High Risk Of Disease Progression Research Articles

The 40-gene Expression Profile (40-GEP) Test Identifies Cutaneous Squamous Cell Carcinoma (cSCC) Patients at High Risk of Metastasis within Lower-Staged Tumors to Better Guide Treatment Decisions

Introduction- The development of metastases has a profound impact on cSCC patient survival. Lower-stage tumors are those that lack factors that portend higher risk for disease progression and therefore not typically considered for increased surveillance or treatment. However, up to one-third of all metastatic events have been reported for patients originally staged as T1. The 40-GEP test is validated to accurately classify risk for regional and/or distant metastasis in patients with primary cSCC with at least one high-risk factor. The current study investigated whether the 40-GEP test could independently improve identification of lower-staged tumors at increased risk of metastasis. 
 Methods- In an IRB-approved, retrospective, multi-center study, primary tumor tissue and associated clinical data from patients with cSCC and one or more clinicopathologic risk factors (n=897) were collected. Within this overall cohort, lower Brigham and Women’s Hospital (BWH) T-staged samples (n=444 T1 and n=335 T2a) were evaluated by Kaplan-Meier survival analysis to determine metastasis-free survival (MFS) according to 40-GEP risk class (Class 1-low metastatic risk; Class 2A-higher risk; Class 2B-highest risk).
 Results- There was a total of 118 metastatic events in the overall cohort, of which 25% (29/118) and 38% (45/118) occurred in BWH T1 and T2a, respectively. BWH T1 tumors had an overall event rate of 6.5% (29/444), with T1/Class 2B tumors having a 5.1-fold increased event rate of 33.3%. BWH T2a tumors had an overall event rate of 13.4% (45/335), with T2a/Class 2B tumors having a 2.7-fold increased event rate of 36.4%. Stratification by the 40-GEP test resulted in significantly different metastasis rates across all three 40-GEP classes within both the T1 and T2a subsets (log-rank tests, p<0.0001 each subset). 
 Conclusion- Within a cohort of cSCC patients considered lower risk by current staging alone, the 40-GEP identified patients with a substantial increase in metastatic risk. The observed rates of metastasis over 10% and 20% are clinically actionable for nodal staging or postoperative adjuvant radiation, respectively. Combining clinicopathologic risk assessment with individual biologic risk, as provided by the 40-GEP test, improves the accuracy of risk assessment used clinically as the basis of treatment decisions.

Dapagliflozin in patients with heart failure and previous myocardial infarction: A participant-level pooled analysis of DAPA-HF and DELIVER.

Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium-glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood. The DAPA-HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant-level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate-adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02-1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72-0.96) and without previous MI (HR 0.76, 95% CI 0.68-0.85; pinteraction = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI. History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI.

Association between comorbidities and survival in patients with metastatic urothelial carcinoma treated with pembrolizumab.

This study aims to investigate the relationship between comorbidities and survival in patients with mUC treated with pembrolizumab as a second-line treatment. From February 2018 to October 2021, we analyzed the data of 185 consecutive patients with metastatic UC who received pembrolizumab as second-line therapy at The Jikei University Hospital and five affiliated hospitals. We used the Charlson Comorbidity Index (CCI) to assess the comorbidities. The outcomes of interest were progression-free survival (PFS) and overall survival (OS). To compare the survival differences, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and the IPTW-adjusted Cox regression hazards model were used. After IPTW adjustment, patient characteristics were well-balanced between patients with high CCI and those with low CCI. The IPTW-adjusted Kaplan-Meier curves of PFS and OS based on CCI revealed that the patients with high CCI (2 or more) had a shorter PFS (median, 1.6 vs. 2.8months) and a shorter OS (median, 12.4 vs. 18.8months) (0-1). Similarly, in the IPTW-adjusted Cox regression hazards model, patients with high CCI had significantly shorter PFS [HR, 1.84 (95% CI 1.26-2.68; p = 0.002)] and OS [HR, 1.98 (95% CI 1.20-3.27; p = 0.008)] than those with lower CCI. High CCI was associated with a higher risk of disease progression as well as overall mortality in mUC patients treated with second-line pembrolizumab.

