microscopy. A replication-competent, oncolytic herpes virus (NV1023) showed an increased ability to enter MG11 and MG14 cells as compared with SCC7 cells. Furthermore, MG11 and MG14 supported increased herpes viral replication and cytotoxicity over SCC7. For all three of the cell lines, viral entry assays revealed that the actively migrating cells were significantly more susceptible to herpes infection than the nonmigrating cells. CONCLUSIONS: These results show that malignant cells with highly migratory and invasive properties may exhibit increased cell surface nectin-1 availability, which may serve as a herpes viral receptor to enhance the efficacy of herpes oncolytic therapy. This finding has implications regarding patient selection for future clinical trials using these promising therapeutic vectors.

Animals↗
PubMed2005

Liver regeneration in humans is characterized by significant changes in cellular phosphorus metabolism: assessment using proton-decoupled 31P-magnetic resonance spectroscopic imaging.

In the present study we applied proton-decoupled 31P magnetic resonance spectroscopic imaging (MRSI) to noninvasively assess liver metabolism in patients who had undergone a partial hepatectomy (PH). Proton-decoupled 31P chemical shift imaging was performed in 47 patients 2-28 days following major hepatectomy, and the results were compared with those from eight control subjects. All studies were performed on a 1.5T MR imager (General Electric, Milwaukee, WI) equipped with a stand-alone proton decoupler. A 31P-1H resonator pair was used for data acquisition, and 31P data were obtained in 34 min. Liver regeneration was characterized by increases in phosphoethanolamine (PE), and decreases in nucleoside triphosphates (NTP), glycerophosphoethanolamine (GPE), and glycerophosphocholine (GPC). These alterations were most marked 48-72 hr after hepatectomy and returned to baseline within 3 weeks. The level of PE measured by MRSI was also found to depend on the percentage of liver that was removed, while changes in levels of cellular high energy phosphates were independent of the size of liver resection. Implementation of proton-decoupling was critical for assessing individual phosphomonoester and phosphodiester components. This study demonstrates that 31P MRSI can be used to assess metabolic changes in humans during liver regeneration, and may be useful for assessing derangement of the regenerative process or guiding adjuvant chemotherapies.

Female↗
PubMed2005

Employing tumor hypoxia for oncolytic therapy in breast cancer.

Hypoxia is a common tumor condition associated with metastases, therapeutic resistance, and poor patient survival. Forty percent of breast cancers are hypoxic, with a median oxygen concentration of 3.9%, and a third of tumors have regions less than 0.3%. Normal breast tissue is reported to have oxygen concentrations greater than 9%. This tumor hypoxia in breast cancer confers resistance to conventional radiation therapy and chemotherapy, as well as making estrogen-receptor-positive tumors less sensitive to hormonal therapy. Novel treatment modalities are needed to target hypoxic tumor cells. Lower tumor oxygen levels compared with surrounding normal tissues may be utilized to target and enhance herpes oncolytic viral therapy in breast cancer. Attenuated oncolytic herpes simplex viruses offer a unique cancer treatment by specifically infecting, replicating within, and lysing tumor cells. They carry genetically engineered mutations to reduce their virulence and attenuate their ability to infect normal tissues. Studies have shown the safety and efficacy of oncolytic herpes simplex viruses in treating breast cancer both in humans and in preclinical models. The placement of essential viral genes under the control of a hypoxia-responsive enhancer, which is upregulated selectively in hypoxic tissue, represents a promising strategy to target oncolytic viruses precisely to hypoxic cancer cells. In this review we describe strategies to harness hypoxia as a trigger for oncolytic viral gene expression in breast cancer, thereby increasing the specificity of viral infection, replication, and cytotoxicity to hypoxic areas of tumor. Such a targeted approach will increase efficacy in the therapy of hypoxic tumors while achieving a reduction in total dose of viral therapy.

Breast Neoplasms↗