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Perspective on This Article from Endothelin Receptor Type B Gene Promoter Hypermethylation in Salivary Rinses Is Independently Associated with Risk of Oral Cavity Cancer and Premalignancy

Supplementary Table 1 - PDF file 90K, Predictive accuracy of risk classification and markers (n=161)

Supplementary Data - PDF file 79K, Supplementary data revised, figure added

Purpose: In certain cancers, MDM2 SNP309 has been associated with early tumor onset in women. In melanoma, incidence rates are higher in women than in men among individuals less than 40 years of age, but among those older than 50 years of age, melanoma is more frequent in men than in women. To investigate this difference, we examined the association among MDM2 SNP309, age at diagnosis, and gender among melanoma patients.Experimental Design: Prospectively enrolled melanoma patients (N = 227) were evaluated for MDM2 SNP309 and the related polymorphism, p53 Arg72Pro. DNA was isolated from patient blood samples, and genotypes were analyzed by PCR-restriction fragment length polymorphism. Associations among MDM2 SNP309, p53 Arg72Pro, age at diagnosis, and clinicopathologic features of melanoma were analyzed.Results: The median age at diagnosis was 13 years earlier among women with a SNP309 GG genotype (46 years) compared with women with TG+TT genotypes (59 years; P = 0.19). Analyses using age dichotomized at each decade indicated that women with a GG genotype had significantly higher risks of being diagnosed with melanoma at ages P = 0.01). Similar observations were not seen among men.Conclusions: Our data suggest that MDM2 may play an important role in the development of melanoma in women. The MDM2 SNP309 genotype may help identify women at risk of developing melanoma at a young age.

Purpose: Promoter hypermethylation has been recently proposed as a means for head and neck squamous cell carcinoma (HNSCC) detection in salivary rinses. In a prospective study of a high-risk population, we showed that endothelin receptor type B (EDNRB) promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy.Experimental Design: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was conducted and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by quantitative methylation-specific PCR.Results:HOXA9, EDNRB, and deleted in colorectal cancer (DCC) methylation were associated (P = 0.012; P < 0.0001; P = 0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (P = 0.0003) or DCC (P = 0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC, and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (P = 0.008; P = 0.026; P = 0.046) and multivariate analysis (P = 0.012; P = 0.037; P = 0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with a similar area under curve [AUC; 0.61, 95% confidence interval (CI) = 0.60–0.81] when compared to EDNRB and DCC combined AUC (0.60, 95% CI = 0.51–0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC, and CRC was optimal AUC (0.67, 95% CI = 0.58–0.76).Conclusions:EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available. Clin Cancer Res; 19(12); 3268–75. ©2013 AACR.

Supplementary Table S1 from Association of MDM2 SNP309, Age of Onset, and Gender in Cutaneous Melanoma

Supplementary Table 2 - PDF file 42K, Association between risk assessment and genes hypermethylation status

Supplementary Figure 1 - PDF file 143K, ROC curves corresponding to the use of gene signatures, clinical exam and a combination of these. A: Risk Classification; B: EDNRB; C: DCC; D: EDNRB and DCC; E: EDNRB and Risk Classification; F: DCC and Risk Classification; G: EDNRB, DCC and Risk Classification

OBJECTIVE The purpose of this research was to build on previous work regarding predictive factors of acute skin failure (ASF) in the critically ill population. METHODS Researchers conducted a retrospective case-control study with a main and validation analysis. Data were extracted from the New York Statewide Planning and Research Cooperative System. For the main analysis, there were 415 cases with a hospital-acquired pressure injury (HAPI) and 194,872 controls without. Researchers then randomly selected 100 cases with a HAPIs and 300 controls without for the validation analysis. A step-up logistic regression model was used. Researchers generated receiver operating characteristic curves for both the main and validation analyses, assessing the overall utility of the regression model. RESULTS Eleven variables were significantly and independently related to ASF: renal failure (odds ratio [OR], 1.4, P = .003), respiratory failure (OR, 2.2; P = < .001), arterial disease (OR, 2.4; P = .001), impaired nutrition (OR, 2.3; P = < .001), sepsis (OR, 2.2; P = < .001), septic shock (OR, 2.3; P = < .001), mechanical ventilation (OR, 2.5; P = < .001), vascular surgery (OR, 2.2; P = .02), orthopedic surgery (OR, 3.4; P = < .001), peripheral necrosis (OR, 2.5; P = .003), and general surgery (OR, 3.8; P = < .001). The areas under the curve for the main and validation analyses were 0.864 and 0.861, respectively. CONCLUSIONS The final model supports previous work and is consistent with the current definition of ASF in the setting of critical illness.

Objective To replicate previous research that found four independent and significant predictors of heel pressure injuries (HPIs) in hospitalized patients using a larger and more diverse patient population. Methods Researchers conducted a retrospective, case-control study with a main and a validation analysis (N = 1,937). The main analysis had 1,697 patients: 323 patients who had HPIs and 1,374 who did not. The validation analysis had 240 patients: 80 patients who developed HPIs and 160 who did not. Researchers used a series of diagnosis codes to define variables associated with an HPI. Data were extracted from the New York Statewide Planning and Research Cooperative System for January 2014 to June 2015. Study authors conducted a series of forward stepwise logistic regression analyses for both samples to select the variables that were significantly and independently associated with the development of an HPI in a multivariable setting. Researchers generated a receiver operating characteristic curve using the final model to assess the regression model's ability to predict HPI development. Results Seven variables were significant and independent predictors associated with HPIs: diabetes mellitus, vascular disease, perfusion issues, impaired nutrition, age, mechanical ventilation, and surgery. The receiver operating characteristic curve demonstrated predictive accuracy of the model. Conclusions Beyond a risk assessment scale, providers should consider other factors, such as comorbidities, which can predispose patients to HPI development.

