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Female inner-city substance users evidence greater crack/cocaine use and are more likely to be dependent on this drug than on any other drug. Additionally, female inner-city substance users evidence greater crack/cocaine use and are more likely to be dependent on this drug than their male counterparts, despite no consistent difference demonstrated in use and dependence across other drugs. Because no published work has empirically examined the factors underlying this link between females and crack/cocaine, the current study examined the role of theoretically relevant personality and environmental variables. Among 152 (37% female) individuals in a residential substance-use treatment program, females evidenced greater use of crack/cocaine (current and lifetime heaviest) and were significantly more likely to evidence crack/cocaine dependence than their male counterparts. In contrast, no gender differences were found for any other substance across alcohol, cannabis, and hallucinogens (including PCP). Surprisingly, females were more impulsive than their male counterparts, with impulsivity serving as a risk factor in the relationship between gender and crack/cocaine dependence and lifetime heaviest use. Females also evidenced higher levels of negative emotionality and childhood abuse, but neither variable served as a risk factor in the relationship between gender and crack/cocaine dependence or use. Limitations and future directions are discussed, including the need for further exploration of impulsivity across its various dimensions as well as the inclusion of additional variables such as social context variables to account more fully for this complex link between gender and crack/cocaine.

Most melanocytic nevi develop on sun-exposed skin during childhood and adolescence and commonly harbor BRAF mutations or, less frequently, NRAS mutations. A small subset of nevi is present at birth, and therefore must develop independently of UV light. To assess whether these nevi have a different mutation spectrum than those that develop on sun-exposed skin, we determined the BRAF and NRAS mutation frequencies in 32 truly congenital nevi. We found no BRAF mutations, but 81% (26/32) harbored mutations in NRAS. Consistently, seven of 10 (70%) proliferating nodules that developed early in life in congenital nevi showed mutations in NRAS. A separate set of nevi that displayed histological features frequently found in nevi present at birth ("congenital pattern nevi") but lacked a definitive history of presence at birth showed an inverse mutation pattern with common BRAF mutations (20/28 or 71%) and less frequent NRAS mutations (7/28 or 25%). Thus, nevi that develop in utero are genetically distinct from those that develop later, and histopathologic criteria alone are unable to reliably distinguish the two groups. The results are consistent with the finding in melanoma that BRAF mutations are uncommon in neoplasms that develop in the absence of sun-exposure.

Epithelial ovarian cancer continues to be the leading cause of death due to gynecologic malignancy, and it is the fifth leading cause of cancer death in women in the USA and seventh worldwide. In most women with ovarian cancer, the disease is diagnosed at an advanced stage and primary cytoreductive surgery is considered standard of care. Traditionally, the gynecologic oncology literature supports the dictum that aggressive radical debulking to reduce intra-abdominal tumor burden to minimal or less than 1 cm of disease has significant impact on overall survival. However, the European Organization for Research and Treatment of Cancer (EORTC) trial found that survival after neoadjuvant followed by interval debulking surgery was similar to survival with the standard approach of primary surgery followed by chemotherapy. Many gynecologic oncologists have now adopted neoadjuvant chemotherapy for the treatment of stage IV ovarian cancer given the complex nature of this disease. Currently, there are conflicting results in the literature with regards to neoadjuvant chemotherapy versus primary debulking for stage IV ovarian cancer. While there is evidence that neoadjuvant treatment is not inferior to primary debulking, the literature also supports that maximizing debulking efforts with radical surgery can provide a survival benefit in patients with stage IV ovarian carcinoma.

Introduction Evaluate use of novel multi-channel applicator (MC) Capri™ to improve vaginal disease coverage achievable by single-channel applicator (SC) and comparable to Syed plan simulation. Materials and methods Twenty-eight plans were evaluated from four patients with primary or recurrent gynecologic cancer in the vagina. Each received whole pelvis radiation, followed by three weekly treatments using HDR brachytherapy with a 13-channel MC. Upper vagina was treated to 5 mm depth to 1500 cGy/3 fractions with a simultaneous integrated boost totaling 2100 cGy/3 fractions to tumor. Modeling of SC and Syed plans was performed using MC scans for each patient. Dosimetry for MC and SC plans was evaluated for PTV700 cGy coverage, maximum dose to 2 cm3 to bladder, rectum, as well as mucosal surface points. Dosimetry for Syed plans was calculated for PTV700 cGy coverage. Patients were followed for treatment response and toxicity. Results Dosimetric analysis between MC and SC plans demonstrated increased tumor coverage (PTV700 cGy), with decreased rectal, bladder, and contralateral vaginal mucosa dose in favor of MC. These differences were significant (p

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.

