Georgiana Onicescu

A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells

We recently demonstrated that human BM cells can be treated in vitro with defined growth factors to induce the rapid generation of myeloid-derived suppressor cells (MDSCs), hereafter defined as BM-MDSCs. Indeed, combination of G-CSF + GM-CSF led to the development of a heterogeneous mixture of immature myeloid cells ranging from myeloblasts to band cells that were able to suppress alloantigen- and mitogen-stimulated T lymphocytes. Here, we further investigate the mechanism of suppression and define the cell subset that is fully responsible for BM-MDSC-mediated immune suppression. This population, which displays the structure and markers of promyelocytes, is however distinct from physiologic promyelocytes that, instead, are devoid of immuosuppressive function. In addition, we demonstrate that promyelocyte-like cells proliferate in the presence of activated lymphocytes and that, when these cells exert suppressive activity, they do not differentiate but rather maintain their immature phenotype. Finally, we show that promyelocyte-like BM-MDSCs are equivalent to MDSCs present in the blood of patients with breast cancer and patients with colorectal cancer and that increased circulating levels of these immunosuppressive myeloid cells correlate with worse prognosis and radiographic progression.

Secondhand Smoke Exposure Among Women and Children: Evidence From 31 Countries

OBJECTIVES We sought to describe the range of exposure to secondhand smoke (SHS) among women and children living with smokers around the world and generate locally relevant data to motivate the development of tobacco control policies and interventions in developing countries. METHODS In 2006, we conducted a cross-sectional exposure survey to measure air nicotine concentrations in households and hair nicotine concentrations among nonsmoking women and children in convenience samples of 40 households in 31 countries. RESULTS Median air nicotine concentration was 17 times higher in households with smokers (0.18 mug/m(3)) compared with households without smokers (0.01 mug/m(3)). Air nicotine and hair nicotine concentrations in women and children increased with the number of smokers in the household. The dose-response relationship was steeper among children. Air nicotine concentrations increased an estimated 12.9 times (95% confidence interval=9.4, 17.6) in households allowing smoking inside compared with those prohibiting smoking inside. CONCLUSIONS Our results indicate that women and children living with smokers are at increased risk of premature death and disease from exposure to SHS. Interventions to protect women and children from household SHS need to be strengthened.

Using Endobronchial Ultrasound Features to Predict Lymph Node Metastasis in Patients With Lung Cancer

PURPOSES Reliable staging of the mediastinum determines TNM classification and directs therapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate predictors of mediastinal lymph node metastasis in patients undergoing endobronchial ultrasound (EBUS). METHODS Patients with known or suspected lung cancer undergoing EBUS for staging were included. Lymph node radiographic characteristics on chest CT/PET scan and ultrasound characteristics of size, shape, border, echogenicity, and number were correlated with rapid on-site evaluation (ROSE) and final pathology. Logistic regression (estimated with generalized estimating equations to account for correlation across nodes within patients) was used with cancer (vs normal pathology) as the outcome. ORs compare risks across groups, and testing was performed with two-sided α of 0.05. RESULTS Two hundred twenty-seven distinct lymph nodes (22.5% positive for malignancy) were evaluated in 100 patients. Lymph node size, by CT scan and EBUS measurements, and round and oval shape were predictive of mediastinal metastasis. Increasing size of lymph nodes on EBUS was associated with increasing malignancy risk (P = .0002). When adjusted for CT scan size, hypermetabolic lymph nodes on PET scan did not predict malignancy. Echogenicity and border contour on EBUS and site of biopsy were not significantly associated with cancer. In 94.8% of lymph nodes with a clear diagnosis, the ROSE of the first pass correlated with subsequent passes. CONCLUSIONS Lymph node size on CT scan and EBUS and round or oval shape by EBUS are predictors of malignancy, but no single characteristic can exclude a visualized lymph node from biopsy. Further, increasing the number of samples taken is unlikely to significantly improve sensitivity.

