Leann Myers

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

Regulatory T (Treg) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen–reactive lymphocytes mediated by Treg cells; however, definitive evidence that Treg cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4+CD25+FOXP3+ Treg cells in 104 individuals affected with ovarian carcinoma, that human tumor Treg cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor Treg cells are associated with a high death hazard and reduced survival. Human Treg cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of Treg cells to the tumor. This specific recruitment of Treg cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking Treg cell migration or function may help to defeat human cancer.

Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity

Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibition of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, virtually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and interferon (IFN)-γ. T cells conditioned with the B7-H1–blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic–severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one approach for cancer immunotherapy.

B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma

Tumor-associated macrophages are a prominent component of ovarian cancer stroma and contribute to tumor progression. B7-H4 is a recently identified B7 family molecule. We show that primary ovarian tumor cells express intracellular B7-H4, whereas a fraction of tumor macrophages expresses surface B7-H4. B7-H4+ tumor macrophages, but not primary ovarian tumor cells, suppress tumor-associated antigen-specific T cell immunity. Blocking B7-H4-, but not arginase-, inducible nitric oxide synthase or B7-H1 restored the T cell stimulating capacity of the macrophages and contributes to tumor regression in vivo. Interleukin (IL)-6 and IL-10 are found in high concentrations in the tumor microenvironment. These cytokines stimulate macrophage B7-H4 expression. In contrast, granulocyte/macrophage colony-stimulating factor and IL-4, which are limited in the tumor microenvironment, inhibit B7-H4 expression. Ectopic expression of B7-H4 makes normal macrophages suppressive. Thus, B7-H4+ tumor macrophages constitute a novel suppressor cell population in ovarian cancer. B7-H4 expression represents a critical checkpoint in determining host responses to dysfunctional cytokines in ovarian cancer. Blocking B7-H4 or depleting B7-H4+ tumor macrophages may represent novel strategies to enhance T cell tumor immunity in cancer.

Component rotation and anterior knee pain after total knee arthroplasty.

All patients undergoing cruciate-retaining primary total knee arthroplasty for degenerative osteoarthritis at one center were studied prospectively. Clinical and radiographic followup was obtained at a minimum 5 years in 102 knees in 73 patients. Patients were asked specifically about the presence of the pain in the anterior aspect of the knee in the vicinity of the patella and rated the severity of the pain on a visual analog scale. Significant anterior knee pain rating at least 3 of 10 on the visual analog scale was present in 16 knees (13 patients). Eleven patients with 14 symptomatic knees agreed to undergo computed tomography scanning to accurately determine the rotation of the tibial and femoral components. The epicondylar axis and tibial tubercle were used as references using a previously validated technique. A control group of 11 asymptomatic patients (14 knees), matched for age, gender, and length of followup also underwent computed tomography scanning. All patients in both groups had normal axial alignment. There was a highly significant difference in tibial component rotation between the two groups with the patients with anterior knee pain averaging 6.2° internal rotation compared with 0.4° external rotation in the control group. There also was a significant difference in combined component rotation with the patients with anterior knee pain averaging 4.7° internal rotation compared with 2.6° external rotation in the control group. There was no significant difference in the degree of radiographic patellar tilt or patellar subluxation between the two groups. Patients with combined component internal rotation were more than five times as likely to experience anterior knee pain after total knee arthroplasty compared with those with combined component external rotation. Component malrotation is a significant factor in the development of anterior knee pain after total knee arthroplasty.

New Findings on Alternative Criteria for PTSD in Preschool Children

OBJECTIVE An alternative set of criteria for posttraumatic stress disorder (PTSD) for preschool children was analyzed for validity. METHOD Sixty-two traumatized children and 63 healthy controls, aged 20 months through 6 years, were assessed. The traumatic experiences included motor vehicle collisions, accidental injuries, abuse, and witnessing violence. The number of symptoms required for clusters C and D and the utility of proposed symptoms were systematically analyzed. RESULTS No cases met the DSM-IV algorithm for PTSD. Cluster B was endorsed 67.9% of the time. The proportion of cases meeting the cluster C threshold was 2% when three symptoms were required, 11% when two symptoms were required, and 39% when one symptom was required. The rate of cluster D was 45% when two symptoms were required and 73% when one symptom was required. Four novel symptoms did not substantially add to the diagnostic validity of the criteria. The optimal algorithm (one cluster B symptom, one cluster C symptom, and two cluster D symptoms) diagnosed PTSD at a rate of 26%. Measures of comorbid symptoms concurrently provided convergent validation to support this revised algorithm. CONCLUSION Revisions to the DSM-IV PTSD criteria continue to be supported so that highly symptomatic young children can be diagnosed.

Patellar Resurfacing in Total Knee Arthroplasty: A Prospective, Randomized, Double-blind Study with Five to Seven Years of Follow-up

Background: Whether to resurface the patella during a primary total knee arthroplasty performed for the treatment of degenerative osteoarthritis remains a controversial issue. Parameters that have been suggested as being useful in guiding this decision include patient height and weight, the presence of anterior knee pain preoperatively, and the grade of chondromalacia encountered intraoperatively. The purpose of this study was to determine whether these parameters were predictive of the clinical result following total knee arthroplasty with or without patellar resurfacing. Methods: Eighty-six patients (118 knees) undergoing primary total knee arthroplasty for the treatment of osteoarthritis were enrolled in a prospective, randomized, double-blind study. All patients received the same posterior-cruciate-sparing total knee prosthetic components. Patients were randomized to treatment with or without resurfacing of the patella. Evaluations consisted of the determination of a Knee Society clinical score, the completion of a patient satisfaction questionnaire, specific questions relating to patellofemoral symptoms, and radiographs. Sixty-seven patients (ninety-three knees) were followed for a minimum of five years (range, sixty to eighty-four months; average, 70.5 months). Results: With the numbers available, there was no significant difference between the groups treated with and without resurfacing with regard to the overall Knee Society score or the pain and function subscores. Obesity, the degree of patellar chondromalacia, and the presence of preoperative anterior knee pain did not predict postoperative clinical scores or the presence of postoperative anterior knee pain. Conclusions: The occurrence of anterior knee pain could not be predicted with any clinical or radiographic parameter studied. On the basis of these results, it seems likely that postoperative anterior knee pain is related either to the component design or to the details of the surgical technique, such as component rotation, rather than to whether or not the patella is resurfaced.