ObjectiveWe aimed to compare access to gynecologic oncology care at a private and a city hospital, both of which closed for a period of time because of Hurricane Sandy.MethodsThis was a cross-sectional study of gynecologic oncology chemotherapy, radiotherapy, and surgical patients from October 29, 2012 (the eve of the storm), to February 7, 2013 (the reopening of the city hospital). New referrals during this time were excluded. Delays in chemotherapy, radiotherapy, and surgery were compared.ResultsAnalysis included 113 patients: 59 private patients (52.2%) and 54 city patients (47.8%). Of the private patients, 33/59 received chemotherapy (55.9%), 1/59 received radiotherapy (1.7%), and 28/59 had planned surgery (47.5%). Of the city patients, 40/54 received chemotherapy (74.1%), 7/54 received radiotherapy (12.3%), and 18/54 had planned surgery (33.3%). The mean delay in chemotherapy was 7.6 days at the private hospital and 21.7 days at the city hospital (P=0.0004). The mean delay in scheduled surgery was 14.2 days at the private hospital and 22.7 days at the city hospital (P=0.3979). The mean delay in radiotherapy was 0.0 days at the private hospital and 25.0 days at the city hospital (P=0.0046). Loss to follow-up rates were 3/59 of the private patients (5.1%) and 3/54 of the city patients (5.6%).ConclusionsGynecologic oncology care was maintained during a natural disaster despite temporary closure and relocation of services. Disparity in care was in access to chemotherapy. (Disaster Med Public Health Preparedness. 2015;9:605–608)

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Refereed/Peer-reviewed

Background In February 1999, the National Cancer Institute (NCI) issued a clinical alert based on five randomized trials that reported better overall survival (OS) with concurrent chemoradiotherapy (CCRT) than with surgery or radiation alone for locoregional cervical cancer. This study analyzes data from the surveillance epidemiology and end results (SEER) program to evaluate the improvement in survival in the era of CCRT. Methods The SEER database was queried for FIGO stages IB2–IVA cervical cancer patients treated with radiotherapy between 1995 and 2002. Patients diagnosed between 1999 and 2002 (CCRT era) were assumed to have received CCRT more frequently than patients diagnosed between 1995 and 1998 (RT era). Cases were stratified by period of diagnosis, age, and SEER region. OS and cause specific survival (CSS) were compared between the two time periods with chi-square log-rank tests. Multivariable Cox models were also used to compare OS and CSS between the two time periods, with adjustment for stratification variables and other covariates. Results The study included 3517 patients. Unadjusted OS and CSS were significantly improved in 1999–2002 compared with 1995–1998 (OS: p

Cognitive remediation is a treatment approach with the potential to translate basic science into more specific, mechanism-based interventions by targeting particular cognitive skills. The present study translated understanding of two well-defined cognitive-affective dysfunctions into novel deficit-matched interventions and evaluated whether cognitive remediation would demonstrate specific and generalizable change. Two antisocial subtypes, individuals with psychopathy and externalizing traits, are characterized by cognitive-affective problems that predispose them to engage in significant substance abuse and criminal behavior, culminating in incarceration. Whereas individuals with psychopathy fail to consider important contextual information, individuals with externalizing traits lack the capacity to regulate affective reactions. Training designed to remedy these subtype-specific deficits led to improvement on both trained and nontrained tasks. Such findings offer promise for changing neural and behavioral patterns, even for what many consider to be the most recalcitrant treatment population, and presage a new era of translating cognitive-affective science into increasingly specific and effective interventions.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis. This research was specifically funded by an MRC Population Health Scientist Fellowship awarded to Dr L Paternoster (MR/J012165/1). D.M.E. is supported by an Australian Research Council Future Fellowship (FT130101709) and a Medical Research Council program grant (MC_UU_12013/4)

Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a third phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on Intraperitoneal Therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.

Recent theories suggest that drug withdrawal does not motivate drug use and relapse. However, data now show that withdrawal produces complex changes over time in at least two symptoms (i.e., negative affect and urges) that are highly predictive of relapse. Evidence suggests that falling levels of the drug in the blood and interruption of the drug self-administration ritual both affect these symptoms. Both of these forms of withdrawal motivate renewed drug use in addicted individuals.

Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease. (Cancer Res 2006; 66(19): 9483-91)

Purpose Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogen-activated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS. Patients and Methods We analyzed array comparative genomic hybridization data from 102 primary melanomas (38 from mucosa, 28 from acral skin, and 18 from skin with and 18 from skin without chronic sun-induced damage) for DNA copy number aberrations specific to melanoma subtypes where mutations in BRAF and NRAS are infrequent. A narrow amplification on 4q12 was found, and candidate genes within it were analyzed. Results Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. Conclusion KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden.

Behavioral and neuroelectric indices of action monitoring were compared for 53 high and low physically active older (60-71 years) and younger (18-21 years) adults during a task-switching paradigm in which they performed a task repeatedly or switched between two different tasks. The error-related negativity (ERN) of a response-locked event-related brain potential (ERP) and behavioral measures of response speed and accuracy were measured during the heterogeneous condition (switching randomly between two tasks) of the switch task. Results indicated that older adults exhibited a greater relative slowing in RT during heterogeneous blocks and smaller ERN amplitude compared to younger adults. Additionally, physical activity differences revealed a relatively smaller global switch cost for physically active older adults and decreased ERN amplitude, as well as increased post-error response slowing for older and younger physically active participants, compared to their less physically active counterparts. The findings suggest that both age and physical activity participation influence behavioral and neuroelectric indices of action monitoring and provide further evidence for the beneficial effects of physical activity on executive control.

This study examined physiological indicants of the neurobiological mediators of negative affect during acute nicotine withdrawal. Eighty subjects (41 male) were assigned to one of four groups (24-h deprived or nondeprived dependent smokers, occasional smokers, and nonsmokers) and participated in an instructed fear conditioning paradigm involving cued administration of electric shock. Negative affective response was measured with fear-potentiated startle during cues that signaled electric shock and during the postcue offset recovery period. Salivary cortisol and self-report measures were also collected. Fear-potentiated startle results indicated that affective recovery postcue offset was delayed in nicotine-deprived women. Nicotine-deprived women also displayed elevated cortisol levels throughout the fear conditioning procedure.

