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James D. Geiger

Bio: James D. Geiger is an academic researcher from University of Michigan. The author has contributed to research in topics: Immunotherapy & Hernia. The author has an hindex of 35, co-authored 104 publications receiving 4085 citations. Previous affiliations of James D. Geiger include Nationwide Children's Hospital & Boston Children's Hospital.


Papers
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Journal Article
TL;DR: It is demonstrated that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden, and the ability of the tumor lysate-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease is demonstrated.
Abstract: Dendritic cells (DCs) have been shown to be a promising adjuvant for inducing immunity to cancer. We evaluated tumor lysate-pulsed DC in a Phase I trial of pediatric patients with solid tumors. Children with relapsed solid malignancies who had failed standard therapies were eligible. The vaccine used immature DC (CD14-, CD80+, CD86+, CD83-, and HLA-DR+) generated from peripheral blood monocytes in the presence of granulocyte/monocyte colony-stimulating factor and interleukin-4. These DC were then pulsed separately with tumor cell lysates and the immunogenic protein keyhole limpet hemocyanin (KLH) for 24 h and then combined. A total of 1 x 10(6) to 1 x 10(7) DC are administered intradermally every 2 weeks for a total of three vaccinations. Fifteen patients (ages 3-17 years) were enrolled with 10 patients completing all vaccinations. Leukapheresis yields averaged 2.8 x 10(8) peripheral blood mononuclear cells (PBMC)/kg, and DC yields averaged 10.9% of starting PBMC. Patients with neuroblastoma, sarcoma, and renal malignancies were treated without obvious toxicity. Delayed-type hypersensitivity (DTH) response was detected in 7 of 10 patients for KLH and 3 of 6 patients for tumor lysates. Priming of T cells to KLH was seen in 6 of 10 patients and to tumor in 3 of 7 patients as demonstrated by specific IFN-gamma-secreting T cells in unstimulated PBMCs. Significant regression of multiple metastatic sites was seen in 1 patient. Five patients showed stable disease, including 3 who had minimal disease at time of vaccine therapy and remain free of tumor with 16-30 months follow-up. Our results demonstrate that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden. The DC can be administered in an outpatient setting without any observable toxicity. Most importantly, we have demonstrated the ability of the tumor lysate/KLH-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease.

332 citations

Journal ArticleDOI
TL;DR: The combined oligonucleotide microarray and proteomic approaches have uncovered novel genes associated with DC differentiation and maturation and has allowed analysis of post-translational modifications of specific proteins as part of these processes.

313 citations

Journal Article
TL;DR: The administration of tumor lysate-pulsed DCs is nontoxic and capable of inducing immunological response to tumor antigen and additional studies are necessary to improve tumor rejection responses.
Abstract: Purpose: The objectives of this study were to assess the toxicity and immunologicalresponse induced by the intradermal (i.d) administration of tumor lysate-pulsed dendritic cells (DCs). Experimental Design: Patients with stage IV solid malignancies were treated in cohorts that received 10 6 , 10 7 , and 10 8 DCs i.d. every 2 weeks for three vaccines. Each vaccine was composed of a mixture of half DCs pulsed with autologous tumor lysate and the other half with keyhole limpet hemocyanin (KLH). Peripheral blood mononuclear cells (PBMCs) harvested 1 month after the last immunization was compared with pretreatment PBMCs for immunological response. Delayed-type hypersensitivity reactivity to tumor antigen and KLH was also assessed. Results: Fourteen patients received all three vaccines and were evaluable for toxicity and/or immunological monitoring. There were no grade 3 or 4 toxicities associated with the vaccines or major evidence of autoimmunity. Local accumulation of CD4 + and CD8 + T cells were found at the vaccination sites. There was a significant proliferative response of PBMCs to KLH induced by the vaccine. In 5 of 6 patients, the vaccine resulted in increased IFN-γ production by PBMCs to KLH in an ELISPOT assay. Using the same assay, 3 of 7 patients’ PBMCs displayed increased IFN-γ production in response to autologous tumor lysate. One patient with melanoma also was observed to have an increased frequency of MART-1- and gp100-reactive CD8 + T cells after vaccination. By delayed-type hypersensitivity testing, 8 of 9 and 4 of 10 patients demonstrated reactivity to KLH and autologous tumor, respectively. Two patients with melanoma experienced a partial and a minor response, respectively. Conclusion: The administration of tumor lysate-pulsed DCs is nontoxic and capable of inducing immunological response to tumor antigen. Additional studies are necessary to improve tumor rejection responses.

