Novel Pharmaceutical Cocrystals of Tegafur: Synthesis, Performance, and Theoretical Studies.

PURPOSE: Tegafur (TF) is one of the most important clinical antitumor drugs with poor water solubility, severely reducing its bioavailability. This work develops new cocrystals to improve the solubility of TF and systematically investigates the intermolecular interactions to provide new insights into the formation of cocrystal and changes in physicochemical properties. METHOD: In this paper, two new 1:1 cocrystals of TF with 2,4 dihydroxybenzoic acid (2,4HBA) and p-nitrophenol (PNP) were synthesized. The cocrystal products were identified and characterized by various solid state analysis techniques. And the high performance liquid chromatography (HPLC) was conducted to determine the solubility and dissolution rate of TF and cocrystals. Moreover, the quantum chemistry calculations of crystal structure provided theoretical support for the results. RESULT: Compared with pure TF, the solubility and dissolution rate of TF-2,4HBA is significantly increased in a pH 6.8 buffer at 37°C. Under accelerated storage conditions (40°C, 75% RH), all cocrystal exhibits excellent stability over 8 weeks. Hirshfeld surface (HS) analysis, atoms in molecules (AIM) analysis, interaction region indicator (IRI) analysis, molecular electrostatic potential surface (MEPS) analysis and frontier molecular orbital (HOMO-LUMO) analysis were integrated to understand the hydrogen bonding interaction more comprehensively. The simulation results are in good agreement with the experimental data. The results show that the analysis of physical and chemical properties of TF-PNP cocrystal and TF crystal by quantum chemistry method is reliable at molecular level. CONCLUSION: These results are helpful to provide guiding methods in the cocrystal development and theoretical study of tegafur.

Bioinformatics-based analysis of the relationship between disulfidptosis and prognosis and treatment response in pancreatic cancer.

Tumor formation is closely associated with disulfidptosis, a new form of cell death induced by disulfide stress-induced. The exact mechanism of action of disulfidptosis in pancreatic cancer (PCa) is not clear. This study analyzed the impact of disulfidptosis-related genes (DRGs) on the prognosis of PCa and identified clusters of DRGs, and based on this, a risk score (RS) signature was developed to assess the impact of RS on the prognosis, immune and chemotherapeutic response of PCa patients. Based on transcriptomic data and clinical information from PCa tissue and normal pancreatic tissue samples obtained from the TCGA and GTEx databases, differentially expressed and differentially surviving DRGs in PCa were identified from among 15 DRGs. Two DRGs clusters were identified by consensus clustering by merging the PCa samples in the GSE183795 dataset. Analysis of DRGs clusters about the PCa tumor microenvironment and differential analysis to obtain differential genes between the two DRG clusters. Patients were then randomized into the training and testing sets, and a prognostic prediction signature associated with disulfidptosis was constructed in the training set. Then all samples were divided into high-disulfidptosis-risk (HDR) and low-disulfidptosis-risk (LDR) subgroups based on the RS calculated from the signature. The predictive efficacy of the signature was assessed by survival analysis, nomograms, correlation analysis of clinicopathological characteristics, and the receiver operating characteristic (ROC) curves. To assess differences between different risk subgroups in immune cell infiltration, expression of immune checkpoint molecules, somatic gene mutations, and effectiveness of immunotherapy and chemotherapy. The GSE57495 dataset was used as external validation, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression levels of DRGs. A total of 12 DRGs with differential expression and prognosis in PCa were identified, based on which a risk-prognosis signature containing five differentially expressed genes (DEGs) was developed. The signature was a good predictor and an independent risk factor. The nomogram and calibration curve shows the signature's excellent clinical applicability. Functional enrichment analysis showed that RS was associated with tumor and immune-related pathways. RS was strongly associated with the tumor microenvironment, and analysis of response to immunotherapy and chemotherapy suggests that the signature can be used to assess the sensitivity of treatments. External validation further demonstrated the model's efficacy in predicting the prognosis of PCa patients, with RT-qPCR and immunohistochemical maps visualizing the expression of each gene in PCa cell lines and the tissue. Our study is the first to apply the subtyping model of disulfidptosis to PCa and construct a signature based on the disulfidptosis subtype, which can provide an accurate assessment of prognosis, immunotherapy, and chemotherapy response in PCa patients, providing new targets and directions for the prognosis and treatment of PCa.