Searching The New Culprit of Optic Neuritis: The Role of Vitamin D

Abstract
 Introduction : Low vitamin D status has long been associated in multiple sclerosis patient with higher risk of disease progression and frequent relapses. Vitamin D plays an important role in modulating the immune process responsible for demyelination. To this date, the study on vitamin D deficiency in optic neuritis case is still rare.
 Case Illustration : Female, 20 years old, presenting with bilateral sudden visual loss since 1 week prior. The patient looked relatively pale and complained of accompanying headache and myalgia. Visual acuity in both eyes were light perception with dilated pupils and posterior segment showing optic disc swelling. CBC, infection and autoimmune screening came within normal limit and brain MRI further confirmed the presence of optic neuritis. The patient was given high dose intravenous steroid but showed no improvement. Later, she was screened for nutrient deficiency and found sign of low serum 25-hydroxyvitamin D. After one week of oral supplementation and neuroprotective agents, her vision drastically improved to 6/6 in both eyes.
 Discussion : Vitamin D deficiency nowadays is getting more prevalent in high risk individuals with low dietary intake and sunlight exposure. Recent study found that mean serum vitamin D level were significantly lower in autoimmune optic neuritis (ON) and were associated with ON attack severity. Vitamin D sufficiency is associated with better inflammatory outcome and long term neurodegenerative measures in demyelinating diseases, as shown by improvement in RNFL thickness after attack.
 Conclusion : Screening for vitamin D deficiency is essential to consider in managing patient with atypical optic neuritis.

Mutational signature and prognosis in adenocarcinoma of bladder.

655 Background: Adenocarcinoma of bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here we aim to reveal mutational and transcriptomic landscapes of adenocarcinoma of bladder and their relationship with prognosis. Methods: Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of bladder were included. These included 16 patients with primary bladder adenocarcinomas and 7 patients with urachal adenocarcinoma. Whole exome sequencing, whole genome sequencing, bulk RNA-Seq and single-cell RNA-Seq were conducted for the specimens. Correlation analysis, survival analysis and t tests were also performed. Results: Prevalent T>A substitutions were observed among somatic mutations, and major tri-nucleotide contexts included 5′-CTC-3′and 5′-CTG-3′. This pattern was mainly contributed by COSMIC Signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes also enriched KEGG term “chemical carcinogenesis”. Transcriptomic analysis implied high immune infiltration and luminal-like feature in majority of samples. Interestingly, a small fraction of samples with APOBEC-derived mutational signature exhibited higher risk of disease progression compared with samples with only chemical carcinogen-related signature, confirming molecular and prognosis heterogeneity in bladder adenocarcinoma. Conclusions: This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and chemical carcinogen-related mutational signature indicates good prognosis in adenocarcinoma of bladder.

Sparsentan is superior to losartan in the gddY mouse model of IgA nephropathy.

The mechanism leading to the development of immunoglobulin A nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist, recently received accelerated approval in the USA for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. Four-week-old gddY mice were given control chow, chow containing sparsentan or drinking water containing losartan until 12 or 20 weeks old. Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, endothelin type A receptor and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared with AT1R antagonism alone.

Genomic classification and outcomes of young patients with polycythemia vera and essential thrombocythemia according to the presence of splanchnic vein thrombosis and its chronology

To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9–4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4–24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET.

