Large and Extensive Multilocular Peritoneal Inclusion Cysts Lack Genomic Alterations and Follow an Indolent Clinical Course Despite Rare Recurrences.

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.

Epidermodysplasia verruciformis-associated eccrine neoplasm: a rare entity with distinctive clinical and histopathologic features.

Most tumors are caused by inherited or acquired genetic changes. However, a subset of tumors is driven by viral infection including Kaposi sarcoma, nasopharyngeal carcinoma, and others. Human papillomavirus (HPV) is an especially common cause of epithelial cancers and hyperplasias. Epidermodysplasia verruciformis (EDV) is a rare type of HPV infection with characteristic histopathologic features and a unique spectrum of HPV subtypes. We report here a distinctive form of EDV-associated eccrine neoplasia. Seven tumors from two patients were analyzed and show highly uniform features including multiple clustered clinical lesions, multifocal epidermal origin, eccrine differentiation with close association with the acrosyringium, an anastomosing growth pattern, and a bland monotonous poroid-to-basaloid cytomorphology. Clinical follow-up for one patient has been benign to date. These tumors show strong similarity to two previously reported cases, suggesting that this type of EDV-associated eccrine neoplasia may represent a rare but reproducible form of skin adnexal tumor with distinctive clinicopathologic features.

Pathologic Evaluation of Therapeutic Biomarkers in Colorectal Adenocarcinoma.

Molecular testing is an essential component of the pathologic evaluation of colorectal carcinoma providing diagnostic, prognostic, and predictive therapeutic information. Mismatch repair status evaluation is required for all tumors. Advanced and metastatic tumors also require determination of tumor mutational burden, KRAS, NRAS, and BRAF mutation status, ERBB2 amplification status, and NTRK and RET gene rearrangement status to guide therapy. Multiple assays, including immunohistochemistry, microsatellite instability testing, MLH1 promoter methylation, and next-generation sequencing, are typically needed. Pathologists must be aware of these requirements to optimally triage tissue. Advances in colorectal cancer molecular diagnostics will continue to drive refinements in colorectal cancer personalized therapy.

A metagenomic analysis of the virome of inverted papilloma and squamous cell carcinoma.

INTRODUCTION: Inverted papilloma (IP) is a sinonasal tumor with a well-known potential for malignant transformation. The role of human papillomavirus (HPV) in its pathogenesis has been controversial. The purpose of this study was to determine the virome associated with IP, with progression to carcinoma in situ (CIS), and invasive carcinoma. METHODS: To determine the HPV-specific types, a metagenomics assay that contains 62,886 probes targeting viral genomes in a microarray format was used. The platform screens DNA and RNA from fixed tissues from eight controls, 16 IP without dysplasia, five IP with CIS, and 13 IP-associated squamous cell carcinoma (IPSCC). Paired with next-generation sequencing, 48 types of HPV with 857 region-specific probes were interrogated against the tumors. RESULTS: The prevalence of HPV-16 was 14%, 42%, 70%, and 73% in control tissue, IP without dysplasia, IP with CIS, and IPSCC, respectively. The prevalence of HPV-18 had a similar progressive increase in prevalence, with 14%, 27%, 67%, and 74%, respectively. The assay allowed region-specific analysis, which identified the only oncogenic HPV-18 E6 to be statistically significant when compared with control tissue. The prevalence of HPV-18 E6 was 0% in control tissue, 25% in IP without dysplasia, 60% in IP with CIS, and 77% in IPSCC. CONCLUSIONS: There are over 200 HPV types that infect human epithelial cells, of which only a few are known to be high-risk. Our study demonstrated a trend of increasing prevalence of HPV-18 E6 that correlated with histologic severity, which is novel and supports a potential role for HPV in the pathogenesis of IP.

Angiomyxoma of the Breast: A Clinicopathologic Analysis of 40 Cases.