Relationship between B7-H4, Regulatory T Cells, and Patient Outcome in Human Ovarian Carcinoma

B7-H4 is a recently identified B7 family member. We previously showed that ovarian tumor and associated macrophages expressed B7-H4; tumor B7-H4+ macrophages and CD4+CD25+FOXP3+ regulatory T cells (Treg cells) suppressed tumor-associated antigen-specific T-cell immunity. To determine the pathologic relationship between B7-H4, macrophages, and Treg cells in the tumor environment, in addition to Treg cell numbers, we quantified B7-H4 expression in the tumor and tumor-associated macrophages in 103 patients with ovarian carcinoma. We observed that the intensity of B7-H4 expression in macrophages was significantly correlated with Treg cell numbers in the tumor. Further, both Treg cells and macrophage B7-H4, but not tumor B7-H4, were negatively associated with patient outcome. Tumor Treg cells enabled macrophages to spontaneously produce interleukin (IL)-10 and IL-6. Tumor macrophages stimulated B7-H4 expression in an autocrine manner through IL-10 and IL-6. Our previous work showed that tumor-associated macrophages spontaneously produced chemokine CCL22 to mediate Treg cell trafficking into tumor, and Treg cells induced B7-H4 on antigen-presenting cells (APC) including macrophages. Altogether, our data support the concept that there is a mechanistic interaction between Treg cells and macrophage, and that Treg cells may convey the suppressive activity to APCs through B7-H4 induction in human ovarian cancer.

Patterns and Correlates of Discontinuation of the Initial Haart Regimen in an Urban Outpatient Cohort

Objectives To describe the patterns and correlates of discontinuation of the initial highly active antiretroviral therapy (HAART) regimen in an urban, outpatient cohort of antiretroviral-naive patients. Design Retrospective cohort of 345 randomly selected antiretroviral-naive patients who initiated HAART on 6 selected regimens between January 1997 and May 2001 in New Orleans, LA. Methods An investigator reviewed medical records to collect information on concurrent medications, symptoms/diagnoses, staging indicators, and reasons for HAART discontinuation. Proportional hazards regression methods were used to identify predictors of discontinuation. Results After a median follow-up of 8.1 months, 61% of patients changed or discontinued their initial HAART regimen; 24% did so because of an adverse event. The events most commonly cited as the cause for discontinuation were nausea, vomiting, and diarrhea. A detectable viral load was associated with discontinuation at any time, while reporting nausea/vomiting or dizziness at the previous visit were associated with discontinuation during the first 3 months on HAART. Nausea/vomiting and not having AIDS at the time of HAART initiation were associated with discontinuation due to an adverse event at any time, while a high viral load, and dizziness or anorexia/weight loss at the previous visit were associated with discontinuation due to an adverse event in the first 3 months on HAART. Conclusions Gastrointestinal adverse events of HAART are the most frequently cited reason for discontinuation of HAART. An effort should be made to educate patients about these events and to encourage continued adherence. Additionally, appropriate prophylaxes for these events are warranted.

Physical and sedentary activity in school children grades 5-8 : the Bogalusa Heart Study

Physical and sedentary activity in children and adolescents has immediate health benefits and can also set a pattern that carries over into adulthood, resulting in long-term health benefits. Activity levels in a free-living biracial sample of children and adolescents, ages 9-15 yr (N = 995), were examined using a 24-h recall instrument, the Self-Administered Physical Activity Checklist. Selected sedentary activities (television watching and video-/computergame playing) were also assessed. Overall, boys were more physically active than girls and engaged in more heavy physical activity, while girls reported a larger percentage of time spent in light and moderate physical activities. Gender and, to a lesser extent, ethnic differences were seen in the types of activities reported. Although most physical activity occurred after school, children who reported no physical education class during school had less physical activity overall. There was a decrease in moderate physical activity with increasing grade levels in school and an increase in sedentary behavior. Black children reported more sedentary activity than white children, and girls reported more than boys. Although this 24-h recall method has limitations, it allows characterization of the activity of groups of children and provides useful data for policy recommendations.

Anterior/posterior lumbar fusion versus transforaminal lumbar interbody fusion: analysis of complications and predictive factors.

No previous study has compared the complications between anterior/posterior and transforaminal interbody fusions. We performed a retrospective analysis of 164 patients to compare the complications and associated predictive factors of the two techniques of circumferential lumbar fusion. Fifty-three had same-day anterior/posterior fusion (group 1), and 111 had transforaminal interbody fusion (group 2). Mean operating time (p < 0.0001) and hospital stay (p < 0.0001) was significantly longer for group 1 patients. Average blood loss was greater for group 1 patients (p < 0.01). Higher complication rates were found in group 1 patients (p < 0.004). Wound infection occurred more frequently in patients with adjunctive treatment (p < 0.04). Hospital stay was an independent predictor of complications in both groups. In group 1, body mass index was independently associated with complications. In group 2, both hospital stay and adjunctive treatment were predictive of complications. Transforaminal lumbar interbody fusion is the preferred technique because it is associated with shorter operating time, less blood loss, shorter hospital stay, and lower incidence of complications.