P962 Clinical and endoscopic remission at 3 months after Acute Severe Ulcerative Colitis is predictive of maintenance therapy outcomes at 12 months - Results from PREDICT UC

Abstract Background The optimal maintenance regimen after rescue therapy for Acute Severe Ulcerative Colitis (ASUC) is unknown. We aimed to evaluate prospectively the impact of different maintenance regimens after successful infliximab (IFX) rescue, along with factors associated with Month 12 remission. Methods Clinical responders at 3 months from PREDICT UC, a randomised trial (NCT02770040) comparing standard and intensified IFX rescue strategies, were evaluated in this prospective cohort study up to Month 12. Maintenance therapies were as follows: (1) Thiopurine monotherapy (azathioprine or mercaptopurine) for thiopurine naïve patients or prior suboptimal thiopurine therapy (TP); (2) Combination thiopurine and IFX therapy 5mg/kg 8-weekly for thiopurine-experienced patients (IFX+TP combo); (3) IFX monotherapy 5mg/kg 8-weekly for thiopurine-intolerant patients (IFX mono). All patients received oral 5-aminosalicylates. Clinical and endoscopic assessments were performed at baseline (Month 3) and Month 12. Clinical remission was defined as a partial Mayo score of 0-1 and endoscopic remission as Mayo Endoscopic Score (MES) of 0-1. Results Of 138 patients randomised, 79 entered the maintenance phase. Of these, 56 (71%) received TP, 16 (20%) received IFX+TP combo and 7 (9%) received IFX mono. Baseline characteristics were similar across the 3 maintenance groups. At 12 months, 42 patients (53%) were in clinical remission, 44 patients (56%) were in endoscopic remission, and one patient underwent colectomy. The 3 maintenance groups had similar rates of clinical remission (TP 55%, IFX+TP combo 56%, IFX mono 29%; P=0.39) and endoscopic remission (TP 55%, IFX+TP combo 56%, IFX mono 57%; P=0.99) at 12 months. Clinical Remission On univariable and multivariable analysis, no factors were associated with clinical remission at 12 months, including baseline CRP, albumin, partial Mayo score, MES, UCEIS or maintenance strategy. Endoscopic Remission Factors associated with endoscopic remission at 12 months included baseline partial Mayo score of 0 (OR 3.36, 95% CI 1.24-9.10, P=0.017), MES of 0-1 (OR 3.48, 95% CI 1.08-11.27, P=0.037) and UCEIS of 0-1 (OR 3.30, 95% CI 1.24-8.76, P=0.016). However, a partial Mayo score cut-off of 0-1 did not reach significance (OR 3.46, P=0.09). No factors associated with endoscopic remission were identified on multivariable analysis. Conclusion In steroid-refractory ASUC patients who received IFX rescue, clinical and endoscopic remission at Month 3 were associated with endoscopic remission at Month 12, particularly among patients with greater depth of remission. Month 3 assessment helps identify patients at higher risk of disease progression for whom more intensive treatment may be required.

Development and validation of pharmacokinetics assays for a novel HER2-targeting antibody-drug conjugate (SHR-A1201): Application to its dose-escalation pharmacokinetic study

Approximately 25% of breast cancer patients with HER2 overexpression tend to have a high risk of disease progression and death. Various HER2-targeting therapies have been approved for treatment. Recently, a novel antibody-drug conjugate, SHR-A1201, is being researched and developed. For the pharmacokinetic study of SHR-A1201, suitable bioanalytical methods are needed for quantifying unconjugated cytotoxin, cytotoxin-conjugated antibodies and total antibodies. In this research, bioanalytical methods involving a highly sensitive LC-MS/MS assay for unconjugated cytotoxic payload DM1 in human plasma, ELISA strategies for DM1-conjugated trastuzumab and total trastuzumab in human serum were developed, validated and successfully applied to a phase I dose-escalation pharmacokinetic study of SHR-A1201. The pharmacokinetic properties and exposure-to-dose proportionality was evaluated for SHR-A1201. According to the bioanalytical method validation guidance, the bioanalytical methods were fully validated and the validation results met the acceptance criteria. The nonspecific binding of DM1 and dimer was avoided for the LC-MS/MS assay. In the dose-escalation pharmacokinetic study of SHR-A1201, a potential dose-proportional pharmacokinetics was observed over the dose from 1.2 mg/kg to 4.8 mg/kg. The validated bioanalytical strategies are robust and reproducible and these bioanalytical methods will contribute to better understanding of the pharmacokinetic properties of SHR-A1201.

