A Simplified Version of the IASLC Grading System for Invasive Pulmonary Adenocarcinomas With Improved Prognosis Discrimination.

Tumor grading enables better management of patients and treatment options. The International Association for the Study of Lung Cancer (IASLC) Pathology Committee has recently released a 3-tier grading system for invasive pulmonary adenocarcinoma consisting of predominant histologic patterns plus a cutoff of 20% of high-grade components including solid, micropapillary, and complex glandular patterns. The goal of this study was to validate the prognostic value of the new IASLC grading system and to compare its discriminatory performance to the predominant pattern-based grading system and a simplified version of the IASLC grading system without complex glandular patterns. This was a single-site retrospective study based on a 20-year data collection of patients that underwent lung cancer surgery. All invasive pulmonary adenocarcinomas confirmed by the histologic review were evaluated in a discovery cohort (n=676) and a validation cohort (n=717). The median duration of follow-up in the combined dataset (n=1393) was 7.5 years. The primary outcome was overall survival after surgery. The 3 grading systems had strong and relatively similar predictive performance, but the best parsimonious model was the simplified IASLC grading system (log-rank P =1.39E-13). The latter was strongly associated with survival in the validation set ( P =1.1E-18) and the combined set ( P =5.01E-35). We observed a large proportion of patients upgraded to the poor prognosis group using the IASLC grading system, which was attenuated when using the simplified IASLC grading system. In conclusion, we identified a histologic simpler classification for invasive pulmonary adenocarcinomas that outperformed the recently proposed IASLC grading system. A simplified grading system is clinically convenient and will facilitate widespread implementation.

Effect of fire on the palatability of plants in an African woodland savanna: varying impacts depending on plant functional groups.

Fire and herbivores are two important drivers of changes in vegetation composition, quality and dynamics and both are highly related to each other. Herbivores are known to respond to fire both in terms of foraging decisions and distribution. However, little is known about the actual changes in plant chemistry following a fire event and how long these changes will last. We investigated the effect of fire on two different plant functional groups (grasses and woody species) in a woodland savanna of southern Africa. We studied chemical compounds known to be important for palatability of five perennial grass and seven woody species (trees and shrubs) common in the woodland savanna and known to be utilized by herbivores. We wanted to know if plant chemistry differs between a recently burned site (burned 2 years ago) and a control site, burned 16 years ago, and if grasses and woody species show similar relative differences between sites (i.e., the plants' response to fire). We found a clear difference in chemical composition patterns between the plant functional groups, with an almost homogenous response to fire among woody species, but higher variability in response among grass species. Furthermore, we found that woody species maintained a higher nutritional value even 2 years after burning, whereas grasses did not show clear differences among the two investigated sites. Hence, few years after burning, woody plants might still serve as an attraction for herbivores, especially browsers, in contrast to grasses. The knowledge about these differences between the two functional groups in response to fire is beneficial for the development of management strategies for large herbivores whether domestic or wild.

ZNF768 Expression Associates with High Proliferative Clinicopathological Features in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer and a leading cause of cancer-related deaths worldwide. Despite important recent advances, the prognosis for LUAD patients is still unfavourable, with a 5 year-survival rate close to 15%. Improving the characterization of lung tumors is important to develop alternative options for the diagnosis and the treatment of this disease. Zinc-finger protein 768 (ZNF768) is a transcription factor that was recently shown to promote proliferation and repress senescence downstream of growth factor signaling. Although ZNF768 protein levels were found to be elevated in LUAD compared to normal lung tissue, it is currently unknown whether ZNF768 expression associates with clinicopathological features in LUAD. Here, using tissue microarrays of clinical LUAD surgical specimens collected from 364 patients, we observed that high levels of ZNF768 is a common characteristic of LUAD. We show that ZNF768 protein levels correlate with high proliferative features in LUAD, including the mitotic score and Ki-67 expression. Supporting a role for ZNF768 in promoting proliferation, we report that ZNF768 depletion severely impairs proliferation in several lung cancer cell lines in vitro. A marked decrease in the expression of key proliferative genes was observed in cancer cell lines depleted from ZNF768. Altogether, our findings support a role for ZNF768 in promoting proliferation of LUAD.

