Transposon-based oncogene integration in Abcb4(Mdr2)-/- mice recapitulates high susceptibility to cholangiocarcinoma in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC), difficult to diagnose and associated with high mortality. Lack of animal models of CCA recapitulating the hepatic microenvironment of sclerosing cholangitis hinders development of novel treatments. Here we sought to develop such PSC-associated CCA model in mice. METHODS: Ten-week-old Mdr2-/- mice with congenital PSC-like disease, and healthy wild-type littermates were subjected to either modified retrograde biliary instillation or hydrodynamic tail vein injection of sleeping beauty transposon-transposase plasmid system with activated AKT (myr-AKT) and Yap (YapS127A) protooncogenes (SB AKT/YAP1). The role of TGFß was interrogated via ALK5 inhibitor (SB-525334) administration. Tumor phenotype, burden and desmoplastic reaction were analyzed histologically and via RNA-seq. RESULTS: While SB AKT/YAP1 plasmids via retrograde biliary injection caused tumors in Mdr2-/-, only 26.67% (4/15) of these tumors were CCA. Alternatively, hydrodynamic tail vein injection of SB AKT/YAP1 resulted in robust tumorigenesis in all fibrotic Mdr2-/- mice with high CCA burden compared to healthy mice. Tumors phenotypically resembled human CCA, expressed multiple CCA (but not hepatocellular carcinoma) markers, and exhibited a profound desmoplastic reaction. RNA-seq analysis revealed profound transcriptional changes in CCA evolving in PSC-like context, with specific alterations in multiple immune pathways. Pharmacological TGFß inhibition led to enhanced immune cell tumor infiltration, reduced tumor burden and suppressed desmoplastic collagen accumulation compared to placebo CONCLUSION: We established a new high-fidelity cholangiocarcinoma model in mice, termed SB CCA.Mdr2-/-, which recapitulates the increased susceptibility to CCA in the setting of biliary injury and fibrosis observed in PSC. Through transcriptomics and pharmacological studies, we show dysregulation of multiple immune pathways and TGFß signaling as potential drivers of CCA in PSC-like microenvironment. IMPACT AND IMPLICATIONS: There is a lack of animal models for primary sclerosing cholangitis (PSC) related cholangiocarcinoma (PSC-CCA). We have developed and characterized a new mouse model of PSC-CCA, termed SB CCA.Mdr2-/-, which features reliable tumor induction in PSC-like background of biliary injury and fibrosis. Global gene expression alterations were identified and standardized tools, including automated whole slide image analysis methodology for tumor burden and feature analysis, were established to enable systematic research into PSC-CCA biology and formal pre-clinical drug testing.

Gastric Non-Hodgkin Lymphoma in a Helicobacter pylori-Infected Patient.

Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a rare gastric malignant neoplasm. While the association between Heliobacter pylori infection and gastric mucosa-assisted lymphoid tissue lymphoma is well established, data supporting its association with DLBCL are less robust. Here we present a rare case of PG-DLBCL diagnosed with H. pylori. An 82-year-old man presented to clinic with complaints of worsening epigastric pain. He underwent an endoscopy which revealed 1 large nonbleeding gastric ulcer. Histopathological and immunohistochemical analysis confirmed PG-DLBCL. He was started on H. pylori eradication (HPE) and subsequently completed 6 cycles of R-mini-CHOP chemotherapy. Since then, the patient maintained clinical and radiological remission for more than a year without recurrence. PG-DLBCL is an aggressive Non-hodgkin lymphoma (NHL) that usually presents late. It has been shown that HPE without chemotherapy in DLBCL codiagnosed with H. pylori is not an effective strategy. Thus, the standard of care for patients would be HPE and chemotherapy as in our patient. More research is needed to better understand association between H. pylori and DLBCL.

The aetiology of pouchitis in patients with inflammatory bowel disease.

