Chang Wang

Neutrophil extracellular traps (NETs) participate in both host defense and the pathogenesis of various diseases, such as infections, thrombosis, and tumors. While they help capture and eliminate pathogens, NETs’ excessive or dysregulated formation can lead to tissue damage and disease progression. Therapeutic strategies targeting NET modulation have shown potential, but challenges remain, particularly in achieving precise drug delivery and maintaining drug stability. Nanoparticle (NP)-based drug delivery systems offer innovative solutions for overcoming the limitations of conventional therapies. This review explores the biological mechanisms of NET formation, their interactions with NPs, and the therapeutic applications of NP-based drug delivery systems for modulating NETs. We discuss how NPs can be designed to either promote or inhibit NET formation and provide a comprehensive analysis of their potential in treating NET-related diseases. Additionally, we address the current challenges and future prospects for NP-based therapies in NET research, aiming to bridge the gap between nanotechnology and NET modulation for the development of novel therapeutic approaches.

Rationale: Patients with relapsed and refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with the T315I mutation are at higher risk of relapse and have shorter overall survival. Patient concerns: A 31-year-old man presented to the hematology department with intermittent fever and pancytopenia. He was diagnosed with Ph+ acute lymphoblastic leukemia and experienced 2 relapses during treatment. A drug-resistant T315I mutation was detected in the ABL kinase region during review. Diagnoses: Morphological examination of the bone marrow revealed approximately 93.5% lymphoid blast. Flow cytometric analysis confirmed the diagnosis of common B-cell ALL with the following phenotype: CD34, CD45dim, CD19, CD10, cCD79a, CD58dim, CD81dim, cTdT, HLA-DR, CD22dim, CXCR4, CD33dim, CD20, CD25, CD13, CD123. The examination of the ABL kinase region mutation suggested a T315I mutation. Interventions: Olverembatinib, a third-generation TKI drug, was administered in combination with inotuzumab ozogamicin to treat the disease. Outcomes: The patient achieved morphological remission with a negative flow cytometry MRD test, and the quantification of BCR-ABL transcripts was 0% after 1 cycle of therapy. Lessons: The third-generation TKI olverembatinib has been proven to be effective in CML patients with the T315I mutation, and it may also be effective in Ph+ acute lymphoblastic leukemia. Some new immune drugs have also shown improvement in the remission rate. Combination therapy with olverembatinib and Ino can achieve a complete molecular response in patients with relapsed and refractory Ph+ ALL with the T315I mutation.

Introduction: Prostate cancer (PCa) is the second most common malignancy in men. Despite multidisciplinary treatments, patients with PCa continue to experience poor prognoses and high rates of tumor recurrence. Recent studies have shown that tumor-infiltrating immune cells (TIICs) are associated with PCa tumorigenesis.Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to derive multi-omics data for prostate adenocarcinoma (PRAD) samples. The CIBERSORT algorithm was used to calculate the landscape of TIICs. Weighted gene co-expression network analysis (WGCNA) was performed to determine the candidate module most significantly associated with TIICs. LASSO Cox regression was applied to screen a minimal set of genes and construct a TIIC-related prognostic gene signature for PCa. Then, 78 PCa samples with CIBERSORT output p-values of less than 0.05 were selected for analysis. WGCNA identified 13 modules, and the MEblue module with the most significant enrichment result was selected. A total of 1143 candidate genes were cross-examined between the MEblue module and active dendritic cell-related genes.Results: According to LASSO Cox regression analysis, a risk model was constructed with six genes (STX4, UBE2S, EMC6, EMD, NUCB1 and GCAT), which exhibited strong correlations with clinicopathological variables, tumor microenvironment context, antitumor therapies, and tumor mutation burden (TMB) in TCGA-PRAD. Further validation showed that the UBE2S had the highest expression level among the six genes in five different PCa cell lines.Discussion: In conclusion, our risk-score model contributes to better predicting PCa patient prognosis and understanding the underlying mechanisms of immune responses and antitumor therapies in PCa.

Accurately predicting the survival prospects of patients suffering from pancreatic adenocarcinoma (PAAD) is challenging. In this study, we analyzed RNA matrices of 182 subjects with PAAD based on public datasets obtained from The Cancer Genome Atlas (TCGA) as training datasets and those of 63 subjects obtained from the Gene Expression Omnibus (GEO) database as the validation dataset. Genes regulating the metabolism of PAAD cells correlated with survival were identified. Furthermore, LASSO Cox regression analyses were conducted to identify six genes (XDH, MBOAT2, PTGES, AK4, PAICS, and CKB) to create a metabolic risk score. The proposed scoring framework attained the robust predictive performance, with 2-year survival areas under the curve (AUCs) of 0.61 in the training cohort and 0.66 in the validation cohort. Compared with the subjects in the low-risk cohort, subjects in the high-risk training cohort presented a worse survival outcome. The metabolic risk score increased the accuracy of survival prediction in patients suffering from PAAD.