Mutational signature and prognosis in adenocarcinoma of the bladder.

Adenocarcinoma of the bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here, we aimed to reveal the mutational and transcriptomic landscapes of adenocarcinoma of the bladder and assess any relationship with prognosis. Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of the bladder were enrolled. These included 16 patients with primary bladder adenocarcinomas and seven patients with urachal adenocarcinoma. Whole exome sequencing (16 patients), whole genome sequencing (16 patients), bulk RNA sequencing (RNA-seq) (19 patients), and single-cell RNA-seq (5 patients) were conducted for the specimens. Correlation analysis, survival analysis, and t-tests were also performed. Prevalent T>A substitutions were observed among somatic mutations, and major trinucleotide contexts included 5'-CTC-3' and 5'-CTG-3'. This pattern was mainly contributed by COSMIC signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes were also enriched in the KEGG term 'chemical carcinogenesis'. Transcriptomic analysis suggested high immune cell infiltration and luminal-like features in the majority of samples. Interestingly, a small fraction of samples with an APOBEC-derived mutational signature exhibited a higher risk of disease progression compared with samples with only a chemical carcinogen-related signature, confirming the molecular and prognostic heterogeneity of bladder adenocarcinoma. This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and indicates that a chemical carcinogen-related mutational signature may be related to a better prognosis compared with an APOBEC signature in adenocarcinoma of the bladder. © 2024 The Pathological Society of Great Britain and Ireland.

Predicting the survival probability of functional neuroendocrine tumors treated with peptide receptor radionuclide therapy: Serbian experience.

Peptide receptor radionuclide therapy (PRRT) is a treatment option for well-differentiated, somatostatin receptor positive, unresectable or/and metastatic neuroendocrine tumors (NETs). Although high disease control rates seen with PRRT a significant number NET patients have a short progression-free interval, and currently, there is a deficiency of effective biomarkers to pre-identify these patients. This study is aimed at determining the prognostic significance of biomarkers on survival of patients with NETs in initial PRRT treatment. We retrospectively analyzed 51 patients with NETs treated with PRRT at the Department for nuclear medicine, University Clinical Center Kragujevac, Serbia, with a five-year follow-up. Eligible patients with confirmed inoperable NETs, were retrospectively evaluated hematological, blood-based inflammatory markers, biochemical markers and clinical characteristics on disease progression. In accordance with the progression og the disease, the patients were divided into two groups: progression group (n=18) and a non-progression group (n=33). Clinical data were compared between the two groups. A total of 51 patients (Md=60, age 25-75 years) were treated with PRRT, of whom 29 (56.86%) demonstrated stable disease, 4 (7.84%) demonstrated a partial response, and 14 (27.46%) demonstrated progressive disease and death was recorded in 4 (7.84%) patients. The mean PFS was a 36.22 months (95% CI 30.14-42.29) and the mean OS was 44.68 months (95% CI 37.40-51.97). Univariate logistic regression analysis displayed that age (p<0.05), functional tumors (p<0.05), absolute neutrophil count (p<0.05), neutrophil-lymphocyte ratio-NLR (p<0.05), C-reactive protein-CRP (p<0.05), CRP/Albumin (p<0.05), alanine aminotransferase-ALT (p<0.05), were risk factors for disease progression. Multivariate logistic regression analysis exhibited that functional tumors (p<0.001), age (p<0.05), CRP (p<0.05), and ALT (p<0.05), were independent risk factors for the disease progression in patients with NETs. Tumor functionality was the most powerful prognostic factor. The median PFS (11.86 ± 1.41 vs. 43.38 ± 3.16 months; p=0.001) and OS (21.81 ± 2.70 vs 53.86 ± 3.70, p=0.001) were significantly shorter in patients with functional than non-functional NETs respectively. The study's results suggest that tumor functionality, and certain biomarkers may serve as prognostic survival indicators for patients with NETs undergoing PRRT. The findings can potentially help to identify patients who are at higher risk of disease progression and tailor treatment strategies accordingly.

