Authors: Tim Schmäche, Juliane Fohgrub, Anna Klimova...

BACKGROUND AND AIMS

This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx).

METHODS

Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13).

RESULTS

EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%).

CONCLUSION

In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

Topics: Humans; Stomach Neoplasms; Combined Modality Therapy; Neoadjuvant Therapy; Adenocarcinoma; Organoids; Fluorouracil; Carbamates; Pyrazines; Pyridines

PubMed: 38200602
DOI: 10.1186/s12943-023-01919-3

Authors: Jiaoyan Li, Jingfeng Chen, Haoshuang Liu...

BACKGROUND

Resection of colorectal adenoma (CRA) prevents colorectal cancer; however, recurrence is common. We aimed to assess the association of the triglyceride-glucose (TyG) index with CRA occurrence and recurrence.

METHODS

Data from 3392 participants at a hospital in China from 2020 to 2022 were analyzed. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A restricted cubic spline was used to fit TyG index dose‒response curves to recurrent adenomas. The discriminatory power of TyG index for predicting later recurrence was assessed with the area under the receiver operating characteristic (ROC) curve in 170 patients with a TyG index at initial adenoma diagnosis.

RESULTS

One thousand five hundred ninety-six adenoma and 1465 normal participants were included in the occurrence analysis, and 179 recurrent and 152 nonrecurrent participants were included in the recurrence analysis. The TyG mutation was an independent risk factor for CRA occurrence and recurrence. After adjusting for confounders, the risk of adenoma in the participants in Q2, Q3, and Q4 groups of TyG was 1.324 (95% CI 1.020-1.718), 1.349 (95% CI 1.030-1.765), and 1.445 (95% CI 1.055-1.980) times higher than that of the Q1, respectively, and the risk of recurrence in the Q3 and Q4 groups was 2.267 (95% CI 1.096-4.691) and 2.824 (95% CI 1.199-6.648) times in Q1 group. Multiple logistic regression showed that the highest quartile of the TyG index was associated with a greater risk of advanced adenoma recurrence (OR 4.456, 95% CI 1.157-17.164), two or more adenomas (OR 5.079, 95% CI 1.136-22.714 [after removal of TyG index extreme values]), and proximal colon or both adenomas (OR 3.043, 95% CI 1.186-7.810). Subgroup analysis revealed that the association was found to be present only in participants of all age groups who were either male or without obesity, hyperglycemia, hypertension, or dyslipidemia (p < 0.05). ROC curves illustrated that the TyG index had good predictive efficacy for identifying recurrence, especially for patients with two or more adenomas (AUC 0.777, 95% CI 0.648-0.907).

CONCLUSIONS

An increase in the TyG index is associated with an increased risk of adenoma occurrence and recurrence, with a stronger association with the latter.

Topics: Humans; Male; Glucose; Retrospective Studies; Adenoma; China; Colorectal Neoplasms; Triglycerides; Blood Glucose; Risk Factors; Biomarkers; Carbamates; Pyrazines; Pyridines

PubMed: 38395868
DOI: 10.1186/s12889-024-18076-x

Randomized Controlled Trial

Authors: Ines Kralj-Hans, Kuo Li, Adrian Wesek...

OBJECTIVE

To evaluate the clinical efficacy and safety of leflunomide (L) added to the standard-of-care (SOC) treatment in COVID-19 patients hospitalised with moderate/critical clinical symptoms.

DESIGN

Prospective, open-label, multicentre, stratified, randomised clinical trial.

SETTING

Five hospitals in UK and India, from September 2020 to May 2021.

PARTICIPANTS

Adults with PCR confirmed COVID-19 infection with moderate/critical symptoms within 15 days of onset.

INTERVENTION

Leflunomide 100 mg/day (3 days) followed by 10-20 mg/day (7 days) added to standard care.

PRIMARY OUTCOMES

The time to clinical improvement (TTCI) defined as two-point reduction on a clinical status scale or live discharge prior to 28 days; safety profile measured by the incidence of adverse events (AEs) within 28 days.

