Nodular fasciitis of the orbit: rapid growth phase post iatrogenic incisional trauma.

Nodular fasciitis (NF) is a benign, reactive, myofibroblastic proliferative solitary lesion that commonly develops in the subcutaneous or superficial fascia. We present a case of a 35-year-old male with a rapidly enlarging upper eyelid mass postiatrogenic incisional trauma. Subsequent en toto excisional biopsy demonstrated NF. Given the rapid clinical course of this patient and the reactive nature of NF, we hypothesize that the initial incisional trauma likely incited an inflammatory response resulting in rapid proliferation and growth of the lesion. NF accounts for <1% of all orbital lesions, and is often a clinically and pathologically difficult diagnosis to make given its propensity to mimic other benign and malignant conditions. Therefore, we recommend that en toto biopsies of orbital lesions in this anatomical area be performed rather than incisional biopsies.

Discovery of quinazoline HPK1 inhibitors with high cellular potency.

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.

Evaluation of Lineage/Site-specific Nuclear Immunohistochemical Markers SATB2, Cyclin D1, SALL4, and BCOR in High-grade Endometrial Carcinomas.

Poorly differentiated malignant neoplasms involving the gynecologic tract routinely include a poorly differentiated endometrial carcinoma (EC) in the differential diagnosis. Some nuclear lineage/site-specific immunohistochemical markers are utilized in this diagnostic setting including SATB2, cyclin D1, SALL4, and BCOR, but their specificity and use in small samples are not clear across the spectrum of ECs. Cases of undifferentiated/dedifferentiated endometrial carcinomas (UEC/DDEC), clear cell carcinoma (CCC), uterine serous carcinoma (USC), FIGO grade 3 endometrial endometrioid carcinoma (EEC), and uterine carcinosarcoma (UCS) were identified and diagnoses confirmed. Whole-section immunohistochemical stains for SATB2, cyclin D1, SALL4, BCOR, and PAX8 were performed. A total of 113 cases were utilized: 15 CCC, 26 EEC, 19 UCS, 22 USC, and 31 UEC/DDEC. Cases were distributed across both low (49%) and high (51%) FIGO clinical stages. SATB2 was expressed by UCS (8/19, 42%), EEC (10/26, 38%), UEC/DDEC (11/30, 37%), and USC (6/22, 27%). Cyclin D1 was expressed by EEC (24/26, 92%), USC (17/22, 77%), UEC/DDEC (15/20 EEC component, 75%; 22/30 UEC, 73%), UCS (10/16 carcinoma, 63%; 11/19 sarcoma, 58%), and CCC (8/15, 53%). SALL4 was expressed most frequently by UEC/DDEC (12/30, 40%), but also USC (7/22, 32%), EEC (5/26, 19%), and UCS (4/16 carcinoma, 25%; 3/19 sarcoma, 16%). BCOR was expressed at low levels in 2 USC, 2 UEC/DDEC, and 2 UCS. PAX8 was generally positive but showed lower expression in UEC/DDEC (17/30, 57%) and in the sarcomatous portions of UCS (6/19, 32%). SATB2, cyclin D1, SALL4, and BCOR stain variable numbers of poorly-differentiated EC and must be carefully interpreted within morphologic and clinical context.

Cervical cancer patient reported gastrointestinal outcomes: intensity/volumetric modulated vs. 3D conformal radiation therapy.

OBJECTIVE: To evaluate gastrointestinal (GI) patient reported outcomes (PROs) in cervical cancer patients treated with definitive radiotherapy (RT), comparing 3D conformal RT (3DCRT) vs. intensity modulated/volumetric modulated arc therapy (IMRT/VMAT). METHODS: An analysis of patients treated with definitive RT between 2015-2018 was performed. GI PROs were prospectively collected at baseline, during RT (acute), ≤12 weeks after RT (subacute), and >12 weeks after RT (late). GI PROs evaluated three symptom domains: bowel problems (BPs), bowel bother (BB), and abdominal problems (APs). Multiple linear regression analysis was performed to investigate associations between mean changes of symptom scores with clinical and dosimetric variables. RESULTS: The cohort included 167 patients. A total of 100 (60%) patients were treated with IMRT/VMAT and 67 (40%) with 3DCRT. In the subacute phase, the mean change of symptom scores from baseline in 3DCRT vs. IMRT/VMAT were +0.9 vs. -1.15 (p=0.004) for BP, +2.18 vs. -0.10 (p=0.019) for BB, and +1.41 vs. -0.38 (p=0.021) for AP. Likewise, in the late phase, mean changes were +0.72 vs. -0.82 (p=0.014) for BP, +1.98 vs. -0.03 (p=0.008) for BB, and +1.29 vs. -0.31 (p<0.001) for AP. On multiple linear regression, use of 3DCRT vs. IMRT/VMAT was associated with greater mean changes in subacute BP (p=0.023) and late phase AP (p=0.019). A higher small bowel V50Gy was associated increased symptom scores in late AP (p=0.012). CONCLUSION: 3DCRT was associated with significantly greater worsening of GI PRO symptom scores in the subacute and late phase. These data support the ongoing use of IMRT/VMAT in routine practice.