Hepatic arterial infusion chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: A tertiary medical center experience.

Background: Unresectable hepatocellular carcinoma (u-HCC) still accounts for the majority of newly diagnosed HCC which with poor prognosis. In the era of systemic therapy, combination therapy with programmed cell death protein-1 (PD-1) inhibitors and tyrosine kinase inhibitors (TKIs) has become mainstream. Hepatic arterial infusion chemotherapy (HAIC) as a local treatment has also shown a strong anti-tumor effect. This study aimed to investigate the efficacy and safety of HAIC, PD-1 inhibitors plus TKIs for u-HCC. Methods: This retrospective study included patients with initially u-HCC between October 2020 to April 2022 who had received at least one cycle of therapy with HAIC, PD-1 inhibitors plus TKIs. The primary outcome included overall response rate (ORR), the disease control rate (DCR), surgical conversion rate, progression-free survival (PFS) and treatment-related adverse events. Results: A total of 145 patients were included in the study. The median treatment cycle of HAIC and PD-1 inhibitors were 3 and 4, respectively. According to the modified RECIST criteria, the best ORR was 57.2% (83/145), 9 had achieved complete response (CR), DCR was 89.7% (130/145). Median time to achieve CR or PR was 65 days. Surgical conversion rate was 18.6% (27/145), seven patients (7/27,25.9%) achieved pathological complete response (pCR). The median follow-up was 12.5 months (4.5-20 months), and the median PFS was 9.7 months. Subgroup analysis showed that Child-pugh A patients had higher DCR (92.2% vs 79.3%, p=0.041) than Child-pugh B patients, as well as increased successful conversion rate (22.4% vs 3.4%, p=0.019). Patients without vascular invasion and extrahepatic metastases showed higher PR (63.4% vs 43.3%, p<0.05) and ORR (73.2% vs 50.0%, p<0.05) than those with vascular invasion. The ORR (73.2% vs 45.5%, p<0.05) and DCR (95.1% vs 78.8%, p<0.05) were also significantly better than those of patients with extrahepatic metastases. HAIC regimen was not related to efficacy (All p>0.05). The incidence rate of grade 3/4 treatment-related AEs was 17.7% without fatal events. Conclusion: The triple combination therapy of HAIC and PD-1 inhibitors plus TKIs for patients with initially unresectable HCC exhibited satisfactory efficacy with tolerable toxicity.

Immune checkpoint inhibitor-induced myocarditis and myositis in liver cancer patients: A case report and literature review.

With the development of immunotherapy, immune checkpoint inhibitors (ICIs) are widely used in clinical oncology and have achieved good results. ICIs could induce immune-related adverse events (irAEs) in cancer treatment, which warrant sufficient attention. Among them, immune myositis can manifest severe symptoms affecting the whole body, and immune myocarditis occurs with a low incidence but high fatality rate. Here we report a case of grade 3/4 adverse reactions in a patient with partial hepatectomy for malignancy after using ICIs and describe the clinical presentation, laboratory results, treatment, and prognosis. It emphasizes that clinicians should focus on being alert to irAEs in liver cancer patients who have received ICI therapy. The case we present is a 56-year-old male diagnosed with hepatocellular carcinoma. Right hepatic lobectomy was performed in April 2019. Postoperative follow-up showed that transcatheter arterial chemoembolization (TACE) combined with sorafenib (400 mg twice daily) failed to stop the recurrence of the tumor. In December 2020, the patient started to use Camrelizumab injections (200mg/injection every 21 days as a cycle). After 3 cycles, the patient had decreased muscle strength in both lower extremities with chest tightness, dyspnea, and expectoration (whitish sputum). The diagnosis was ICIs injection-induced immune myocarditis and myositis accompanied. The patient's condition improved considerably by steroid pulse therapy timely. The case emphasizes that clinicians should focus on being alert to irAEs in liver cancer patients who have received ICI therapy.