Histological Outcomes Research Articles

Effect of Esophageal Dilation History on Efficacy Outcomes in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension

INTRODUCTION: The effect of esophageal dilation history on efficacy outcomes in patients with eosinophilic esophagitis (EoE) receiving swallowed corticosteroids is not well established. METHODS: This post hoc analysis assessed data from a 12-week, randomized, double-blind, placebo-controlled phase 3 study (NCT02605837) of budesonide oral suspension (BOS) 2.0 mg twice daily in patients aged 11–55 years with EoE and dysphagia. Co-primary efficacy outcomes were histologic (≤6 eosinophils per high-power field [eos/hpf]) and dysphagia symptom (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] scores from baseline) responses at week 12. Secondary efficacy outcomes included histologic response (<15 eos/hpf) and change from baseline to week 12 in DSQ scores and EoE Endoscopic Reference Scores (EREFS). Data were analyzed post hoc by esophageal dilation history (dilation history vs no dilation history). RESULTS: Of 318 patients who received ≥1 dose of study drug, 42.8% had a history of esophageal dilation (dilation history: BOS, n=91; placebo, n=45; no dilation history: BOS, n=122; placebo, n=60). Histologic responses (≤6 and <15 eos/hpf) were similar regardless of dilation history. Fewer BOS-treated patients with dilation history than no dilation history achieved a dysphagia symptom response (44.0% vs 59.0%); conversely a slightly greater improvement from baseline in total EREFS was observed for BOS-treated patients with dilation history than no dilation history (LS mean [standard error of the mean]: −4.1 [0.3] vs −3.4 [0.4]). CONCLUSIONS: Esophageal dilation history may confound the association between histologic outcomes and dysphagia symptom or endoscopic efficacy outcomes in patients with EoE receiving swallowed corticosteroids.

Clinical, histological, molecular, and toxicokinetic renal outcomes of per-/polyfluoroalkyl substances (PFAS) exposure: Systematic review and meta-analysis.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals present in the environment that can negatively affect health. Kidney is the major target organ of PFAS exposure, yet the renal impact of PFAS is not completely understood. Here we review the effects of PFAS exposure on kidney health to identify gaps in our understanding and mark potential avenues for future research. PubMed and SCOPUS databases were searched for studies that examined the association between PFAS exposure and kidney-related outcomes. We included all epidemiological, animal, and cell studies and categorized outcomes into four categories: clinical, histological, molecular and toxicokinetic. We identified 169 studies, including 51 on clinical outcomes, 28 on histological changes, 42 on molecular mechanisms, and 68 on toxicokinetics. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) exposure were associated with kidney dysfunction, chronic kidney diseases, and increased risk of kidney cancer. Various histological changes were reported, especially in tubular epithelial cells, and the etiology of PFAS-induced kidney injury included various molecular mechanisms. Although PFOA and PFOS are not considered genotoxic, they exhibit several characteristics of carcinogens. Toxicokinetics of PFOA and PFOS differed significantly between species, with renal elimination influenced by various factors such as sex, age, and structure of the compound. Evidence suggests that PFAS, especially PFOA and PFOS, negatively affects kidney health, though gaps in our understanding of such effects call for further research.

Histopathological and radiological evaluation of the efficacy of hydroxyapatite-boric acid and hydroxyapatite-magnesium coated Kirschner wires on fracture healing in femoral diaphyseal fractures: an experimental study.

Biomaterials used in fracture healing hold a significant place in orthopedics. This study aimed to develop biomaterials coated with hydroxyapatite (HA), boric acid (BA), and magnesium (Mg) and investigate their effects on fracture healing. Sixty female Wistar Albino rats were included in the study. The subjects were randomized into five groups. Cytotoxicity tests were performed on HA, BA, and Mg, and cell viability rates were calculated. Coatings were applied to Kirschner (K) wires at determined ratios. Group I was the control group with a steel K wire, Group II used HA-coated K wires, Group III used HA + BA-coated K wires, Group IV used HA + BA + Mg-coated K wires, and Group V used HA + Mg-coated K wires. A fracture was induced in the right femur of the subjects, followed by fixation with intramedullary K wires. The subjects were randomly divided into equal numbers and sacrificed at 6 and 12 weeks. Radiological and histopathological evaluations were performed. In direct cytotoxicity tests, the highest viability rate was observed in Group IV, while in indirect cytotoxicity tests, it was highest in Group II. In radiological evaluation at the 6th week, the highest scores were in Groups IV and V, while the lowest was in Group III. At the 12th week, the highest scores were in Groups II and V, while the lowest was in Group I. No significant differences were found between the groups (p = 0.837, p = 0.0479). In histopathological evaluation, a significant difference was observed between the groups (p < 0.001), with the highest scores in Group V. A correlation was found between the radiological and histopathological scores (p < 0.001, r = 0.438). It was found that HA + Mg significantly improved histological outcomes in fracture healing. Good histological results can be achieved with the use of Mg-containing implants in both early and late-stage fracture healing. Coating the biomaterials used in fracture fixation with Mg may lead to positive outcomes in fracture healing.

