Use of patient-derived tumor organoid platform to predict the benefit of postoperative adjuvant chemotherapy for poor responders to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Postoperative adjuvant chemotherapy (AC) for poor responders to neoadjuvant chemoradiotherapy (nCRT) remains debatable among patients with locally advanced rectal cancer (LARC), necessitating biomarkers to accurately predict the benefits of AC. This study aimed to develop a patient-derived tumor organoid (PDTO) platform to predict the benefit of AC in LARC patients showing poor nCRT response. PDTOs were established using irradiated rectal cancer specimens with poor nCRT responses, and their sensitivity to chemotherapy regimens was tested. The half-maximal inhibitory concentration (IC50) value for the PDTO drug test was defined based on the clinical outcomes, and the accuracy of the PDTO prognostic predictions was calculated. Predictive models were developed and validated using the PDTO drug test results. Between October 2018 and December 2021, 86 PDTOs were successfully constructed from 138 specimens (success rate 62.3%). The optimal IC50 cut-off value for the organoid drug test was 39.31 µmol/L, with a sensitivity of 84.75%, a specificity of 85.19%, and an accuracy of 84.88%. Multivariate Cox regression analysis revealed that the PDTO drug test was an independent predictor of prognosis. A nomogram based on the PDTO drug test was developed, showing good prognostic ability in predicting the 2-year and 3-year disease-free survivals (AUC of 0.826 [95% CI, 0.721-0.931] and 0.902 [95% CI, 0.823-0.982], respectively) and overall survivals (AUC of 0.859 [95% CI, 0.745-0.973] and 0.885 [95% CI, 0.792-0.978], respectively). The PDTO drug test can predict the benefit of postoperative AC in poor responders with LARC to nCRT.

Cutoff value of IC50 for drug sensitivity in patient-derived tumor organoids in colorectal cancer.

Patient-derived tumor organoids (PDTOs) have the potential to be used to predict the patient response to chemotherapy. However, the cutoff value of the half-maximal inhibition concentration (IC50) for PDTO drug sensitivity has not been validated with clinical cohort data. We established PDTOs and performed a drug test in 277 samples from 242 CRC patients who received FOLFOX or XELOX chemotherapy. After follow-up and comparison of the PDTO drug test and final clinical outcome results, the optimal IC50 cutoff value for PDTO drug sensitivity was 43.26 µmol/L. This PDTO drug test-defined cutoff value could predict patient response with 75.36% sensitivity, 74.68% specificity, and 75% accuracy. Moreover, this value distinguished groups of patients with significant differences in survival benefit. Our study is the first to define the IC50 cutoff value for the PDTO drug test to effectively distinguish CRC patients with chemosensitivity or nonsensitivity and predict survival benefits.

A bioartificial transgenic porcine whole liver expressing human proteins alleviates acute liver failure in pigs.

BACKGROUND: Preventing heterologous protein influx in patients is important when using xenogeneic bioartificial livers (BALs) to treat liver failure. The development of transgenic porcine livers synthesizing human proteins is a promising approach in this regard. Here, we evaluated the safety and efficacy of a transgenic porcine liver synthesizing human albumin (hALB) and coagulation factor VII (hFVII) within a bioartificial system. METHODS: Tibetan miniature pigs were randomly subjected to different interventions after surgery-induced partially ischemic liver failure. Group A (n = 4) was subjected to basic treatment; group B (n = 4) was to standard medical treatment and wild-type porcine BAL perfusion, and group C (n = 2) was to standard medical treatment and transgenic BAL perfusion. Biochemical parameters, coagulation status, survival time, and pathological changes were determined. Expressions of hALB and hFVII were detected using immunohistochemistry and enzyme-linked immunosorbent assays. RESULTS: The survival time in group A was 9.75 ± 1.26 days; this was shorter than that in both perfused groups, in which all animals reached an endpoint of 12 days (P = 0.006). Ammonia, bilirubin, and lactate levels were significantly decreased, whereas albumin and fibrinogen levels were increased after perfusion (all P < 0.05). hALB and hFVII were detected in transgenic BAL-perfused pig serum and ex vivo in the liver tissues. CONCLUSIONS: The humanized transgenic pig livers could synthesize and secrete hALB and hFVII ex vivo in a whole organ-based bioartificial system, while maintaining their metabolism, detoxification, transformation, and excretion functions, which were comparable to those observed in wild-type porcine livers. Therefore, the use of transgenic bioartificial whole livers is expected to become a new approach in treating acute liver failure.