This report used emotion-modulated startle to refine theoretically critical claims about negative affect during tobacco withdrawal. Forty-eight dependent smokers (assigned to either a 24-hr nicotine withdrawal condition or a continued smoking condition) and 48 nonsmokers participated in this study. Participants viewed a series of neutral and unpleasant photographic images and were instructed to enhance, suppress, or maintain their emotional response during specific trials. Participants' startle response was measured before and after this regulation instruction to index 2 components of emotional response: initial negative emotional response intensity and emotion regulation. Compared with the nonwithdrawn groups (continuing smokers and nonsmokers), withdrawal significantly increased self-reported negative affect. However, startle response indicated that emotional response intensity and emotion regulation success were not affected by withdrawal. These results are important because they constrain interpretation of the predominantly self-report literature on the affective consequences of tobacco withdrawal.

BACKGROUND Most gynecologists determine therapy based on current International Society of Gynecologic Pathologists (ISGP)/World Health Organization classification of endometrial hyperplasia, the reproducibility of which has been questioned. The Gynecologic Oncology Group (GOG) initiated a protocol to assess the efficacy of hormonal therapy of atypical endometrial hyperplasia (AEH). Primary goals of the first phase (Part A) were to prospectively determine reproducibility of referring institution's pathologist's diagnosis of AEH by a panel of 3 gynecologic pathologists and to determine reproducibility of diagnoses by panel members. METHODS Three hundred six women were entered on this protocol with a referring institution's pathologist diagnosis of AEH based on biopsy or curettage. Available slides were assessed independently and interpreted by each of a panel of 3 gynecologic pathologists who used International Society of Gynecologic Pathologists (ISGP)/World Health Organization criteria. The majority diagnosis was based on diagnostic concordance by at least 2 of the 3 panelists. RESULTS The referring institution's pathologist's diagnosis of AEH was supported by the majority of the panel in only 38% of cases. Overall kappa value for the panel diagnosis of AEH was 0.28. The majority diagnosis was adenocarcinoma in 29%, cycling endometrium in 7%, and nonatypical hyperplasia in 18% of cases. Unanimous agreement for any diagnosis was reached among all 3 of the panel in 40% of cases. For the panel, paired kappa values for any diagnosis ranged 0.34–0.43, with an overall kappa value of 0.40. CONCLUSION Reproducibility of referring institution's pathologists' diagnosis of AEH by a panel of gynecologic pathologists is poor. Both underestimation and overestimation of the severity of the lesion are very common. The level of reproducibility among subspecialist panel members for diagnosis of AEH in these specimens also is poor. Better criteria and better sampling are needed to improve reproducibility of this diagnosis, particularly if it is to be used for clinical decisions. Cancer 2006. © 2006 American Cancer Society.

The negative affective priming of aggression was examined across different aversive contexts (general stress exposure and frustration) with a laboratory aggression paradigm that measured the intensity of shocks participants delivered to a putative employee. Participants' emotional responses were gauged via startle eyeblink reactions and self-report mood ratings. Aside from gender differences in overall aggression, men but not women exposed to general stress showed significant increases in aggression across blocks. However, frustration produced increases in aggression in both genders. Although both genders showed robust startle increases during stress, startle activation was related to increases in aggression in men and decreases in aggression in women. These findings suggest that general stress and experiences of negative emotion trigger physical aggressive responses more strongly in men than in women.

Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light.We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas.We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89 percent accuracy. Eighty-one percent of melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway.The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.

The present study examines the effects of early emotional experiences on children's regulation or strategic control of attention in the presence of interpersonal hostility. Abused children's reactions to the unfolding of a realistic interpersonal emotional situation were measured through multiple methods including autonomic nervous system changes and overt behavioral performance. Although physically abused and non-physically abused 4-year-old children did not differ in terms of their baseline levels of arousal, marked differences in physically abused children's regulatory responses to background anger emerged. These data suggest that the emergence of anger leads to increases in anticipatory monitoring of the environment among children with histories of abuse. Results are discussed in terms of risk factors in the development of psychopathology.

There were two specific goals for the current study: (1) to demonstrate that adolescents display drug-specific cue reactivity to alcohol and cigarette visual cues that varies based on drug-use history and (2) to test the unique contribution of adolescents' avoidance reactions to alcohol and cigarette cues, independent of approach/craving reaction.Adolescents (N = 143; age 13-20 years; 58 males) with varied substance-use histories were recruited from school and community sites. Adolescents were presented with a series of alcohol, cigarette, and nondrug comparison visual cues and reported their approach/craving and avoidance reactions. They also completed individual difference measures related to their alcohol and cigarette use and experiences.When adolescents were grouped according to their current alcohol or cigarette use (no use, low use, high use), increased use of alcohol or cigarettes was associated with stronger reactions (increased approach, decreased avoidance) to cues for that substance but not to nondrug control cues. Simultaneous regression analyses demonstrated that after controlling for approach/craving reactions, avoidance cue reactions predicted unique and/or incremental variance in measures of alcohol and cigarette usage, recent change in patterns of use, alcohol expectancies, alcohol restraint and parental alcohol problems.Adolescents displayed robust alcohol and cigarette cue-specific reactions that varied systematically with their current use of these drugs. Across numerous clinically relevant individual difference variables, predictive power was greatly enhanced through the inclusion of both avoidance and approach reactions.

