A biodegradable microgrooved and tissue mechanocompatible citrate-based scaffold improves bladder tissue regeneration.

Chronic bladder dysfunction due to bladder disease or trauma is detrimental to affected patients as it can lead to increased risk of upper urinary tract dysfunction. Current treatment options include surgical interventions that enlarge the bladder with autologous bowel tissue to alleviate pressure on the upper urinary tract. This highly invasive procedure, termed bladder augmentation enterocystoplasty (BAE), significantly increases the risk of patient morbidity and mortality due to the incompatibility between bowel and bladder tissue. Therefore, patients would significantly benefit from an alternative treatment strategy that can regenerate healthy tissue and restore overall bladder function. Previous research has demonstrated the potential of citrate-based scaffolds co-seeded with bone marrow-derived stem/progenitor cells as an alternative graft for bladder augmentation. Recognizing that contact guidance can potentially influence tissue regeneration, we hypothesized that microtopographically patterned scaffolds would modulate cell responses and improve overall quality of the regenerated bladder tissue. We fabricated microgrooved (MG) scaffolds using the citrate-based biomaterial poly (1,8-octamethylene-citrate-co-octanol) (POCO) and co-seeded them with human bone marrow-derived mesenchymal stromal cells (MSCs) and CD34+ hematopoietic stem/progenitor cells (HSPCs). MG POCO scaffolds supported MSC and HSPC attachment, and MSC alignment within the microgrooves. All scaffolds were characterized and assessed for bladder tissue regeneration in an established nude rat bladder augmentation model. In all cases, normal physiological function was maintained post-augmentation, even without the presence of stem/progenitor cells. Urodynamic testing at 4-weeks post-augmentation for all experimental groups demonstrated that bladder capacity increased and bladder compliance was normal. Histological evaluation of the regenerated tissue revealed that cell-seeded scaffolds restored normal bladder smooth muscle content and resulted in increased revascularization and peripheral nerve regeneration. The presence of microgrooves on the cell-seeded scaffolds increased microvasculature formation by 20 % and urothelial layer thickness by 25 % in the regenerating tissue. Thus, this work demonstrates that microtopography engineering can influence bladder tissue regeneration to improve overall anatomical structure and re-establish bladder physiology.

Histone H3 trimethylation on lysine 27 immunostaining pattern in DICER1-associated tumors.

Background: DICER1-associated tumors are heterogeneous and affect several organs. DICER1-associated primary intracranial sarcoma is associated with histone H3 trimethylation on lysine 27 (H3K27me3) loss in nucleus by immunohistochemistry. Methods: We explored the H3K27me3 immunostaining pattern in other DICER1-associated tumors. Twelve tumors from eleven patients with confirmed DICER1 mutations (sporadic and germline) data from a pancancer next-generation sequencing panel, and four tumors of pleuropulmonary blastoma (PPB) were retrieved from our database and stained with anti-H3K27me3 antibody. Results: The H3K27me3 expression in the nucleus showed heterogeneous mosaic loss in neoplastic Sertoli cell components in three of the five cases of moderately to poorly differentiated Sertoli-Leydig cell tumors. Among two tumors of DICER1-associated primary intracranial sarcoma, one showed complete loss of H3K27me3 in all neoplastic cells, whereas the other showed mosaic loss in the sarcomatous spindle cells. One DICER1-associated tumor with epithelial and mesenchymal differentiation, including pulmonary blastoma and PPB, showed mosaic loss of glandular epithelial and mesenchymal components. Four cases of type II PPB and a single case of type III PPB showed a similar mosaic loss of H3K27me3 staining restricted to large spindle cell components. All other components in all tumors-including Leydig cells; the areas of epithelial, cartilaginous, and rhabdomyomatous differentiation; and all cells of the remaining three cases (one papillary thyroid carcinoma and two cases of PPB type I)-demonstrated retained H3K27me3 staining. Conclusions: H3K27me3 expression is not universally lost in DICER1-associated tumors and thus is not predictive of DICER1 mutation status. The mosaic regional loss of H3K27me3 immunostaining is consistent in PPB type II and III, which can be a helpful diagnostic marker for these tumors and suggests a similarity to DICER1-associated intracranial sarcoma.

Miniaturized implantable temperature sensors for the long-term monitoring of chronic intestinal inflammation.