An Intraoperative Ultrasound Evaluation of Axillary Lymph Nodes: Cassandra Predictive Models in Patients with Breast Cancer—A Multicentric Study

Background and Objectives: Axillary lymph node (ALN) staging is crucial for the management of invasive breast cancer (BC). Although various radiological investigations are available, ultrasound (US) is the preferred tool for evaluating ALNs. Despite its immediacy, widespread use, and good predictive value, US is limited by intra- and inter-operator variability. This study aims to evaluate US and Elastosonography Shear Wave (SW-ES) parameters for ALN staging to develop a predictive model, named the Cassandra score (CS), to improve the interpretation of findings and standardize staging. Materials and Methods: Sixty-three women diagnosed with BC and treated at two Italian hospitals were enrolled in the study. A total of 529 lymph nodes were surgically removed, underwent intraoperative US examination, and were individually sent for a final histological analysis. The study aimed to establish a direct correlation between eight US-SWES features (margins, vascularity, roundness index (RI), loss of hilum fat, cortical thickness, shear-wave elastography hardness (SWEH), peripheral infiltration (PI), and hypoechoic appearance) and the histological outcome (benign vs. malignant). Results: Several statistical models were compared. PI was strongly correlated with malignant ALNs. An ROC analysis for Model A revealed an impressive AUC of 0.978 (S.E. = 0.007, p &lt; 0.001), while in Model B, the cut-offs of SWEH and RI were modified to minimize the risk of false negatives (AUC of 0.973, S.E. = 0.009, p &lt; 0.001). Model C used the same cut-offs as Model B, but excluded SWEH from the formula, to make the Cassandra model usable even if the US machine does not have SW-ES capability (AUC of 0.940, S.E. = 0.015, p &lt; 0.001). A two-tiered model was finally set up, leveraging the strong predictive capabilities of SWEH and RI. In the first tier, only SWES and RI were evaluated: a positive result was predicted if both hardness and roundness were present (SWES &gt; 137 kPa and RI &lt; 1.55), and conversely, a negative result was predicted if both were absent (SWES &lt; 137 kPa and RI &gt; 1.55). In the second tier, if there was a mix of the results (SWES &gt; 137 kPa and RI &gt; 1.55 or SWES &lt; 137 kPa and RI &lt; 1.55), the algorithm in Model B was applied. The model demonstrated an overall prediction accuracy of 90.2% in the training set, 87.5% in the validation set, and 88.9% across the entire dataset. The NPV was notably high at 99.2% in the validation set. This model was named the Cassandra score (CS) and is proposed for the clinical management of BC patients. Conclusion: CS is a simple, non-invasive, fast, and reliable method that showed a PPV of 99.1% in the malignancy prediction of ALNs, potentially being also well suited for young sonographers.

Prostate-specific antigen, digital rectal examination, and prostate cancer detection: A study based on more than 7000 transrectal ultrasound-guided prostate biopsies in Ghana

Purpose of the studyThis study aims to determine the role of serum prostate-specific antigen (PSA) levels and digital rectal examination (DRE) in predicting the histological outcomes of prostate biopsies by analyzing a database of over 7000 patients who underwent transrectal ultrasound (TRUS)-guided prostate biopsies. MethodsWe conducted a retrospective analysis of men who underwent TRUS-guided prostate biopsies at Korle Bu Teaching Hospital, a tertiary referral center in Accra, Ghana, from July 2005 to December 2022. The biopsies, which included 10 to 12 core samples, were prompted by PSA levels greater than 4.0 ng/mL, abnormal DRE findings, or both. We then correlated histopathology results with PSA and DRE findings. ResultsOut of 7,338 patients who presented for biopsy, 76.3% were between the ages of 60 and 79. Histology reports were available for 5,289 patients, of whom 2,564 (48.5%) were diagnosed with prostate cancer. Cancer detection rates based on PSA levels were as follows: 21.6% for PSA <4 ng/mL, 21.7% for PSA 4-10 ng/mL, 32.7% for PSA 10-20 ng/mL, 53.0% for PSA 20-50 ng/mL, 71.5% for PSA 50-100 ng/mL, and 92.0% for PSA >100 ng/mL. When DRE findings were classified according to the 2016 TNM System (AJCC 8th Edition) as T1, T2, T3, and T4, cancer detection rates were 26.8%, 51.8%, 87.6%, and 95.7%, respectively. The overall cancer detection rate was significantly higher with abnormal DRE findings (64.6% vs. 26.7%, p < 0.001). Additionally, 78.2% of the detected cancers were high-grade (Gleason score of 7 or more). ConclusionThis extensive study of Ghanaian men undergoing TRUS biopsies reveals a high prostate cancer detection rate, with nearly 80% of the detected cancers being high-grade. These findings underscore the importance of PSA and DRE in the early detection of prostate cancer and should be considered in patient counseling and discussions regarding the implementation of prostate cancer screening programs in this population.