BACKGROUND Widespread disparities in care have been documented in women with gynecologic cancer in the United States. This study was designed to determine whether structural barriers to optimal care were present during the preoperative period for patients with gynecologic cancer. METHODS A retrospective review was conducted for patients undergoing surgery for a gynecologic malignancy at a public hospital or a private hospital staffed by the same team of gynecologic oncologists between July 1, 2013 and July 1, 2014. RESULTS Two hundred fifty-seven cases were included for analysis (public hospital, 69; private hospital, 188). Patients treated at the private hospital were older (58 vs 52 years; P = .004) and had similar medical comorbidities (median Charlson comorbidity index at both hospitals, 6) but required fewer hospital visits in preparation for surgery (2 vs 4; P < .001). Public hospital patients had a longer wait time from the diagnosis of disease to surgery (63 vs 34 days; P < .001). According to a multiple linear regression model, the public hospital setting was associated with a longer interval from diagnosis to surgery with adjustments for the insurance status, age at diagnosis, cancer stage, and number of preoperative hospital visits (P < .001). CONCLUSIONS Patients at the public hospital were subject to a greater number of preoperative visits and had to wait longer for surgery than patients at the private hospital. Attempts to reduce health care disparities should focus on improving efficiency in health care delivery systems once contact has been established. Cancer 2016;122:859–67. © 2016 American Cancer Society.

Background Women receiving radiation to the breast will likely be recommended to use a topical cream to minimize and delay the development of radiation dermatitis. Although many topical products are commercially available and have been tested for safety and efficacy, few studies have compared various products to one another for superiority and cost effectiveness. Objectives The purpose of this pilot study was to compare three commonly used skin care products prospectively to one other in a homogenously controlled group of women undergoing whole breast irradiation to assess superiority in minimizing the common toxicity criteria grade of radiation dermatitis, effect on quality of life, and cost. Methods The authors conducted a systematic review to determine the three types of skin care products with the strongest evidence of minimizing radiation dermatitis. Patients were voluntarily enrolled and randomized to one of three possible skin care topical regimens. Patients completed a quality-of-life survey to assess their preference in topical skin care regimen. The cost of each arm's topical product was assessed at the completion of patient participation. Findings No statistical difference was noted in the severity or occurrence of radiation dermatitis among the groups. In addition, no statistical difference was found among the three treatment arms in quality-of-life score changes, and no patients required a treatment interruption in their radiation or in the skin care product during treatment. A cost difference among the treatment arms was noted.

Purpose To develop and validate a method of predicting whether patients will develop a heel pressure ulcer during their hospital stay. Design This retrospective case-control study used 2 separate data sets, one for an initial analysis followed by a second data set for validation analysis. Subjects and setting From 2009 to 2011, medical records of discharged patients with a DRG code for heel pressure ulcers in our urban, tertiary medical center were retrospectively reviewed. Using age as the matching criterion, we then reviewed cases of patients without heel pressure ulcers. The initial analysis comprised 37 patients with hospital-acquired heel pressure ulcers and 300 without. The validation analysis included 12 patients with heel pressure ulcers and 68 without. Method In order to develop this method of identifying patients with heel pressure ulcers, logistic regression modeling was used to select a set of patient characteristics and hospital conditions that, independently and in combination, predicted heel pressure ulcers. Logistic modeling produced adjusted and unadjusted odds ratios for each of the significant predictor variables. The validation analysis was employed to test the predictive accuracy of the final model. Results Initial analysis revealed 4 significant and independent predictors for heel pressure ulcer formation during hospitalization: diabetes mellitus, vascular disease, immobility, and an admission Braden Scale score of 18 or less. These findings were also supported in the validation analysis. Conclusion Beyond a risk assessment scale, staff should consider other factors that can predispose a patient to heel pressure ulcer development during their hospital stay, such as comorbid conditions (diabetes mellitus and vascular disease) and immobility.

Background Due to the devastating late effects associated with cranial irradiation in young children with central nervous system (CNS) tumors, treatment for these patients has evolved to include the use of intensive chemotherapy to either avoid or postpone irradiation. While survival outcomes have improved, late effects data in survivors treated on such regimens are needed. Objective This multi-institutional study comprehensively describes late effects in survivors treated on the Head Start I/II protocols. Methods Survivors of CNS tumors treated on Head Start I/II protocols were enrolled. Late effects data were collected using a validated parent-report questionnaire. Social, emotional, and behavioral functioning and quality of life were assessed using parent-report on the BASC-2 and CHQ-PF50 questionnaires. Results Twenty-one survivors (medulloblastoma = 13, sPNET = 4, ATRT = 1, ependymoma = 3) were enrolled. Ten (48%) were irradiation-free. Late effects (frequency; median time of onset since diagnosis) included ≥grade III hearing loss (67%; 3.9 years), vision (67%; 4.1 years), hypothyroidism (33%; 4 years), growth hormone (GH) deficiency (48%; 4.7 years), dental (52%; 7.1 years), and no cases of secondary leukemia. Irradiation-free (vs. irradiated) survivors reported low rates of hypothyroidism (0/10 vs. 7/11; P = 0.004) and GH deficiency (2/10 vs. 8/11; P = 0.03). The BASC-2 and CHQPF-50 mean composite scores were within average ranges relative to healthy comparison norms. Neither age at diagnosis nor irradiation was associated with these scores. Conclusions Irradiation-free Head Start survivors have lower risk of hypothyroidism and GH deficiency. Secondary leukemias are not reported. With extended follow-up, survivors demonstrate quality of life, social, emotional, and behavioral functioning within average ranges. Pediatr Blood Cancer 2014;61:1644–1672. © 2014 Wiley Periodicals, Inc.

