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Aims: Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft‐tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumour (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of paediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors. Methods and results: Eight patients with tyrosine kinase‐altered mesenchymal neoplasms with pre‐ and posttreatment samples were identified. Tumours occurred in five females and three males with a median age at presentation of 6.5 years. Tumour sites were bone/somatic soft‐tissue (n = 5) and viscera (n = 3). Pretreatment diagnoses were: IMT (n = 3), epithelioid inflammatory myofibroblastic sarcoma (n = 1), and descriptive diagnoses (n = 4) such as "kinase‐driven spindle cell tumor." Fusions identified were ETV6::NTRK3 (n = 2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n = 3), ALK or ALK/ROS1 inhibitors (n = 3), and MEK inhibitors (n = 2). Posttreatment tumours exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumour was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases). Conclusion: Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show a pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumour response after targeted therapy. [ABSTRACT FROM AUTHOR]

Objective: Sinonasal inverted papilloma (IP) is a typically benign sinonasal tumor with a tendency to recur and the potential for malignant transformation. Varying degrees of dysplasia may be present, of which carcinoma in situ (CIS) is most advanced. We hereby describe the biological and clinical behavior of IP with CIS (IPwCIS).Study Design: Retrospective cohort.Setting: Tertiary academic referral center.Subjects and Methods: Patients who underwent surgical resection for IP between 2002 and 2017. Pertinent clinical data were obtained, and all IPwCIS cases were histologically confirmed.Results: In total, 37 of 215 cases (17.2%) were identified with IPwCIS. Mean age was 57 years and 86.5% of patients were male. Median follow-up was 82 months, and the recurrence rate was 27%. The maxillary sinus was the most common primary site (37.8%) and 14 tumors (37.8%) demonstrated multifocal attachment, which was associated with recurrence (odds ratio [OR], 9.7; 95% confidence interval [CI], 1.4-112.8; P = .028). IPwCIS was also associated with multiple recurrences (OR, 2.71; 95% CI, 1.246-5.814; P = .021). Most patients were treated with surgery alone (89.1%) and 4 patients received adjuvant radiotherapy (8.1%). Only 1 patient (2.7%) demonstrated malignant transformation after definitive surgery.Conclusions: IPwCIS represents the most severe degree of dysplasia prior to malignant transformation and is associated with higher recurrence rate and multifocal involvement but low rate of conversion to invasive carcinoma. The need for adjuvant therapy remains controversial, and further research into the etiology of the disease is warranted. [ABSTRACT FROM AUTHOR]

Abstract: The perineuronal net (PN), a component of the neural extracellular matrix (ECM), is a dynamic structure whose expression decreases following diminished physiological activity. Here, we analyzed the effects of increased neuronal activity on the development of aggrecan, a component of the PN, in the hippocampus. We show aggrecan expression to be prominent around parvalbumin (PV) interneurons in the postnatal hippocampus. Moreover, after seizure induction in early life there was a significant increase in aggrecan expression in a region specific manner during the course of development. We conclude that increased neuronal activity leads to accelerated expression of PNs in the hippocampus that attenuates in the adult hippocampus. This study shows the dynamic nature of the PN component of the ECM and the role neuronal activity has in molding the extracellular milieu of inhibitory interneurons. [Copyright &y& Elsevier]