239 citations

Journal ArticleDOI
TL;DR: Delayed management of acute nonperforated appendicitis allows greater efficiency and effective use of physician and hospital resources, including decreased resident involvement in operations during the night.

210 citations

Patent
24 Jan 2007
TL;DR: In this paper, a surgical instrument for treating a tissue includes a handpiece and a tissue engaging portion arranged to be received by the handpiece, where the first and second opposed jaw members are arranged to receive surgical energy from a surgical generator.
Abstract: A surgical instrument for treating a tissue includes a handpiece and a tissue engaging portion arranged to be received by the handpiece. The tissue engaging portion includes first and second opposed jaw members having an open position and a closed position for engaging the tissue therebetween, where the first and second jaw members are arranged to receive surgical energy from a surgical generator. The tissue engaging portion further includes at least one cooling member spaced from at least one of the first and second jaw members, where the cooling member has an open position and a closed position for engaging the tissue. Positioning the jaw members in their closed position and applying surgical energy to the tissue allows for treatment of the tissue, and positioning the cooling member in its closed position provides at least one of a pressure gradient or a thermal gradient between the jaw members and the cooling member.

174 citations


Cited by
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Journal ArticleDOI
TL;DR: Results in cancer vaccine trials are considered and alternate strategies that mediate cancer regression in preclinical and clinical models are highlighted.
Abstract: Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.

2,983 citations

Journal ArticleDOI
TL;DR: Dendritic cells are an essential target in efforts to generate therapeutic immunity against cancer owing to their ability to control both immune tolerance and immunity.
Abstract: Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.

1,737 citations

Journal Article
TL;DR: Male circumcision significantly reduces the risk of HIV acquisition in young men in Africa and should be integrated with other HIV preventive interventions and provided as expeditiously as possible.

1,692 citations

Journal ArticleDOI
TL;DR: This is the first report that polysaccharide degradation products of the extracellular matrix produced during inflammation might serve as an endogenous ligand for the TLR-4 complex on DCs.
Abstract: Low molecular weight fragmentation products of the polysaccharide of Hyaluronic acid (sHA) produced during inflammation have been shown to be potent activators of immunocompetent cells such as dendritic cells (DCs) and macrophages. Here we report that sHA induces maturation of DCs via the Toll-like receptor (TLR)-4, a receptor complex associated with innate immunity and host defense against bacterial infection. Bone marrow–derived DCs from C3H/HeJ and C57BL/10ScCr mice carrying mutant TLR-4 alleles were nonresponsive to sHA-induced phenotypic and functional maturation. Conversely, DCs from TLR-2–deficient mice were still susceptible to sHA. In accordance, addition of an anti–TLR-4 mAb to human monocyte–derived DCs blocked sHA-induced tumor necrosis factor α production. Western blot analysis revealed that sHA treatment resulted in distinct phosphorylation of p38/p42/44 MAP-kinases and nuclear translocation of nuclear factor (NF)-κB, all components of the TLR-4 signaling pathway. Blockade of this pathway by specific inhibitors completely abrogated the sHA-induced DC maturation. Finally, intravenous injection of sHA-induced DC emigration from the skin and their phenotypic and functional maturation in the spleen, again depending on the expression of TLR-4. In conclusion, this is the first report that polysaccharide degradation products of the extracellular matrix produced during inflammation might serve as an endogenous ligand for the TLR-4 complex on DCs.

1,363 citations

Journal ArticleDOI
TL;DR: Two representative models are examined, the regulation of eukaryotic initiation factor-2α by phosphorylation and internal ribosome initiation through the internal Ribosome-entry site, which illustrate the importance of translational control in the cellular stress response and apoptosis.
Abstract: Cells respond to stress stimuli through coordinated changes in gene expression. The regulation of translation is often used under these circumstances because it allows immediate and selective changes in protein levels. There are many examples of translational control in response to stress. Here we examine two representative models, the regulation of eukaryotic initiation factor-2alpha by phosphorylation and internal ribosome initiation through the internal ribosome-entry site, which illustrate the importance of translational control in the cellular stress response and apoptosis.

1,328 citations