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Jonathan S Zager

Publications and source records attributed to Jonathan S Zager.

8 recordsLinked to original sources
PubMed2005

Lymphatic mapping and sentinel node biopsy: a surgical perspective.

Lymphatic mapping and sentinel node biopsy has been rapidly and widely adopted by the surgical community as an oncologic equivalent elective lymphadenectomy for regional node staging in both melanoma and breast cancer. Despite being the de facto standard of care, it remains a highly unstandardized procedure surrounded by many unresolved controversies for surgeons who perform the procedure. The controversies are as basic as the definition of the real sentinel node and as specific as the appropriate localization pharmaceutical(s), site of injection, timing of the injection, and utility of external scintigraphy (dynamic versus. static). Furthermore, questions regarding surgical training, indications, and contraindications remain unanswered. Because there are few long-term studies stratified by technique and indication, the resolution of these surgical controversies are unlikely in the near future.

Breast Neoplasms↗
PubMed2004

Up-regulation of GADD34 mediates the synergistic anticancer activity of mitomycin C and a gamma134.5 deleted oncolytic herpes virus (G207).

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.

Animals↗
PubMed2004

Effect of murine liver cell proliferation on herpes viral behavior: implications for oncolytic viral therapy.

Replication-competent herpes simplex oncolytic viruses are promising anticancer agents that partly target increased DNA synthesis in tumor cells. Investigators have proposed that these DNA viruses may be combined with liver resection to enhance killing of liver malignancies. Whether or not the cellular alterations associated with hepatic regeneration affect the efficacy and toxicity of these promising anticancer agents is unknown. This study examined the behavior of two oncolytic viruses, NV1020 and G207, during liver regeneration. When delivered during the peak of liver regeneration, replication and appearance of both G207 and NV1020 in hepatic tissue are enhanced as demonstrated by histochemical staining for the marker gene lac Z, immunohistochemical staining, and quantitative polymerase chain reaction. This increased appearance of virus in liver tissue correlates with increases in cellular ribonucleotide reductase activity and DNA synthesis and is also associated with increased viral binding. However, increased viral presence is transient, and viral detection declines to baseline within 7 days. When these viruses were delivered to animals even as early as 7 days after hepatectomy, there proved to be no measurable viral replication in any organ and no increased morbidity or mortality. In conclusion, the early stages of hepatic regeneration after resection provide an environment suitable for viral replication. Administration of replication-competent herpes simplex virus during the peak of hepatocyte regeneration (24-48 hours) permits viral productivity in tissue that otherwise does not support viral growth. The increase in hepatotoxicity after hepatectomy is short-lived and can be predicted by peak hepatocyte DNA synthesis.

Animals↗
PubMed2002

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.

Animals↗
PubMed2002

Replication-competent herpes virus NV1020 as direct treatment of pleural cancer in a rat model.

OBJECTIVE: Innovative treatments are needed for metastatic disease involving the pleura. NV1020 is a novel, multimutated, replication-restricted herpes simplex virus under investigation for its ability to selectively kill tumors by means of direct cell lysis. This study examines NV1020 in a rat model of pleura-based lung cancer. METHODS: Cytotoxicity and viral proliferation were evaluated in vitro by exposure of the human non-small cell lung cancer cell line A549 to virus. NV1020 was also tested in an in vivo pleura-based cancer model established by injecting 1 x 10(7) A549 cells into the thoracic cavity of nude rats. Intrapleural treatments (1 x 10(7) viral particles) were given 3 hours or 3 days after tumor injection to model treatment of microscopic or macroscopic disease (n = 8-9/group). Tumor burden was assessed at 5 weeks. NV1020 infection and dissemination within the thoracic cavity was determined by means of immunohistochemistry. RESULTS: In vitro, at multiplicities of infection (viral particles per tumor cell) of 0.01, 0.1, and 1.0, cell killing of A549 by NV1020 was 66%, 90%, and 97%, respectively, at 7 days after infection. Viral burst occurred by day 2. Intrapleural treatment was effective for both the microscopic (P <.001) and macroscopic (P <.05) in vivo tumor models. Virus was detectable by means of immunohistochemistry in tumors but not in adjacent normal intrathoracic tissues. CONCLUSIONS: NV1020 is not only highly cytotoxic to the human lung cancer line A549 in vitro but can be delivered in a clinically relevant fashion to safely and effectively treat pleura-based tumor in vivo in a rat model.

Adenocarcinoma↗
PubMed2002

Efficacy of multiagent herpes simplex virus amplicon-mediated immunotherapy as adjuvant treatment for experimental hepatic cancer.

OBJECTIVE: To evaluate the use of herpes simplex viral (HSV) amplicon vectors for production of tumor vaccines and to determine if such vaccines expressing combinations of immunostimulatory agents may be effective in the treatment of experimental liver cancer. METHODS: A hepatic metastatic tumor model using CT-26 colorectal cancer in syngeneic Balb/C mice was utilized. Tumor vaccines were produced by brief (20 minutes) exposure of irradiated tumor cells to herpes amplicon vectors carrying the transgene for RANTES, B7.1, or GM-CSF. The antitumor efficacy of vaccination using tumor cells secreting GM-CSF (single agent) or a combination of RANTES/B7.1/GM-CSF (multiagent) was tested. The effect of 60% hepatectomy or T-cell depletion was also tested in this model. RESULTS: In vitro assays confirmed high-level cytokine or costimulatory molecule production by cells transduced with amplicons. Antitumor efficacy was observed with single-agent or multiagent treatment. Without hepatectomy, immunization with single-agent or multiagent vaccine therapy appears equivalent. When administered in the setting of hepatectomy, multiagent regimens produced a higher cure rate than single-agent therapy (50% vs. 12.5%, =.03). Animals treated with GM-CSF alone had an average nodule count of 40 +/- 19 ( <.006 vs. Hep control 232 +/- 30), while animals treated with multiagent therapy had an average nodule count of 11 +/- 7 ( <.0004 vs. control). CD4 and CD8 lymphocyte blockade abrogated observed efficacy, confirming a lymphocyte-mediated response. CONCLUSIONS: Tumor vaccines produced using HSV amplicon-mediated gene transfer may be useful in the treatment of liver malignancies. In the setting of hepatectomy, multiagent vaccine therapy offers an advantage over single-agent therapy. These data encourage consideration of such HSV-based neoadjuvant immunotherapy for treatment of liver malignancies.

Animals↗
PubMedDate not supplied

The role of ultrasound in the surgical management of patients diagnosed with ductal carcinoma in situ of the breast.

The purpose of this study was to determine the usefulness of ultrasound (US) as an adjunct to mammography (MMG) in the surgical treatment planning for patients with ductal carcinoma in situ (DCIS) of the breast. A total of 119 patients diagnosed with DCIS, who were treated between 1999 and 2002, were identified from the institutional database. US and MMG size of suspicious abnormalities, pathologic tumor size, and findings of axillary US and surgical axillary evaluation were analyzed. The median size difference of US versus pathologic tumor size and MMG versus pathologic tumor size was 1.0 and 2.0 cm, respectively. Correlation coefficients for US versus pathologic tumor size and MMG versus pathologic tumor size were 0.53 and -0.09, respectively. The negative and positive predictive values of axillary US to predict nodal disease were 93% and 27%, respectively. US evaluation appears to be a useful tool in conjunction with MMG in determining the extent of disease in patients diagnosed with DCIS. However, the low positive predictive value of US for evaluating metastases to axillary lymph nodes does not justify the routine use of this modality for axillary evaluation in patients with DCIS. Therefore the use of US for patients diagnosed with DCIS needs further investigation.

Adult↗