The current study utilized a sample of 123 inner-city drug users in residential treatment, comparing sexual risk behavior (SRB) across primary users of (a) heroin and not crack/cocaine, (b) crack/cocaine and not heroin, and (c) both heroin and crack/cocaine. Additional analyses also examined impulsivity as a mediator of drug choice and SRB. Results indicated that SRB was higher in primary crack/cocaine users than in primary heroin users, with those using both drugs evidencing intermediate levels of SRB. Beyond differences in SRB, a similar pattern across drugs was found for impulsivity. Finally, impulsivity mediated the relationship between drug choice and SRB. Although further research is necessary to establish causal relationships, these results support a relationship between SBR and crack/cocaine, and suggest that disinhibition processes including impulsivity may underlie this relationship.

The Web environment produces new challenges for Human Factor specialists who are transitioning their development organizations and clients from traditional software media to Web-based applications. While the Web offers new potential for deployment, its technical capabilities often limit techniques for user interaction and data manipulation PC-based GUIs offer. Conventions for operation of web applications are still ill-formed; concepts for website design rarely translate well to the design of task-based, enterprise-level applications; and stakeholders often mistake their own, idiosyncratic operation of websites as premises for effective design. This paper teaches practitioners techniques for creating or migrating software applications from traditional media to the Web, based on a case study of creating a web-access cargo management system. Discussion includes dealing with unrealistic visions of an application's operation in relation to the user population who will be operating it, developing alternatives to traditional forms of personnel training, and creating new controls and interaction schema.

We examined the hypothesis that unintentional race-biased responses may occur despite the activation of neural systems that detect the need for control. Participants completed a sequential priming task that induced race-biased responses on certain trials while electroencephalography was recorded. The error-related negativity (ERN) wave, a component of the event-related potential with an anterior cingulate generator, was assessed to index neural signals detecting the need for control. Responses attributed to race bias produced larger ERNs than responses not attributed to race bias. Although race-biased responses were prevalent across participants, those with larger ERNs to race-biased responses showed higher levels of control throughout the task (e.g., greater accuracy and slowed responding following errors). The results indicate that race-biased responses may be made despite the activation of neural systems designed to detect bias and to recruit controlled processing.

Three mutant mice with pigmentation phenotypes were recovered from a genomewide random mouse chemical mutagenesis study. White toes (Whto; MGI:1861986), Belly spot and white toes (Bswt; MGI:2152776) and Dark footpads 2 (Dfp2; MGI:1861991) were identified following visual inspection of progeny from a male exposed to the point mutagen ethylnitrosourea (ENU). In order to rapidly localize the causative mutations, genome-wide linkage scans were performed on pooled DNA samples from backcross animals for each mutant line. Whto was mapped to proximal mouse chromosome (Mmu) 7 between Cen (the centromere) and D7Mit112 (8.0 cM from the centromere), Bswt was mapped to centric Mmul between D1Mit214 (32.1 cM) and D1Mit480 (32.8 cM) and Dfp2 was mapped to proximalMmu4 between Cen and D4Mit18 (5.2 cM). Whto, Bswt and Dfp2 may provide novel starting points in furthering the elucidation of genetic and biochemical pathways relevant to pigmentation and associated biological processes.

An arousal-control and cross-over design was used to evaluate the reliability, specificity, and validity of the Normative Appetitive Picture System (NAPS), a cue exposure protocol with sets of visual alcohol, cigarette, and control cues. The authors also examined the utility of conceptualizing cue reactivity as a multidimensional phenomenon involving independent approach and avoidance dimensions. University student participants (n=369) rated multiple cue images in terms of arousing properties and capacity to elicit separate approach and avoidance inclinations. They also completed a battery of substance-related individual-difference measures. Results indicated that NAPS protocol reactivity profiles had good reliability and high specificity across cue types and individuals with different substance use histories. Avoidance reactivity independently predicted self-reports of substance-related behaviors, after controlling for approach reactivity.

The authors tested the hypothesis that impaired behavioral performance during intoxication results partly from alcohol's deleterious effects on cognitive control. The impact of alcohol on perseverative behavior was examined with an n-back working memory task that included manipulations of task complexity and prepotency of inclinations to respond or withhold responding. Thirty-two social drinkers (16 men) participated in either an alcohol (.075g/100ml) or a no-alcohol condition. Alcohol increased perseveration of prepotent, task-inappropriate response patterns only under cognitively demanding (heavy memory load) conditions. This effect was evident for both commission errors (response persistence despite contingencies altered to require restraint) and omission errors (failure to respond when contingencies were revised to encourage action). Findings suggested that alcohol-induced perseveration arises from impairments in cognitive control.

Intraperitoneal chemotherapy (IP) for the treatment of ovarian cancer has been studied in clinical trials and has shown clinical benefit when used as primary adjuvant therapy. IP chemotherapy also may play a role as consolidation after intravenous treatment. In 1998, a pilot study seas initiated using IP cisplatin (or carboplatin) combined with floxuridine (FUDR). Patients received a mean of 3.2 cycles of FUDR, which was accompanied by cisplatin or carboplatin in 88% of cycles. The median follow-up time was 20 months (range 6.0 to 57.6 months). Eight patients have had disease recurrence, with median time to recurrence 19.4 months from onset of protocol treatment. Only one patient has died of disease at 38.8 months from onset of protocol. Extra-abdominal recurrences (lung, brain, inguinal nodes) tended to occur earlier than peritoneal recurrences. Demonstration of an impact on progression-free survival and overall survival requires confirmation in a phase III trial.