To develop a reliable rating scale to assess functional capacity in children with familial dysautonomia, evaluate changes over time, and determine whether severity within a particular functional category at a young age affected survival.Ten functional categories were retrospectively assessed in 123 patients with familial dysautonomia at age 7 years ± 6 months. Each of the 10 Functional Severity Scale categories (motor development, cognitive ability, psychological status, expressive speech, balance, oral coordination, frequency of dysautonomic crisis, respiratory, cardiovascular, and nutritional status) were scored from 1 (worst or severely affected) to 5 (best or no impairment). Changes over time were analyzed further in 22 of the 123 patients who were also available at ages 17 and 27 years.Severely impaired cardiovascular function and high frequency of dysautonomic crisis negatively affected survival (P.005 and P.001, respectively). In the 22 individuals followed up to age 27 years, psychological status significantly worsened (P = .01), and expressive speech improved (P = .045). From age 17 to 27 years, balance worsened markedly (P = .048).The Functional Severity Scale is a reliable tool to measure functional capacity in patients with familial dysautonomia. The scale may prove useful in providing prognosis and as a complementary endpoint in clinical trials.

In this case-control study of euthyroid first-cycle IVF patients ≥38 years old with singleton baby, miscarriage, biochemical pregnancy, and no pregnancy outcomes from 2005–2008, we assayed frozen serum for autoimmune thyroid disease (AITD) and thyroid function at cycle start, trigger, and 4 and 5 weeks' gestation. AITD prevalence in older infertile women was similar across clinical outcomes, and although AITD was associated with a higher baseline TSH, TSH remained within acceptable ranges, suggesting that T 4 supplementation may not affect maternal outcomes in older euthyroid AITD patients through 5 weeks gestation.

Background: There are little data on the appropriate endpoint for slow pathway ablation that balances acceptable procedural times, recurrence rates, and complication rates. This study compared recurrence rates of three commonly utilized endpoints of slow pathway ablation for atrioventricular nodal reentrant tachycardia (AVNRT). Methods: We performed a meta-analysis of AVNRT slow pathway ablation cohorts by searching electronic databases, the Internet, and conference proceedings. Inclusion criteria were age >18 years, >20 human subjects per study, primary AVNRT ablation, English language publication, and >1 month of follow-up. Data were analyzed with a fixed-effects model using Comprehensive Meta-Analysis software version 2.2.046 (Biostat, Englewood, NJ, USA). Results: We included 10 studies encompassing 1,204 patients with a mean age of 41–53 years. Endpoints were complete slow pathway ablation, residual jump only, and single remaining echo beat. Pooled estimates revealed 28 of 641 patients (4.4%) with complete slow pathway ablation, 13 of 192 patients (6.8%) with a residual jump only, and 24 of 371 patients (6.5%) with one echo had recurrences. With uniform isoproterenol use after ablation, there was no significant difference in recurrence rates among the endpoints. However, when isoproterenol was utilized after ablation only if needed to induce AVNRT before ablation, a significantly higher recurrence rate occurred in patients with a residual jump (P = 0.002), a single echo (P = 0.003), or the combined group of a residual jump and/or one echo (P = 0.001). Conclusions: Isoproterenol should be used routinely after slow pathway modification, when a residual jump and/or single echo remain. (PACE 2011; 34:269–277)

We investigated whether abnormal concentrations of first-trimester free-beta subunit human chorionic gonadotropin (fsshCG) and pregnancy-associated plasma protein A (PAPP-A) are associated with preterm delivery in twin gestations. This was a hospital-based, retrospective study of 70 twin gestations between 11 (1)/ (7) and 13 (6)/ (7) weeks' gestation undergoing first-trimester screening. Free betahCG and PAPP-A multiples of the median were determined by our laboratory standards. Odds ratios (ORs) were estimated that compared the prevalence of very preterm (32 weeks), preterm (or = 32 and37 weeks), and term birth (or = 37 weeks) between the lower and higher percentile groups for each analyte. FsshCG levelsor = 25th percentile were associated with very preterm birth32 weeks' gestation (OR 5.10; 95% confidence interval [CI]: 1.19 to 21.95), but not with preterm birthor = 32 and37 weeks' gestation (OR 0.50; 95% CI: 0.16 to 1.61). PAPP-A was not associated with very preterm (OR 2.95; 95% CI: 0.69 to 12.60) or preterm birth (OR 0.71; 95% CI: 0.23 to 2.21). Low first-trimester fsshCG was a strong predictor for very preterm birth in twin gestations. Low first-trimester PAPP-A was associated with a trend in increased risk of very preterm birth.

Familial dysautonomia (FD) is caused by an intronic splice mutation in the IkappaB kinase-associated protein gene (IKBKAP) that leads to partial skipping of exon 20 and tissue-specific reduction of IkappaB kinase-associated protein/elongator protein 1 (IKAP/ELP-1 protein). Kinetin increases IKBKAP mRNA and protein expression in FD cell lines. To determine whether oral kinetin alters IKBKAP splicing in vivo, we administered kinetin to 29 healthy carriers of the major FD mutation for 8 d. Adverse effects, kinetin, and IKBKAP mRNA levels were monitored. In the highest dosing cohorts (23.5 mg/kg/d), the target plasma kinetin level was achieved in 91% of subjects at 2 h. After 8 d, IKBKAP mRNA expression in leukocytes increased as kinetin levels increased. There is a linear association between log plasma kinetin level and corresponding log change from baseline in IKBKAP mRNA expression that allows estimation of IKBKAP mRNA levels because of kinetin ingestion. Adverse effects were transient and mild. This is the first report of in vivo IKBKAP splicing modification and strongly suggests kinetin's therapeutic potential in FD and perhaps in other splicing disorders. Furthermore, our findings support our hypothesis that treatments, which target a particular splicing mutation, can be successfully developed.