Superficial angiomyxoma is an uncommon benign mesenchymal neoplasm that usually arises in dermis/subcutis of the extremities or trunk. Some tumors are associated with Carney complex. When arising in breast, these tumors are not well-recognized, mainly due to a lack of uniform nomenclature in the literature. This study therefore aims to improve recognition of angiomyxomas of the breast region. Forty cases were identified: demographics, presence of Carney complex, imaging and histologic features, PRKAR1A expression, and outcomes were evaluated. There were 22 female and 18 male patients (median age 40 years, range: 14 to 72). Most tumors presented as slowly-growing masses (77%). All but one were solitary, and median size was 1.5 cm. Tumors were superficial (dermal/subcutaneous) in 52.5% and deep/parenchymal in 47.5%. Nine involved the nipple-areola complex. All showed characteristic features of superficial angiomyxoma: poorly circumscribed, hypocellular, myxoid neoplasms with lobulated (55%) or infiltrative (45%) architecture, bland spindled fibroblasts, prominent thin-walled vessels, and admixed neutrophils. Tumors involving the nipple-areola complex infiltrated through areolar smooth muscle, and deep/parenchymal tumors showed entrapment of lobules mimicking myxoid fibroadenoma. Mitoses were typically absent, as was significant atypia. Cystic change was common. Two-thirds showed loss of PRKAR1A expression by immunohistochemistry. Two patients had Carney complex (7%). Recurrence after incomplete excision occurred in 1 patient. Angiomyxoma of breast may arise at superficial, nipple-areola or deep/parenchymal locations, where it can be difficult to recognize classic histologic features. Loss of expression of PRKAR1A is not invariable, but may be a helpful diagnostic clue. Recognizing angiomyxoma is important for 2 reasons: first, the recurrence rate is low and therefore wide excision is not essential, and second, it may allow detection of Carney complex in some patients.

Histologic characterization of paediatric mesenchymal neoplasms treated with kinase-targeted therapy.

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.

Targeted gene expression profiling of inverted papilloma and squamous cell carcinoma.

BACKGROUND: Inverted papilloma (IP) is a sinonasal tumor with a well-known potential for malignant transformation. The purpose of this study was to identify the genes and pathways associated with IP, with progression to carcinoma-in-situ and invasive carcinoma. METHODS: To determine genes and molecular pathways that may indicate progression and correlate with histologic changes, we analyzed six IP without dysplasia, five IP with carcinoma-in-situ, and 13 squamous cell carcinoma ex-IP by targeted sequencing. The HTG EdgeSeq Oncology Biomarker Panel coupled with next-generation sequencing was used to evaluate 2560 transcripts associated with solid tumors. RESULTS: Progressive upregulation of 11 genes were observed (CALD1, COL1A1, COL3A1, COL4A2, COL5A2, FN1, ITGA5, LGALS1, MMP11, SERPINH1, SPARC) in the order of invasive carcinoma > carcinoma-in-situ > IP without dysplasia. When compared with IP without dysplasia, more genes are differentially expressed in invasive carcinoma than carcinoma-in-situ samples (341 downregulated/333 upregulated vs. 195 downregulated/156 upregulated). Gene set enrichment analysis determined three gene sets in common between the cohorts (epithelial mesenchymal transition, extracellular matrix organization, and coagulation). CONCLUSIONS: Progressive upregulation of genes specific to IP malignant degeneration has significant clinical implications. This panel of 11 genes will improve concordance of histologic classification, which can directly impact treatment and patient outcomes. Additionally, future studies on larger tumor sets may observe upregulation in the gene panel that preceded histologic changes, which may be useful for further risk stratification.

Nuclear expression of DDIT3 distinguishes high-grade myxoid liposarcoma from other round cell sarcomas.