Surgery for Crohn’s Disease Is Associated With a Dysbiotic Microbiome and Metabolome: Results From Two Prospective Cohorts

Background and AimsCrohn’s disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn’s disease surgery. MethodsPatients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn’s Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with 1H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry. ResultsIntestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, E lenta, A equalofaciens and G pamelaeae were lower in abundance among patients with prior surgery in both cohorts. ConclusionsIn two different populations, prior surgery in Crohn’s disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria E lenta and related actinobacteria as well as secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.

Retrospective analysis of the progression of early dry age-related macular degeneration in patients receiving versus not receiving a multi-component nutraceutical for four years

Purpose: To retrospectively analyze the optical coherence tomography (OCT) changes in retinal morphology and progression in these changes in patients with early dry age-related macular degeneration (AMD) receiving versus not receiving a multi-component nutraceutical daily for four years. Material and Methods: We retrospectively analyzed disease progression in 52 patients (98 eyes) with early dry AMD who had been regularly followed up for four years. Group 1 was comprised of 24 patients (98 eyes) who had been receiving vitamin and mineral tablets containing the AREDS2 formulation plus resveratrol and vitamin D daily for four years. Group 2 was comprised of 28 patients (53 eyes) who had not been receiving any nutritional supplement. Retinal morphology was assessed by OCT and OCT angiography. Results: In group 1, best-corrected visual acuity (BCVA) did not change after completion of the 4-year observation period compared to baseline (0.6 ± 02, p = 0.72). In group 2, BCVA was 0.6 ± 0.2 at baseline and decreased to 0.2 ± 0.2 in four years (p ≤ 0.001). In patients with a low to moderate risk of progression in groups 1 and 2, the four-year progression rate was 15.4% and 45.4%, respectively, which corresponds to an annual progression rate of 3.8% and 11.3%, respectively. In patients with a high risk of progression in groups 1 and 2, the four-year progression rate was 26.3% and 80%, respectively, which corresponds to an annual progression rate of 6.5% and 20%, respectively. Patients who had early dry AMD eyes with a low to moderate risk of progression (and a high risk of progression) at baseline and were not taking the nutritional supplement, had 4.58 greater odds (95% CI, 1.291 – 16.267; р = 0.018) [and 11.2 greater odds (95% CI, 2.505 – 50.081; р = 0.0016)] of having AMD progression than those receiving the nutritional supplement daily for four years. Conclusion: A regular intake of tablets containing the AREDS2 formulation plus resveratrol and vitamin D slows the progression of early dry AMD, especially in eyes with a high risk of disease progression, and contributes to the preservation of visual function.

Validation of disease severity index for predicting complicated disease in Crohn's disease: A comparison study with Lémann index

BackgroundDisease Severity Index (DSI) provides comprehensive assessment of bowel damage (BD). AimsTo evaluate DSI in patients with Crohn's disease (CD) at high risk of disease progression, compared to Lémann Index (LI). MethodsPatients with CD in our center were reviewed consecutively between 2017 and 2019. DSI, LI, and complicated CD course were analyzed. ResultsThe median LI and DSI of included 300 patients were 1.63 (IQR 1.25–3.13) and 42 (IQR 32–51), respectively. 152 patients (50.7%) experienced a complicated disease course (median 5.1 months; IQR 1.1–20.2). DSI (AUC 0.66; 95% CI 0.60–0.72) better predicted a complicated course of CD over LI (AUC 0.56; 95% CI 0.50–0.63; P = 0.007). The cumulative probability of complicated CD course in severe patients was higher than those with ‘mild CD’ (P < 0.001). The Cox analysis identified DSI>43 (HR 2.18; 95% CI 1.54–3.09; P < 0.001), B2/3 vs. B1 (HR 2.80; 95% CI 1.99–3.94; P < 0.001), and a higher level of CRP (HR 1.01; 95% CI 1.00–1.02; P = 0.005) as independent prognostic factors for complicated CD. However, LI was not associated with complicated CD (P = 0.164). ConclusionsHigher DSI was associated with complicated disease outcomes. DSI might play a better role than LI in identifying patients at high risks of disease progression.