The purpose of this learning activity is to provide information regarding the differentiation between pressure ulcers and acute skin failure (ASF) in critically ill patients.This continuing education activity is intended for physicians and nurses with an interest in skin and wound care.After participating in this educational activity, the participant should be better able to:1. Describe the purpose, methodology and impact of this research.2. Differentiate the pathophysiology of pressure ulcers and ASF.3. Identify risk factors and diagnostic criteria for ASF.To develop a statistical model to predict the development of acute skin failure in patients admitted to the intensive care unit (ICU) and to validate this model.Retrospective case-control, logistic regression modeling552 ICU patientsIntensive care unit patients with and without pressure ulcers (PrUs) were studied and compared on key variables sorted into the following categories: (1) disease status, (2) physical conditions, and (3) conditions of hospitalization.The variables, peripheral arterial disease (odds ratio [OR], 3.8; P = .002), mechanical ventilation greater than 72 hours (OR, 3.0; P.001), respiratory failure (OR, 3.2; P.001), liver failure (OR, 2.9; P = .04), and severe sepsis/septic shock (OR, 1.9; P = .02), were found to be statistically significant and independent predictors of acute skin failure in ICU patients. These variables created a predictor model for acute skin failure in the ICU.Lack of objective criteria to define acute skin failure presents a clinical conundrum for practitioners-the acknowledgment that skin failure exists, but no clear-cut diagnostic criteria in which to support its existence as a result of a paucity of empirical evidence. In certain populations, such as the critically ill patient, the phenomenon of acute skin failure may be occurring, and with the current level of evidence, these ulcers may be incorrectly identified as PrUs. Accurately distinguishing risk factors that lead to a PrU from factors that result in a lesion due to acute skin failure is crucial in the quest to provide evidence-based practice to patients.

Widespread disparities in care have been documented in women with gynecologic cancer in the United States. This study was designed to determine whether structural barriers to optimal care were present during the preoperative period for patients with gynecologic cancer.A retrospective review was conducted for patients undergoing surgery for a gynecologic malignancy at a public hospital or a private hospital staffed by the same team of gynecologic oncologists between July 1, 2013 and July 1, 2014.Two hundred fifty-seven cases were included for analysis (public hospital, 69; private hospital, 188). Patients treated at the private hospital were older (58 vs 52 years; P = .004) and had similar medical comorbidities (median Charlson comorbidity index at both hospitals, 6) but required fewer hospital visits in preparation for surgery (2 vs 4; P.001). Public hospital patients had a longer wait time from the diagnosis of disease to surgery (63 vs 34 days; P.001). According to a multiple linear regression model, the public hospital setting was associated with a longer interval from diagnosis to surgery with adjustments for the insurance status, age at diagnosis, cancer stage, and number of preoperative hospital visits (P.001).Patients at the public hospital were subject to a greater number of preoperative visits and had to wait longer for surgery than patients at the private hospital. Attempts to reduce health care disparities should focus on improving efficiency in health care delivery systems once contact has been established.

The aim of this study is to determine the diagnostic value of cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE), cine imaging, and resting first-pass perfusion (FPP) in the evaluation for ischemic (IC) versus non-ischemic (NIC) cardiomyopathy in new onset heart failure with reduced (≤40%) left ventricular ejection fraction (HFrEF). A retrospective chart review analysis identified 83 patients between January 2009 and June 2012 referred for cardiac magnetic resonance imaging (CMR) evaluation for new onset HFrEF with coronary angiography performed within 6 months of CMR. The diagnosis of IC was established using Felker’s criteria on coronary angiography. CMR sequences were evaluated for the presence of patterns suggestive of severe underlying coronary artery disease as the cause of HFrEF (subendocardial and/or transmural LGE, regional wall motion abnormality on cine, regional hypoperfusion defect on resting FPP). Discriminative power was assessed using receiver operator characteristics curve analysis. Coronary angiography identified 36 patients (43%) with IC. Presence of subendocardial and/or transmural LGE alone demonstrated good discriminative power (c-statistic 0.85, 95% confidence interval 0.76–0.94) for the diagnosis of IC. The presence of an ischemic pattern on both LGE and cine sequences resulted in a specificity of 87% for the diagnosis of IC, while the absence of an ischemic pattern on both LGE and cine sequences resulted in a specificity of 94% for the diagnosis of NIC. Addition of resting FPP on a subset of patients did not improve diagnostic values. In conclusion, CMR has potential value in the diagnostic evaluation of IC versus NIC.

INTRODUCTION Goal-directed echocardiography (GDE) is used to answer specific clinical questions that provide invaluable information to physicians managing a hemodynamically unstable patient. We studied perception and ability of house staff previously trained in GDE to accurately diagnose common causes of cardiac arrest during simulated advanced cardiac life support (ACLS); we compared their results with those of expert echocardiographers. METHODS Eleven pulmonary and critical care medicine fellows, 7 emergency medicine residents, and 5 cardiologists board certified in echocardiography were enrolled. Baseline ability to acquire 4 transthoracic echocardiography views was assessed, and participants were exposed to 6 simulated cardiac arrests and were asked to perform a GDE during ACLS. House staff performance was compared with the performance of 5 expert echocardiographers. RESULTS Average baseline and scenario views by house staff were of good or excellent quality 89% and 83% of the time, respectively. Expert average baseline and scenario views were always of good or excellent quality. House staff and experts made the correct diagnosis in 68% and 77% of cases, respectively. On average, participants required 1.5 pulse checks to make the correct diagnosis. Of house staff, 94% perceived this study as an accurate assessment of ability. CONCLUSIONS In an ACLS-compliant manner, house staff are capable of diagnosing management-altering pathologies the majority of the time, and they reach similar diagnostic conclusions in the same amount of time as expert echocardiographers in a simulated cardiac arrest scenario.