Iron Chelators Augment Large Osteochondral Allograft Osseointegration in a Preclinical Canine Model.

Osteochondral allograft transplantation (OCAT) can be a successful joint restoration treatment option for large post-traumatic articular defects but is still associated with significant revision and failure rates. Despite recent advances that have improved OCAT success, insufficient osteochondral allograft (OCA) osseointegration remains a major cause of failure. Deferoxamine (DFO) is an effective angiogenic and osteo-anabolic iron chelator that consistently promotes bone neovascularization and regeneration. This study was designed to investigate local delivery of DFO for augmenting OCA osseointegration using a preclinical canine model for OCAT in the knee and hip as commonly affected joints. On Institutional Animal Care and Use Committee (IACUC) approval, 12 purpose-bred dogs underwent OCAT of the femoral head or femoral condyles with DFO or DFO-free (controls) microspheres in recipient sites. OCA revascularization, cellular repopulation, and integration were evaluated based on functional, diagnostic imaging, microcomputed tomography, histology, and immunohistochemistry outcome measures. Local delivery of DFO into OCAT recipient sites was associated with maintained or improved joint function, superior radiographic appearance, significantly greater trabecular thickness, higher bone volume, and new bone ingrowth compared with DFO-free controls. OCA osseointegration is dependent on cellular repopulation and neovascularization, resulting in new bone ingrowth through creeping substitution, and insufficient osseointegration with resorption and subsidence of the OCA remains a major cause of failure after transplantation. The results of this study suggest that local delivery of DFO using a controlled microsphere release system may reduce resorption and improve revascularization and cellular repopulation to increase new bone ingrowth, potentially expediting OCA osseointegration after transplantation.

Locally advanced cervical cancer: Neoadjuvant chemotherapy plus radical surgery an alternative approach to chemo-radiation in a low-income setting: A descriptive study.

To describe the treatment outcomes of locally advanced cervical cancer managed with neoadjuvant chemotherapy (NACT) plus radical surgery at a gynecology oncology center in Ethiopia. This was a retrospective descriptive study of management of locally advanced cervical cancer (LACC) at St. Paul's Hospital Millennium Medical College (Ethiopia) over 5 years. Data were collected by reviewing patient records. Data were analyzed using SPSS version 23. Simple descriptive analysis was employed to analyze clinical, histologic, and treatment outcomes of LACC managed with NACT+ radical surgery. Frequency and proportions were used to present the results' significance. A total of 98 patients were analyzed. One-third (31.6%) of cervical cancer patients with locally advanced disease were operable after neoadjuvant chemotherapy. Out of this, nodal metastasis was found in 2 patients (all pelvic lymph node metastasis). Disease recurrence within 2 years was 3% (1 recurrence within 6-12 months and 2 recurrences at 12-24 months). This study supports utilization of NACT plus radical surgery for locally advanced cervical cancer, where chemoradiation is not readily available. Our findings imply that this treatment modality is a life-saving alternative treatment in a low-income setting, which is often married by shortage or unavailability of radiotherapy at the needed time before disease progression ensues.

Nephroprotective role of resveratrol in renal ischemia-reperfusion injury: a preclinical study in Sprague-Dawley rats.

Renal ischemia-reperfusion injury (IRI) is a significant contributor to renal dysfunction, acute kidney injury (AKI), and associated morbidity and mortality. Resveratrol, a polyphenol and phytoalexin, is known for its anti-inflammatory, antioxidant, and anti-cancer properties. This study investigates the nephroprotective potential of resveratrol in a rat model of renal IRI. Twenty-eight male Sprague-Dawley rats were divided into four groups: Sham, IRI, DMSO, and Resveratrol. The Sham group underwent identical procedures without renal pedicle clamping, while the IRI group experienced 30min of ischemia followed by 2h of reperfusion. The DMSO group received dimethyl sulfoxide (DMSO) intraperitoneally 30min before ischemia, and the Resveratrol group received 30mg/kg resveratrol intraperitoneally 30min before ischemia. Biochemical parameters (Urea, creatinine, IL-1β, NF-κβ, SOD, GSH, Bcl-2, and caspase-3) and histopathological changes were assessed. IRI caused a substantial increase in serum creatinine, Urea, IL-1β, NF-κβ, and caspase-3 levels, while simultaneously decreasing SOD, GSH, and Bcl-2 levels. Resveratrol treatment mitigated these effects by lowering inflammatory and apoptotic markers, enhancing antioxidant defenses, and improving histological outcomes. Resveratrol demonstrates significant nephroprotective effects in renal IRI, primarily through its antioxidant, anti-inflammatory, and anti-apoptotic properties.

