Clinicopathologic characteristics and outcomes of endometrial Cancer patients with mismatch repair deficiency in the era of universal Lynch syndrome screening.

OBJECTIVE: To evaluate clinicopathologic characteristics and survival impact associated with mismatch repair (MMR) deficient subgroups of endometrial cancer (EC) in patients undergoing universal screening for Lynch Syndrome. METHODS: A retrospective cohort study using a prospectively maintained gynecologic oncology registry of patients who underwent surgery for EC was conducted. All pathology specimens underwent tumor testing using immunohistochemistry for MMR deficiency with reflex MLH1 promotor methylation testing. Tumors were classified as MMR-I (intact MMR expression), MMR-DM (MMR deficient due to MLH1 methylation), and MMR-DU (MMR deficient without MLH1 methylation). Univariate and multivariate analysis performed to determine factors associated with MMR-DM. Progression-free survival (PFS) and overall survival (OS) analyzed by stage and endometrioid subgroup. RESULTS: From 2012 to 2016, 1018 EC patients were identified and screened. Overall, 71.6% were classified as MMR-I, 23.8% MMR-DM, and 4.6% MMR-DU. In comparison to MMR-DU, MMR-DM tumors were associated with older age, postmenopausal status, lymphovascular space invasion, and pure endometrioid histology. Compared to MMR-I, MMR-DM tumors were associated with older age, endometrioid histology, lymphovascular space invasion, and higher grade on multivariable analysis. There was no difference in PFS and OS between the three groups overall. In patients with endometrioid EC, MMR-DM tumors were associated with lower PFS vs. MMR-I (HR:2.51, CI:1.54, 4.10, P < 0.001). This effect persisted for stage I/II endometrioid EC (HR 2.66, CI:1.34, 5.26 p = 0.005). No difference in PFS or OS was noted among stage III/IV endometrioid tumors. CONCLUSION: MMR deficiency is associated with adverse prognostic factors and worse PFS among endometrioid tumors, particularly in early stage EC. MMR testing outside of LS screening has prognostic value, warranting consideration for inclusion as a biomarker in prospective clinical trials.

Concurrent Alcohol Use and Waterpipe Tobacco Smoking: Smoking Topography, Toxicant Exposure, and Abuse Liability.

INTRODUCTION: Relative to non-waterpipe (WP) smokers, WP smokers are more than twice as likely to use alcohol and frequently consume alcohol before or during smoking sessions. Co-use of alcohol and WP may result in greater toxicant exposure compared to WP smoking alone. To date, no study systematically has investigated the impact of acute alcohol intoxication on WP smoking topography, exposure to tobacco-related toxicants, or abuse liability. METHODS: Dyads of current WP smokers and drinkers (N = 42; age = 21-32 years) completed two in-laboratory ad libitum smoking sessions (≤2 hours) following 12-hour nicotine abstinence in a double-blind, randomized crossover design in which they consumed a placebo versus active drink (sustained breath alcohol concentration = .08). Exhaled carbon monoxide (eCO) and plasma nicotine concentration were assessed. Questionnaires assessed smoking experience and smoking urge. Smoking topography was measured continuously throughout each smoking session. RESULTS: The alcohol session was associated with increased inhaled volume, flow rate, and WP session duration compared to placebo. Compared to placebo, participants reported a more positive overall smoking experience following the alcohol session and greater smoking urges pre- and post-smoking session. Although both sessions resulted in significant increases in eCO and plasma nicotine, no significant differences emerged in eCO or nicotine exposure between the active and placebo sessions. CONCLUSIONS: Co-use of alcohol and WP may contribute to the maintenance of WP smoking through enhanced smoking experiences, increased urge to smoke, and significant exposure to addictive nicotine. Regulations may be necessary to limit the sale of alcohol in WP smoking lounges and reduce exposure to secondhand smoke. IMPLICATIONS: The findings suggest co-use of alcohol and WP tobacco likely maintain WP use and dependence by enhancing the smoking experience and increasing urges to smoke. These findings have implications for regulations aimed at limiting co-use of alcohol and WP tobacco in WP lounges and limiting exposure to secondhand smoke. CLINICAL TRIALS REGISTRATION: NCT03096860.

Distinguishing True Progression From Radionecrosis After Stereotactic Radiation Therapy for Brain Metastases With Machine Learning and Radiomics.