A Coreceptor-Independent Transgenic Human TCR Mediates Anti-Tumor and Anti-Self Immunity in Mice

Recent advancements in T cell immunotherapy suggest that T cells engineered with high-affinity TCR can offer better tumor regression. However, whether a high-affinity TCR alone is sufficient to control tumor growth, or the T cell subset bearing the TCR is also important remains unclear. Using the human tyrosinase epitope-reactive, CD8-independent, high-affinity TCR isolated from MHC class I-restricted CD4+ T cells obtained from tumor-infiltrating lymphocytes (TIL) of a metastatic melanoma patient, we developed a novel TCR transgenic mouse with a C57BL/6 background. This HLA-A2–restricted TCR was positively selected on both CD4+ and CD8+ single-positive cells. However, when the TCR transgenic mouse was developed with a HLA-A2 background, the transgenic TCR was primarily expressed by CD3+CD4−CD8− double-negative T cells. TIL 1383I TCR transgenic CD4+, CD8+, and CD4−CD8− T cells were functional and retained the ability to control tumor growth without the need for vaccination or cytokine support in vivo. Furthermore, the HLA-A2+/human tyrosinase TCR double-transgenic mice developed spontaneous hair depigmentation and had visual defects that progressed with age. Our data show that the expression of the high-affinity TIL 1383I TCR alone in CD3+ T cells is sufficient to control the growth of murine and human melanoma, and the presence or absence of CD4 and CD8 coreceptors had little effect on its functional capacity.

Normothermia to prevent surgical site infections after gastrointestinal surgery: holy grail or false idol?

Objective:To analyze the association between perioperative normothermia (temperature ≥36°C) and surgical site infections (SSIs) after gastrointestinal (GI) surgery. Summary of Background Data:Although active warming during colorectal surgery reduces SSIs, there is limited evidence that perioperative normothermia is associated with lower rates of SSI. Nonetheless, hospitals participating in the Surgical Care Improvement Project must report normothermia rates during major surgery. Methods:We conducted a nested, matched, case-control study; cases consisted of GI surgery patients enrolled in our National Surgical Quality Improvement Program database between March 2006 and March 2009 who developed SSIs. Patient/surgery risk factors for SSI were obtained from the National Surgical Quality Improvement Program database. Perioperative temperature/antibiotic/glucose data were obtained from medical records. Cases/controls were compared using univariate/random effects/logistic regression models. Independent risk factors for SSIs were identified using multivariate/random effects/logistic regression models. Results:A total of 146 cases and 323 matched controls were identified; 82% of patients underwent noncolorectal surgery. Cases were more likely to have final intraoperative normothermia compared with controls (87.6% vs. 77.8%, P = 0.015); rates of immediate postoperative normothermia were similar (70.6% vs. 65.3%, respectively, P = 0.19). Emergent surgery/higher wound class were associated with higher rates of intraoperative normothermia. Independent risk factors for SSI were diabetes, surgical complexity, small bowel surgery, and nonlaparoscopic surgery. There was no independent association between perioperative normothermia and SSI (adjusted odds ratio, 1.05; 95% confidence interval, 0.48–2.33; P = 0.90). Conclusions:Pay-for-reporting measures focusing on perioperative normothermia may be of limited value in preventing SSI after GI surgery. Studies to define the benefit of active warming after noncolorectal GI surgery are warranted.

Estimating the Risks and Benefits of Nicotine Replacement Therapy for Smoking Cessation in the United States

OBJECTIVES To compare potential population-wide benefits and risks, we examined the potential impact of increased nicotine replacement therapy (NRT) use for smoking cessation on future US mortality. METHODS We developed a simulation model incorporating a Monte Carlo uncertainty analysis, with data from the 2005 National Health Interview Survey and Cancer Prevention Study II. We estimated the number of avoided premature deaths from smoking attributable to increased NRT use, before and after incorporating assumptions about NRT harm. RESULTS We estimate that a gradual increase in the proportion of NRT-aided quit attempts to 100% by 2025 would lead to 40,000 (95% credible interval=31,000, 50,000) premature deaths avoided over a 20-year period. Most avoided deaths would be attributable to lung cancer and cardiovascular disease. After we incorporated assumptions about potential risk from long-term NRT, the estimate of avoided premature deaths from all causes declined to 32 000. CONCLUSIONS Even after we assumed some harm from long-term NRT use, the benefits from increased cessation success far outweigh the risks. However, the projected reduction in premature mortality still reflects a small portion of the tobacco-related deaths expected over a 20-year period.