Restorative proctocolectomy with ileal pouch-anal anastomosis is a treatment option for patients with refractory ulcerative colitis. Pouchitis is the most common complication, representing a spectrum of diseases ranging from acute antibiotic-responsive type to chronic antibiotic-refractory. Early accurate diagnosis using a combined assessment of symptoms, endoscopy and histology is important for both treatment and prognostication. Most patients respond well to antibiotic therapy; however, management of chronic antibiotic-refractory pouchitis remains a challenge, and treatment options are based on small studies. Pouchitis is thought to be driven by the interaction between genetics, the immune system and the environment but as yet a causal relationship has yet to be identified. Further longitudinal assessment of the pouch integrating new technologies may help us understand the factors driving pouchitis. This review outlines the currently understood risk factors and aetiology of pouchitis.

Micropulse transscleral cyclophotocoagulation (MP-CPC): efficacy endpoints for the treatment of refractory paediatric glaucoma - a retrospective case-series.

BACKGROUND: This study evaluates the efficacy and safety of micropulse transscleral cyclophotocoagulation (MP-CPC) in paediatric patients. METHODS: This retrospective case-series recruited 44 eyes for glaucoma patients who were younger than 17 years and were treated with MP-CPC and followed for at least one year. Pre- and post-intervention intraocular pressure (IOP) was compared out to at least one year postoperatively. Success rates at 6 months and 1 year postoperatively were assessed. P < 0.05 was considered statistically significant. RESULTS: There were 35 (79.5%) eyes with a history of glaucoma surgery. IOP decreased statistically significantly from a baseline of 32.7 (standard deviation:8.7 mmHg) to 23.2 (8.6) and 21.7 (7.9) mmHg at the 6 months and 1-year follow-up, respectively (P < 0.0001, all comparisons). Overall success was noted in 19 (47.5%) eyes at the 6 months follow-up, and 23 (53.5%) eyes at 1 year. CONCLUSIONS: MP-CPC reduces IOP and the burden of medications in paediatric patients with glaucoma. Additionally, its safety profile favours the use of MP-CPC as an adjunctive modality for refractory glaucoma.

Coronavirus disease-19 and headache; impact on pre-existing and characteristics of de novo: a cross-sectional study.

BACKGROUND: Coronavirus disease-19 is caused by the severe acute respiratory syndrome coronavirus 2 Headache is a common symptom during and after Coronavirus disease-19. We aimed to study headache character in relation to COVID-19. METHODS: This was a cross-sectional study. Patients who had Coronavirus disease-19, confirmed by reverse transcription polymerase chain reaction technique and presented to the headache clinic within 3 months after the onset of infections were identified to the study. Study included patients diagnosed as primary headache disorders according to The International Classification of Headache Disorders, 3rd edition. Participants were grouped into categories according to having previous or de novo headache. Descriptive data, paired sample t-test and the chi-squared test (X2) were used for statistical analyses of the data. RESULTS: A total of 121 patients were included in this study. Their mean age was 35.29 + 9.54 and most of them were females (83.5%). Prior to Coronavirus disease-19 infections, 78 (64.5%) had migraine and 11(9.1%) experienced a tension-type headache while 32 (26.4) reported de novo headache post Coronavirus disease-19. Patient had significant increase in headache days 11.09 ± 8.45 post Coronavirus disease-19 compared with 8.66 ± 7.49 headache days before Coronavirus disease-19 infection (p < 0.006). Post Coronavirus disease-19, the usage of analgesic increased significantly by the patient with migraine (2.31 ± 1.65 vs 3.05 ± 2.09, p = 0.002) while the patient with tension type headache had statistically significant increase in severity (5.556 ± 1.86 vs 7 ± 2.25, p = 0.033) and frequency (7 ± 6.29 vs 12.72 ± 7.96, p = 0.006) of headache attacks. Bi-frontal and temporal headache are the most reported (40.6% each) headache site among de novo headache group. Patients younger than 40 years had longer duration of the headache attack (18.50 ± 16.44 vs 5.5 ± 9.07, p = 0.045) post COVID-19. Male patients compared to females (8.66 ± 1.15 versus 5.93 ± 2.01 p = 0.04) had more severe headache post Coronavirus disease-19. De novo headache resolved within 1 month in most of patients (65.3%). CONCLUSION: Primary headache get worse after Coronavirus disease-19. De novo primary headache is frequent post Coronavirus disease-19 and resolve within 1 month. Headaches related to Coronavirus disease-19 are severe, present as migraine phenotype. Young male patients with Coronavirus disease-19 tend to have worse headache.