Background: Although cerebral palsy is reported to have a higher prevalence in low-resource settings, there are few studies describing risk factors for cerebral palsy in these settings. A better understanding of the unique risk factors affecting children with cerebral palsy in low-resource settings could optimize both resource allocation and preventative strategies.Methods: A case-control study comparing children with cerebral palsy at ages two to 18 years with age-matched healthy control subjects was conducted between 2013 and 2014 at a referral center in Gaborone, Botswana. Study participants were enrolled from inpatient and outpatient settings, and data were collected through caregiver interviews, review of medical records, and physical examination of subjects. Risk factors were evaluated using conditional logistic regression models.Results: We studied 56 subjects with cerebral palsy and 56 age-matched control subjects. Significant risk factors for cerebral palsy included a history of serious neonatal infection (odds ratio 15.0, P = 0.009), complications during delivery (odds ratio 13.5, P < 0.001), and maternal human immunodeficiency virus (HIV) infection (odds ratio 3.5, P = 0.03). Maternal HIV infection remained a significant risk factor after adjusting for potential confounders and covariates (adjusted odds ratio 13.2, P = 0.05).Conclusions: Major risk factors for cerebral palsy in Botswana differ from those described in high-resource settings. Modifiable risk factors such as maternal HIV infection should be targeted as a potential strategy to reduce the incidence of cerebral palsy in Botswana. Further studies are necessary to determine optimal preventative and treatment strategies in this population. [ABSTRACT FROM AUTHOR]

Background: Children with cerebral palsy in low-resource settings are at high risk of malnutrition, which further increases their risk of poor health outcomes. However, there are few available data on specific risk factors for malnutrition among children with cerebral palsy in the developing world.Methods: We performed a case-control study among children with cerebral palsy receiving care at a tertiary care hospital in Gaborone, Botswana. Children with cerebral palsy and malnutrition were identified according to World Health Organization growth curves and compared with subjects with cerebral palsy without malnutrition. Risk factors for malnutrition were identified using multivariable logistic regression models. These risk factors were then used to generate a Malnutrition Risk Score, and Receiver Operating Characteristic curves were used to identify optimal cutoffs to identify subjects at high risk of malnutrition.Results: We identified 61 children with cerebral palsy, 26 of whom (43%) met criteria for malnutrition. Nonambulatory status (odds ratio 13.8, 95% confidence interval [CI] 3.8-50.1, P < 0.001) and a composite measure of socioeconomic status (odds ratio 1.6, 95% CI 1.0-2.5, P = 0.03) were the strongest risk factors for malnutrition. A Malnutrition Risk Score was constructed based on these risk factors, and receiver operating characteristic curve analysis demonstrated excellent performance characteristics of this score (area under the curve 0.92, 95% CI 0.89-0.94).Conclusions: Malnutrition is common among children with cerebral palsy in Botswana, and a simple risk score may help identify children with the highest risk. Further studies are needed to validate this screening tool and to determine optimal nutritional interventions in this population. [ABSTRACT FROM AUTHOR]

Background: Cerebral palsy is the most common cause of motor dysfunction in children worldwide and is often accompanied by multiple comorbidities. Although cerebral palsy has been studied extensively in high-resource settings, there are few published studies on cerebral palsy etiology, outcomes and comorbidities in low-resource settings.Methods: Children with cerebral palsy were prospectively enrolled from inpatient and outpatient settings at a referral center in Gaborone, Botswana, in a cross-sectional study conducted from 2013 to 2014. Cerebral palsy etiology, outcomes, and comorbidities were determined through caregiver interviews, review of medical records, and direct physical examination.Results: Sixty-eight children with cerebral palsy were enrolled. Subjects were 41% male, with a median age of 4 years (interquartile range = 2 to 7). The most common etiologies for cerebral palsy in our cohort were intrapartum hypoxic events (18%), postnatal infections (15%), prematurity (15%), focal ischemic strokes (10%), and prenatal infections (10%). Severe motor impairment was common, with the most severe category present in 41%. The predominant comorbidities were cognitive impairment (84%), epilepsy (77%), and visual impairment (46%).Conclusions: Cerebral palsy in Botswana has different etiologies and is associated with poorer outcomes and higher prevalence of comorbidities than what has been reported in high-resource settings. Further studies are necessary to determine optimal preventative and treatment strategies in this population. [ABSTRACT FROM AUTHOR]

