Lana Y. Schumacher

Outcome after total hip arthroplasty: Comparison of a traditional disease-specific and a quality-of-life measurement of outcome

The purpose of this study was to examine the relationship between the Harris Hip Score (HHS), a traditional method of patient assessment of a total hip arthroplasty (THA), and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), a commonly used health-related quality-of-life survey. One hundred forty patients returning for routine clinical follow-up evaluation of a primary THA were asked to fill out the SF-36 quality-of-life survey, as well as questions concerning their perceptions of their THA. The patients surgeon assessed the THA with the traditional HHS. The correlations between the HHS and the SF-36 domains were highest in the physical component summary scores for male patients of all ages and female patients 65 years of age or older. The correlations were lower for the mental component summary scores of all patients, but particularly in female patients younger than 65. When the SF-36 scores were compared with age and sex-matched population norms, both age and sex were found to be important. Men younger than 65 had scores lower than norms in the physical function domains, but were comparable in the mental health domains. The older men had scores comparable to the norms in all domains. Female patients of all ages, however, had lower scores in the physical function domains. The greatest differences were noted in the female patients younger than 65. The HHS is commonly used to assess disease-specific pain and function in THA patients; however, the results of this study suggest that the SF-36 health survey can capture additional important quality-of-life domains that are influenced by a THA and that these domains are influenced by the age and sex of the patient. The combination of a disease-specific scoring system and a quality-of-life survey would allow a more global assessment of a THA in all patients. Studies evaluating the results of THAs should either assess the results of male and female patients separately when sample size is sufficiently large or use sex as a possible covariate in a multivariate analysis.

Immunosensitization of Tumor Cells to Dendritic Cell-Activated Immune Responses with the Proteasome Inhibitor Bortezomib (PS-341, Velcade)

Proteasome inhibition results in proapoptotic changes in cancer cells, which may make them more sensitive to immune effector cells. We established a murine model to test whether the proteasome inhibitor bortezomib could sensitize established B16 melanoma tumors to dendritic cell (DC)-activated immune effector cells. Day 3-established s.c. B16 tumors had significantly decreased tumor outgrowth when treated with a combination of bortezomib and DC, regardless of whether the DC were loaded or not with a tumor Ag. In vivo Ab-depletion studies demonstrated that the effector cells were NK and CD8+ cells, but not CD4+ cells. NF-κB nuclear transcription factor assay and gene-expression profiling of B16 treated with bortezomib was consistent with inhibition of NF-κB target genes leading to a proapoptotic phenotype. In vitro lytic assays demonstrated that TNF-α, but not perforin, Fas-ligand, or TRAIL, was responsible for bortezomib-sensitized B16 cytotoxicity. In conclusion, the proteasome inhibitor bortezomib can pharmacologically sensitize tumor cells to the lytic effects of DC-activated immune effector cells.

Human dendritic cell maturation by adenovirus transduction enhances tumor antigen-specific T-cell responses.

Abstract: Dendritic cells (DCs) have been shown to require a degree of maturation to stimulate antigen-specific, type 1 cytotoxic T lymphocytes in numerous murine models. Limited data in humans suggest that immature DCs (DC) can induce tolerance, yet a variety of nonmatured DC used clinically have induced antigen-specific type 1 T cells in vivo to various tumor-associated antigens. Use of adenovirus to engineer DCs is an efficient method for delivery of entire genes to DC, but the data on the biologic effects of viral transduction are contradictory. The authors demonstrate that DCs transduced with adenovirus (AdV) clearly become more mature by the phenotypic criterion of upregulation of CD83 and downregulation of CD14. Transduced DCs also decrease production of IL-10, and a subset of transduced DCs produce increased levels of IL-12 p70. This level of maturation is superior to that achieved by treatment of these cells with tumor necrosis factor-&agr; or interferon-&agr; but less pronounced than with CD40L trimer or CD40L + interferon-γ. Maturation by AdV transduction alone leads to efficient stimulation of antigen-specific T cells from both healthy donors and patients with advanced cancer using two defined human tumor-associated antigens, MART-1 and AFP. Given the pivotal role of DCs in immune activation, it is important to understand the direct biologic effects of AdV on DCs, as well as the impact these biologic changes have on the stimulation of antigen-specific T cells. This study has important implications for the design of DC-based clinical trials.

Enhanced Tumor Responses to Dendritic Cells in the Absence of CD8-Positive Cells

Wild-type mice immunized with MART-1 melanoma Ag-engineered dendritic cells (DC) generate strong Ag-specific immunity that has an absolute requirement for both CD8+ and CD4+ T cells. DC administration to CD8α knockout mice displayed unexpectedly enhanced levels of protection to tumor challenge despite this deficiency in CD8+ T cells and the inability to mount MHC class I-restricted immune responses. This model has the following features: 1) antitumor protection is Ag independent; 2) had an absolute requirement for CD4+ and NK1.1+ cells; 3) CD4+ splenocytes are responsible for cytokine production; 4) lytic cells in microcytotoxicity assays express NK, but lack T cell markers (NK1.1+ αβTCR− CD3−); and 5) the lytic phenotype can be transferred to naive CD8α knockout mice by NK1.1+ splenocytes. Elucidation of the signaling events that activate these effective cytotoxic cells and the putative suppressive mechanisms in a wild-type environment may provide means to enhance the clinical activity of DC-based approaches.