Small bowel obstruction precipitated by intussusception of Meckel's diverticulum.

Small bowel obstruction (SBO) secondary to intussusception of Meckel's diverticulum (MD) is a rare cause of acute abdominal pain that may warrant urgent surgical treatment. Volvulus or intussusception of the small bowel with presence of MD as the lead point is the most commonly reported etiology of Meckel's related obstructions. We report an interesting case of a small bowel obstruction caused by the intussusception of an MD within its own lumen. The case involves a 30-year-old male who presented to the emergency room with acute, severe abdominal pain with an abdominal computed tomography (CT) showing a distal high-grade SBO. Decision was made to take the patient to the operating room urgently due to his clinical examination and radiologic imaging, specifically CT scan. Diagnostic laparoscopy was performed and subsequently converted to an exploratory laparotomy, which revealed the intussuscepted MD with focal necrosis into the distal small bowel causing an SBO. A segmental small bowel resection with hand sewn primary anastomosis was performed. The case presents an interesting challenge in deciding when to take a patient with an SBO to the operating room versus initial conservative management and what the treatment should be if an MD is encountered. In addition, the case emphasizes the importance of history and physical exam findings in coordination with radiologic imaging in helping to make appropriate decisions in a timely manner for operative vs conservative management of an SBO. It reminds us that, Meckel's diverticulum, although less commonly the cause of a small bowel obstruction in the adult population, needs to be on the differential diagnosis and we need to have a high clinical suspicion for this possibility to ensure appropriate treatment in a timely manner.

Clinical factors associated with positive corneal culture in suspected microbial keratitis.

AIMS: Determine demographic and clinical characteristics associated with positive culture in suspected microbial keratitis. METHODS: Retrospective audit of patients that had corneal scrapings between October 1999-September 2004 at Princess Alexandra Hospital. Clinical information was gathered from medical records, smear and culture results from the local microbiology database. Univariate and multivariate analyses of variables associated with positive cultures and calculation of population attributable risk percentage (PAR). RESULTS: Univariate analysis showed that positive cultures were associated with patients over 60 years (81% vs 55%; p < 0.001), presenting visual acuity (VA) of 6/24 or worse (74% vs 57%; p = 0.012) or contact lens-related keratitis (CLK 77% vs 62%; p = 0.08). Analysis of patients' clinical presentation showed that positive culture was associated with a central epithelial defect (74% vs 57%; p = 0.012), anterior chamber reaction of 2 + cells or worse (73% vs 56%; p = 0.03), an epithelial defect of 2 mm or more in diameter (71% vs 50%; p = 0.006) or no prior treatment with antibiotics (68% vs 56%; p = 0.053). Multivariate analysis showed the independent variables associated with positive cultures were VA of 6/24 or worse on presentation, contact lens-related keratitis, age greater than 60 years, an anterior chamber reaction of 2 + cells or worse and no prior treatment with antibiotics. The factor with the highest attributable risk (PAR%) for a positive corneal scraping was VA of 6/24 or worse on presentation (21%). CONCLUSIONS: In this series positive cultures were associated with poor presenting VA contact lens keratitis (CLK), older age, anterior chamber reaction and no prior treatment with antibiotics.

Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System*.