RESULTS

Eligible patients (n=214; age 56.3±14.9 years; 33% female) were randomised to SOC+L (n=104) and SOC group (n=110), stratified according to their clinical risk profile. TTCI was 7 vs 8 days in SOC+L vs SOC group (HR 1.317; 95% CI 0.980 to 1.768; p=0.070). Incidence of serious AEs was similar between the groups and none was attributed to leflunomide. In sensitivity analyses, excluding 10 patients not fulfilling the inclusion criteria and 3 who withdrew consent before leflunomide treatment, TTCI was 7 vs 8 days (HR 1.416, 95% CI 1.041 to 1.935; p=0.028), indicating a trend in favour of the intervention group. All-cause mortality rate was similar between groups, 9/104 vs 10/110. Duration of oxygen dependence was shorter in the SOC+L group being a median 6 days (IQR 4-8) compared with 7 days (IQR 5-10) in SOC group (p=0.047).

CONCLUSION

Leflunomide, added to the SOC treatment for COVID-19, was safe and well tolerated but had no major impact on clinical outcomes. It may shorten the time of oxygen dependence by 1 day and thereby improve TTCI/hospital discharge in moderately affected COVID-19 patients.

TRIAL REGISTRATION NUMBERS

EudraCT Number: 2020-002952-18, NCT05007678.

Topics: Adult; Humans; Female; Middle Aged; Aged; Male; COVID-19; Leflunomide; SARS-CoV-2; Prospective Studies; Treatment Outcome; Oxygen

PubMed: 37055207
DOI: 10.1136/bmjopen-2022-068179

Authors: Brendan Mullen, Eric R Houpt, Josh Colston...

Because epidemiologic and environmental risk factors for nontuberculous mycobacteria (NTM) have been reported only infrequently, little information exists about those factors. The state of Virginia, USA, requires certain ecologic features to be included in reports to the Virginia Department of Health, presenting a unique opportunity to study those variables. We analyzed laboratory reports of Mycobacterium avium complex (MAC) and M. abscessus infections in Virginia during 2021-2023. MAC/M. abscessus was isolated from 6.19/100,000 persons, and 2.37/100,000 persons had MAC/M. abscessus lung disease. M. abscessus accounted for 17.4% and MAC for 82.6% of cases. Saturated vapor pressure was associated with MAC/M. abscessus prevalence (prevalence ratio 1.414, 95% CI 1.011-1.980; p = 0.043). Self-supplied water use was a protective factor (incidence rate ratio 0.304, 95% CI 0.098-0.950; p = 0.041). Our findings suggest that a better understanding of geographic clustering and environmental water exposures could help develop future targeted prevention and control efforts.

Topics: Nontuberculous Mycobacteria; Virginia; Mycobacterium avium Complex; Mycobacterium abscessus; Water; Carbamates; Pyrazines; Pyridines

PubMed: 38407146
DOI: 10.3201/eid3003.231162

Authors: Zhao-Jun Chen, Jie Xiao, Hai-Hua Chen...