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: diagnostic and therapeutic aspects. Review

The increase in the prevalence of non‑alcoholic fatty liver disease (NAFLD) occurs in parallel with the global epidemic of obesity and type 2 diabetes mellitus (T2DM) in the world. T2DM is an independent risk factor for the development of NAFLD. At the same time, researchers found that patients diagnosed with NAFLD have a two‑fold increased risk of developing T2DM. NAFLD is encompasses a spectrum of liver manifestations ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. NASH is an aggressive form of NAFLD, associated with an increased risk of liver and non‑liver‑related mortality. Liver‑biopsy remains the gold standard for diagnosis, but the majority of patients liver damage can be diagnosed accurately by noninvasive methods.&#x0D; The presence of NAFLD in a patient with T2DM makes it difficult to achieve adequate glycemic control, deepens the manifestations of insulin resistance and atherogenic dyslipidemia, increases the risk of serious cardiovascular events and chronic kidney disease. Lifestyle modification and treatment of concomitant T2DM should be undertaken in all patients with NAFLD. To reduce the severity of liver steatosis, weight reduction by 3—5% is necessary, to reduce the inflammatory‑necrotic process, a more significant reduction may be required — up to 10% within 6—12 months. Physical activity increases the sensitivity of insulin receptors, and in combination with diet leads to a significantly significant improvement in biochemical and histological indicators in patients with NAFLD. Early identification and management of patients with intensive dietary and lifestyle modification are essential to prevent the development of advanced liver disease and its complications. Pharmacological therapy should be administered to patients with NASH purposed on the fibrosis inhibition, especially in case of the established predictors of high risk of disease progression (age &gt;50 years, metabolic syndrome, T2DM, or increase in the activity of alanine aminotransferase), as well as to the patients with active NASH with high inflammatory activity.&#x0D; At the congress of the European Association for the Study of the Liver (EASL), which took place in Vienna on June 21—24, 2023, a new classification and nomenclature of NAFLD was adopted. It was proposed to replace the term «non‑alcoholic fatty liver disease» to the term «metabolic dysfunction‑associated steatotic liver disease» (MASLD). This diagnosis is established in patients with confirmed steatosis of the liver and one of five cardiometabolic risk factors: obesity, T2DM, insulin resistance, hyperlipidemia, atherosclerosis. The concept of «non‑alcoholic steatohepatitis» (NASH) has been changed to the concept of «metabolic dysfunction‑ associated steatohepatitis» (MASH). Coordination of the views of international and domestic experts in the field of studying this pathology will be important for clinical practice and scientific research.&#x0D;

A novel location classification system for Crohn's disease based on small bowel involvement: a better predictor of disease progression.

Small bowel involvement is related to poor prognosis in Crohn's disease (CD), which may be a potential marker to stratify patients with a high risk of progression. This study aimed to establish a novel location classification system for CD and to develop a predictive model for disease progression. Consecutive patients with non-stricturing/non-penetrating CD were retrospectively included in the Sixth Affiliated Hospital, Sun Yat-sen University (Guangzhou, P. R. China) between January 2012 and January 2018. Patients were classified into two groups according to disease location: small bowel involvement group and isolated colon group. The primary outcome was disease progression to stricturing or penetrating phenotypes. Progression-free survival was estimated using Cox proportional hazards regression analysis and Kaplan-Meier method. A total of 463 patients were analysed, with a median follow-up time of 55.3 months. Patients with small bowel involvement had a higher risk of disease progression than those with isolated colon disease (hazard ratio = 1.998, P = 0.007), while no differences were found between Montreal location classification and disease progression. Median progression-free survival was higher in the isolated colon group than in the small bowel involvement group (84.5 vs 77.3 months, P = 0.006). Four independent factors associated with disease progression were identified: small bowel involvement, duration of onset of >1 year, deep mucosal ulcer, and C-reactive protein levels of ≥10 mg/L (all P < 0.05). The nomogram model based on these factors showed good performance in predicting disease progression, with a C-index of 0.746 (95% confidence interval, 0.707-0.785). Classifying CD based on small bowel involvement and isolated colon was superior to the Montreal location classification for predicting disease progression.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial

ObjectiveIn the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors,...