Tuberculosis is a global health problem caused by infection with the Mycobacterium tuberculosis (Mtb) bacteria. Although antibiotic treatment has dramatically reduced the impact of tuberculosis on the population, the existence and spreading of drug resistant strains urgently demands the development of new drugs that target Mtb in a different manner than currently used antibiotics. The prokaryotic ubiquitin-like protein (Pup) proteasome system is an attractive target for new drug development as it is unique to Mtb and related bacterial genera. Using a Pup-based fluorogenic substrate, we screened for inhibitors of Dop, the Mtb depupylating protease, and identified I-OMe-Tyrphostin AG538 (1) and Tyrphostin AG538 (2). The hits were validated and determined to be fast-reversible, non-ATP competitive inhibitors. We synthesized >25 analogs of 1 and 2 and show that several of the synthesized compounds also inhibit the depupylation actions of Dop on native substrate, FabD-Pup. Importantly, the pupylation activity of PafA, the sole Pup ligase in Mtb, was also inhibited by some of these compounds.

Outcomes of stereotactic body radiotherapy 60 Gy in 8 fractions when prioritizing organs at risk for central and ultracentral lung tumors.

BACKGROUND: For stereotactic body radiotherapy (SBRT) to central (C) and ultracentral (UC) lung tumors, our provincial practice has been to prioritize organs at risk (OARs) constraints by compromising target volume coverage if needed. The objectives are to report the treatment's efficacy and safety. METHODS: We conducted a retrospective analysis of all provincial patients who underwent SBRT at 60Gy in 8 fractions to C and UC lung tumors, from 2013 to 2017. RESULTS: Ninety-eight lesions were treated, 57 (58.2%) C and 41 (41.8%) UC. The median follow-up was 22.9 months (range 2.5-64.8 months). The 1- and 3-year local control (LC) was 97.8 and 84.5% respectively, with no differences between C and UC groups (p = 0.662). Fifty-three (54.1%) cases had optimal dose coverage (V60Gy ITV&PTV > 95%), 29 (29.6%) had compromised PTV coverage (V60Gy ITV > 95%/PTV < 95%), and 16 (16.3%) had both compromised ITV and PTV coverage (V60Gy ITV&PTV < 95%). No significant difference in LC was detected at 2 years between the 3 groups (95.6, 91.8 and 90.9%, p = 0.717). There were 3 episodes of grade 3 toxicity in the C group (2 dyspnea, 1 pneumonitis) and 2 in the UC group (1 dyspnea, 1 hemoptysis). There were no gr4/5 toxicities. On multivariable Cox regression analysis, ITV size was found to be a predictor for LC (p = 0.001). CONCLUSIONS: SBRT at 60Gy in 8 fractions achieves high rates of LC with low risks of significant toxicities, even if target volume coverage is reduced to meet OARs constraints.

Characterization of Guided Entry of Tail-Anchored Proteins 3 Homologues in Mycobacterium tuberculosis.

We characterized an operon in Mycobacterium tuberculosis, Rv3679-Rv3680, in which each open reading frame is annotated to encode "anion transporter ATPase" homologues. Using structure prediction modeling, we found that Rv3679 and Rv3680 more closely resemble the guided entry of tail-anchored proteins 3 (Get3) chaperone in eukaryotes. Get3 delivers proteins into the membranes of the endoplasmic reticulum and is essential for the normal growth and physiology of some eukaryotes. We sought to characterize the structures of Rv3679 and Rv3680 and test if they have a role in M. tuberculosis pathogenesis. We solved crystal structures of the nucleotide-bound Rv3679-Rv3680 complex at 2.5 to 3.2 Å and show that while it has some similarities to Get3 and ArsA, there are notable differences, including that these proteins are unlikely to be involved in anion transport. Deletion of both genes did not reveal any conspicuous growth defects in vitro or in mice. Collectively, we identified a new class of proteins in bacteria with similarity to Get3 complexes, the functions of which remain to be determined.IMPORTANCE Numerous bacterial species encode proteins predicted to have similarity with Get3- and ArsA-type anion transporters. Our studies provide evidence that these proteins, which we named BagA and BagB, are unlikely to be involved in anion transport. In addition, BagA and BagB are conserved in all mycobacterial species, including the causative agent of leprosy, which has a highly decayed genome. This conservation suggests that BagAB constitutes a part of the core mycobacterial genome and is needed for some yet-to-be-determined part of the life cycle of these organisms.

Synthesis and SAR development of quinoline analogs as novel P2X7 receptor antagonists.