Diagnosing and monitoring inflammatory bowel diseases, such as Crohn's disease, involves the use of endoscopic imaging, biopsies and serology. These infrequent tests cannot, however, identify sudden onsets and severe flare-ups to facilitate early intervention. Hence, about 70% of patients with Crohn's disease require surgical intestinal resections in their lifetime. Here we report wireless, miniaturized and implantable temperature sensors for the real-time chronic monitoring of disease progression, which we tested for nearly 4 months in a mouse model of Crohn's-disease-like ileitis. Local measurements of intestinal temperature via intraperitoneally implanted sensors held in place against abdominal muscular tissue via two sutures showed the development of ultradian rhythms at approximately 5 weeks before the visual emergence of inflammatory skip lesions. The ultradian rhythms showed correlations with variations in the concentrations of stress hormones and inflammatory cytokines in blood. Decreasing average temperatures over the span of approximately 23 weeks were accompanied by an increasing percentage of inflammatory species in ileal lesions. These miniaturized temperature sensors may aid the early treatment of inflammatory bowel diseases upon the detection of episodic flare-ups.

Multipotent bone marrow cell-seeded polymeric composites drive long-term, definitive urinary bladder tissue regeneration.

To date, there are no efficacious translational solutions for end-stage urinary bladder dysfunction. Current surgical strategies, including urinary diversion and bladder augmentation enterocystoplasty (BAE), utilize autologous intestinal segments (e.g. ileum) to increase bladder capacity to protect renal function. Considered the standard of care, BAE is fraught with numerous short- and long-term clinical complications. Previous clinical trials employing tissue engineering approaches for bladder tissue regeneration have also been unable to translate bench-top findings into clinical practice. Major obstacles still persist that need to be overcome in order to advance tissue-engineered products into the clinical arena. These include scaffold/bladder incongruencies, the acquisition and utility of appropriate cells for anatomic and physiologic tissue recapitulation, and the choice of an appropriate animal model for testing. In this study, we demonstrate that the elastomeric, bladder biomechanocompatible poly(1,8-octamethylene-citrate-co-octanol) (PRS; synthetic) scaffold coseeded with autologous bone marrow-derived mesenchymal stem cells and CD34+ hematopoietic stem/progenitor cells support robust long-term, functional bladder tissue regeneration within the context of a clinically relevant baboon bladder augmentation model simulating bladder trauma. Partially cystectomized baboons were independently augmented with either autologous ileum or stem-cell-seeded small-intestinal submucosa (SIS; a commercially available biological scaffold) or PRS grafts. Stem-cell synergism promoted functional trilayer bladder tissue regeneration, including whole-graft neurovascularization, in both cell-seeded grafts. However, PRS-augmented animals demonstrated fewer clinical complications and more advantageous tissue characterization metrics compared to ileum and SIS-augmented animals. Two-year study data demonstrate that PRS/stem-cell-seeded grafts drive bladder tissue regeneration and are a suitable alternative to BAE.

A biodegradable microgrooved and tissue mechanocompatible citrate-based scaffold improves bladder tissue regeneration.

Chronic bladder dysfunction due to bladder disease or trauma is detrimental to affected patients as it can lead to increased risk of upper urinary tract dysfunction. Current treatment options include surgical intervention that enlarge the bladder with autologous bowel tissue to alleviate pressure on the upper urinary tract. This highly invasive procedure, termed bladder augmentation enterocystoplasty (BAE), significantly increases risk of patient morbidity and mortality due to the incompatibility between the bowel and bladder tissue. Therefore, patients would significantly benefit from an alternative treatment strategy that can regenerate healthy tissue and restore overall bladder function. Previous research has demonstrated the potential of citrate-based scaffolds co-seeded with bone marrow-derived stem/progenitor cells as an alternative graft for bladder augmentation. Recognizing that contact guidance is known to influence tissue regeneration, we hypothesized that patterned scaffolds would modulate cell responses and improve overall quality of the regenerated bladder tissue. We fabricated microgrooved (MG) scaffolds using citrate-based biomaterial poly(1,8-octamethylene-citrate-co-octanol) (POCO) and co-seeded them with human bone marrow derived mesenchymal stem cells (MSCs) and CD34+ hematopoietic stem/progenitor cells (HSPCs). Microgrooved POCO scaffolds supported MSC and HSPC attachment, and MSC alignment within the microgrooves. All scaffolds were characterized and assessed for bladder tissue regeneration in an established nude rat bladder augmentation model. In all cases, normal physiological function was maintained post-augmentation, even without the presence of stem/progenitor cells. Urodynamic testing at 4-weeks post-augmentation for all experimental groups demonstrated that capacity increased and compliance was normal. Histological evaluation of the regenerated tissue revealed that cell-seeded scaffolds restored normal bladder smooth muscle content and resulted in increased revascularization and peripheral nerve regeneration. The presence of microgrooves on the cell-seeded scaffolds increased microvasculature formation by 20% and urothelium layer thickness by 25% in the regenerating tissue. Thus, this work demonstrates that micropatterning affects bladder regeneration to improve overall anatomical structure and re-establish bladder physiology.