Myxoid liposarcoma (MLPS) is a malignant adipocytic neoplasm with predilection for the extremities. MLPS is genetically defined by a t(12;16) translocation leading to FUS-DDIT3 (95%) or more rarely t(12;22) leading to EWSR1-DDIT3. Low-grade MLPS is characterized by bland spindle cells within a myxoid matrix containing delicate "chicken-wire" vasculature, whereas high-grade ("round cell") MLPS may be indistinguishable from other round cell sarcomas. In many cases, cytogenetic or molecular genetic techniques are applied to confirm the diagnosis. A recent study documented the utility of DDIT3 immunohistochemistry (IHC) in the differential diagnosis of adipocytic and myxoid soft tissue tumors. The purpose of this study was to evaluate DDIT3 IHC as a surrogate for molecular testing in high-grade MLPS. IHC was performed using a mouse monoclonal antibody directed against the N-terminus of DDIT3 on whole tissue sections from 50 high-grade MLPS cases and 319 histologic mimics used as controls (170 on whole tissue sections and 149 on a tissue microarray). Histologic mimics included Ewing sarcoma, CIC-rearranged sarcoma, sarcomas with BCOR genetic alterations, poorly differentiated synovial sarcoma, alveolar and embryonal rhabdomyosarcomas, mesenchymal chondrosarcoma, desmoplastic small round cell tumor, and neuroblastoma. Nuclear staining in >5% of cells was considered positive. By IHC, 48 (96%) high-grade MLPS showed strong diffuse nuclear staining for DDIT3. Of the controls, 2% of cases were positive, with no more than 25% nuclear staining. An additional 19% of control cases displayed less than 5% nuclear staining. Overall, DDIT3 IHC showed 96% sensitivity and 98% specificity for high-grade MLPS; strong, diffuse staining is also 96% sensitive but is 100% specific. IHC using an antibody directed against the N-terminus of DDIT3 is highly sensitive and specific for high-grade MLPS among histologic mimics and could replace molecular genetic testing in many cases, although limited labeling may be seen in a range of other tumor types.

Synovial Sarcoma of the Female Genital Tract: A Protean Mimic of Müllerian Neoplasia.

Synovial sarcoma most commonly occurs in the extremities but has rarely been described in the female genital tract. In this series, we describe the clinical, morphologic, immunohistochemical, and molecular features of 7 cases of vulvovaginal synovial sarcoma (vulva, n=6; vagina, n=1). We emphasize their wide morphologic spectrum, which can overlap significantly with other more common tumors at these sites, as highlighted by 2 cases initially diagnosed as other entities (endometrioid carcinoma and malignant peripheral nerve sheath tumor). The average patient age was 41 (range: 23 to 62) years and tumor size ranged from 0.8 to 7 cm. Histologically, the tumors were biphasic (n=6) and monophasic (n=1). All cases were confirmed with fluorescence in situ hybridization or sequencing, and 5/5 cases were positive for the novel immunohistochemical markers SSX and SS18-SSX. In 3 cases with follow-up, 2 patients died of disease and 1 was alive with no evidence of disease. Previously described cases arising in the female genital tract are also reviewed. Vulvovaginal monophasic synovial sarcoma raises a broad differential diagnosis, including smooth muscle tumors, spindled carcinomas, and melanoma. Biphasic synovial sarcoma may mimic Müllerian carcinosarcoma, endometrioid carcinoma with spindled, corded, and hyalinized elements, and mesonephric-like adenocarcinoma. Awareness that synovial sarcoma can occur in the female genital tract with a wide variety of histologic appearances is critical for correctly diagnosing this rare entity. In particular, synovial sarcoma should be considered for any deeply situated "adenocarcinoma" in the vulva, with attention to subtle spindle cell differentiation.

A Novel SS18-SSX Fusion-specific Antibody for the Diagnosis of Synovial Sarcoma.