Histological Evaluation of Polyacid-Modified Composite Resin and Conventional Composite Resin Used for Primary Molars Restoration

Background: The present study evaluated the histological outcomes of two dental restorative materials, polyacid-modified composite resin (compomer) and conventional composite resin, in the primary molars of puppies. Materials and Methods: Twenty sound primary molars in four puppies were used. The puppies were rendered unconscious using general anesthesia. Similar cylindrical Class V cavities were prepared in 16 of the 20 selected primary molars. The teeth were divided into three groups: Group I: Eight cavities were restored with compomer; Group II: Eight cavities were restored with conventional composite resin; Group III: Four teeth remained untreated and were used as controls. In Groups I and II, four teeth were examined histologically after 2 weeks and the other four after 6 weeks. The histological findings were analyzed and compared to determine the effects of each type of resin material on the dentine and the pulp. Results: At 6 weeks, the specimens tested for compomer showed obvious destructive changes in the central region and the region of the pulp adjacent to the cavity. The specimens tested for conventional composite resin revealed, at 6 weeks, massive destruction of the pulp tissues and abscess formation was observed. All the specimens tested in the control group showed normal cellularity, normal vascularity, and proper alignment of odontoblast cells. Conclusions: The teeth restored with compomer demonstrated more favorable pulpal reactions when compared with the teeth restored with conventional composite resin after 6 weeks.

Perinatal Caffeine Administration Improves Outcomes in an Ovine Model of Neonatal Hypoxia-Ischemia.

Neonatal hypoxic-ischemic encephalopathy disproportionately affects low- and middle-income countries, where ≈96% of affected infants reside. The current standard of care, therapeutic hypothermia, is frequently ineffective in this setting, likely because injury may be occurring earlier during labor. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal caffeine administration in near-term lambs following global ischemic injury to support the development of earlier treatment strategies targeting the fetus in utero as well as the infant postnatally. Ewes were randomly assigned to receive either 1 g IV caffeine citrate or placebo before delivery and placental transport assessed. Near-term lambs (141-143 days) of both sexes were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Lambs that received caffeine in utero also received 20 mg/kg IV caffeine citrate following resuscitation and 10 mg/(kg·d) IV for 2 days. An additional cohort received 60 mg/kg followed by 30 mg/(kg·d) (low dose versus high dose) postnatally. Biochemical, histological, and neurological outcome measures in lambs were assessed over a 6-day period. Perinatal caffeine administration demonstrated excellent placental transport kinetics and was well tolerated with lamb plasma levels comparable to those targeted in neonates with apnea of prematurity. Caffeine administration resulted in a systemic immunomodulatory effect, evidenced by significant reductions in proinflammatory IP-10 levels. Treated lambs demonstrated improved neurodevelopmental outcomes, while histological analysis revealed that caffeine reduced gray matter injury and attenuated inflammation in the cingulate and parasagittal cortex. This neuroprotective effect was greater and via a different mode of action than we previously reported for azithromycin. A higher caffeine dosing regimen demonstrated significant toxicity. Perinatal caffeine administration is well tolerated, attenuates systemic and brain inflammation, and contributes to improvements in histological and neurological outcomes in an ovine model of neonatal hypoxic-ischemic encephalopathy.

Fermented Moringa oleifera seed-cassava inclusion improves protein and selected biochemical indices in alloxan-induced diabetes in animal model