Pediatric Sertoli-Leydig Cell Tumors of the Ovary: An Integrated Study of Clinicopathological Features, Pan-cancer-Targeted Next-generation Sequencing and Chromosomal Microarray Analysis From a Single Institution.

Sertoli-Leydig cell tumors (SLCTs) are currently classified into 3 molecular subtypes: DICER1 -mutant (younger patient age), FOXL2 -mutant, and DICER1/FOXL2 -wildtype. However, it is not clear whether all pediatric SLCTs are DICER1 -mutant molecular subtypes and whether other molecular genetic aberrations besides DICER1 are involved in the pathogenesis and prognosis of these tumors. We studied comprehensive data for 8 cases of pediatric SLCTs, including clinicopathological features, pan-cancer-targeted next-generation sequencing/OncoKids panel, and chromosomal microarray analysis, to further analyze the correlation among clinicopathological features, molecular genetic aberrations, and prognosis. The ages of the patients ranged from 4 to 16 years (median, 14 y). Seven cases were moderately differentiated, and one was poorly differentiated with heterologous mesenchymal elements. Two cases had heterologous epithelium or retiform elements. Follow-up was available for all 8 patients (median, 49.5 mo). Seven patients were alive without evidence of recurrence or metastasis, and only case 5 developed metastases (synchronous bilateral pulmonary tumors with rhabdomyosarcomatous differentiation). All 8 tumors were found to harbor somatic hotspot DICER1 mutations, and 5 patients carried germline DICER1 mutations (2 of them had the phenotype of DICER1 syndrome). Together with recent studies, the DICER1 mutation frequency is 100% in pediatric SLCTs (n=27, age≤16 y). Copy number alterations were detected in 3 tumors; the only recurrent copy number alterations was the gain of whole chromosome 6 in case 5 and case 8. This is the first report describing clinicopathological features and molecular alterations in pediatric SLCTs. Our results demonstrate that all pediatric SLCTs belong to the DICER1 -mutant molecular subtype, highlighting that somatic hotspot DICER1 mutation detection has high sensitivity (100%) for the auxiliary diagnosis of pediatric SLCTs (age ≤16 y). Some pediatric SLCTs harbor molecular genetic aberrations other than DICER1 mutation, and their significance needs further study.

Comparative Clinicopathologic and Genomic Analysis of Hepatocellular Neoplasm, Not Otherwise Specified, and Hepatoblastoma.

Accurate diagnosis and treatment of hepatocellular neoplasm, not otherwise specified (HCN-NOS), poses significant challenges. Our study aimed to investigate the clinicopathologic and genomic similarities and differences between HCN-NOS and hepatoblastoma (HB) to guide diagnostic and treatment strategies. The clinicopathologic characteristics of 16 patients with HCN-NOS and 23 patients with HB were compared. Molecular studies, including the OncoKids DNA- and RNA-based next-generation sequencing panel, chromosomal microarray, and targeted Sanger sequencing analyses of CTNNB1 and TERT promoters, were employed. We found that patients with HCN-NOS were older (P < .001) and more frequently classified as high risk (P < .01), yet they showed no significant differences in alpha fetoprotein levels or survival outcomes compared with those with HB. HCN-NOS and HB had a comparable frequency of sequence variants, with CTNNB1 mutations being predominant in both groups. Notably, TERT promoter mutations (37.5%) and rare clinically significant variants (BRAF, NRAS, and KMT2D) were exclusive to HCN-NOS. HCN-NOS demonstrated a higher prevalence of gains in 1q, encompassing the MDM4 locus (17/17 vs 11/24; P < .001), as well as loss/loss of heterozygosity (LOH) of 1p (11/17 vs 6/24; P < .05) and chromosome 11 (7/17 vs 1/24; P < .01) when compared with HB. Furthermore, the recurrent loss/LOH of chromosomes 3, 4p, 9, 15q, and Y was only observed in HCN-NOS. However, no significant differences were noted in gains of chromosomes 2, 8, and 20, or loss/LOH of 4q and 11p between the 2 groups. Notably, no clinically significant gene fusions were detected in either group. In conclusion, our study reveals that HCN-NOS exhibits high-risk clinicopathologic features and greater structural complexity compared with HB. However, patients with HCN-NOS exhibit comparable alpha fetoprotein levels at diagnosis, CTNNB1 mutation rates, and survival outcomes when subjected to aggressive treatment, as compared with those with HB. These findings have the potential to enhance diagnostic accuracy and inform more effective treatments for HCN-NOS.