Comprehensive assessment of PD-L1 immunohistochemistry on paired tissue and cytology specimens from non-small cell lung cancer.

OBJECTIVES: PD-L1 staining assessed by immunohistochemistry (IHC) is a predictive biomarker used to select advanced stage non-small cell lung carcinoma (NSCLC) patients who are likely to respond to PD-1/PD-L1 inhibitors. Cytology specimens represent a significant percentage of the diagnostic samples and additional data are required to show that they provide reliable PD-L1 results when compared to tissue specimens. We aimed to compare PD-L1 staining obtained from patient-matched tissue and cytology specimens. We also want to assess the feasibility of PD-L1 testing on cell blocks with two assays by evaluating the intra- and inter-observer agreement and the level of difficulty for determining the percentage of stained tumor cells (TPS). MATERIALS AND METHODS: Forty-six patients with NSCLC were selected. Each patient provided a surgical specimen and a cytology sample (cell block) and/or a biopsy at diagnosis. PD-L1 staining using Agilent PD-L1 IHC 28-8 pharmDx and VENTANA PD-L1 (SP263) assays was evaluated by four pathologists using the TPS. Sixty slides were rescored to document intra-observer agreement. Pathologists were asked to score the level of difficulty for evaluating PD-L1 TPS for each slide. Fleiss's and Cohen's kappas (k) were used to assess the agreement between paired specimens as well as intra- and inter-observer agreement. RESULTS: The concordance in PD-L1 TPS between cell blocks and surgical specimens (k varying from 0.56 to 0.82) or biopsies (k from 0.43 to 0.81) was moderate to substantial, depending on the cut-off. On cell blocks, inter-observer agreement was substantial (k from 0.74 to 0.82) and intra-observer agreement was almost perfect (k from 0.85 to 0.93). The perceived difficulty of PD-L1 evaluation of cell blocks was not different from surgical specimens but more difficult than biopsy samples. CONCLUSION: PD-L1 TPS was concordant between cell blocks and tissue specimens, mainly at 10, 25 and 50 % cut-offs. PD-L1 evaluation on cell blocks was feasible and reproducible between different observers and assays.

Development and Validation of Diffuse Idiopathic Pulmonary Neuroendocrine Hyperplasia Diagnostic Criteria.

INTRODUCTION: Diffuse idiopathic pulmonary neuroendocrine hyperplasia (DIPNECH) is a rare condition that is likely underdiagnosed owing to the lack of established and validated diagnostic criteria. These clinical guidelines are empirical and created on the basis of a limited number of studies. This study was designed to validate the existing criteria and to identify new clinical parameters that can accurately diagnose DIPNECH. METHODS: Patients with DIPNECH were identified from a cohort that underwent surgical lung resection for pulmonary carcinoids. The study cohort included a total of 105 consecutive cases with neuroendocrine lesions. Initial diagnostic predictors of DIPNECH were selected from the literature. We employed univariate and multivariate models to evaluate the association of clinical, pathologic, radiologic variables with the likelihood of DIPNECH. RESULTS: Univariate analysis identified age, sex, chronic obstructive pulmonary disease diagnosis, obstructive abnormalities, pulmonary nodules, mosaicism, absolute numbers of pulmonary neuroendocrine lesions (PNELs), and the number of tumorlets as significant DIPNECH predictors (for p < 0.05). After adjustment for sampling variations, the ratio of the total number of PNELs to the number of bronchioles was found to be considerably higher in DIPNECH category. Multivariate analysis identified the total number of PNELs and multiple pulmonary nodules (>10) as independent predictors of DIPNECH. The performance of our criteria revealed an accuracy of 76% in detecting DIPNECH cases. CONCLUSIONS: We proposed a set of diagnostic criteria for DIPNECH on the basis of an expert-panel approach integrating pathological features, radiology, and clinical data. Our findings will help identify DIPNECH patients, without a pathological confirmation of a neuroendocrine lesion. Before the implementation of these criteria in clinical practice, they require further validation in multi-institutional cohorts.