Despite the availability of many pharmacological interventions for diabetes management, current evidence shows an alarming rising trend in the occurrence of undesirable complications, confirming that other complementary approaches are required. This study evaluated the nutraceutical properties of fermented Moringa oleifera seed-Cassava (FMOC) inclusion on selected biochemical parameters in rats induced with diabetes. Portions of cassava was substituted with moringa seed at 100:0 (control), 80:20 (not fermented:T1), 80:20 (fermented;T2) and 70:30% (fermented:T3). Fermentation was achieved using a starter culture containing Lactic acid bacteria for 36 h. Thirty-six (36) male albino rats were randomly divided into six groups (n=6/group). Groups B-F were rendered diabetic using alloxan (150 mg/kg. bw; IP) while group A served as the normal control. The effects of FMOC on proximate and selected biochemical indices of diabetic rats were evaluated. Results showed that protein increased significantly (p&lt;0.05) (2.43}0.1 to 20.44} 02 g/100g) in the fermented sample as against non fermented control. All test diets (especially T2) counteracted the diabetic effects in rats by lowering (P&lt;0.05) the elevated serum levels of glucose (249.0 to 105.6 mg/dl), Cholesterol (6.73 to 4.13mmol/L), TAG (2.43 to 1.99mmo/L), LDL (3.72 to 2.66mmol/L), Urea (35.3 to 23.2mmol/L) and malondialdehyde (2.34 to 1.29mg/dl) compared with diabetic group. It also improved (P&lt;0.05) glutathione (2.69-3.76mg/dl) and catalase enzyme activity (1.52-2.90 U/mg). No significant effect was recorded for HDL (P&gt;0.05). Histological outcomes of pancreas corroborated these findings. A food–based approach incorporating fermented M. oleifera seed could be considered an effective strategy to manage the complications that might arise from diabetes.

Median Arcuate Ligament Syndrome: Where Are We Today?

Median arcuate ligament syndrome, or celiac artery compression syndrome (eponym: Dunbar syndrome), has historically been attributed to pathophysiologic vascular compression causing downstream ischemic symptoms of the organs supplied by the celiac trunk. However, the more we learn about the histology, clinical presentation, and treatment outcomes, health care providers are increasingly correlating the symptoms of MALS with the long-term, repetitive compression of the celiac ganglion rather than the celiac trunk. This article provides a comprehensive review of current MALS literature, emphasizing the multidisciplinary approach these patients require in all phases of their care. With most patients with MALS waiting an average of 10.5months to 2.6years, 9, 10 our need for better diagnostic protocols and clearer understanding of the pathophysiology of the disease is paramount. Further investigation into patient outcomes, associated conditions, and linked pathophysiology would help better characterize this disease with hopes of moving it from a diagnosis of exclusion to one of standard work-up with decreased time to treatment and symptom relief for patients.

The RECONCILE study protocol: Exploiting image-based risk stratification in early prostate cancer to discriminate progressors from non-progressors (RECONCILE).

RECONCILE (ClinicalTrials.gov:NCT04340245) will identify molecular and radiomic markers associated with clinical progression and radiological progression events in a cohort of localised, newly diagnosed Gleason 3 + 4 tumours. Molecular markers will be correlated against standard of care MRI-targeted histology and oncological outcomes. RECONCILE is an ethics approved (20/LO/0366) single centre, prospective, longitudinal, observational cohort study of recently diagnosed (within 12 months), organ-confined Gleason 3 + 4 cancers (MCCL ≤10mm) currently under active surveillance. 60 treatment-naïve participants with a concordant MRI lesion (Likert score 4 or 5) and PSA ≤ 15 ng/ml will be recruited. Blood, urine and targeted prostate tissue cores will be subject to next generation sequencing at baseline and one year in all participants. Semen will be collected from a specified sub-population. Baseline and interval MR images will be extracted from standard of care prostate MRI ahead of radiomic analysis. Data extracted from radiological and biological samples will be used to derive the association of molecular change and radiological progression, the primary outcome of the study. To compensate for spatial intratumoral heterogeneity and inherent sampling bias, a molecular index will be derived for each participant using the molecular profile of tumour tissue at both baseline (MolBL) and one year (MolFU). We will extract a ΔMolBL:MolFU score for each participant. Molecular progression will be defined as a MolBL:MolFU score >95% CI of the combined ΔMolBL scores. Radiological progression is defined as a PRECISE score of 4 or 5. The study is powered to detect an association with a statistical power of 80%. Recruitment began in July 2020 (n = 62). To date, 37 participants have donated tissue for analysis. We have designed and implemented a prospective, longitudinal study to evaluate the underlying molecular landscape of intermediate risk, MR-visible prostate tumours. Recruitment is ongoing.

Evaluating diagnostic accuracy and agreement of TI-RADS scoring in thyroid nodules: A comparative analysis between sonographers and radiologists.

