Nerve Bundle Density and Expression of NGF and IL-1ß Are Intra-Individually Heterogenous in Subtypes of Endometriosis.

Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin-1ß (IL-1ß). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes of endometriosis (deep, superficial peritoneal, endometrioma) at surgery, with at least two surgically excised subtypes available for analysis. Immunolocalization for nerve bundle density around endometriosis using protein gene product 9.5 (PGP9.5), as well as NGF and IL-1ß histoscores in endometriosis epithelium/stroma, was performed to evaluate differences in scores between lesions and anatomic subtypes per patient. Intra-individual heterogeneity in scores across lesions was assessed using the coefficient of variation (CV). The degree of score variability between subtypes was evaluated using the percentage difference between mean scores from one subtype to another subtype for each marker. PGP9.5 nerve bundle density was heterogenous across multiple subtypes of endometriosis, ranging from 50.0% to 173.2%, where most patients (8/12) showed CV ≥ 100%. The percentage difference in scores showed that PGP9.5 nerve bundle density and NGF and IL-1ß expression were heterogenous between anatomic subtypes within the same patient. Based on these observations of intra-individual heterogeneity, we conclude that markers of neuroproliferation in endometriosis should be stratified by anatomic subtype in future studies of clinical correlation.

Whole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers.

The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.

Decreased ß-catenin Protein in Lungs From Human Congenital Diaphragmatic Hernia Archival Pathology Specimens: A Case-control Study.

BACKGROUND: Lung hypoplasia contributes to congenital diaphragmatic hernia (CDH) associated morbidity and mortality. Changes in lung wingless-type MMTV integration site family member (Wnt)-signalling and its downstream effector beta-catenin (CTNNB1), which acts as a transcription coactivator, exist in animal CDH models but are not well characterized in humans. We aim to identify changes to Wnt-signalling gene expression in human CDH lungs and hypothesize that pathway expression will be lower than controls. METHODS: We identified 51 CDH cases and 10 non-CDH controls with archival formalin-fixed paraffin-embedded (FFPE) autopsy lung tissue from 2012 to 2022. 11 liveborn CDH cases and an additional two anterior diaphragmatic hernias were excluded from the study, leaving 38 CDH cases. Messenger ribonucleic acid (mRNA) expression of Wnt-signalling effectors WNT2B and CTNNB1 was determined for 19 CDH cases and 9 controls. A subset of CDH cases and controls lung sections were immunostained for ß-catenin. Clinical variables were obtained from autopsy reports. RESULTS: Median gestational age was 21 weeks. 81% (n = 31) of hernias were left-sided. 47% (n = 18) were posterolateral. Liver position was up in 81% (n = 31) of cases. Defect size was Type C or D in 58% (n = 22) of cases based on autopsy photos, and indeterminable in 42% (n = 16) of cases. WNT2B and CTNNB1 mRNA expression did not differ between CDH and non-CDH lungs. CDH lungs had fewer interstitial cells expressing ß-catenin protein than non-CDH lungs (13.2% vs 42.4%; p = 0.006). CONCLUSION: There appear to be differences in the abundance and/or localization of ß-catenin proteins between CDH and non-CDH lungs. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Case-Control Study.

Autopsy-Based Growth Charts May under-Detect Fetal Growth Restriction at Autopsy.

Background: Accurate identification of fetal growth restriction in fetal autopsy is critical for assessing causes of death. We examined the impact of using a chart derived from ultrasound measurements of healthy fetuses (World Health Organization fetal growth chart) versus a chart commonly used by pathologists (Archie et al.) derived from fetal autopsy-based populations in diagnosing small-for-gestational-age (SGA) birth in perinatal deaths. Study Design: We examined perinatal deaths that underwent autopsy at BC Women's Hospital, 2015-2021. Weight centiles were assigned using the ultrasound-based fetal growth chart for birthweight and autopsy-based growth chart for autopsy weight. Results: Among 352 fetuses, 30% were SGA based on the ultrasound-based fetal growth chart versus 17% using the autopsy-based growth chart (p < 0.001). Weight centiles were lower when using the ultrasound-based versus autopsy-based growth chart (median difference of 9 centiles [IQR 2, 20]). Conclusions: Autopsy-based growth charts may under-classify SGA status compared to ultrasound-based fetal growth charts.