We identified two novel mouse mutants with abnormal head-shaking behavior and neural tube defects during the course of independent ENU mutagenesis experiments. The heterozygous and homozygous mutants exhibit defects in the orientation of sensory hair cells in the organ of Corti, indicating a defect in planar cell polarity. The homozygous mutants exhibit severe neural tube defects as a result of failure to initiate neural tube closure. We show that these mutants, spin cycle and crash, carry independent missense mutations within the coding region of Celsr1, encoding a large protocadherin molecule [1]. Celsr1 is one of three mammalian homologs of Drosophila flamingo/starry night, which is essential for the planar cell polarity pathway in Drosophila together with frizzled, dishevelled, prickle, strabismus/van gogh, and rhoA[2, 3]. The identification of mouse mutants of Celsr1 provides the first evidence for the function of the Celsr family in planar cell polarity in mammals and further supports the involvement of a planar cell polarity pathway in vertebrate neurulation.

The clinical presentations of 119 canine seizures from 41 Standard Poodles and 11 Dalmatians were classified according to a modified version of the International League Against Epilepsy (ILAE) seizure classification system. Standardized use of the ILAE system with dogs not only should facilitate research in veterinary medicine, which has no standard criteria for seizure classification, but also should facilitate comparisons between canine and human seizures. We found that for more than 80% of both breeds, at least some of their seizures had partial onsets. However, because it was common for partial seizures to secondarily generalize, the majority of Poodles (81%) and Dalmatians (91%) experienced at least some generalized seizures. Among partial seizures, complex partial were more frequent than simple partial. For both breeds, two thirds of those with partial onset seizures had exclusively complex partial. Among dogs with primary or secondarily generalized seizures, 80% of both breeds had tonic-clonic seizures.

Background. Mullerianadenosarcoma is a rare pelvic malignancy that most commonly arises from the endometrium. These tumors are relatively insensitive to chemotherapy and radiation and are primarily treated by surgical resection. We report a case of mullerian adenosarcoma arising outside of the uterus from a background of endometriosis treated with a combination of surgical resection and medroxyprogesterone acetate. Case. A 43-year-old woman with a history of endometriosis was diagnosed with advanced extrauterine mullerian adenosarcoma. After suboptimal tumor dubulking surgery she was treated with medroxyprogesterone acetate. Ten months postoperatively she remains without evidence of disease. Conclusion. Medroxyprogesterone acetate may be a useful drug in the treatment of advanced mullerian adenosarcoma.

PURPOSE: To evaluate the outcomes of intraperitoneal (IP) chemotherapy compared with those of intravenous (IV) chemotherapy in patients with advanced ovarian cancer treated either with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or with primary debulking surgery (PDS). METHODS: Patients diagnosed with FIGO stage III or IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma treated at our institutions with PDS or NACT and IDS from 2006-2014 were identified. Covariates were compared using chi-square analyses, t-tests and Mann-Whitney tests. Survival rates were calculated using the Kaplan-Meier method and compared with log rank tests and Cox multivariate regression models. RESULTS: Sixty one patients received NACT and underwent IDS with residual disease of ≤ 1 cm; 40 patients (65.6%) received IP chemotherapy and 21 patients (34.4%) were given IV chemotherapy after IDS. The median number of chemotherapy cycles was three (range 3-8), and 34 patients (85.0%) completed the prescribed dose of IP chemotherapy. The median progression free survival was 16.5 months in the IP group and 15.0 months in the IV group (p = 0.88). The estimated median overall survival was 64.0 months in the IP group and 42.0 months in the IV group (p = 0.12). During the same study period, 148 patients underwent optimal PDS after which 93 patients (83.6%) received IP chemotherapy and 55 patients (37.2%) were given IV chemotherapy. Patients after IP chemotherapy had improved survival outcomes when compared to patients after IV chemotherapy. The median progression free survival was 29.0 months after IP chemotherapy and 16.0 months after IV chemotherapy (p < 0.0001) and the median overall survival was 93.0 months after IP chemotherapy and 43.0 months after IV chemotherapy (p < 0.0001). CONCLUSIONS: Although IP chemotherapy after PDS showed improved survival, IP chemotherapy after NACT and IDS, while tolerable with high rates of completion, did not demonstrate a survival advantage over IV chemotherapy in our patients. Citation Format: Jessica Lee MD, John P Curtin MD, Franco M Muggia MD, Bhavana Pothuri MD, Leslie R. Boyd MD, Jing-Yi Chern MD, Melissa K Frey MD, Stephanie V Blank MD. INTRAPERITONEAL CHEMOTHERAPY AFTER PRIMARY OR INTERVAL DEBULKING SURGERY FOR ADVANCED EPITHELIAL OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-096.