The Thyroid Imaging Reporting and Data System (TI-RADS) is an essential tool for assessing thyroid nodules, primarily used by radiologists. This study aimed to compare the agreement of TI-RADS scores between sonographers and radiologists and to assess the diagnostic performance of these scores against histological findings in suspicious thyroid nodules. In a retrospective analysis, 168 patients with suspicious thyroid nodules classified as TR3 and above by the radiologists were included. Both sonographers and radiologists independently assigned the American College of Radiologists (ACR) TI-RADS scores, which were then compared for inter-reader agreement using Cohen's Kappa statistic. The scores were also evaluated for diagnostic performance against histological results based on the Bethesda system. The study revealed a moderate overall agreement between sonographers and radiologists in TI-RADS scoring (κ = 0.504; 95% CI: 0.409-0.599), with poor agreement noted specifically for nodule margin scores (κ = 0.102; 95% CI: -1.430-0.301). In terms of diagnostic performance against histological outcomes, sonographers' TI-RADS scores showed a sensitivity of 100% and a specificity of 44.6%, while radiologists' scores showed a sensitivity of 100% but a lower specificity of 29.3%. The findings indicate moderate agreement in TI-RADS scoring between sonographers and radiologists, with reproducibility challenges especially in scoring nodule margins. The marginally superior diagnostic performance of sonographers' scores suggests potential efficiency benefits in involving sonographers in preliminary assessments. Future research should aim to encompass a wider range of TI-RADS categories and focus on minimizing scoring variability to enhance the system's clinical utility.

Functional outcome and histologic analysis of late onset total type brachial plexus injury treated with intercostal nerve transfer to median nerve with local umbilical cord-derived mesenchymal stem cells or secretome injection: a double-blinded, randomized control study.

Intercostal nerve transfer is a surgical technique used to restore function in patients with total brachial plexus injury. Stem cell and secretome therapy has been explored as a potential treatment for brachial plexus injuries. This study aimed to compare the functional and histologic outcome of intercostal nerve transfer to median nerve with local stem cells or secretome injection in total type brachial plexus injuries. This was a double-blinded, randomized controlled study (RCT). We included patients with neglected total type brachial plexus injury (BPI) who underwent nerve transfer and local injection of either umbilical cord-derivedmesenchymal stem cells (UC-MSC) or secretome into median nerve-flexor digitorum superficialis (FDS) neuromuscular junction (NMJ). We measured preoperative and 8-month postoperative FDS muscle strength, SF-36, DASH score, and histologic assessment. We then analyzed the difference outcome between those two groups. A total of 15 patients were included in this study. Our study found that after nerve transfer and implantation with either UC-MSC or secretome, significant postoperative improvements were observed in physical functioning, role limitations, energy/fatigue, emotional well-being, social functioning, pain, general health, and DASH scores, particularly in the overall cohort and the secretome group. When we compared the mean difference of clinical outcome from preoperative to postoperative between UC-MSC and secretome groups, the UC-MSC group showed better improvement of health change in SF-36 subgroup compared to secretome group. From the analysis, there was no significant difference in the histologic outcomes (inflammation, regeneration, and fibrosis) in overall cohort between preoperative and postoperative cohort. There was also no significant difference in mean change of the histologic outcomes (inflammation, regeneration, and fibrosis) preoperative and postoperatively between UC-MSC and secretome groups. Implantation of either UC-MSC or secretome along with nerve transfer may provide clinical improvement, while to achieve histologic improvement, further conditioning should be performed.

Subtyping of pancreatic neuroendocrine tumors by transcription factors, hormones, histology, and patient outcome.

Pancreatic neuroendocrine tumors (PanNETs) show pronounced heterogeneity in terms of hormone and transcription factor (TF) expression. TFs such as ARX and PDX1 are related to alpha- and beta-cell-type features, respectively, and partly associate with patient outcome. However, detailed studies correlating hormone expression, histology, and clinical data are lacking. The aim of this study was to identify subtypes of PanNETs that associate with histological, hormonal, and prognostic findings. Atotal of 185resected PanNETs were divided into five subtypes (types A1, A2, B, C, and D) by cluster analysis based on expression of four TFs (ARX, PDX1, ISL1, and CDX2) and correlated to the expression of hormones and DAXX/ATRX as well as ALT activation status, histology, and progression-free survival. Subgroup A1 (ISL1+/ARX+/PDX-/CDX2-) was most frequent (46%), followed by typeB (18%; ISL1+/ARX-/PDX+/CDX2-), A2 (15%; ISL1+/ARX+/PDX+/CDX2-), C(15%; ISL1-/ARX-/PDX-/CDX2-), and D(5%; ISL1-/ARX-/PDX+/CDX2+). Subgroups A1 and A2 showed astrong association with atrabecular growth pattern and glucagon and pancreatic polypeptide (PP) expression (p < 0.001), while A2 was in addition associated with gastrin expression. SubgroupB was associated with insulin production (p < 0.001) and included all 17insulinomas. SubgroupC was associated with solid morphology and expression of serotonin, calcitonin, and adrenocorticotropic hormone (ACTH). SubgroupD showed solid morphology, expression of ACTH, somatostatin, or serotonin and had the shortest disease-free survival (p < 0.01). ALT positivity was associated with poorer outcome in types A1 and A2 but not in other types. PanNETs can be categorized into five subgroups based on different TF signatures, which associate strongly with histology, hormone production, functionality, and patient outcome.