The P2X7 receptor (P2X7R) plays an important role in diverse conditions associated with tissue damage and inflammation, suggesting that the human P2X7R (hP2X7R) is an attractive therapeutic target. In the present study, the synthesis and structure-activity relationship (SAR) of a novel series of quinoline derivatives as P2X7R antagonists are described herein. These compounds exhibited mechanistic activity (YO PRO) in an engineered HEK293 expressing hP2X7R as well as a functional response (IL-1ß) in human THP-1 (hTHP-1) cellular assays. Compound 19 was identified as the most promising compound in this series with excellent cellular potency, low liver microsomal clearance, good permeability and low efflux ratio. In addition, this compound also displayed good pharmacokinetic properties and acceptable brain permeability (Kp,uu of 0.37).

Reliability of neural activation and connectivity during implicit face emotion processing in youth.

Face emotion imaging paradigms are widely used in both healthy and psychiatric populations. Here, in children and adolescents, we evaluate the test-retest reliability of blood oxygenation-level dependent (BOLD) activation and task-based functional connectivity on a widely used implicit face emotion processing task (i.e., gender labeling). Twenty-five healthy youth (M age = 13.97 year s; 60% female) completed two functional magnetic resonance imaging (fMRI) scan sessions approximately two months apart. Participants identified the gender of faces displaying angry, fearful, happy, and neutral emotions. A Bayesian adaptation of the intraclass correlation (ICC) assessed reliability of evoked BOLD activation and amygdala seed-based functional connectivity on task events vs. baseline as well as contrasts between face emotions. For each face emotion vs. baseline, good reliability of activation was demonstrated across key emotion processing regions including middle, medial, and inferior frontal gyri. However, contrasts between face emotions yielded variable results. Contrasts of angry to neutral or happy faces exhibited good reliability of amygdala connectivity to prefrontal regions. Contrasts of fearful to happy faces exhibited good reliability of activation in the anterior cingulate. Findings inform the reproducibility literature and emphasize the need for continued evaluation of task reliability.

A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth.

Importance: Comorbidity is ubiquitous in psychiatry, but it is unclear how to differentiate neural mechanisms of co-occurring symptoms. Pediatric irritability and anxiety symptoms are prevalent and frequently co-occur. Threat orienting is pertinent to both phenotypes and is an ideal context in which to examine their unique and common neural mechanisms. Objectives: To decompose the unique and shared variances of pediatric irritability and anxiety symptoms and to determine neural correlates of these differentiated phenotypes during threat orienting. Design, Setting, and Participants: This investigation was a cross-sectional functional magnetic resonance imaging study. The setting was a research clinic at the National Institute of Mental Health. Participants were youth aged 8 to 18 years spanning multiple diagnostic categories (141 youth with disruptive mood dysregulation disorder, anxiety disorder, and/or attention-deficit/hyperactivity disorder and 56 healthy youth). This combination provided wide variation in levels of irritability and anxiety symptoms. Data were acquired between June 30, 2012, and June 28, 2016. Main Outcomes and Measures: Participants and parents rated youth's irritability on the Affective Reactivity Index and anxiety on the Screen for Child Anxiety Related Emotional Disorders. Bifactor analysis decomposed the unique and shared variances. A functional magnetic resonance imaging dot-probe task assessed attention orienting to angry (ie, threat) vs neutral faces. Whole-brain analyses examined associations between the bifactor-derived phenotypes and both neural activity and amygdala functional connectivity. Results: Among 197 participants included in the final analysis, the mean (SD) age was 13.1 (2.7) years, and 91 (46.2%) were female. The best-fit bifactor model (Comparative Fit Index, 0.959; Root Mean Square Error of Approximation, 0.066) included unique factors of parent-reported irritability, youth-reported irritability, and anxiety, as well as a common factor of negative affectivity. When the task required attention away from threat, higher parent-reported irritability was associated with increased activity in the insula, caudate, dorsolateral and ventrolateral prefrontal cortex, and inferior parietal lobule (t189≥4.15 for all, P < .001 for all). In contrast, higher anxiety was associated with decreased amygdala connectivity to the cingulate, thalamus, and precentral gyrus (t189≤-4.19 for all, P < .001 for all). These distinctive neural correlates did not emerge using a diagnostic approach. Conclusions and Relevance: A latent variable approach to parsing co-occurring symptom dimensions revealed a novel double dissociation. During orientation away from threat, only irritability was associated with neural activity, whereas only anxiety was associated with amygdala connectivity. Despite the challenges of symptom co-occurrence for clinical neuroscience, data-driven phenotyping may facilitate a path forward.