e13024 Background: Genetic assessment (GA) is recommended for all women with ovarian cancer however little is known about the psychological implications of this intervention. We sought to evaluate the psychological response to GA in newly diagnosed ovarian cancer patients as part of our facilitated genetics referral pathway. Methods: English-speaking patients with ovarian cancer undergoing GA at the time of cancer diagnosis completed three validated anxiety, stress and depression survey instruments immediately prior to and following GA and again 6-9 months after GA. Results: Forty-eight English-speaking patients underwent GA; 43 (90%) completed the pre-GA survey, 32 (67%) post-GA survey and 11 (23%) 6-9 months follow-up survey. Eight patients (17%) had documented psychiatric diagnoses (5 anxiety, 2 depression, 1 anxiety+depression) prior to cancer diagnosis. Overall, patients demonstrated mild to moderate stress, clinically significant anxiety and borderline depression (Table 1). There was no change in depression, anxiety or stress scores when comparing pre- to post-GA surveys. Age, stage, method of treatment, performance status at enrollment and history of psychiatric disorders were not associated with anxiety, stress or depression. Conclusions: A genetic testing pathway whereby GA is encouraged and facilitated at the time of diagnosis has not increased patient depression, anxiety or stress in our cohort. Concern about causing additional emotional distress should not deter clinicians from early genetics referral. [Table: see text]

e13022 Background: Obesity and Lynch syndrome are well-known risk factors for the development of endometrial cancer. However, there is a paucity of data comparing patients across multiple ethnicities. Methods: All patients diagnosed with endometrial cancer or complex atypical hyperplasia between 2012 and 2015 were retrospectively identified and evaluated. Comparative statistical analyses were performed and stratified by ethnicity with appropriate two-sided statistical tests. Results: A total of 506 patients were diagnosed with endometrial cancer (n = 447) or complex atypical hyperplasia (n = 59) and of these, 31 were East Asian (EA, 6.3%). The remaining 475 patients (93.9%) were of Caucasian, black, Latino, South Asian, Southeast Asian or other unspecified ethnicity. Compared to other patients, EA were diagnosed at a younger age (median age 53 vs 62, p = 0.0003) and had lower body mass indices (BMI) (median BMI 23.0 vs 30.7, p < 0.0001). There were no differences in stage, tumor grade or histology. Differences in age and BMI remained significant despite controlling for these factors on multivariate analysis. Of the EA group, 10 of 31 patients (32.3%) underwent genetic testing and of these, three (30.0%) were found to have a germline mutation in a mismatch repair (MMR) gene. All three patients were of Chinese ancestry, and two had mutations in MLH1 and one in MSH2. In comparison, 69 (14.5%) of the remaining 475 had genetic testing, and six (8.7%) were diagnosed with Lynch syndrome. Chinese patients were more likely to have Lynch syndrome (42.9% vs 8.7%, p= 0.04). There were no differences found in family history of Lynch-related cancers between Chinese and other patients. There was no correlation between germline mutations and MMR testing on tumor immunohistochemistry. All three Chinese patients with Lynch syndrome had negative MMR tumor testing. Conclusions: EA patients with endometrial cancer are diagnosed at younger ages and with lower BMIs compared to patients of other ethnic backgrounds. Chinese patients have a high rate of germline Lynch mutations despite negative tumor MMR testing. EA, particularly Chinese patients, may represent a high-risk cohort, and referral for genetic counseling regardless of tumor MMR testing should be considered.

BACKGROUND: Genetic variants in endotoxin signaling pathway are important in modulating the effect of environmental endotoxin on asthma and atopic phenotypes. Our objective was to determine the single nucleotide polymorphisms (SNPs) in the endotoxin signaling pathway that may influence in vitro IgE synthesis and to investigate the relationship between these variants and endotoxin exposure in relation to the development of asthma and atopy in a birth cohort. METHODS: Peripheral blood mononuclear cells from 45 children with asthma were stimulated with 2 and 200�ng/ml lipopolysaccharide in vitro and IgE was measured in the culture supernatants. Children were genotyped for 121 SNPs from 30 genes in the endotoxin signaling pathway. Variants with a dose-response IgE production in relation to lipopolysaccharide (LPS) were selected for replication in a population-based birth cohort, in which we investigated the interaction between these SNPs and endotoxin exposure in relation to airway hyper-responsiveness, wheeze, and atopic sensitization. RESULTS: Twenty-one SNPs in nine genes (CD14, TLR4, IRF3, TRAF-6, TIRAP, TRIF, IKK-1, ST-2, SOCS1) were found to modulate the effect of endotoxin on in vitro IgE synthesis, with six displaying high linkage disequilibrium. Of the remaining 15 SNPs, for seven we found significant relationships between genotype and endotoxin exposure in the genetic association study in relation to symptomatic airway hyper-responsiveness (CD14-rs2915863 and rs2569191, TRIF-rs4807000), current wheeze (ST-2-rs17639215, IKK-1-rs2230804, and TRIF-rs4807000), and atopy (CD14-rs2915863 and rs2569192, TRAF-6-rs5030411, and IKK-1-rs2230804). CONCLUSIONS: Variants in the endotoxin signaling pathway are important determinants of asthma and atopy. The genotype effect is a function of the environmental endotoxin exposure.