Natural killer cells play a critical role in the immune response following immunization with melanoma-antigen-engineered dendritic cells

Tumor antigen gene-modified dendritic cells (DC) generates robust antigen-specific protective antitumor responses. Though the role of CD4 positive and CD8 positive cells in the immunological response to gene-modified DC has been well-characterized, the role of NK cells in this response has been somewhat less clear. Owing to the significant contribution of innate immunity in other model systems, we postulated that NK cells would hold a critical position in the generation of an immune response following immunization with tumor antigen-engineered DC. Immunization with MART-1 melanoma antigen-engineered DC in C57BL/6 mice resulted in the generation of antigen-specific cytotoxic T lymphocytes and in vivo protective responses to the murine B16 melanoma. These responses were dependent on the presence of functional NK cells, although NK cells alone were not sufficient in generating protective responses. Adoptive transfer of NK cells into an NK-deficient but T-cell-competent environment restored the protective response to gene-modified DC immunization. In conclusion, protective immunity after tumor antigen gene-modified DC immunization requires collaboration between CD4+ and CD8+ T cells and NK cells.

High grade soft tissue sarcoma of the flexor fossae. Size rather than compartmental status determine prognosis

Background. High grade soft tissue sarcoma arising in the popliteal space, axilla, and antecubital fossae (flexor fossae tumors) have by convention been classified as extracompartmental tumors by the accepted staging and grading criteria of the Musculoskeletal Tumor Society (MSTS). Advances in neoadjuvant chemotherapy and radiation therapy have made surgical resection more feasible. The hypothesis to be tested is that compartmental status may not be of prognostic significance if the tumor is adjusted for size, histologic grade, and distant metastasis after undergoing adjuvant chemotherapy and radiation.

Endoscopic clipping of a post-whipple pancreatic bleed

BackgroundBleeding after pancreaticoduodenectomy most often occurs from the gastro- or duodeno-jejunal anastomosis. Bleeding at the pancreatic surface would be the most difficult to treat because it typically requires surgical resection of the pancreatic remnant—a surgery that has significant morbidity and mortality. Data that describe the role of endoscopy in the management of pancreaticojejunostomy bleeding are limited.CaseWe present the case of a 69-year-old man who had massive upper gastrointestinal bleeding on postoperative day 2 after a pyloric sparing Whipple procedure for cholangiocarcinoma. We endoscopically approached this massive upper gastrointestinal bleed by understanding the postsurgical anatomy to consider all of the potential bleeding sources: duodenojejunostomy, hepaticojejunstomy, and the pancreaticojejunostomy. Using a pediatric colonoscope with water jet capabilities, active bleeding could be seen originating from the cut pancreatic surface. Complete hemostasis was achieved after placement of two␣clips. We clipped again two clays later due to a minor rebleeding episode. We repeated endoscopy on postoperative day 6 for surveillance of the site. All clips were in place and there was no evidence of bleeding. The patient did well without recurrent bleeding and was discharged home on postoperative day 7. Six-month follow-up showed no recurrent bleeding episodes or development of fistulas [1–3].ConclusionEndoscopic treatment of a bleeding site on the pancreatic surface of a pancreaticojejunostomy can be successful during the immediate postoperative period. Such an attempt at endoscopic hemostasis may prevent the need for completion pancreatectomy.

Esophageal Cancer: Initial Staging

The incidence of esophageal cancer is increasing. Worldwide it is the ninth most common malignancy and is endemic in many parts of the world, particularly in the developing countries. There were 14,550 new cases and 13,770 deaths from esophageal cancer in the United States in 2006. Esophageal cancer has two pathological subtypes: squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma is most common in geographic areas where esophageal cancer is endemic due to environmental or dietary factors. Squamous cell carcinoma occurs more frequently among men than women, and it is classically associated with alcohol and tobacco use. In addition, these patients often have a history of other squamous cell head and neck cancers. In the economically developed world adenocarcinoma is more common and its incidence is rapidly increasing. The reason for the substantial increase in the incidence of adenocarcinoma is multifactorial and may be due to an increasing frequency of gastroesophageal reflux disease (GERD) which currently affects up to 30% of the Western population. The majority of patients with adenocarcinoma also have evidence of Barrett’s esophagus, a metaplastic change in the lining of the esophagus from normal squamous to columnar intestinal epithelium. Proper and accurate staging for esophageal cancer is essential because treatment modalities should be based not only on the staging information but also on the prognosis. Patients with metastatic disease should not undergo surgical resection. Therefore, there is a large emphasis on studying the most effective staging modalities which would allow patients to forgo expensive and invasive treatments which would offer no survival benefit in Stage IV (metastatic) disease.