Chiral Hydrogel Nerve Conduit Boosts Peripheral Nerve Regeneration via Regulation of Schwann Cell Reprogramming.

The Schwann cell (SC) is essential in peripheral nerve regeneration by reprogramming into a stem-like "repair Schwann cell" (rSC) phenotype; however, maintaining the rSC stemness remains an unmet challenge. Chirality is a fundamental factor controlling cell fate, and its potential role in regulation of SC reprogramming has long been ignored and remains poorly understood. Herein, inspired by natural chiral components in the SC microenvironment, chiral hydrogel nerve conduits are prepared by supramolecular assembly of l/d-phenylalanine derivatives (l/d-Phe) in polymeric chitosan-gelatin conduits. Right-handed l-Phe fibers within hydrogel conduits maintain the stemness of rSC through enhanced stereoselective interaction between collagen IV and l-Phe fibers triggered by collagen IV-Integrin α1β1, MAPK, and YAP/TAZ signaling pathways and finally activate the key regulator of SC reprogramming, the c-Jun pathway. In the rat model of a sciatic nerve defect, the l-Phe hydrogel nerve conduit significantly enhances nerve regeneration, exhibiting markedly improved histological, electrophysiological, and functional outcomes. The findings reveal the chirality-dependent regulation of SC reprogramming in a pioneering way, offering potential strategies for nerve regeneration therapies.

7864 Accurate Machine Learning-Based Diagnosis of At-Risk MASH and MASLD Subtypes Using Categorical Gradient Boosting and Select Clinical, Biochemical, and Metabolomic Measurements: Building Highly Robust Models With Few Variables Through a Multinational, Multi-Center, Biopsy-Proven Cohort

Abstract Disclosure: K. Stefanakis: None. E. Axarloglou: None. C.S. Mantzoros: None. Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by intrahepatic lipid accumulation, may precipitate steatohepatitis (MASH) and liver fibrosis, and is a significant cardiometabolic risk factor. Liver biopsy, though invasive and costly, is the diagnostic gold standard, thus creating an unmet clinical need for accurate and reliable non-invasive diagnostic methods to diagnose MASLD, particularly the combination of MASH and significant fibrosis, classified as “at-risk MASH” and known to markedly increase morbidity and mortality. We aimed to leverage novel machine-learning (ML) algorithms to create lightweight but highly precise models that may accurately diagnose at-risk MASH and related histological outcomes through a top-down approach. This is a study of 443 participants from two Gastroenterology-Hepatology Clinics (Greece, Australia) and one Metabolic Surgery Clinic (Italy), including healthy controls and MASLD patients across the entire spectrum of the disease. All participants underwent liver biopsies, anthropometric, standard biochemical and additional hormonal measurements, and global serum metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry, followed by robust batch correction and quality control, eventually identifying 687 known and 152 unknown metabolites. The dataset was randomly divided into a discovery (n=353) and a validation cohort (n=90) ensuring a balanced distribution of at-risk MASH and clinic. Our main ML pipeline implemented Categorical Gradient Boosting Machines using the CatBoost package for R. We pre-specified domain knowledge variables and implemented recursive feature elimination, among additional techniques, to build models through an iterative, algorithm-based process. The models were tested in the validation and entire cohort using k-fold and leave-one-out cross-validation with random resampling, and further assessed on relevant subgroups (MASLD status, obesity, diabetes, clinic, country). The main ML model consists of three routine clinical and biochemical variables, supplemented by two aminoacid metabolites (full model to be shown), and can detect the presence of at-risk MASH with a mean AUROC of 93% and mean accuracy of 92% in the validation cohort, and AUCS&amp;gt;93% with very high sensitivities and specificities per J-statistic in all subgroups. We likewise present ML models for the detection of MASLD, MASH, and fibrosis grades, with AUCs of over 90% in the validation cohort and all subgroups. Our models significantly outperform all applicable biomarker-based indices per DeLong’s tests. Further enhancement with lipidomic and proteomic variables will fully delineate the circulating biochemical snapshot of MASLD and likely lead to even more accurate, similarly structured models. Presentation: 6/1/2024

Network Meta-Analysis: Histologic and Histo-Endoscopic Improvement and Remission With Advanced Therapy in Ulcerative Colitis.