FGFR1 gene fusions in a subset of pediatric mesenchymal tumors: Expanding the genetic spectrum of tumors sharing histologic overlap with infantile fibrosarcoma and "NTRK-rearranged" spindle cell neoplasms.

As the classification of kinase-driven spindle cell tumors continues to evolve, we describe the first series of pediatric mesenchymal tumors harboring FGFR1 gene fusions that share histologic overlap with infantile fibrosarcoma and "NTRK-rearranged" spindle cell neoplasms. Herein, we present three cases of FGFR1-rearranged pediatric mesenchymal tumors, including one case with FGFR1::PARD6B gene fusion and two cases with FGFR1::EBF2 gene fusion. The tumors involved infants ranging from 3 to 9 months in age with a male-to-female ratio of 2:1. All tumors involved the deep soft tissue of the gluteal, pelvic, or perirectal region. Histologically, the tumors comprised a cellular spindle cell neoplasm with primitive stellate cells, focal myxoid stroma, focal epithelioid features, no necrosis, and occasional mitotic figures (2-6 per 10 high-power field). By immunohistochemistry, the neoplastic cells focally expressed CD34 but lacked expression of S100 protein, SMA, desmin, myogenin, MyoD1, pan-TRK, and ALK. These three cases, including a case with long-term clinical follow-up, demonstrate that FGFR1 fusions occur in a subset of newly described pediatric kinase-driven mesenchymal tumors with locally aggressive behavior. Importantly, knowledge of these genetic alterations in this spectrum of pediatric tumors is key for diagnostic and targeted therapeutic purposes.

Independent Assessment of the Children's Hepatic Tumors International Collaboration Risk Stratification for Hepatoblastoma and the Association of Tumor Histological Characteristics With Prognosis.

Importance: Hepatoblastoma is the most common pediatric liver malignant neoplasm, and accurate risk stratification is essential for guiding treatment. Objective: To validate the Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) in an independent cohort of patients with hepatoblastoma and evaluate the association of pretreatment hepatoblastoma histological subtype with prognosis. Design, Setting, and Participants: This is a single-institution retrospective cohort study of 96 pediatric patients with hepatoblastoma diagnosed and treated between June 1, 2000, and December 31, 2016, with recent therapy and independent of the CHIC-HS discovery cohort. Each patient was assigned a risk group according to CHIC-HS. The histological characteristics of each tumor were assessed based on the International Pediatric Liver Tumor Consensus Classification. Data were analyzed from May 2018 to May 2019. Main Outcomes And Measures: The main outcomes were event-free survival (EFS) and overall survival (OS). Cox regression analysis was used to examine the associations of patient characteristics and tumor histological characteristics with survival. Results: A total of 96 patients (median [range] age, 1.9 [0.4-18] years; 36 [38%] girls and 60 [63%] boys) were assessed, including 15 with very low risk, 28 with low risk, 23 with intermediate risk, and 30 with high risk, according to CHIC-HS criteria. There were a total of 13 cancer-related deaths; median (range) follow-up was 3.5 (0.1-17.8) years for those alive at the last follow-up. The estimated 5-year OS rates were 100% in the very low-risk group, 94.7% (95% CI, 68.1%-99.2%) in the low-risk group, 89.2% (95% CI, 63.1%-97.2%) in the intermediate-risk group, and 57.9% (95% CI, 34.6%-75.5%) in the high-risk group. In a multivariable analysis, we confirmed that CHIC-HS significantly estimated EFS (high-risk group vs very low- and low-risk groups: hazard ratio [HR], 45.59; 95% CI, 9.39-209.5; P < .001) and OS (high-risk group vs very low- and low-risk groups: HR, 21.95; 95% CI, 2.76-174.29; P < .001). In the subcohort of 84 patients for whom pretreatment tumor histological data were available, tumor epithelial histological subtypes were found to be significantly associated with both EFS and OS. Patients in the CHIC-HS high-risk group and with embryonal-only histological subtype had the highest risk of relapse or disease progression (high-risk: HR, 42.62; 95% CI, 9.91-203.9; embryonal: HR, 3.28; 95% CI, 1.21-8.9) and death (high-risk: HR, 18.78; 95% CI, 2.31-152.84; embryonal: HR, 7.12; 95% CI, 1.51-33.52). Conclusions and Relevance: This cohort study found that CHIC-HS performed as expected in an independent cohort that was more recently treated. Incorporation of pretreatment tumor histological data into CHIC-HS may provide additional prognostic value.