COVID-19 has spread all over the world which poses a serious threat to social economic development and public health. Despite enormous progress has been made in the prevention and treatment of COVID-19, the specific mechanism and biomarker related to disease severity or prognosis have not been clarified yet. Our study intended to further explore the diagnostic markers of COVID-19 and their relationship with serum immunology by bioinformatics analysis. The datasets about COVID-19 were downloaded from the Gene Expression Omnibus (GEO) dataset. The differentially expressed genes (DEGs) were selected via the limma package. Then, weighted gene co-expression network analysis (WGCNA) was conducted to identify the critical module associated with the clinic status. The intersection DEGs were processed for further enrichment analysis. The final diagnostic genes for COVID-19 were selected and verified through special bioinformatics algorithms. There were significant DEGs between the normal and COVID-19 patients. These genes were mainly enriched in cell cycle, complement and coagulation cascade, extracellular matrix (ECM) receptor interaction, and the P53 signaling pathway. As much as 357 common intersected DEGs were selected in the end. These DEGs were enriched in organelle fission, mitotic cell cycle phase transition, DNA helicase activity, cell cycle, cellular senescence, and P53 signaling pathway. Our study also identified CDC25A, PDCD6, and YWAHE were potential diagnostic markers of COVID-19 with the AUC (area under curve), 0.958 (95% CI 0.920-0.988), 0.941(95% CI 0.892-0.980), and 0.929 (95% CI 0.880-0.971). Moreover, CDC25A, PDCD6, and YWAHE were correlated with plasma cells, macrophages M0, T cells CD4 memory resting, T cells CD8, dendritic cells, and NK cells. Our study discovered that CDC25A, PDCD6, and YWAHE can be used as diagnostic markers for COVID-19. Moreover, these biomarkers were also closely associated with immune cell infiltration, which plays a pivotal role in the diagnosis and progression of COVID-19.

Topics: Humans; Tumor Suppressor Protein p53; COVID-19; Cell Cycle; Computational Biology; Calcium-Binding Proteins; Apoptosis Regulatory Proteins

PubMed: 37222960
DOI: 10.1007/s10528-023-10400-1

Authors: Xiaodan Zhang, Tianhong Cheng, Ellie Cho...

Many drugs have been discontinued during phase II/III breast cancer clinical trials due to lack of clinical efficacy, indicating shortcomings in predictive value of preclinical data. Nutrient availability in the tumour cell microenvironment and the dimensionality of in vitro tumour cells likely impact on drug responsiveness. Global proteomics experiments were conducted to assess the impact of nutrient availability and dimensionality of culture. Protein set enrichment analyses identified "pathways in cancer", "focal adhesion" and "ECM receptor in interaction" related to cell culture dimensionality in MDA-MB-231 cells. In MCF-7 cells, 4 pathways were influenced by medium composition, and 2 pathways were influenced by cell culture dimensionality (2D vs. 3D). These pathways were also identified using KEGG analyses. Eight drugs were selected for investigation according to the differential expression of their putative or known target proteins. The influence of medium composition on drug effectiveness was explored using the "Melbourne Medium" (MM), developed to have nutritionally physiological levels of metabolites as compared with conventional (hyper-nutritional) cell culture medium (CM). The influence of dimensionality on drug effectiveness was also explored, using an innovative 3D viability assessment combining automated confocal microscopy and image analysis. Dimensionality of culture appeared to have a greater influence on the proteome and drug effects than variation in nutrient levels. The number of differentially expressed proteins in the different media was greater in 2D than 3D. We conclude that the risk of qualifying inactive compounds in preclinical assessment may be mitigated using additional models incorporating physiological media and 3-dimensionality.

Topics: Humans; Breast Neoplasms; Proteomics; Antineoplastic Agents; Female; Culture Media; Cell Culture Techniques; Cell Line, Tumor; MCF-7 Cells; Cell Culture Techniques, Three Dimensional

PubMed: 39603575
DOI: 10.1016/j.phrs.2024.107519

Authors: Sven Knecht, Ivan Zeljkovic, Patrick Badertscher...

BACKGROUND

Non-pulmonary vein (PV) triggers play a role in the initiation of atrial fibrillation (AF), with the superior vena cava (SVC) being a common location. The aim of the current study was to investigate a strategy of empirical SVC isolation (SVCI) in addition to re-isolation of PV in patients with recurrence of AF after index PV isolation (PVI).

METHODS

We retrospectively analyzed consecutive patients from two centers with recurrence of AF after index PVI, undergoing a repeat ablation. Whereas only a re-isolation of the PV was intended in patients with reconnections of equal or more than two PV (PVI group), an additional SVCI was aimed for in patients with < 2 isolated PV in addition to the re-isolation of the PV (PVI + group). Analysis was performed as-treated and per-protocol.