Impact of Specimen Characteristics on PD-L1 Testing in Non-Small Cell Lung Cancer: Validation of the IASLC PD-L1 Testing Recommendations.

INTRODUCTION: Molecules targeting programmed cell death 1 or its ligand programmed death ligand 1 (PD-L1) revolutionized the treatment of patients with NSCLC. The only approved biomarker for predicting treatment response is the PD-L1 tumor proportion score (TPS) determined by immunohistochemistry. According to International Association for the Study of Lung Cancer recommendations, specimens that include fewer than 100 tumor cells or are older than 3 years should not be used for PD-L1 testing and the reliability of cell blocks has yet to be validated. METHODS: This retrospective study included 1249 consecutive patients with NSCLC who were tested for PD-L1 (using the clone 22C3) between September 2016 and April 2017. The associations between the presence of suboptimal characteristics (specimens with <100 tumor cells, specimens older than 3 years, or cell blocks) and PD-L1 TPS were examined by using a multinomial logistic regression. RESULTS: Specimens from 35.5% of the patients had at least one suboptimal characteristic. For patients with a PD-L1 TPS of higher than 50%, there was a significantly higher probability that they had a specimen with more than 100 tumor cells (OR = 1.97, p = 0.008) and a more recent block (within 30 days versus after >3 years) (OR = 2.46, p = 0.023). There was no statistical difference in PD-L1 TPS between cell blocks and tissue specimens (biopsy OR = 0.99 [p = 0.996] and surgery OR = 0.73 [p = 0.302]). CONCLUSIONS: Our results suggest that specimens containing fewer than 100 tumor cells or older than 3 years may lead to an underestimation of PD-L1 status. Our findings also provide support for the use of cell blocks for PD-L1 testing, although further research is needed.

Identification of Grossing Criteria for Intraoperative Evaluation by Frozen Section of Lung Cancer Resection Margins.

Because of a lack of official guidelines, systematic use of intraoperative frozen section for the evaluation of surgical margins in lung oncology constitutes standard practice in many pathology departments. This costly and time-consuming procedure seems unjustified as reported rates of positive margins remain low. We aimed to evaluate clinicopathologic criteria associated with positive margins and establish evidence-based recommendations regarding the use of frozen sections. This retrospective cohort included 1903 consecutive patients with a lung resection for malignant neoplasm between 2006 and 2015. Clinicopathologic data were retrieved from medical files. Univariate and multivariate analyses were used to identify variables associated with a positive margin. Receiver operating characteristic curves and a probability table of positive margins based on tumor-margin distance were created. Our results were confirmed in a validation cohort of 27 patients with positive margins. The rate of positive margins was 3.8%. A positive margin status changed the surgical management in 48.6% of patients. A short macroscopic tumor-margin distance was associated with a higher risk of positive bronchovascular and parenchymal margins in univariate and multivariate analyses. Selecting a 2.0 cm tumor-margin distance cut-off for performing a frozen section would result in a 55.3% reduction of intraoperative evaluations, with a risk of missing a positive margin of 0.61%. Overall, we showed that systematic use of frozen section for intraoperative evaluation of surgical margins is unnecessary. A better selection of patients with a higher risk of a positive margin can be achieved with tumor-margin distance as a simple gross evaluation parameter.

A dominance shift in arid savanna: An herbaceous legume outcompetes local C4 grasses.