Histology has prognostic value in ulcerative colitis (UC). However, direct comparisons of histological endpoints are lacking. To perform a network meta-analysis (NMA) to compare histological endpoints with biologics and small molecules. We searched four databases up until July 2024 for randomised controlled trials (RCTs) on advanced therapies for moderate-to-severe UC reporting histological endpoints. Outcomes included histological improvement or remission, and histo-endoscopic improvement after induction or during maintenance. We used a random-effects frequentist model and have reported outcomes as relative risk and 95% confidence interval. We estimated relative drug efficacy with the P-score. We conducted subgroup analysis by trial phase and evaluated risk of bias and evidence certainty. We included 24 RCTs (15 therapies, 8874 patients). Nineteen provided data on induction and 10 on maintenance; outcome definitions were similar. Etrasimod 2 mg/day ranked highest in achieving histologic improvement (P-score 0.98) and remission (P-score 0.90) following induction. Globally, guselkumab 200-400 mg ranked first for histo-endoscopic improvement, while etrasimod 2 mg/day and upadacitinib 45 mg/day were superior in the subgroup analysis. During maintenance, upadacitinib 30 mg/day was superior in achieving histologic improvement and remission (P-score 0.88 for both) and histo-endoscopic improvement (P-score 0.94). Etrasimod 2 mg/day ranked second for histologic remission (P-score 0.70) and histo-endoscopic improvement (P-score 0.73), while mirikizumab 200 mg/month ranked second for histologic improvement. These results support the ability of small molecules to achieve stringent endpoints in moderate-to-severe UC. Histological outcome data for biologics was sparser, particularly during maintenance. Head-to-head RCTs are imperative to better inform clinical practice.

Soluble allogenic telocollagen as a direct protein therapeutic: Results of serial injections in a rodent rotator cuff tear model

HypothesisDelivery of soluble allogeneic type I telocollagen (allo-telocollagen) will accelerate and improve the healing of damaged tendons. Our hypothesis draws from known mechanochemical properties of type I collagen that direct its incorporation into damaged connective tissue. We further suggest that allo-telocollagen will raise a minimal immunogenic reaction due to homology within species. MethodsSeventy-eight shoulders (39 Sprague-Dawley rats) had their supraspinatus tendon surgically detached from its footprint on the humerus and repaired (72 shoulders) or left uninjured (6 shoulders). The repaired tissue was treated with an injection of 100 μl of saline, 10 mg/ml allogeneic atelocollagen (allo-atelocollagen), or 10 mg/ml allo-telocollagen at 0-, 1-, and 2-weeks post-surgery. At 30- and 60-days post-surgery, the tendons were assessed by mechanical testing (failure load, failure stress, stiffness, and relaxation) and by semiquantitative histological scoring. ResultsAt 30-days post-surgery, the mechanical and histological outcomes were not statistically different. However, at day 60, allo-telocollagen improved the failure strength of the supraspinatus (29.9 ± 4.7 N) relative to saline (20.0 ± 3.5 N; P value <= 0.001) or allo-atelocollagen (23.2 ± 1.5 N; P value = 0.025) treated tendons, and it approached that of uninjured controls (36.9 ± 5.0 N; P value = 0.021). Allo-telocollagen improved the failure stress of the supraspinatus (34.1 ± 9.3 MPa) relative to the saline treated tendons (21.4 ± 6.0 MPa; P value = 0.031; 160% improvement) and was no different than uninjured controls (33.4 ± 9.9 MPa; P value = 0.999) or allo-atelocollagen (32.3 ± 7.4 MPa; P value = 0.977). The stiffness of uninjured controls was far greater than any of injured/treated tendons (>200% stiffer). Histological scoring showed that the allo-telocollagen treated tendons produced better collagen fiber arrangement (1.55 ± 0.17) than saline (2.50 ± 0.29; P value = 0.001) or allo-atelocollagen (2.23 ± 0.28; P value = 0.042) treated tendons and that it did not increase markers of immunogenesis (1.10 ± 0.42) relative to either saline (1.44 ± 0.20; P value = 0.369) or allo-atelocollagen (0.68 ± 0.41; P value = 0.1058). ConclusionsWhile all three treatments produced similar results at 30 days, by 60 days, soluble allo-telocollagen clearly separated from the other interventions, yielding better mechanical and histological outcomes in a torn/repaired rotator cuff rat model. Allo-telocollagen treated tendons also approached the failure strength and matched the failure stresses of uninjured control tendons. The data suggest a new use for allo-telocollagen as a deliverable direct protein mechanotherapeutic that can improve both healing quality and speed.