Fear of certain threat and anxiety about uncertain threat are distinct emotions with unique behavioral, cognitive-attentional, and neuroanatomical components. Both anxiety and fear can be studied in the laboratory by measuring the potentiation of the startle reflex. The startle reflex is a defensive reflex that is potentiated when an organism is threatened and the need for defense is high. The startle reflex is assessed via electromyography (EMG) in the orbicularis oculi muscle elicited by brief, intense, bursts of acoustic white noise (i.e., “startle probes”). Startle potentiation is calculated as the increase in startle response magnitude during presentation of sets of visual threat cues that signal delivery of mild electric shock relative to sets of matched cues that signal the absence of shock (no-threat cues). In the Threat Probability Task, fear is measured via startle potentiation to high probability (100% cue-contingent shock; certain) threat cues whereas anxiety is measured via startle potentiation to low probability (20% cue-contingent shock; uncertain) threat cues. Measurement of startle potentiation during the Threat Probability Task provides an objective and easily implemented alternative to assessment of negative affect via self-report or other methods (e.g., neuroimaging) that may be inappropriate or impractical for some researchers. Startle potentiation has been studied rigorously in both animals (e.g., rodents, non-human primates) and humans which facilitates animal-to-human translational research. Startle potentiation during certain and uncertain threat provides an objective measure of negative affective and distinct emotional states (fear, anxiety) to use in research on psychopathology, substance use/abuse and broadly in affective science. As such, it has been used extensively by clinical scientists interested in psychopathology etiology and by affective scientists interested in individual differences in emotion.

BACKGROUND: We investigated the interaction between genetic variants in endotoxin signalling pathway and domestic endotoxin exposure in relation to asthma presence, and among children with asthma we explored the association of these genetic variants and endotoxin exposure with hospital admissions due to asthma exacerbations. METHODS: In a case-control study, we analysed data from 824 children (417 asthmatics, 407 controls; age 5-18 years). Amongst asthmatics, we extracted data on hospitalisation for asthma exacerbation from medical records. Endotoxin exposure was measured in dust samples collected from homes. We included 26 single nucleotide polymorphisms (SNPs) in the final analysis (5 CD14, 7LY96 and 14 TLR4). RESULTS: Two variants remained significantly associated with hospital admissions with asthma exacerbations after correction for multiple testing: for CD14 SNP rs5744455, carriers of T allele had decreased risk of repeated hospital admissions compared to homozygotes for C allele (OR [95% CI], 0.42 [0.25-0.88], p=0.01, FDR p=0.02); for LY96 SNP rs17226566, C allele carriers were at a lower risk of hospital admissions compared to T allele homozygotes (0.59 [0.38-0.90], p=0.01, FDR p=0.04). We observed two interactions between SNPs in CD14 and LY96 with environmental endotoxin exposure in relation to hospital admissions due to asthma exacerbation which remained significant after correction for multiple testing (CD14 SNPs rs2915863 and LY96 SNP rs17226566). CONCLUSION: Amongst children with asthma, genetic variants in CD14 and LY96 may increase the risk of hospital admissions with acute exacerbations. Polymorphisms in endotoxin pathway interact with domestic endotoxin exposure in further modification of the risk of hospitalisation. This article is protected by copyright. All rights reserved.

Although the enterprise of experimental psychopathology has been around for quite some time, the integrative role that it plays in psychological science has not received explicit attention. This issue sits on the backdrop of theoretical and empirical evidence that, as an enterprise, experimental psychopathology has the potential to tie together psychological processes studied both in basic and applied domains. In this article, the authors discuss the nature of experimental psychopathology, focusing on its research agenda, historical perspective, and why and how it can be improved to have more of a direct impact in the study of psychopathology.

To determine the outcome for patients with recurrent gynecologic tumors treated with radical resection and combined high-dose intraoperative radiation therapy (HDR-IORT).Between November 1993 and June 1998, 17 patients with recurrent gynecologic malignancies underwent radical surgical resection and high-dose-rate brachytherapy. The mean age of the study group was 49 years (range 28-72 years). The site of the primary tumor was the cervix in 9 (53%) patients, the uterus in 7 (41%) patients, and the vagina in 1 (6%) patient. The treatment for the primary disease was surgery with or without adjuvant radiation in 14 (82%) patients and definitive radiation in 3 (18%) patients. The current surgery consisted of exenterative surgery in 10 (59%) patients and tumor resection in 7 (41%) patients. Complete gross resection was achieved in 13 (76%) patients. The mean HDR-IORT dose was 14 Gy (range 12-15). Additional radiation in the form of permanent Iodine-125 implant was given to 3 of 4 patients with gross residual disease. The median peripheral dose was 140 Gy.With a median follow-up of 20 months (range 3-65 months), the 3-year actuarial local control (LC) rate was 67%. In patients with complete gross resection, the 3-year LC rate was 83%, compared to 25% in patients with gross residual disease, p0.01. The 3-year distant metastasis disease-free and overall survival rates were 54% and 54%, respectively. The complications were as follows: gastrointestinal obstruction, 4 (24%); wound complications, 4 (24%); abscesses, 3 (18%); peripheral neuropathy, 3 (18%); rectovaginal fistula, 2 (12%); and ureteral obstruction, 2 (12%).Radical surgical resection and combined IORT for patients with recurrent gynecologic tumors seems to provide a reasonable local-control rate in patients who have failed prior surgery and/or definitive radiation. Patient selection is very important, however, as only those patients with complete gross resection at completion of surgery appear to benefit most from this radical approach in the salvage setting.