PURPOSE: Treatment effect or radiation necrosis after stereotactic radiosurgery (SRS) for brain metastases is a common phenomenon often indistinguishable from true progression. Radiomics is an emerging field that promises to improve on conventional imaging. In this study, we sought to apply a radiomics-based prediction model to the problem of diagnosing treatment effect after SRS. METHODS AND MATERIALS: We included patients in the Johns Hopkins Health System who were treated with SRS for brain metastases who subsequently underwent resection for symptomatic growth. We also included cases of likely treatment effect in which lesions grew but subsequently regressed spontaneously. Lesions were segmented semiautomatically on preoperative T1 postcontrast and T2 fluid-attenuated inversion recovery magnetic resonance imaging, and radiomic features were extracted with software developed in-house. Top-performing features on univariate logistic regression were entered into a hybrid feature selection/classification model, IsoSVM, with parameter optimization and further feature selection performed using leave-one-out cross-validation. Final model performance was assessed by 10-fold cross-validation with 100 repeats. All cases were independently reviewed by a board-certified neuroradiologist for comparison. RESULTS: We identified 82 treated lesions across 66 patients, with 77 lesions having pathologic confirmation. There were 51 radiomic features extracted per segmented lesion on each magnetic resonance imaging sequence. An optimized IsoSVM classifier based on top-ranked radiomic features had sensitivity and specificity of 65.38% and 86.67%, respectively, with an area under the curve of 0.81 on leave-one-out cross-validation. Only 73% of cases were classifiable by the neuroradiologist, with a sensitivity of 97% and specificity of 19%. CONCLUSIONS: Radiomics holds promise for differentiating between treatment effect and true progression in brain metastases treated with SRS. A predictive model built on radiomic features from an institutional cohort performed well on cross-validation testing. These results warrant further validation in independent datasets. Such work could prove invaluable for guiding management of individual patients and assessing outcomes of novel interventions.

Xanthogranulomatous Oophoritis Presenting as an Adnexal Mass and Bowel Obstruction. A Case Report.

BACKGROUND: Xanthogranulomatous inflammation of the female genital tract is a rare entity. When the gynecological organs are affected, it is particularly unusual for xanthogranulomataus inflammation to involve only the ovary. CASE: A 45-year-old woman with an intrauterine device, long-term exposure to nicotine, and hyperlipidemia presented with an adnexal mass and bowel obstruction. She underwent 2 exploratory laparotomies, ureteral stent placement, left salpingooophorectomy, and rectosigmoid resection with end colostomy. Pathology revealed xanthogranulomatous oophoritis without involvement of the associated fallopian tube. CONCLUSION: The synergistic effects of intrauterine device use, abnormal lipid levels, and long-term nicotine exposure may have contributed to the development of this patient's condition. Knowledge of xanthogranulomatous inflammation is essential to avoid misdiagnosis of malignancy and excessive surgical intervention.

CD62L- memory T cells enhance T-cell regeneration after allogeneic stem cell transplantation by eliminating host resistance in mice.

A major challenge in allogeneic hematopoietic cell transplantation is how to transfer T-cell immunity without causing graft-versus-host disease (GVHD). Effector memory T cells (CD62L(-)) are a cell subset that can potentially address this challenge because they do not induce GVHD. Here, we investigated how CD62L(-) T cells contributed to phenotypic and functional T-cell reconstitution after transplantation. On transfer into allogeneic recipients, CD62L(-) T cells were activated and expressed multiple cytokines and cytotoxic molecules. CD62L(-) T cells were able to deplete host radioresistant T cells and facilitate hematopoietic engraftment, resulting in enhanced de novo T-cell regeneration. Enhanced functional immune reconstitution was demonstrated in CD62L(-) T-cell recipients using a tumor and an influenza virus challenge model. Even though CD62L(-) T cells are able to respond to alloantigens and deplete host radioresistant immune cells in GVHD recipients, alloreactive CD62L(-) T cells lost the reactivity over time and were eventually tolerant to alloantigens as a result of prolonged antigen exposure, suggesting a mechanism by which CD62L(-) T cells were able to eliminate host resistance without causing GVHD. These data further highlight the unique characteristics of CD62L(-) T cells and their potential applications in clinical hematopoietic cell transplantation.

Agreement of visual estimation of coronary artery calcium from low-dose CT attenuation correction scans in hybrid PET/CT and SPECT/CT with standard Agatston score.