Prognostic and predictive value of a pathomics signature in gastric cancer.

The current tumour-node-metastasis (TNM) staging system alone cannot provide adequate information for prognosis and adjuvant chemotherapy benefits in patients with gastric cancer (GC). Pathomics, which is based on the development of digital pathology, is an emerging field that might improve clinical management. Herein, we propose a pathomics signature (PSGC) that is derived from multiple pathomics features of haematoxylin and eosin-stained slides. We find that the PSGC is an independent predictor of prognosis. A nomogram incorporating the PSGC and TNM staging system shows significantly improved accuracy in predicting the prognosis compared to the TNM staging system alone. Moreover, in stage II and III GC patients with a low PSGC (but not in those with a high PSGC), satisfactory chemotherapy benefits are observed. Therefore, the PSGC could serve as a prognostic predictor in patients with GC and might be a potential predictive indicator for decision-making regarding adjuvant chemotherapy.

A novel, simplified, and reproducible porcine model of acute ischemic liver failure with portal vein preservation.

The current ischemic models of liver failure are difficult and usually time-consuming to produce. The aim of this study was to develop a simplified and reproducible porcine model of acute liver failure for use in preclinical research. Eighteen Bama miniature pigs were randomly divided into Groups A, B, and C. The hepatic artery and common bile duct were ligated in all groups. While the portal vein was completely preserved in Group A, it was narrowed by 1/3 and 1/2 in Groups B and C, respectively. Results of biochemical analyses, encephalopathy scores, and survival times were compared among the groups. Results of hematoxylin-eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Masson staining, and Ki-67 analyses were recorded. Survival times in Groups B and C were 11.67 ± 1.86 and 2.16 ± 0.75 days, respectively, shorter than that in Group A (>15 days). Following surgery, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, total bilirubin, and direct bilirubin levels significantly increased relative to baseline values in all groups (P<0.05). Groups B and C exhibited a significant decrease in encephalopathy scores and a significant increase in ammonia levels, which were negatively correlated with one another. Pathological analysis revealed obvious necrosis of liver cells, which correlated closely with the degree of portal vein constriction. Our simple, highly reproducible model effectively mimics the clinical characteristics of acute liver failure in humans and provides a foundation for further research on artificial liver support system development.

PYY modulates the tumorigenesis and progression of colorectal cancer unveiled by proteomics.

Despite decrease in mortality caused by colorectal cancer (CRC), there remains no effective therapeutic method for patients with CRC. We attempted to screen biomarkers with therapeutic values in CRC. Proteomic analysis was performed on tumor, tumor-adjacent, and normal tissues derived from five patients with colon adenocarcinoma (COAD) via label-free proteome profiling. Differentially expressed proteins (DEPs) were identified, and functional annotation was performed based on the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The effect of marker proteins on CRC was determined via cell function experiments and using tumor organoid models. The localization of the marker proteins was determined via immunofluorescence. A total of 126 DEPs were identified in COAD tissues compared with normal tissues, of which Peptide YY (PYY) overlapped among the tumor, adjacent, and normal groups. DEPs in the cancer group vs. normal group were enriched in the regulation of cell cycle checkpoint, developmental process, focal adhesion, and apoptosis-related pathways. The low expression of PYY in CRC tissues was verified via qRT-PCR, western blotting, and immunohistochemistry. Overexpression of PYY promoted apoptosis and inhibited the proliferation, migration, and invasion of HCT116 and HT29 cells. Furthermore, PYY was secreted by neurons and its supplementation suppressed tumor organoid growth in a dose-dependent manner. In conclusion, PYY exerted inhibitory action on CRC and could be a therapeutic target for CRC.

[Progression in bowel dysfunction after sphincter-preserving operation for rectal cancer].

The progress in the idea and technology of rectal cancer improve the rate of sphincter-preservation, while bowel dysfunction is the major problem puzzling patients after sphincter-preserving operation. Recent researches reveal bowel dysfunction is closely associated with the postoperative change of anatomy, nerve damage and sphincter functional injury based on the mechanism of defecation function change through the analysis of anatomy, physiology and dynamics. This paper summarizes the mechanism and epidemiology of bowel dysfunction after rectal cancer operation, and elucidate the role of such mechanism in treatment and prevention of above bowel dysfunction.