Peritoneal inclusion cysts (PICs) are unilocular or multilocular cystic lesions lined by bland mesothelial cells. While most are small and localized, rare examples may be large or multifocal with diffuse peritoneal involvement, causing clinical and even pathologic concern for malignancy. We examined 20 PIC, including 8 large solitary and 12 multifocal lesions. Solitary PIC were found in 7 female and 1 male patients ranging from 19 to 55 (median: 37) years. Expanded collagenous (n=2) or edematous (n=1) areas were occasionally seen in the septae, and 1 had microscopic foci of myxoid stroma. Four had hobnail cells, and 1 had minor areas of papillary mesothelial hyperplasia. Multifocal PICs occurred in 9 female and 3 male patients ranging from 26 to 80 (median: 53) years. Three showed extensive associated fibrosis with entrapment of preexisting adipose tissue, 2 had areas resembling granulation tissue, and 3 had scattered foci of myxoid stroma. Hobnail cells were present in 9, papillary mesothelial hyperplasia in 2, entrapped single cells in 1, and 2 had areas resembling adenomatoid tumors. Two of the multifocal PICs had limited local recurrences at 18 and 21 months. No patients died of disease. Clonal alterations were not identified in any of the tested PICs (mutational and fusion analysis in 5, chromosomal microarray in 1). Despite limited local recurrences, we demonstrate that even large and multifocal PICs may lack identifiable genomic alterations and are associated with benign outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective  Sinonasal undifferentiated carcinoma (SNUC) is an aggressive neoplasm, with conflicting existing literature regarding prognosis and treatment due to the rarity of disease. Characterization of optimal SNUC management is necessary for improved outcomes. Study Design  Case series with planned data collection and analysis. Setting  Hospital of the University of Pennsylvania and Pennsylvania Hospital. Participants  Patients with pathologically confirmed SNUC treated within a 15-year period were identified, and records were obtained and evaluated for several demographic characteristics. Main Outcomes Measures  Disease-specific survival from diagnosis was the primary endpoint, while disease recurrence was a secondary endpoint of the study. Results  Twenty-seven patients with established SNUC were included in this cohort, with a median age of 55 years. Eighty-five percent of patients were surgically treated, and 85% of patients presented with stage IV disease. Two-year disease-specific survival was 66% and 5-year disease-specific survival was 46%. Ninety-six percent of patients received both chemotherapy and radiation as adjuvant treatment. Nodal disease at presentation and disease recurrence both significantly decreased patient survival ( p  < 0.05). Conclusions  The majority of patients at this institution presented with clinically advanced disease, and most were managed with a multimodal approach of surgical resection, chemotherapy, and radiation. Extent of disease at presentation and progression of disease following treatment are poor prognostic signs and may merit a more aggressive approach, while early detection and treatment may improve survival and decrease patient morbidity.

While improved surgical techniques, post-operative care, and immunosuppression regimens have reduced morbidity and mortality associated with orthotopic liver transplantation (OLT), further improvement of outcomes requires personalized treatment and a better understanding of genomic mechanisms involved. Gene expression profiles of ischemia/reperfusion (I/R) injury, regeneration, and rejection, may suggest mechanisms for development of better predictive tools and treatments. The liver is unique in its regenerative potential, recovering lost mass and function after injury from ischemia, resection, and rejection. I/R injury, an inevitable consequence of perfusion cessation, cold storage, and reperfusion, is regulated by the interaction of the immune system, inflammatory cytokines, and reduced microcirculatory blood flow in the liver. Rejection, a common post-operative complication, is mediated by the recipient's immune system through T-cell-dependent responses activating proinflammatory and apoptotic pathways. Characterizing distinctive gene expression signatures for these events can identify therapies to reduce injury, promote regeneration, and improve outcomes. While certain markers of liver injury and regeneration have been observed in animals, many of these are unverified in human studies. Further investigation of these genomic signatures and mechanisms through new technology offers promise, but continues to pose a significant challenge. An overview of the current fund of knowledge in this area is reviewed., (Copyright © 2014 Elsevier Inc. All rights reserved.)