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone's efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisone-treated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression.

To analyze the impact of resection margin status and histologic prognosticators on local recurrence (LR) and overall survival (OS) for patients with oral squamous cell carcinoma (OSCC). This study was both retrospective and prospective in design. Cohort 1 refers to the entire group of 292 patients with OSCC. The slides from the earliest resection specimens from Cohort 1 were examined in an exploratory manner for multiple parameters. Cohort 2 refers to a subset of 203 patients, who did not receive any neoadjuvant therapy and had outcome data. Cohort 3 represents a subset of Cohort 2 (n = 168) wherein the histologic resection margin status could be reconfirmed. Cohort 4 refers a subset of 85 patients with tongue/floor of mouth tumors. Margin status was designated as follows: group 1, clearance ofor =5 mm with intraoperative analysis, no need for supplemental margins (n = 46); group 2, initial margins were measured as5 mm during intraoperative frozen section; supplemental resection margins were negative on final pathology (n = 73); group 3, the final pathology revealed resection margins5 mm (n = 30); group 4, the final pathology revealed frankly positive resection margins (n = 19). The endpoints of LR and OS were queried with respect to T stage, tumor site, margin status, and numerous histologic variables, by Cox regression and Kaplan-Meier survival analyses. Tumor stage (T) was significantly associated with LR (P = 0.028). Kaplan-Meier analysis for stage and for intraoral site was significantly associated with LR for T4 tumors. The increased likelihood of LR was higher for T4 OSCC of the buccal mucosa (75%), sinopalate (50%), and gingiva (100%) compared with mobile tongue (27%), and oropharynx (13%) (P = 0.013). Margin status was not associated with LR or OS (Cohort 3). This was so when all tumors were grouped together and when separate analyses were performed by tumor stage and oral subsite. No significance was demonstrated when margin status was examined for patients with similar treatment (surgery alone or surgery with adjuvant RT). However, the administration of adjuvant RT did significantly increase local disease-free survival (P = 0.0027 and P = 0.001 for T1 and T2 SCC, respectively). On exploratory analyses of histologic parameters, worst pattern of invasion was significantly associated with LR (P = 0.015) and OS (P0.001). Perineural invasion involving large nerves (1 mm) was associated with LR (P = 0.005) and OS (P = 0.039). Limited lymphocytic response was also significantly associated with LR (P = 0.005) and OS (P = 0.001). When used as covariates in a multivariate Cox regression model, worst pattern of invasion, perineural invasion, and lymphocytic response were significant and independent predictors of both LR and OS, even when adjusting for margin status. Thus, these factors were used to generate our risk assessment. Our risk assessment classified patients into low-, intermediate-, or high-risk groups, with respect to LR (P = 0.0004) and OS (P0.0001). This classification retained significance when examining patients with uniform treatment. In separate analyses for each risk group, we found that administration of adjuvant radiation therapy is associated with increased local disease-free survival for high-risk patients only (P = 0.0296) but not low-risk or intermediate-risk patients. Resection margin status alone is not an independent predictor of LR and cannot be the sole variable in the decision-making process regarding adjuvant radiation therapy. We suggest that the recommendation for adjuvant radiation therapy be based on, not only traditional factors (inadequate margin, perineural invasion, bone invasion) but also histologic risk assessment. If clinicians want to avoid the debilitation of adjuvant radiation therapy, then a 5-mm margin standard may not be effective in the presence of high-risk score.

As the use of marijuana among adolescents remains high, more effective interventions are needed. We conducted this cross–sectional survey at an outpatient, university–based, adolescent clinic to determine the prevalence of marijuana use in an inner–city adolescent population and to examine the relationship of stress and coping methods to marijuana user status (never user, experimenter, and frequent user). The subjects were 918 adolescents aged 12–21 years. Lifetime use in this population was 59% (n = 611) with 18.4% (n = 191) reporting frequent weekly use. Almost all (97%) marijuana users acknowledged marijuana use by friends. Stepwise logistic regression analysis showed that negative life events, greater use of the negative coping method of anger and less frequent use of the positive coping method of parental support were significantly and independently related to marijuana user status. In the presence of high peer use, exploring parent–child relationships and use of anger coping and intervening accordingly may decrease marijuana use.

Our objective was to compare health problems and medical coverage of homeless and housed children who used a school-based health center (SBHC) for comprehensive care.Medical charts of homeless children (n = 76) and housed children (n = 232) seen for comprehensive care at an SBHC in New York City during the 1998-99 school year were systematically reviewed and compared.Controlled for ethnicity and medical coverage, homeless children were 2.5 times as likely (P.001) to have health problems and 3 times as likely (P.001) to have severe health problems as housed children. The most common health problems identified in the homeless population were asthma (33%), vision (13%), mental health (9%), and acute problems (8%). Lack of medical coverage was evident in 58% of homeless children, compared with 15% of housed children (P.001).Study findings identify homeless children as being at increased risk for health problems and lack of medical coverage. These findings support use of an SBHC for comprehensive care by underserved segments of the population and a need for increased vigilance on the part of health care providers caring for homeless children.