Proteasome substrate capture and gate opening by the accessory factor PafE from Mycobacterium tuberculosis.

In all domains of life, proteasomes are gated, chambered proteases that require opening by activators to facilitate protein degradation. Twelve proteasome accessory factor E (PafE) monomers assemble into a single dodecameric ring that promotes proteolysis required for the full virulence of the human bacterial pathogen Mycobacterium tuberculosis Whereas the best characterized proteasome activators use ATP to deliver proteins into a proteasome, PafE does not require ATP. Here, to unravel the mechanism of PafE-mediated protein targeting and proteasome activation, we studied the interactions of PafE with native substrates, including a newly identified proteasome substrate, the ParA-like protein, Rv3213c, and with proteasome core particles. We characterized the function of a highly conserved feature in bacterial proteasome activator proteins: a glycine-glutamine-tyrosine-leucine (GQYL) motif at their C termini that is essential for stimulating proteolysis. Using cryo-electron microscopy (cryo-EM), we found that the GQYL motif of PafE interacts with specific residues in the α subunits of the proteasome core particle to trigger gate opening and degradation. Finally, we also found that PafE rings have 40-Å openings lined with hydrophobic residues that form a chamber for capturing substrates before they are degraded, suggesting PafE has a previously unrecognized chaperone activity. In summary, we have identified the interactions between PafE and the proteasome core particle that cause conformational changes leading to the opening of the proteasome gate and have uncovered a mechanism of PafE-mediated substrate degradation. Collectively, our results provide detailed insights into the mechanism of ATP-independent proteasome degradation in bacteria.

Behavioral and Neural Sustained Attention Deficits in Disruptive Mood Dysregulation Disorder and Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Disruptive mood dysregulation disorder (DMDD), characterized by severe irritability, and attention-deficit/hyperactivity disorder (ADHD) are highly comorbid. This is the first study to characterize neural and behavioral similarities and differences in attentional functioning across these disorders. METHOD: Twenty-seven healthy volunteers, 31 patients with DMDD, and 25 patients with ADHD (8 to 18 years old) completed a functional magnetic resonance imaging attention task. Group differences in intra-subject variability in reaction time (RT) were examined. The present functional magnetic resonance imaging analytic approach precisely quantified trial-wise associations between RT and brain activity. RESULTS: Group differences manifested in the relation between RT and brain activity (all regions: p < .01, F > 2.54, partial eta-squared [ηp2] > 0.06). Patients with DMDD showed specific alterations in the right paracentral lobule, superior parietal lobule, fusiform gyrus, and cerebellar culmen. In contrast, patients with DMDD and those with ADHD exhibited blunted compensatory increases in activity on long RT trials. In addition, youth with DMDD exhibited increased activity in the postcentral gyrus, medial frontal gyrus, and cerebellar tonsil and declive (all regions: p < .05, F > 2.46, ηp2 > 0.06). Groups in the imaging sample did not differ significantly in intra-subject variability in RT (F2,79 = 2.664, p = .076, ηp2 = 0.063), although intra-subject variability in RT was significantly increased in youth with DMDD and ADHD when including those not meeting strict motion and accuracy criteria for imaging analysis (F2,96 = 4.283, p = .017, ηp2 = 0.083). CONCLUSION: Patients with DMDD exhibited specific alterations in the relation between pre-stimulus brain activity and RT. Patients with DMDD and those with ADHD exhibited similar blunting of compensatory neural activity in frontal, parietal, and other regions. In addition, patients with DMDD showed increased RT variability compared with healthy youth. This work is the first to identify common and unique behavioral and neural signatures of DMDD and ADHD.

Mycobacterium tuberculosis proteasomal ATPase Mpa has a ß-grasp domain that hinders docking with the proteasome core protease.

Mycobacterium tuberculosis (Mtb) has a proteasome system that is essential for its ability to cause lethal infections in mice. A key component of the system is the proteasomal adenosine triphosphatase (ATPase) Mpa, which captures, unfolds, and translocates protein substrates into the Mtb proteasome core particle for degradation. Here, we report the crystal structures of near full-length hexameric Mtb Mpa in apo and ADP-bound forms. Surprisingly, the structures revealed a ubiquitin-like ß-grasp domain that precedes the proteasome-activating carboxyl terminus. This domain, which was only found in bacterial proteasomal ATPases, buries the carboxyl terminus of each protomer in the central channel of the hexamer and hinders the interaction of Mpa with the proteasome core protease. Thus, our work reveals the structure of a bacterial proteasomal ATPase in the hexameric form, and the structure finally explains why Mpa is unable to stimulate robust protein degradation in vitro in the absence of other, yet-to-be-identified co-factors.