OBJECTIVES: We sought to evaluate the accuracy and reproducibility of visual estimation of coronary artery calcium (CAC) from computed tomography attenuation correction (CTAC) scans performed for hybrid positron emission tomography (PET)/computed tomography (CT) and single-photon emission computed tomography (SPECT)/CT myocardial perfusion imaging (MPI). BACKGROUND: At the time of MPI, hybrid systems obtain a low-dose, non-electrocardiogram (ECG)-gated CT scan that is used to perform attenuation correction. Utility of this CTAC scan in estimating actual CAC as measured by Agatston score (AS) on standard ECG-gated scans has not been previously studied. METHODS: A total of 492 patients, from 3 centers, receiving both MPI with CTAC and a standard CAC scan were studied. At each site, experienced readers blinded to AS reviewed CTAC images, visually estimating CAC on a 6-level scale: classifying patients as estimated AS of 0, 1 to 9, 10 to 99, 100 to 300, 400 to 999, or ≥1,000. Agreement between visually estimated coronary artery calcium (VECAC) on CTAC and AS, measured standardly and converted to the same scale, was evaluated, as was inter-reader agreement. RESULTS: Although CTAC images are low dose and nongated, a high degree of association was observed between VECAC and AS, with 63% of VECACs in the same category as the AS category and 93% within 1 category. Weighted kappa was 0.89 (95% confidence interval: 0.88 to 0.91, p < 0.0001). High weighted kappa statistics were observed for each site, scanner type, and sex. Readers reported identical scores in 65% of cases and scores within 1 category in 93%. CONCLUSIONS: CAC can be visually assessed from low-dose CTAC scans with high agreement with AS. CTAC scans should be routinely assessed for VECAC.

Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse.

Several groups, including our own, have independently demonstrated that effector memory T cells from non-alloantigen-primed donors do not cause graft-versus-host disease (GVHD). In the current study, we further investigated whether this approach could be extended to all memory T cells, and we studied the underlying mechanisms. Neither total memory T cells nor purified central memory T cells were able to induce GVHD. Memory T cells were at least 3-log less potent than bulk T cells in mediating GVHD. As expected, memory T cells failed to elicit cytotoxicity and proliferated poorly against alloantigens in standard 5-day mixed-lymphocyte cultures. However, the proliferative responses of memory T cells were more comparable with those of bulk and naive T cells when the culture time was shortened. Moreover, the frequencies of IL-2-secreting cells measured by 42-hour enzyme-linked immunosorbent spot (ELISPOT) assay were similar among naive, memory, and bulk T cells. These data indicated that memory T cells are able to respond to alloantigens initially but fail to develop to full potential. The abortive immune response, which was mediated by non-alloantigen-specific memory T cells in response to alloantigens, may explain why memory T cells from unprimed and non-alloantigen-primed donors could not induce GVHD.

Oxidative stress regulated genes in nigral dopaminergic neuronal cells: correlation with the known pathology in Parkinson's disease.

Oxidative stress (OS) is a primary pathogenic mechanism of nigral dopaminergic (DA) cell death in Parkinson's disease (PD). Oxidative damage, Lewy body formation and decreased mitochondrial complex I activity are the consistent pathological findings in PD. In nigral DA neurons, however, it is unknown whether any gene expressional changes induced by OS contribute to the typical PD pathology. Here, using microarray analysis, we identified several groups of genes in the nigral DA cell line, SN4741 [J. Neurosci. 19 (1999) 10; J. Neurochem. 76 (2001) 1010], that were regulated by OS. Approximately 36 significantly regulated genes that encode functional molecules of nuclear subunits of mitochondrial complex I, exocytosis and membrane trafficking proteins, markers for OS and oxidoreductases, regulatory molecules of apoptosis and unidentified EST clones were further analysed. OS modulated the expression of specific genes, of which physiological dysfunctions have been implicated in PD. For instance, the expression of the nuclear-encoded subunits of mitochondrial complex I, B8 and B17, were significantly down-regulated by OS, possibly contributing to selective defect in mitochondrial complex I activity in PD. Furthermore, syntaxin 8 and heme oxygenase-1 (HO-1) are most dramatically up-regulated by OS in DA cells. Syntaxin 8 is a SNARE protein, regulating lipid vesicle docking and fusion as well as early endosome membrane recycling. Lipid membranes are significantly oxidative-damaged in PD. HO-1 is an important cytoplasmic constituent of Lewy bodies, a pathological hallmark of idiopathic PD. Thus, our findings provide novel molecular probes that may be useful in unraveling the molecular mechanism(s) of OS-induced pathogenesis in PD. Further functional characterization of the affected genes including ESTs can help elucidate the underlying molecular pathology as well as develop biomarkers for monitoring degenerating DA neurons in PD.