OBJECTIVE Myeloid dendritic cell (mDC) dysfunction during HIV infection may hinder the formation of both innate and adaptive immune responses and contribute to pathogenesis. Our objective was to determine whether circulating factors during chronic HIV infection impair mDC function with respect to secretion of IL-12, a pro-Th1 cytokine, and T-cell stimulatory capacity. Particular focus was placed on the effect of combination antiretroviral therapy (cART) and the role of HIV itself on mDC function. METHODS Monocyte-derived DC (moDC) from uninfected donors were exposed to plasma from HIV-infected individuals before Toll-like receptor (TLR) stimulation. Cytokine secretion was measured via cytokine bead arrays, and T-cell proliferation and IFNγ secretion was evaluated after coculture with naive CD4 T cells. Expression of genes central to TLR-mediated signal transduction was analyzed via quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) arrays and western blot. RESULTS Exposure of monocyte-derived DC to plasma from untreated HIV-infected donors suppressed secretion of IL-12, and impaired Th1-skewing of CD4 T cells. The suppressive effect was less by plasma donors receiving cART. Removal of virus from plasma did not relieve suppression nor was IL-12 secretion decreased on addition of HIV to control plasma. On a transcriptional level, decreased expression of IKKβ, a key regulator in the TLR/NF-kappaB signaling pathway, corresponded to suppressed cytokine secretion. CONCLUSIONS Plasma factors during chronic HIV infection impair mDC function in a manner that likely impacts the formation of immune responses to HIV, opportunistic pathogens, and vaccines. Despite partial alleviation by cART, this suppression was not directly mediated by HIV.

Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA +) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA + predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA +, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31–83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA + versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4–21.6] versus 8.1 months (95% CI: 6.1–10.3; P = 0.009); overall survival (OS) 56.8 months (95% CI: 32.5–indeterminate) versus 22.6 months (95% CI: 17.0–34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08–2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18–3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93–2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance. Mol Cancer Ther; 10(10); 2000–7. ©2011 AACR.

International audience; Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and overexpressed by many tumors. Here, we documented the presence of MMP-2-specific CD4(+) T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4(+) T cells displayed an inflammatory T(H)2 profile, i.e., mainly secreting TNF-α, IL-4, and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naïve CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type 2 "conditioner" and may play a role in the observed prevalence of detrimental type 2 responses in melanoma.

Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-α and to activate adaptive immune responses. Although IFN-α inhibits HIV-1 replication in vitro, the production of IFN-α by HIV-activated pDCs in vivo may contribute more to HIV pathogenesis than to protection. We have now shown that HIV-stimulated human pDCs allow for persistent IFN-α production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-α production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-α/β receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-α pathway but weak activation of the NF-κB pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-α-producing phenotype we observed. We demonstrated that HIV preferentially traffics to the early endosome in human pDCs and therefore skews pDCs toward a partially matured, persistently IFN-α-secreting phenotype.

There are little data on the appropriate endpoint for slow pathway ablation that balances acceptable procedural times, recurrence rates, and complication rates. This study compared recurrence rates of three commonly utilized endpoints of slow pathway ablation for atrioventricular nodal reentrant tachycardia (AVNRT).We performed a meta-analysis of AVNRT slow pathway ablation cohorts by searching electronic databases, the Internet, and conference proceedings. Inclusion criteria were age18 years,20 human subjects per study, primary AVNRT ablation, English language publication, and1 month of follow-up. Data were analyzed with a fixed-effects model using Comprehensive Meta-Analysis software version 2.2.046 (Biostat, Englewood, NJ, USA).We included 10 studies encompassing 1,204 patients with a mean age of 41-53 years. Endpoints were complete slow pathway ablation, residual jump only, and single remaining echo beat. Pooled estimates revealed 28 of 641 patients (4.4%) with complete slow pathway ablation, 13 of 192 patients (6.8%) with a residual jump only, and 24 of 371 patients (6.5%) with one echo had recurrences. With uniform isoproterenol use after ablation, there was no significant difference in recurrence rates among the endpoints. However, when isoproterenol was utilized after ablation only if needed to induce AVNRT before ablation, a significantly higher recurrence rate occurred in patients with a residual jump (P = 0.002), a single echo (P = 0.003), or the combined group of a residual jump and/or one echo (P = 0.001).Isoproterenol should be used routinely after slow pathway modification, when a residual jump and/or single echo remain.

Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination. Cancer Prev Res; 3(9); 1093–103. ©2010 AACR.

To evaluate circulating endothelial lineage cells (ELCs) as biomarkers of tumor neovascularization in patients with pancreatic ductal adenocarcinoma (PDAC).ELCs were isolated from the peripheral blood of patients with PDAC (n=14) or controls (n=17) before and after tumor resection/surgery and quantified using flow cytometry. Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were detected in tumor using immunohistochemistry and in plasma using an ELISA technique.Circulating ELC levels were increased in patients with PDAC compared to controls. After PDAC resection, ELC levels declined. ELC level increases were associated with cancer recurrence. VEGF and PlGF were identified in cancer cells and exocrine pancreas cells. Only PlGF was detected in tumor-associated inflammatory cells. Plasma levels of PlGF were higher in patients with PDAC compared to controls.Circulating ELCs are a potential biomarker of PDAC neovascularization, and PlGF may be an important target in treatment of PDAC.