Mycobacterium tuberculosis Proteasome Accessory Factor A (PafA) Can Transfer Prokaryotic Ubiquitin-Like Protein (Pup) between Substrates.

The protein degradation machinery of Mycobacterium tuberculosis includes a proteasome and a ubiquitin-like protein (Pup). Proteasome accessory factor A (PafA) attaches Pup to proteins to target them for degradation by the proteasome. Free Pup is unstable and never observed in extracts of M. tuberculosis, an observation that led us to hypothesize that PafA may need alternative sources of Pup. Here, we show that PafA can move Pup from one proteasome substrate, inositol 1-phosphate synthetase (Ino1), to two different proteins, malonyl coenzyme A (CoA)-acyl carrier protein transacylase (FabD) and lonely guy (Log). This apparent "transpupylation" reaction required a previously unrecognized depupylase activity in PafA, and, surprisingly, this depupylase activity was much more efficient than the activity of the dedicated depupylase Dop (deamidase of Pup). Thus, PafA can potentially use both newly synthesized Pup and recycled Pup to doom proteins for degradation.IMPORTANCE Unlike eukaryotes, which contain hundreds of ubiquitin ligases, Pup-containing bacteria appear to have a single ligase to pupylate dozens if not hundreds of different proteins. The observation that PafA can depupylate and transpupylate in vitro offers new insight into how protein stability is regulated in proteasome-bearing bacteria. Importantly, PafA and the dedicated depupylase Dop are each required for the full virulence of Mycobacterium tuberculosis Thus, inhibition of both enzymes may be extremely attractive for the development of therapeutics against tuberculosis.

Empirically derived patterns of psychiatric symptoms in youth: A latent profile analysis.

BACKGROUND: By conceptualizing domains of behavior transdiagnostically, the National Institute of Mental Health Research Domain Criteria (NIMH RDoC) initiative facilitates new ways of studying psychiatric symptoms. In this study, latent profile analysis (LPA) was used to empirically derive classes or patterns of psychiatric symptoms in youth that transect traditional nosologic boundaries. METHODS: Data were drawn from 509 children and adolescents (ages 7-18 years; mean age =12.9 years; 54% male) who were evaluated in the NIMH Emotion and Development Branch and were heterogeneous with respect to presenting diagnoses and symptoms. Youth and/or their parents completed measures of several core symptom dimensions: irritability, anxiety, depression, and attention deficit hyperactivity disorder (ADHD). LPA was used to parse response patterns into distinct classes, based on the levels of, and interrelations among, scores on the different measures. RESULTS: Five classes emerged: low levels of symptomatology (52% of sample); anxiety and mild depressive symptoms (17%); parent-reported irritability and ADHD (16%); irritability and mixed comorbid symptoms (10%); and high levels of irritability, anxiety, depression, and ADHD (5%). Importantly, these latent classes cut across informants and the clinical conditions for which youth were initially evaluated. Further, the classes characterized by irritability exhibited the poorest overall functioning. LIMITATIONS: These data were cross-sectional. Examination of external validators, including neurobiological correlates and symptom course, is warranted. CONCLUSIONS: Results inform our understanding of the structure of psychiatric symptoms in youth and suggest new ways to operationalize psychopathology and examine it in relation to neurobiology.

Management of impulse control disorders in Parkinson's disease.

BACKGROUND: Impulse control disorders (ICDs) have become a widely recognized non-motor complication of Parkinson's disease (PD) in patients taking dopamine replacement therapy (DRT). There are no current evidence-based recommendations for their treatment, other than reducing their dopaminergic medication. METHODS: This study reviews the current literature of the treatment of ICDs including pharmacological treatments, deep brain stimulation, and psychotherapeutic interventions. RESULTS: Dopamine agonist withdrawal is the most common and effective treatment, but may lead to an aversive withdrawal syndrome or motor symptom degeneration in some individuals. There is insufficient evidence for all other pharmacological treatments in treating ICDs in PD, including amantadine, serotonin selective reuptake inhibitors, antipsychotics, anticonvulsants, and opioid antagonists (e.g. naltrexone). Large randomized control trials need to be performed before these drugs can be routinely used for the treatment of ICDs in PD. Deep brain stimulation remains equivocal because ICD symptoms resolve in some patients after surgery but may appear de novo in others. Cognitive behavioral therapy has been shown to improve ICD symptoms in the only published study, although further research is urgently needed. CONCLUSIONS: Further research will allow for the development of evidence-based guidelines for the management of ICDs in PD.