Cost-Effectiveness of Oral Nirmatrelvir/Ritonavir in Patients at High Risk for Progression to Severe COVID-19 in the United States

ObjectivesNirmatrelvir/ritonavir (NMV/r) is an orally administered antiviral indicated for the outpatient treatment of patients with mild-to-moderate COVID-19 at high risk for disease progression to severe illness. We estimated the cost-effectiveness of NMV/r versus best supportive care for patients with mild-to-moderate COVID-19 at high risk for progression to severe illness from a US health sector perspective. MethodsA cost-effectiveness model was developed using a short-term decision-tree (1 year) followed by a lifetime 2-state Markov model (alive and dead). The short-term decision-tree captured costs and outcomes associated with the primary infection and healthcare utilization; survivors of the short-term decision-tree were followed until death assuming US quality-adjusted life years (QALYs), adjusted in the short-term for survivors of mechanical ventilation. Baseline rate of hospitalization and NMV/r effectiveness were taken from an Omicron-era US real-world study. Remaining inputs were informed by previous COVID-19 studies and publicly available US sources. Sensitivity analyses were conducted for all model inputs to test the robustness of model results. ResultsNMV/r was found to decrease COVID-19 related hospitalizations (−0.027 per infected case) increase QALYs (+0.030), decrease hospitalization costs (−$1110), and increase total treatment cost (+$271), resulting in an incremental cost-effectiveness ratio of $8931/QALY. Results were most sensitive to baseline risk of hospitalization and NMV/r treatment effectiveness parameters. The probabilistic analysis indicated that NMV/r has a >99% probability of being cost-effective at a $100 000 willingness-to-pay threshold. ConclusionsNMV/r is cost-effective vs best supportive care for patients at high risk for severe COVID-19 from a US health sector perspective.

Physiologically-based pharmacokinetic model of sparsentan to evaluate drug-drug interaction potential.

Sparsentan is a dual endothelin/angiotensin II receptor antagonist indicated to reduce proteinuria in patients with primary IgA nephropathy at high risk of disease progression. Invitro data indicate that sparsentan is likely to inhibit or induce various CYP enzymes at therapeutic concentrations. Sparsentan as a victim and perpetrator of CYP3A4 mediated drug-drug interactions (DDIs) has been assessed clinically. A mechanistic, bottom-up, physiologically-based pharmacokinetic (PK) model for sparsentan was developed based on invitro data of drug solubility, formulation dissolution and particle size, drug permeability, inhibition and induction of metabolic enzymes, and P-glycoprotein (P-gp) driven efflux. The model was verified using clinical PK data from healthy adult volunteers administered single and multiple doses in the fasted and fed states for a wide range of sparsentan doses. The model was also verified by simulation of clinically observed DDIs. The verified model was then used to test various DDI simulations of sparsentan as a perpetrator and victim of CYP3A4 using an expanded set of inducers and inhibitors with varying potency. Additional perpetrator and victim DDI simulations were performed using probes for CYP2C9 and CYP2C19. Simulations were conducted to predict the effect of complete inhibition of P-gp inhibition on sparsentan absorption and clearance. The predictive simulations indicated that exposure of sparsentan could increase greater than two-fold if co-administered with a strong CYP3A4 inhibitor, such as itraconazole. Other potential DDI interactions as victim or perpetrator were all within two-fold of control. The effect of complete P-gp inhibition on sparsentan PK was negligible.

37 Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: A retrospective cohort study

37 Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: A retrospective cohort study