The characteristic vegetation structure of arid savannas with a dominant layer of perennial grass is maintained by the putative competitive superiority of the C4 grasses. When this competitive balance is disturbed by weakening the grasses or favoring the recruitment of other species, trees, shrubs, single grass, or forb species can increase and initiate sudden dominance shifts. Such shifts involving woody species, often termed "shrub encroachment", or the mass spreading of so-called increaser species have been extensively researched, but studies on similar processes without obvious preceding disturbance are rare. In Namibia, the native herbaceous legume Crotalaria podocarpa has recently encroached parts of the escarpment region, seriously affecting the productivity of local fodder grasses. Here, we studied the interaction between seedlings of the legume and the dominant local fodder grass (Stipagrostis ciliata). We used a pot experiment to test seedling survival and to investigate the growth of Crotalaria in competition with Stipagrostis. Additional field observations were conducted to quantify the interactive effect. We found germination and growth of the legume seedlings to be facilitated by inactive (dead or dormant) grass tussocks and unhindered by active ones. Seedling survival was three times higher in inactive tussocks and Crotalaria grew taller. In the field, high densities of the legume had a clear negative effect on productivity of the grass. The C4 grass was unable to limit the recruitment and spread of the legume, and Crotalaria did outcompete the putative more competitive grass. Hence, the legume is able to spread and establish itself in large numbers and initiate a dominance shift in savannas, similar to shrub encroachment.

Sequential Latent Structure Analysis of Segregated System Material in the Doll Play of Maltreated Children.

A range of assessment methodologies pertaining to attachment in children have been developed and validated during the past decades. The present study examined the validity of a sequential, profile-centered approach to the assessment of attachment disorganization using a doll play methodology developed by George and Solomon (1990). The sample was composed of sixty-two children between the age of 5 and 12 who had been removed from their family of origin due to abuse or neglect. Latent Markov Models performed on markers of defensive dysregulation (Frightening, Chaos, Constriction) yielded three distinct states, characterized respectively by themes of fear or chaos, presence of at least partial constriction, and absence of segregated system markers across doll play stories. The states generally showed a high degree of stability across scenarios. The Frightening-Chaotic state was positively associated with sexual abuse, placement in a specialized setting and caregiver-reported externalizing problems whereas the Constricted state was associated with placement in a specialized setting and self-reported hyperactivity and attention problems. These results provide support for the validity and clinical utility of this approach to assessing attachment disorganization on the doll play.

Aggressive Drive Derivatives in the Rorschachs of Maltreated Children and Adolescents: Latent Structure and Clinical Correlates.

Psychological assessment can play an important role in informing the intervention process with child and adolescent victims of maltreatment. This study investigated the validity of the Rorschach in assessing aggressive drive derivatives using a profile-based approach, with a sample of 108 children and adolescents in foster care. Aggression indicators were derived from the work of Gacono and Meloy ( 1994 ). Latent class analysis yielded a 4-class model including gender and age as covariates. The first 2 classes were characterized by low prevalence rates across all indicators of aggression, and were distinguished primarily on the basis of participant's age. The 3rd class was characterized by the presence of Aggressive Vulnerability (AgV) responses, whereas the 4th showed higher occurrence of all markers except AgV. Modest associations were found between characteristics of abuse, select classes, and behavior problems. The 4th class showed the strongest link with behavior problems, albeit only in the presence of ego impairment. These findings support a contextualized, developmentally informed use of aggression markers on the Rorschach in the context of child maltreatment.

Cycle of coercion: experiences of maltreatment and disciplinary measures in Canadian inmates.