Comparative analysis of rectal dose parameters in image-guided high-dose-rate brachytherapy for cervical cancer with and without a rectal retractor.

PURPOSE: The objective of this study was to determine if use of a rectal retractor (RR) in high-dose-rate intracavitary brachytherapy for cervical cancer reduces rectal dose parameters. METHODS AND MATERIALS: We reviewed data obtained from patients treated with intracavitary brachytherapy for cervical cancer with and without an RR. Treatment plans for each brachytherapy fraction were separated into two groups; R group with use of an RR and P group with use of vaginal packing. Dose-volume parameters for high-risk clinical target volume (HR-CTV), rectum, sigmoid, small bowel, and vaginal surface were collected for each fraction. Rectal D2cc and International Commission on Radiation Units & Measurements (ICRU) rectal point doses were compared between groups using Student's t tests. Predictors of higher rectal D2cc were determined by univariate and multivariate regression analyses. RESULTS: Four hundred sixty-three brachytherapy fractions from 114 patients were used for analysis, 377 fractions with a RR (R group) and 86 with vaginal packing only (P group). Both groups were similar except for slightly higher mean HR-CTV and mean bladder volume in P group. Both mean ICRU rectal point dose (241.1 vs. 269.9 cGy, p = 0.006) and rectal D2cc (240.6 vs. 283.6 cGy, p < 0.001) were significantly higher in P group. Point A dose, HR-CTV, stage, and use of an RR were significant predictors of rectal D2cc on multivariate analysis. CONCLUSIONS: Our data show that use of an RR leads to lower rectal dose parameters compared with vaginal packing. Further study is needed to determine if this will lead to less long-term toxicity.

High-grade glioma radiation therapy target volumes and patterns of failure obtained from magnetic resonance imaging and 18F-FDOPA positron emission tomography delineations from multiple observers.

PURPOSE: The objective of this study was to compare recurrent tumor locations after radiation therapy with pretreatment delineations of high-grade gliomas from magnetic resonance imaging (MRI) and 3,4-dihydroxy-6-[(18)F]fluoro-L-phenylalanine ((18)F-FDOPA) positron emission tomography (PET) using contours delineated by multiple observers. METHODS AND MATERIALS: Nineteen patients with newly diagnosed high-grade gliomas underwent computed tomography (CT), gadolinium contrast-enhanced MRI, and (18)F-FDOPA PET/CT. The image sets (CT, MRI, and PET/CT) were registered, and 5 observers contoured gross tumor volumes (GTVs) using MRI and PET. Consensus contours were obtained by simultaneous truth and performance level estimation (STAPLE). Interobserver variability was quantified by the percentage of volume overlap. Recurrent tumor locations after radiation therapy were contoured by each observer using CT or MRI. Consensus recurrence contours were obtained with STAPLE. RESULTS: The mean interobserver volume overlap for PET GTVs (42% ± 22%) and MRI GTVs (41% ± 22%) was not significantly different (P=.67). The mean consensus volume was significantly larger for PET GTVs (58.6 ± 52.4 cm(3)) than for MRI GTVs (30.8 ± 26.0 cm(3), P=.003). More than 95% of the consensus recurrence volume was within the 95% isodose surface for 11 of 12 (92%) cases with recurrent tumor imaging. Ten (91%) of these cases extended beyond the PET GTV, and 9 (82%) were contained within a 2-cm margin on the MRI GTV. One recurrence (8%) was located outside the 95% isodose surface. CONCLUSIONS: High-grade glioma contours obtained with (18)F-FDOPA PET had similar interobserver agreement to volumes obtained with MRI. Although PET-based consensus target volumes were larger than MRI-based volumes, treatment planning using PET-based volumes may not have yielded better treatment outcomes, given that all but 1 recurrence extended beyond the PET GTV and most were contained by a 2-cm margin on the MRI GTV.