Synovial sarcoma (SS), an aggressive soft tissue sarcoma with a predilection for the extremities of young adults, harbors the pathognomonic t(X;18)(p11;q11) translocation, resulting in SS18-SSX rearrangements. SS includes monophasic, biphasic, and poorly differentiated variants, which show considerable histologic overlap with a range of other tumor types, making the diagnosis challenging on limited biopsies. Immunohistochemistry (IHC) is routinely used in the differential diagnosis; however, presently available markers lack specificity. Thus, cytogenetic or molecular genetic techniques are often employed to confirm the diagnosis. Here, we report the development and characterization of 2 novel antibodies: an SS18-SSX fusion-specific antibody (E9X9V, designed to the breakpoint) as well as an SSX-specific antibody (E5A2C, designed to the SSX C-terminus). We validated the selectivity and specificity of the antibodies using immunoblotting, immunoprecipitation, and chromatin immunoprecipitation followed by next-generation sequencing in SS cell lines and demonstrated that both antibodies capture SS18-SSX on chromatin at established target sites (eg, TLE1 and BCL2) genome-wide. Using IHC in whole sections from 400 tumors including 100 genetically confirmed cases of SS and 300 histologic mimics, the SS18-SSX fusion-specific antibody revealed strong diffuse nuclear staining in 95 of 100 (95%) SS cases, whereas none of the 300 control tumors showed any staining. The SSX antibody showed strong diffuse nuclear staining in all 100 (100%) SS cases; 13 (4%) of the 300 other tumors were also positive, 5 of which displayed >50% nuclear staining. In summary, a novel SS18-SSX fusion-specific antibody is highly sensitive (95%) and specific (100%) for SS, and an antibody to the SSX C-terminus is also highly sensitive (100%), but slightly less specific (96%). IHC using the SS18-SSX antibody could replace molecular genetic or cytogenetic testing in most cases, and these reagents together will also provide the research community with valuable tools for further biochemical and genomic interrogation of the SS18-SSX fusion protein.

Soft Tissue Special Issue: Fibroblastic and Myofibroblastic Neoplasms of the Head and Neck.

Fibroblastic and myofibroblastic neoplasms of the head and neck encompass a group of rare tumor types with often overlapping clinicopathologic features that range in biologic potential from benign to overtly malignant. Even neoplasms with no metastatic potential may provide significant therapeutic challenges in this region due to the unique anatomy of the head and neck. This review will cover the following entities, highlighting important clinical aspects of each neoplasm and then focusing on their characteristic histomorphology, immunophenotype, and molecular alterations: nodular and cranial fasciitis, fibrous hamartoma of infancy, nasopharyngeal angiofibroma, nuchal-type and Gardner fibromas, desmoid fibromatosis, dermatofibrosarcoma protuberans and giant cell fibroblastoma, solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, infantile fibrosarcoma, low-grade fibromyxoid sarcoma, and sclerosing epithelioid fibrosarcoma. While some of these neoplasms characteristically arise in the head and neck, others are rarely described in this anatomic region and may therefore be particularly difficult to recognize. Distinction between these entities, however, is crucial, particularly as the molecular pathogenetic basis for these neoplasms are being rapidly elucidated, in some instances allowing for targeted therapeutic approaches.

Clinical Implications of Carcinoma In Situ in Sinonasal Inverted Papilloma.

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.

Sinonasal Undifferentiated Carcinoma: A 15-Year Single Institution Experience.

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.

Risk Factors for Cerebral Palsy in Children in Botswana.

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.

Risk Factors for Malnutrition Among Children With Cerebral Palsy in Botswana.

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.

Increased metalloproteinase activity in the hippocampus following status epilepticus.

Increased neuronal plasticity and neuronal cell loss has been implicated in the development of epilepsy following injury. Parvalbumin fast spiking inhibitory interneurons have a robust extracellular matrix coating their cell bodies and the proximal dendrites called the perineuronal net (PNN). The role of the PNN is not clear but it has been implicated in closing of the critical period, altering seizure thresholds and providing neuronal protection from oxidative stress. The PNN is susceptible to degradation following a prolonged seizure and there is an increase in proteolytic-fragments of the PNN enriched proteoglycan aggrecan (Dzwonek et al., 2004). Here we demonstrate an increase in matrix metalloproteinase (MMP) activity in the hippocampus following status epilepticus (SE). We further assessed MMP3 and 13, two of 24 identified MMPs, both MMP3 and 13 mRNA increase in the hippocampus after SE and MMP13 activity increases by functional assay as well as it co-localizes with PNN in rat brain. In contrast, two of the brain expressed ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) also implicated in aggrecan degradation, did not consistently increase following SE though ADAMTS4 is highly expressed in glia and ADAMTS5 in neuronal cell bodies and their processes. The increase in MMP activity following SE suggests that in the future studies, MMP inhibitors are candidates for blocking PNN degradation and assessing the role of the PNN loss in epileptogenesis and cellular function.