Abnormalities in dopamine neurotransmission at the dopamine D2 receptor (DRD2) have been implicated in both migraine and Parkinson's disease. Positive associations have also been found between polymorphisms within the DRD2 gene and both of these conditions. The -141C Ins/Del polymorphism in the DRD2 receptor gene is a putative functional polymorphism. The purpose of this study was to determine whether it and any genes in linkage disequilibrium with this marker are involved in either of these conditions. We have compared the genotype and allele frequencies of the -141C Ins/Del polymorphism in 200 migraineurs and 260 Parkinson's disease cases with 464 controls. We have found no association between the receptor gene and either condition (P = 0.89 and P = 0.56 respectively). Our findings do not support the hypothesis that this polymorphism is involved in the aetiology of migraine or Parkinson's disease. Psychiatr Genet 11:49-52 (C) 2001 Lippincott Williams & Wilkins.

PURPOSE: A phase II trial of paclitaxel was initiated in advanced nonsquamous carcinoma of the cervix to determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients had at least one measurable lesion. The starting dose of paclitaxel was 170 mg/m2 (135 mg/m2 for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalation to 200 mg/m2 and de-escalation to 110 mg/m2 were allowed based on adverse effects. RESULTS: In this trial, 42 assessable patients were initially entered onto the study, and 13 responses were seen; four patients had a complete response, and nine patients had a partial response. The overall response rate was 31%. The primary and dose-limiting toxicity was neutropenia. CONCLUSION: The response rate to paclitaxel exceeds the rates reported using other single agents in nonsquamous carcinoma of the cervix.

Cancer of the uterine cervix is the seventh most common malignancy among women and the fifth most common cause of cancer mortality worldwide. In the United States, the use of the Papanicolaou (Pap) smear for screening has meant a significant decline in the incidence and mortality from cervical cancer over the past five decades. However, there are still approximately 12,800 new cases diagnosed per year in the U.S. and 4,800 deaths are estimated in 1999. Both surgery and radiation therapy have long-established roles in management. Surgery has the advantages of shorter treatment time, removal of the primary tumor, more limited tissue injury, and the potential to preserve ovarian function; radiation therapy has the capacity to treat tumor that involves the bladder and/or rectum while preserving their function. Therefore, the role of surgery is more suited to the management of early-stage disease and centrally located recurrences that occur after radiation therapy. Studies from our institution have played an integral role in the development of the modern surgical approach to cervical cancer. Reviews on early-stage disease helped define the role of conization and simple hysterectomy for microinvasive cervical cancer and identified patients who were at high risk for recurrence after radical hysterectomy. The classic work of Brunschwig has given gynecologic surgeons the ability to offer hope and life to select patients who previously could have expected only pain and death. Future investigation into the techniques of intra-operative radiation therapy may increase the pool of patients for whom surgically based salvage therapy may be offered. Semin. Surg. Oncol. 17:161–167, 1999. © 1999 Wiley-Liss, Inc.

This study introduces a new methodology for investigating the impact of active avoidance and behavioral control on defensive emotional reactivity using the startle reflex. A between-groups yoked design was devised that permitted manipulation of participants' perception of control over an aversive event (loud noise) while precisely controlling motor activity and noxious stimulation. Startle responses to tactile (airpuff) probes were compared during threat/performance trials and neutral trials. Results conclusively demonstrated cross-modal startle potentiation in the context of a continuous motor performance task. Also, consistent with prior research, heart rate increased with perceived control. However, behavioral control per se did not appear to mitigate defensive emotion as indexed by startle potentiation. These findings indicate that other parameters may mediate the efficacy of active coping in addition to control, and that the startle probe paradigm can provide a valuable tool for investigating these parameters in future research.

Objective. The aim of this study was to determine the feasibility and efficacy of intraperitoneal cisplatin and mitoxantrone in patients with very small-volume residual disease at second-look surgery after completion of primary platinum-based intravenous chemotherapy. Patients and methods. Between February 1992 and February 1994, 42 patients were treated with up to five cycles of intraperitoneal cisplatin (100 mg/m 2 )/mitoxantrone (10 mg/m 2 ). Patients were evaluated for surgically defined response rate and followed for progression-free (PFS) and overall survival (OS) using an intention-to-treat analysis, and grouped according to disease volume at initiation of treatment. Results. The mean age of all patients was 48.5 years. Thirty patients (71%) were Stage III at diagnosis; 18 patients (43%) had microscopic disease at the initiation of IP therapy, and 24 patients (57%) had macroscopic disease. Twenty-eight patients completed three or more cycles of protocol therapy, and 14 patients were changed to standard intravenous therapy after receiving fewer than three cycles of treatment secondary to catheter-related problems (12 patients), cisplatin ototoxicity (1 patient), or withdrawal from study (1 patient). Using an intention-to-treat analysis, the median PFS was 22.5 months, and the median OS of all patients ( N = 42) was 47 months (6–72 months) with a median follow-up of 62.7 months. When grouped according to size of disease at initiation of treatment, the OS has not been reached at 62.7 months of follow-up in patients ( N = 18) with microscopic disease. Conclusions. (1) The combination of IP mitoxantrone and cisplatin has an unacceptable catheter failure rate due to mitoxantrone toxicity; (2) PFS and OS is longer in patients with microscopic rather than macroscopic residual disease; and (3) intraperitoneal platinum-based chemotherapy in patients with very small-volume residual disease may result in improved survival.