Secondhand Smoke Exposure in Young People and Parental Rules Against Smoking at Home and in the Car

Objectives. Secondhand smoke (SHS) exposure is an important cause of morbidity in children. We assessed the impact of family rules about smoking in the home and car on SHS exposure prevalence in students in grades six to 12. Methods. We studied never-smoking young people (n= 1,698) in the random sample cross-sectional South Carolina Youth Tobacco Survey, a 2006 survey of middle and high school students in South Carolina. Results. Overall, 40% of the students reported SHS exposure in either the home or car in the past week; among these, 85% reported exposure in cars. Subsequent analyses focused on students who lived with a smoker (n=602). Compared with those whose families prohibited smoking in the home or car, SHS exposure prevalence was 30% (p<0.0001) higher for households with smoke-free rules for only one place (home or car) and 36% (p<0.0001) higher for households with no rules. Compared with students from households with strict rules, SHS exposure prevalence was 48% greater (p<0.0001) among those with only partial rules against smoking in the home or car, and 55% (p<0.0001) greater among those from households with no rules. Similarly, compared with students with strict family rules for home and car that were adhered to, SHS exposure prevalence was significantly higher (p<0.0001) among students when only one or no rules were followed. Conclusions. Young people from families that made and enforced strong rules against smoking in homes and cars were much less likely to report SHS exposure. Parents would be wise to endorse and enforce strong smoke-free policies for both homes and cars.

Comparison of intraoperatively built custom linked seeds versus loose seed gun applicator technique using real-time intraoperative planning for permanent prostate brachytherapy.

PURPOSE To report our dosimetric results using a novel push-button seed delivery system that constructs custom links of seeds intraoperatively. METHODS AND MATERIALS From 2005 to 2007, 43 patients underwent implantation using a gun applicator (GA), and from 2007 to 2008, 48 patients underwent implantation with a novel technique allowing creation of intraoperatively built custom links of seeds (IBCL). Specific endpoint analyses were prostate D90% (pD90%), rV100% > 1.3 cc, and overall time under anesthesia. RESULTS Final analyses included 91 patients, 43 GA and 48 IBCL. Absolute change in pD90% (ΔpD90%) between intraoperative and postoperative plans was evaluated. Using GA method, the ΔpD90% was -8.1 Gy and -12.8 Gy for I-125 and Pd-103 implants, respectively. Similarly, the IBCL technique resulted in a ΔpD90% of -8.7 Gy and -9.8 Gy for I-125 and Pd-103 implants, respectively. No statistically significant difference in ΔpD90% was found comparing methods. The GA method had two intraoperative and 10 postoperative rV100% >1.3 cc. For IBCL, five intraoperative and eight postoperative plans had rV100% >1.3 cc. For GA, the mean time under anesthesia was 75 min and 87 min for Pd-103 and I-125 implants, respectively. For IBCL, the mean time was 86 and 98 min for Pd-103 and I-125. There was a statistical difference between the methods when comparing mean time under anesthesia. CONCLUSIONS Dosimetrically relevant endpoints were equivalent between the two methods. Currently, time under anesthesia is longer using the IBCL technique but has decreased over time. IBCL is a straightforward brachytherapy technique that can be implemented into clinical practice as an alternative to gun applicators.

Joint disease mapping of cervical and male oropharyngeal cancer incidence in blacks and whites in South Carolina.

Human papillomavirus (HPV) infection is an established causal agent for cervical cancer and a subset of oropharyngeal cancers. It is hypothesized that orogenital transmission results in oral cavity infection. In this paper we explore the geographical association between cervical and male oropharyngeal cancer incidence in blacks and whites in South Carolina using Bayesian joint disease mapping models fit to publicly available data. Our results suggest weak evidence for county-level association between the diseases, and different patterns of joint disease behavior for blacks and whites.

The comparative effectiveness of a team-based versus group-based physical activity intervention for cancer survivors

PurposePhysical activity benefits cancer survivors, but the comparative effectiveness of a team-based delivery approach remains unexplored. The hypothesis tested was that a team-based physical activity intervention delivery approach has added physical and psychological benefits compared to a group-based approach. A team-based sport accessible to survivors is dragon boating, which requires no previous experience and allows for diverse skill levels.MethodsIn a non-randomized trial, cancer survivors chose between two similarly structured 8-week programs, a dragon boat paddling team (n = 68) or group-based walking program (n = 52). Three separate intervention rounds were carried out in 2007–2008. Pre–post testing measured physical and psychosocial outcomes.ResultsCompared to walkers, paddlers had significantly greater (all p < 0.01) team cohesion, program adherence/attendance, and increased upper-body strength. For quality-of-life outcomes, both interventions were associated with pre–post improvements, but with no clear-cut pattern of between-intervention differences.ConclusionsThese hypothesis-generating findings suggest that a short-term, team-based physical activity program (dragon boat paddling) was associated with increased cohesion and adherence/attendance. Improvements in physical fitness and psychosocial benefits were comparable to a traditional, group-based walking program. Compared to a group-based intervention delivery format, the team-based intervention delivery format holds promise for promoting physical activity program adherence/attendance in cancer survivors.