RESULTS

Of the 344 patients included in the study (age 60 ± 10 years, 73% male, 66% paroxysmal AF), PVI only was performed in 269 patients (77%) and PVI plus SVCI (PVI +) in 75 patients (23%). Overall, freedom from AF/AT after repeat PVI was 80% (196 patients) in the PVI group and 73% in the PVI + group (p = 0.151). In multivariable Cox regression analysis, presence of persistent AF (HR 2.067 (95% CI 1.389-3.078), p < 0.001) and hypertension (HR 1.905 (95% CI 1.218-2.980), p = 0.005) were identified as only significant predictors of AF/AT recurrence. The per-protocol results did not differ from this observation.

CONCLUSIONS

A strategy of an empirical additional SVCI at repeat PVI ablation for recurrence of AF/AT does not improve outcome compared to a PVI only approach.

Topics: Humans; Male; Middle Aged; Aged; Female; Atrial Fibrillation; Vena Cava, Superior; Retrospective Studies; Catheter Ablation; Treatment Outcome; Pulmonary Veins; Recurrence

PubMed: 35980512
DOI: 10.1007/s10840-022-01314-w

Authors: O Pérez, C Valenzuela, E Delpón...

1. The electrophysiological effects of CI-980, a new tubulin-binding agent that inhibits assembly of cytoplasmic microtubules, on transmembrane action potential characteristics were studied in right ventricular papillary muscles from guinea-pig hearts. 2. In papillary muscles driven at 1 Hz, CI-980 at concentrations > or = 10(-5) M produced a concentration-dependent increase in the maximum upstroke velocity (Vmax) and a lengthening of the action potential duration at 50% (APD50) and 90% (APD90) of repolarization without affecting the resting membrane potential. Prolongation of the APD90 was accompanied by a parallel lengthening of the effective refractory period (ERP) so that the ERP/APD90 ratio remained unaltered at all drug concentrations tested. 3. CI-980 exhibits a reverse use-dependent effect on APD90 values, that is, drug-induced APD90 prolongation become exagerated at slow rates and attenuated at fast rates. 4. CI-980 at concentrations > or = 10(-6) M lengthened the APD of the slow action potentials elicited by isoprenaline in papillary muscles depolarized by high K+ (27 mM) solution. 5. At 10(-5) M, CI-980 produced a small tonic Vmax block. However, in muscles driven at rates between 0.5 and 3 Hz it produced an exponential decline in Vmax (use-dependent Vmax block) which was augmented at higher rates of stimulation. At 3 Hz the onset kinetics of the use-dependent Vmax block was fitted by a monoexponential function with a K value 0.07 +/- 0.01 per AP. The recovery time constant (tau re) from the use-dependent Vmax block was prolonged from 21.6 +/- 2.6 ms to 3.5 +/- 0.2 s. 6. The curve relating membrane potential and Vmax was shifted by CI-980 (10(-5) M) in the hyperpolarizing direction by 2.3 +/- 1.1 mV. 7. It is concluded that in guinea-pig papillary muscles, CI-980 produces a use-dependent inhibition of Vmax and a reverse use-dependent prolongation of the ventricular action potential, thus exhibiting class I and class III antiarrhythmic actions, respectively. From the onset and offset kinetics of use-dependent Vmax block, CI-980 can be considered to be an intermediate kinetics (IA) Na+ channel blocker.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Carbamates; Female; Guinea Pigs; In Vitro Techniques; Male; Papillary Muscles; Pyrazines; Pyridines; Sodium Channel Blockers

PubMed: 9117108
DOI: 10.1038/sj.bjp.0700878

Clinical Trial

Authors: R P Whitehead, J M Unger, L E Flaherty...

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.

Topics: Adult; Aged; Antineoplastic Agents; Carbamates; Drug Administration Schedule; Female; Humans; Male; Melanoma; Middle Aged; Pyrazines; Pyridines; Skin Neoplasms; Survival Rate; Treatment Outcome

PubMed: 11561681
DOI: 10.1023/a:1010624702340