PURPOSE: In spite of past and current efforts at implementing effective rehabilitative interventions in carceral settings, institutions of confinement are primarily concerned with the maintenance of order within their walls. The purpose of this paper is to better understand associations between inmates' developmental background and the experience of institutional discipline, to collect information on childhood maltreatment and disciplinary measures for a sample of Canadian prisoners. DESIGN/METHODOLOGY/APPROACH: Information relative to socio-economic background, childhood maltreatment and experience of discipline while in custody was obtained using face-to-face interviews and institutional file review for a sample of 416 male and 106 female offenders in Canadian provincial institutions. FINDINGS: Results from logistic regression analyses provided support for the association between childhood maltreatment and the experience of discipline, specifically in the form of increased monitoring from correctional staff. Furthermore, this association was found to be more pronounced for female offenders. RESEARCH LIMITATIONS/IMPLICATIONS: The findings highlight the need to incorporate a developmental perspective to current understanding of the use of disciplinary interventions in a prison environment. Such an approach may allow for preventing the enactment of a cycle of coercion, with negative consequences for the inmates. ORIGINALITY/VALUE: This study is original in its use of latent variable analytic methods to uncover the structure underlying the construct of childhood maltreatment in adult offenders. In addition, it provides valuable data of interest to researchers, corrections personnel and policy makers on the possible links between earlier developmental experiences and adjustment to the prison environment.

Unresolved attachment status and trauma-related symptomatology in maltreated adolescents: an examination of cognitive mediators.

Attachment Theory has received increasing interest as a framework allowing for a more refined understanding of the potential consequences of early relational trauma on psychological and social adjustment. Research has provided support for the role of disorganized attachment, both as a sequela of traumatic experiences and as a risk factor for subsequent maladjustment. This study investigated the associations between unresolved/disorganized attachment, cognitive functioning, and dissociative symptomatology in a sample of 60 adolescents with a history of maltreatment. A model with cognitive efficiency as a mediator variable was tested using hierarchical multiple regression analysis, with a bootstrapping procedure to examine indirect effects. Results provided support for the association between unresolved attachment, cognitive efficiency (but not verbal or thinking ability), and dissociation. Working memory was a strong mediator of the link between attachment and dissociation. These results highlight the importance of assessing attachment status and cognitive functioning in the context of clinical work with maltreated youth. In addition, it is proposed that greater attention be paid to internal models of attachment relationships and how they impact psychosocial functioning at different levels in maltreated populations.

Use of the Adult Attachment Projective Picture System in an assessment of an adolescent in foster care.

Child maltreatment has been associated with a host of negative outcomes including impaired social relationships (Rogosch, Cicchetti, & Aber, 1995), depression (Toth, Manly, & Cicchetti, 1992), poor self-concept and motivation (Vondra, Barnett, & Cicchetti, 1990), and delinquency and conduct problems (Cook et al., 2005; Grotevant et al., 2006; McCabe, Lucchini, Hough, Yeh, & Hazen, 2005; Ryan & Testa, 2005). An assessment of the mental representation of attachment relationships could offer additional relevant and useful information to the evaluation of youth in foster care, and could inform treatment and placement considerations. The Adult Attachment Projective Picture System (AAP) is a relatively new measure of internal representations of attachment based on the analysis of a set of stimuli designed to systematically activate the attachment system (George, West, & Pettem, 1997). This article considers the use of the AAP with a maltreated adolescent in a clinical setting and uses a case study to illustrate the components of the AAP that are particularly relevant to case conceptualization and interventions.

Psychometric refinement of an outpatient, visit-specific satisfaction with doctor questionnaire.

Measuring patient's satisfaction with their physician is gaining interest but requires a questionnaire that is valid, reliable and acceptable to patients. We previously published a self-administered visit-specific satisfaction with physician questionnaire for cancer patients. Eighty outpatients at a Canadian Cancer Center completed the Princess Margaret Hospital Patient Satisfaction with Doctor Questionnaire and the FACT-G questionnaires along with demographic information just after clinic visit and again 3-5 days later. Exploratory factor analysis extracted two factors, labeled 'physician disengagement' and 'perceived support,' with average coefficient alpha values of 0.93 and 0.90. Test-retest reliability was 0.83 and 0.73, respectively, for the two factors. Confirmatory factor analysis applied to the data from 174 patients in the original study indicated excellent goodness of fit. PMH/PSQ-MD correlated moderately with FACT-G (average r=0.37, p<0.005). The PMH/PSQ-MD questionnaire is a brief, valid and reliable questionnaire that taps two complementary facets of patient satisfaction.