Cost-effectiveness analysis of nivolumab plus standard chemotherapy versus chemotherapy alone for the first-line treatment of unresectable advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

Background Nivolumab plus standard chemotherapy has significant clinical benefits for unresectable advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC). However, nivolumab is expensive, necessitating a cost-effectiveness evaluation. Aim This study aimed to evaluate the cost-effectiveness of nivolumab plus standard chemotherapy vs. chemotherapy alone for unresectable advanced or metastatic GC/GEJC/EAC from the Chinese healthcare system perspective. This study was based on randomized clinical trial data from the CheckMate-649 clinical trial (NCT02872116) published in Lancet (June 2021). Method A Markov model was used to assess the cost-effectiveness of nivolumab plus standard chemotherapy versus chemotherapy alone for unresectable advanced or metastatic GC/GEJC/EAC. Drug costs were collected from Tianjin Medical Purchasing Center in 2021, and utility values of health states were obtained from the literature. The reliability of model was assessed with one-way and probabilistic sensitivity analyses. Main outcome measure The main outcomes were costs, quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). Results Over a 10-year horizon, the outputs were 1.19 QALYs at a cost of $78,814.9 and 0.88 QALYs at a cost of $19,522.3 with nivolumab plus chemotherapy and chemotherapy alone, respectively. The ICER for nivolumab plus chemotherapy versus chemotherapy alone was $191,266/QALY, exceeding the willingness-to-pay (WTP) threshold ($33,436/QALY). One-way sensitivity analysis revealed nivolumab cost was the most influential parameter. Conclusion Adding nivolumab is not cost-effective for unresectable advanced or metastatic GC/GEJC/EAC in the current Chinese healthcare environment.

An Integrative Morphologic and Molecular Approach for Diagnosis and Subclassification of Rhabdomyosarcoma.

CONTEXT.­: Rhabdomyosarcoma, the most common soft tissue sarcoma of children, is currently classified into the following 4 subtypes: embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma, based on recent molecular genetic knowledge and morphologic features. OBJECTIVE.­: To highlight the most recent advances of molecular genetic alterations, and to familiarize pathologists with most recent genotype and phenotype correlation in rhabdomyosarcoma. DATA SOURCES.­: Data were derived from the World Health Organization Classification of Soft Tissue and Bone Tumors, fifth edition, recently published literature (PubMed), and clinical practice experience. CONCLUSIONS.­: Current classification has been significantly impacted by genotype and phenotype correlation, especially with PAX-FOXO1 fusion-positive rhabdomyosarcoma versus fusion-negative rhabdomyosarcoma, and with the emergence of 3 distinct new subtypes of spindle cell/sclerosing rhabdomyosarcoma. Although all rhabdomyosarcomas were considered a single diagnostic entity in the past, they are now considered to be a group of histologically similar but biologically diverse entities because their clinical behavior and underlying molecular alterations dramatically differ. This review outlines recent molecular genetic developments, corresponding morphologic features, and current challenges faced by pathologists in daily practice.

Emergency department disposition: Do surgical residents contribute to inefficiency?