BACKGROUND: The aim of this study was to calculate and analyze the cost of treatment for stage IV pressure ulcers. METHODS: A retrospective chart analysis of patients with stage IV pressure ulcers was conducted. Hospital records and treatment outcomes of these patients were followed up for a maximum of 29 months and analyzed. Costs directly related to the treatment of pressure ulcers and their associated complications were calculated. RESULTS: Nineteen patients with stage IV pressure ulcers (11 hospital-acquired and 8 communityacquired) were identified and their charts were reviewed. The average hospital treatment cost associated with stage IV pressure ulcers and related complications was $129,248 for hospital-acquired ulcers during 1 admission, and $124,327 for community-acquired ulcers over an average of 4 admissions. CONCLUSIONS: The costs incurred from stage IV pressure ulcers are much greater than previously estimated. Halting the progression of early stage pressure ulcers has the potential to eradicate enormous pain and suffering, save thousands of lives, and reduce health care expenditures by millions of dollars.

Purpose: In certain cancers, MDM2 SNP309 has been associated with early tumor onset in women. In melanoma, incidence rates are higher in women than in men among individuals less than 40 years of age, but among those older than 50 years of age, melanoma is more frequent in men than in women. To investigate this difference, we examined the association among MDM2 SNP309, age at diagnosis, and gender among melanoma patients. Experimental Design: Prospectively enrolled melanoma patients (N = 227) were evaluated for MDM2 SNP309 and the related polymorphism, p53 Arg72Pro. DNA was isolated from patient blood samples, and genotypes were analyzed by PCR-restriction fragment length polymorphism. Associations among MDM2 SNP309, p53 Arg72Pro, age at diagnosis, and clinicopathologic features of melanoma were analyzed. Results: The median age at diagnosis was 13 years earlier among women with a SNP309 GG genotype (46 years) compared with women with TG+TT genotypes (59 years; P = 0.19). Analyses using age dichotomized at each decade indicated that women with a GG genotype had significantly higher risks of being diagnosed with melanoma at ages Conclusions: Our data suggest that MDM2 may play an important role in the development of melanoma in women. The MDM2 SNP309 genotype may help identify women at risk of developing melanoma at a young age.

Primary CNS germ cell tumors (GCT) arise in the suprasellar and pineal regions. Suprasellar GCT may remain radiographically occult during the early symptomatic period. Although theoretically possible, it is more difficult to identify presymptomatic disease in the pineal region. Given the sensitivity of GCT to cytotoxic therapy, a decrease in size of the "normal" pineal gland following chemotherapy (CHT) could divulge preexisting disease. Such information may impact radiation treatment (RT). The authors reviewed MRIs of 15 patients with suprasellar GCT treated with pre-RT CHT. They defined a > or =50% reduction in volume of the pineal gland as a substantial decrease suspicious for preexisting occult disease. As controls, MRIs of 11 medulloblastoma patients who received cytotoxic therapy were reviewed. Pineal gland volumes could be determined for 12 of 15 patients with GCT and 7 of 11 patients with medulloblastoma. The study radiologists concurred that 2/12 GCT patients and 0/7 medulloblastoma patients had > or =50% volumetric reduction. When radiation is delivered as the sole treatment modality, the pineal region is included in at least the initial volume, but in certain clinical trials RT volume is reduced to only the suprasellar region if a complete response is achieved following pre-RT CHT. Noting changes in the "normal" pineal gland following CHT may indicate disease. CHT alone may not be sufficient to control this disease, even in cases in which a complete response is achieved. If the intent is to deliver RT to all areas of initial disease and this phenomenon can be demonstrated on a larger scale, inclusion of the pineal should be considered for patients demonstrating a substantial decrease in the size of the pineal gland after CHT.

The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IkappaB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IkappaB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.

Whether histologic subtype of non-small cell lung cancer (NSCLC) has an important effect on prognosis after surgery is unknown.We hypothesized that we could predict mortality more effectively by integrating precise tumor size and histology rather than relying on conventional staging.We used the SEER (Surveillance, Epidemiology, and End Results) registry. Inclusion criteria were as follows: (1) primary squamous cell or adenocarcinoma; (2) potentially curative surgery, defined as a lobectomy or bilobectomy; (3) lymph node dissection performed; and (4) pathologic stage IA or IB.From 1988 to 2000, 7,965 patients were included. For both all-cause and lung cancer-associated mortality, tumor size demonstrated the strongest association (log-rank P0.0001 for each). When tumors were small (/=2 cm), lung cancer-associated mortality was similar for adenocarcinoma when compared with squamous cell carcinoma. When tumors were 3 cm or larger in size, lung cancer-associated mortality was higher for adenocarcinoma. The increased risk of lung cancer-associated mortality with adenocarcinoma was more pronounced in those younger than 65 years. Survival prediction using precise size and histology had much better discriminatory power than conventional TNM (tumor-node-metastasis) staging (P = 0.005).Staging that takes into account size, histology, late recurrence risk, and patient age is more accurate than the current TNM system and is clinically relevant because improved prediction can facilitate better decisions on the use of adjuvant chemotherapy.

Objective—Apolipoprotein E (apoE) reduces mouse atherosclerosis progression independent of plasma cholesterol level effects. A mouse artery injury model was used to examine whether apoE exhibits beneficial lipid-independent effects on neointimal formation.Methods and Results—ApoE-deficient (apoE−/−), wild-type (WT), and transgenic apoE−/− mice (secreting apoE at different levels from adrenal glands) underwent femoral artery injury. Mice with low expression of plasma apoE (0.1% of WT) had cholesterol levels approximately half those of apoE−/− littermates (but still ≈6× >WT). Mice with higher expression (HE; 2% to 3% of WT) of plasma apoE had cholesterol levels approximately twice those of WT. Injured WT mouse (versus apoE−/−) arteries had a smaller mean intima-to-media (I/M) ratio (0.87 versus 1.96;PP>0.05 versus apoE−/− mice). Multiple regression analysis indicated that apoE levels were significantly associated with reduced I/M ratios, but plasma cholesterol levels were not, before or after adjusting for apoE. In addition, foam cell content of the neointima and media of injured arteries, a negative prognostic indicator in postangioplasty human lesions, was inversely related to plasma apoE levels.Conclusions—Similar to its effects on atherosclerosis progression, in a mouse model of restenosis, a subphysiological level of apoE was associated with beneficial effects on lesion size/composition.