Pediatric Cerebral Palsy in Botswana: Etiology, Outcomes, and Comorbidities.

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.

Perineuronal net degradation in epilepsy.

OBJECTIVE: We previously reported loss of perineuronal net (PN) immunohistochemical staining around parvalbumin-positive interneurons in the hippocampus of rats after an episode of status epilepticus (SE). We hypothesized that the loss of the PN could alter seizure susceptibility and that matrix metalloproteinases (MMPs) were candidates for degradation of the PN following SE. METHODS: The pilocarpine chemoconvulsant rodent epilepsy model was used to characterize the degradation of the aggrecan component of the PN in the hippocampus following SE. Chondroitinase ABC (ChABC) was used to degrade the PN in mice. Onset, number, and duration of pentylenetetrazole (PTZ)-induced seizures were assessed. RESULTS: The loss of the PN in the hippocampus following SE is at least partially related to degradation of the aggrecan PN component by MMP activity. Forty-eight hours after SE, a neoepitope created by MMP cleavage of aggrecan was present and concentrated around parvalbumin-positive interneurons. The increase in aggrecan cleavage products was found at 48 h, 1 week, and 2 months after SE, with different fragments predominating over time. We demonstrate ongoing aggrecan proteolysis and fragment accumulation in the hippocampus of adult control rats, as well as in SE-treated animals. Degradation of the PN alters the seizure response to PTZ. ChABC treatment caused an increase in myoclonic seizures following PTZ administration, a delayed onset of Racine stage 4/5 seizure, and a decreased duration of Racine stage 4/5 seizure. SIGNIFICANCE: Status epilepticus increases MMP proteolysis of aggrecan, pointing to MMP activity as one mechanism of PN degradation post-SE. There is accumulation of aggrecan fragments in adult rat hippocampus of both control and SE-exposed animals. Loss of the PN was associated with increased numbers of myoclonic seizures; it also, delayed and shortened the duration of Racine stage 4/5 seizures, suggesting a complex relationship between the PN and seizure susceptibility.

Serum hypoalbuminemia predicts late mortality on the liver transplant waiting list.

BACKGROUND: The reduction of liver transplant wait list mortality remains a priority for transplant programs and depends on the accurate stratification of patients by mortality risk. Although estimation of 90-day mortality by Model for End-Stage Liver Disease (MELD) score has improved wait list survival, it is unclear how contemporary wait list mortality can best be diminished given the preponderance of listed patients with low MELD scores and long wait times. METHODS: In this intention-to-treat analysis of 289 consecutively listed patients with over 5 years of follow-up, we aimed to determine the contribution of late mortality to overall wait list outcome and identify clinical predictors that would help discriminate long-term survivors from fatalities. RESULTS: Seventy percent of wait list deaths occurred in patients listed with MELD scores less than 20, and 40% of deaths occurred in patients waiting longer than 1 year. Hypoalbuminemia at listing was a significant predictor of late mortality in all patients in both univariate and multivariate analyses, and it was most discriminatory among patients with MELD scores of 20 or less. CONCLUSION: Our data suggest that hypoalbuminemia at listing reveals a vulnerable population of low MELD patients who are underserved by their MELD score over time. Such patients comprise almost 40% of the contemporary wait list and contribute substantially to list mortality given their poor access to transplantation. Targeting these at-risk patients with grafts from living or extended criteria donors may thus significantly diminish overall list mortality, and future initiatives to decrease overall wait list mortality must focus on improved risk stratification for low MELD patients.