BACKGROUND: Residents are often viewed as contributors to Emergency Department (ED) prolongation of length of stay (LOS). To understand this proposition, we performed a study to identify ED patient care intervals and how each contributed to LOS. METHODS: We performed a retrospective review of prospectively gathered data on 145 ED surgery consults. Residents prospectively documented patient names, page times, and time of plan. Key ED patient care intervals were then retrospectively extracted from the patient's chart. A time analysis was then performed. RESULTS: Average arrival to disposition time was 305 min, and residents averaged 47 min to see and staff consults. The longest intervals were arrival to imaging (75 min) and imaging time (73 min). Average disposition to discharge time was 170 min (36% of LOS). CONCLUSIONS: Surgery residents see and staff consults within the norms for care established by the hospital. Imaging time is a bottleneck hindering disposition. Access block also significantly increases ED LOS.

Massive unilateral fetal axillary lymphangioma: A case report.

We report a substantial axillary lymphangioma in a fetus delivered at 38 weeks of gestation. Detailed fetal survey at 20 weeks revealed a 5.45 × 3.72 cm nonvascular cystic axillary structure without other malformations; amniocentesis was negative. Serial surveillance was performed throughout the pregnancy. A male infant weighing 3000 g with a 16 × 12 × 9 cm septated cystic mass arising from the left axilla was delivered via cesarean section. The newborn period was complicated by cellulitis overlying the mass and interval cystic hemorrhage requiring sclerotherapy and subsequent excision. Nonnuchal lymphangiomas may be etiologically distinct entities. The prognostic factors include anatomic location, presence of septa, and association with other congenital abnormalities. A thorough evaluation, multidisciplinary approach, and close surveillance should be undertaken to optimize neonatal outcomes.

Pediatric Benign Tumors With a Skeletal Muscle Component: Myogenin Expression, Diagnostic Pitfalls, and New Molecular Insights.

OBJECTIVES: Benign tumors with skeletal muscle differentiation are rare and their characterization in the literature is limited. We present a series of twelve pediatric benign tumors with rhabdomyomatous differentiation including seven rhabdomyomatous mesenchymal hamartomas, four fetal rhabdomyomas, and one benign triton tumor, analyzing myogenic markers as well as clinicopathologic and molecular features. A review of the literature was also performed with an emphasis on myogenic marker expression and correlation with molecular features. METHODS AND RESULTS: Cases obtained from three tertiary pediatric hospitals were retrospectively reviewed. Eleven of twelve cases expressed myogenin in rare to greater than 15% of cells. Five of nine cases had rare to 70-80% of cells positive for MyoD1. One fetal rhabdomyoma demonstrated homozygous deletions in ZEB2. The benign triton tumor harbored a CTNNB1 mutation. Review of the literature identified 160 pediatric benign tumors with skeletal muscle differentiation of which 9 reported myogenin positivity. CONCLUSIONS: Myogenin and MyoD1 may be variably expressed in benign lesions with skeletal muscle differentiation. Recognition of key morphologic features remains critical to diagnose these lesions and, in rhabdomyoma, to exclude malignancy. Our series expands the knowledge of the relationship between rhabdomyoma and rhabdomyosarcoma (RMS) by identifying a shared molecular alteration in ZEB2.

Primary Knee Intra-articular Synovial Sarcoma in Pediatric and Adolescent Patients.

Synovial sarcoma (SS) arising within a knee joint is extremely rare, with 10 reported cases in pediatric and adolescent patients in English literature. Its rarity and nonspecific clinical and radiological features pose a diagnostic challenge. We present two cases of primary intra-articular SS of left knee to enhance awareness of this entity. One patient is a 17-year-old male complained of left knee pain and gait abnormality for 9 years. The other one is a 13-year-old female presented with left knee pain for one year. Both cases were clinically diagnosed as benign joint lesion and underwent biopsies. Histological examination, immunohistochemical staining and molecular study confirmed that both patients had primary intra-articular SS, monophasic spindle cell type. Intraarticular SS should be considered as a potential diagnosis with unexplained long-standing knee pain.