To compare perceived reasons for continued smoking and withdrawal symptoms between current smokers and quitters in an inner-city adolescent population. To examine the relationship of nicotine dependence, stress, and coping methods between smokers and quitters and, using the Transtheoretical Model of Change, among adjacent smoking cessation stages.A cross-sectional study using a self-administered questionnaire.The study comprised 354 clinic patients between the ages of 12 and 21 years who reported past or present smoking.Demographic characteristics, smoking status, perceived reasons for continued smoking, attempts to quit, and withdrawal symptoms, as well as standardized scales assessing nicotine dependence, stress, and coping methods.The overall prevalence of smoking in this population was 26%. Smokers were significantly more likely to report smoking more cigarettes per day as well as higher levels of physical addiction (P.01), greater levels of perceived stress (P.02), and less use of cognitive coping methods (P.02) than quitters (P.005). However, comparison of consecutive stages revealed a significant difference only between precontemplation and contemplation in cognitive coping methods (P.01). Three of 20 withdrawal symptoms (cravings, difficulty dealing with stress, and anger) were reported more frequently among current smokers who had attempted to quit in the last 6 months than among former smokers (P.01).Interventions for inner-city adolescents who smoke should be designed to target those with the highest levels of nicotine dependence, stress, and decreased use of cognitive coping methods because they are the least likely to quit on their own, rather than developing stage-specific models.

To examine the relationship of stress and coping methods to smoking status (never-smoker, experimenter, and current smoker) among an inner-city, clinic-based, adolescent population, as well as to examine the prevalence of smoking and related behaviors in this population using a cross-sectional survey.A self-administered questionnaire that included the Perceived Stress Scale (PSS), negative life events (LES), and a coping measures scale was used with 954 clinic patients aged 12-21 years. Demographic characteristics were compared using analysis of variance and Chi-square test. The Kruskal-Wallis analysis of variance was used to compare the values of each scale among smoking-status groups. Logistic regression analysis was used to determine the relationship of smoking status to PSS, LES, and coping methods.The overall prevalence of smoking in this population was 26%. The age of onset was 13.3 years for current smokers vs. 15.5 for experimenters (p.01). Perceived stress and negative life events, adjusting for demographic variables, were highest among current smokers, less so in experimenters, and lowest in the never-smokers (p.001). Stepwise logistic regression analysis showed that negative life events, perceived stress, greater use of the negative coping methods of anger and helplessness, and less use of the positive coping methods of parental support and cognitive coping were significantly and independently related to smoking status.One in four inner-city youth report smoking. Higher levels of stress and greater use of negative coping methods were found in current smokers than in experimenters and never-smokers.

5043 Background: Does BRCA status affect outcome of rEOC patients treated with PLD? Tumors deficient in homologous recombination (HR) DNA repair are sensitive to platinums. Recurrences likely reflect acquired platinum resistance, perhaps from recovering BRCA function (as suggested in preclinical studies). We now investigate whether sensitivity to PLD and other DNA damaging agents is retained in BRCA mutation carriers (BRCA+) with rEOC. Methods: We retrospectively analyzed rEOC patients treated with PLD as second- or third-line from 1998 to 2009 in 4 institutions (Israel, Italy, NY):155 rEOC patients have been evaluated of which 38 (24.5%) are BRCA+ and 117 (75.5%) non-hereditary consisting of 35 (22.5%) who tested negative and 82 (53%) untested, (excluding 10 patients with a family history in a first-degree relative). Results: Median age is 59 (31-83) years; 44 (28%) patients have a platinum free interval (PFI) of 6 months; 104 (67%) received PLD as second-line and 55 (33%) ...

3002 Background: Dendritic cell (DC) vaccines have been widely used in clinical trials to treat cancer. However, no study has compared the immunogenicity of the most commonly used DC type (cytokine-matured, monocyte-derived DCs) to more traditional vaccine adjuvants. We performed a randomized controlled trial comparing the immunogenicity of cytokine-matured DCs loaded with 6 HLA-A2-restricted peptide antigens and a foreign protein, KLH, to a vaccine containing the same antigens emulsified in the mineral oil adjuvant Montanide ISA 51 VG. Methods: 51 HLA-A2+ patients with resected stage IIb-IIIc melanoma were randomized to receive DCs (25 patients) or Montanide (26 patients). DCs were differentiated from autologous blood monocytes with IL-4 and GM-CSF, then matured with IL- 1β, IL-6, TNFα and PGE2. 18 million DCs were given i.d. every 4 weeks x 4, and immune responses analyzed (MHC multimers, T cell proliferation, cytokine secretion, antibodies). A 3-fold increase over baseline was considered a response. Results: Both vaccines were well tolerated. Immunogenicity was significantly greater with Montanide, as demonstrated by response rates to Flu, Melan-A and NY-ESO-1 peptides by IFNγ ELISPOT. Similar results were obtained by MHC multimer staining, with higher response rates seen using pre-sensitized assays. T cell proliferation to KLH was seen in both arms (90% DC, 100% Montanide), but the magnitude of response was significantly higher for Montanide (36-fold vs. 14-fold increase over baseline, p=0.002, Wilcoxon). KLH-specific CD4+ T cells that produced IFNγ, TNFα and IL-2 were seen only with Montanide, and all Montanide patients, but only 5% of DC patients, developed antibodies to KLH (p [Table: see text] [Table: see text]