Histopathologic features of alveolar capillary dysplasia with misalignment of pulmonary veins with atypical clinical presentation.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare neonatal lung disease with fatal outcome. Typically, respiratory symptoms present in the first 24 hours of life and patients die within the neonatal period. Atypical, delayed clinical presentations and/or longer survival have also been reported. Here, we studied the clinicopathologic relationship of ACD/MPV by examining 16 cases of ACD/MPV, focusing on atypical features. Based on the presence of diffuse vs. focal/patchy ACD/MPV histopathologic changes, we divided the cases into classic and nonclassic pathology groups. MPV was found in all ACD/MPV. Ten of 16 cases exhibited classic diffuse abnormalities, while 6 of 16 had a nonclassic focal/patchy distribution. However, among 7 patients with atypical clinical features, only 2 had nonclassic pathology, while 4 out of 9 clinically typical cases had nonclassic ACD/MPV pathology. Marked intrapulmonary aberrant arteriovenous vessels were present in all atypical cases. In conclusion, clinical presentation is not always correlated with histopathology in ACD/MPV. Atypical ACD/MPV should be suspected in any infants with fulminant pulmonary hypertension. Abnormal pulmonary veins and aberrant intraseptal vessels are the most important clues for diagnosis. Additional studies are needed for further elucidation of diagnostic histological criteria of atypical ACD/MPV and to explore its pathogenesis.

Screening for perinatal depression with the Patient Health Questionnaire depression scale (PHQ-9): A systematic review and meta-analysis.

OBJECTIVES: Perinatal depression (PND) is a prevalent and disabling problem both during pregnancy and the postpartum period. The legacy screening measure has been the Edinburgh Postnatal Depression Scale (EPDS). This systematic review examines the validity of the PHQ-9 as a screener for PND. METHODS: The following databases were searched from January 2001 (when the PHQ-9 was first published) through June 2020: MEDLINE, Embase, and PsychInfo. Studies that compared the PHQ-9 to a criterion standard psychiatric interview were used to determine the operating characteristics of sensitivity, specificity and area under the curve (AUC). Studies comparing the PHQ-9 to the EPDS and other depression scales evaluated convergent validity. RESULTS: A total of 35 articles were eligible for criterion (n = 10) or convergent (n = 25) validity. Meta-analysis of the 7 criterion validity studies using the standard PHQ-9 cut point ≥10 showed a pooled sensitivity, specificity and AUC of 0.84, 0.81 and 0.89, respectively. Operating characteristics of the PHQ-9 and EPDS were nearly identical in head-to-head comparison studies. The median correlation between the PHQ-9 and EPDS was 0.59, and categorical agreement was moderate. CONCLUSIONS: The PHQ-9 appears to be a viable option for perinatal depression screening with operating characteristics similar to the legacy EPDS.

Custom Pediatric Oncology Next-Generation Sequencing Panel Identifies Somatic Mosaicism in Archival Tissue and Enhances Targeted Clinical Care.

BACKGROUND: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders. METHODS: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention. RESULTS: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues. CONCLUSIONS: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management.

Clinicopathologic Characteristics of Late Acute Antibody-mediated Rejection in Pediatric Liver Transplantation.

BACKGROUND: An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients. METHODS: We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients. RESULTS: Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6 of 7 patients; and arteritis was seen in 3 of 7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years. CONCLUSIONS: Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.

Phox2b Immunohistochemical Staining in Detecting Enteric Neural Crest Cells in Hirschsprung Disease.

BACKGROUND: It can be challenging to recognize undifferentiated/immature ganglion cells, especially single forms. Ganglion cells and glia are derived from enteric neural crest cells (ENCCs), a group of autonomic nervous system (ANS)-lineage neural crest progenitors that PHOX2B regulates. Phox2b is an excellent marker for neoplastic and non-neoplastic ANS cells (eg, peripheral neuroblastic tumors [pNTs]). We hypothesized that Phox2b immunohistochemical staining (IHC) would also be useful for detecting ENCCs. METHODS: Hematoxylin and eosin, calretinin IHC, and Phox2b IHC were reviewed on 21 pull-through specimens and on a cohort of 12 rectal biopsies. RESULTS: Phox2b IHC demonstrated nuclear positivity in all of the ganglion cells across the different phases of differentiation without background staining. The Phox2b result correlated with the morphological findings, calretinin IHC results, and diagnoses based on the routine diagnostic method. The intensity was uniformly strong in the undifferentiated/immature forms and became variable in the mature forms; this pattern was similar to that seen in pNTs. CONCLUSION: Phox2b IHC was highly sensitive and specific for detecting ganglion cells. It worked especially well for immature ganglion cells, seen in premature neonates, and scattered single forms in transition zones. In basic research settings, Phox2b can be a useful marker for early differentiation of ENCCs.