Mutations in KRAS (codon 12/13), NRAS, BRAF^V600E, and amplification of ERBB2 and MET account for 70–80% of anti-epidermal growth factor receptor (EGFR) monoclonal antibody primary resistance. However, the list of anti-EGFR monoclonal antibody primary resistance biomarkers is still incomplete. Herein, we report a case of wild-type RAS/BRAF metastatic colorectal cancer (CRC) with resistance to anti-EGFR monoclonal antibody and chemotherapy. Initially, mutation detection in postoperative tumor tissue by using amplification-refractory mutation system polymerase chain reaction indicated wild-type RAS/BRAF without point mutations, insertion deletions, or fusion mutations. Therefore, we recommended combined therapy of cetuximab and FOLFIRI after failure of platinum-based adjuvant chemotherapy, but the disease continued to progress. Next generation sequencing analysis of the postoperative tumor tissue revealed that KRAS copy number was increased and detected SMAD4, RNF43, and PREX2 mutations. This is the first case of advanced CRC with increased copy numbers of KRAS resistant to cetuximab and chemotherapy, which results in poor patient survival, and other mutated genes may be associated with the outcomes. Our findings indicate KRAS copy number alterations should also be examined, especially with anti-EGFR monoclonal antibody therapy in CRC, since it may be related with the primary resistance to these drugs.

Multiple primary malignant tumors are two or more malignancies in an individual without any relationship between the neoplasms. In recent years, an increasing number of cases have been reported. However, concomitant primary gastric and pancreatic cancer reported a relatively small incidence, involving no pancreatic acinar cell carcinoma reports. Here, we present the first case of concomitant pancreatic acinar cell carcinoma and gastric adenocarcinoma. A 69-year-old male presented to our department with a history of vomiting, epigastric pain, and weight loss. Imaging revealed space-occupying lesions in the stomach and the tail of the pancreas, respectively. The patient underwent laparoscopic radical gastrectomy and pancreatectomy simultaneously. The pathologies of surgical specimens were completely different: The resected gastric specimen was moderate to poorly differentiated adenocarcinoma, whereas the pancreatic tumor was consistent with acinar cell carcinoma. The patient was treated with six cycles of oxaliplatin and S-1 chemotherapy. As of March 2021, the patient was healthy without any recurrence or metastasis. After thoroughly reviewing the literature on simultaneous pancreatic and gastric cancers at home and abroad, we discussed the clinical characteristics of these rare synchronous double cancers. Most of the cases had undergone surgery and adjuvant chemotherapy, and all of the cases were pathologically confirmed by the postoperative specimen. Synchronous pancreatic acinar cells and gastric adenocarcinoma can occur and should be considered when tumors are found in these organs.

Background: Approximately 5.0–24.2% of colorectal cancers (CRCs) have inactivating mutations in SMAD4, making it one of the frequently mutated genes in CRC. We thus carried out a comprehensive system review and meta-analysis investigating the prognostic significance and clinicopathological features of SMAD4 gene mutation in CRC patients. Methods: A detailed literature search was conducted in PubMed, Web of Science and Embase databases to study the relationship between SMAD4 mutations and the demographic and clinicopathological characteristics in CRC patients. The hazard ratios (HRs) with 95% confidence intervals (CI) were used to evaluate the effect of SMAD4 mutations on overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS). Results: Ten studies enrolling 4394 patients were eligible for inclusion. Data on OS were available from 5 studies and data on PFS/RFS were available from 3 studies. Comparing SMAD4-mutated CRC patients with SMAD4 wild-type CRC patients, the summary HR for OS was 1.46 (95% CI 1.28–1.67, P = 0.001), the summary HR for PFS/RFS was 1.59 (95% CI 1.14–2.22, P = 0.006). In terms of clinicopathology parameters, 9 studies have data that can be extracted, SMAD4 mutations were associated with tumor location (odds ratio [OR] = 1.15, colon/rectum, 95% CI 1.01–1.31, P = 0.042), TNM stage (OR = 1.28, stage IV/I–III, 95% CI 1.03–1.58, P = 0.025), lymph node metastasis (OR = 1.42, N1 + N2/N0, 95% CI 1.20–1.67, P < 0.001), mucinous differentiation (OR = 2.23, 95% CI 1.85–2.70, P < 0.001) and rat sarcoma viral oncogene homolog (RAS) mutation status (OR = 2.13, 95% CI 1.37–3.34, P = 0.001). No connection was found with age, gender, tumor grade, microsatellite instability status and b-viral oncogene homolog B1 mutation status. Besides, publication bias was not observed in any study. Conclusions: This meta-analysis suggests that SMAD4 mutation was associated with OS, PFS/RFS, and clinicopathological parameters, including tumor site, disease stage, RAS status, lymph node metastasis and mucinous differentiation. Our meta-analysis indicated that SMAD4 mutations could predict the poor prognosis and aggressive clinicopathological characteristics of CRC. More large-sample cohort studies are needed to confirm this conclusion. Since SMAD4 mutations are closely related to RAS mutations, their relationship warrants further investigation.

Background Approximately 5.0%-24.2% of colorectal cancers (CRCs) have activating mutations in SMAD4, making it one of the frequently mutated genes in CRC. We thus carried out a comprehensive system review and meta-analysis investigating the prognostic significance and clinicopathological features of mutation of SMAD4 gene in CRC. Methods A detailed literature search was conducted in PubMed, Web of Science and Embase databases to study the relationship between mutations of SMAD4 gene and the demographic and clinicopathological characteristics in patients with CRC. The hazard ratios with 95% confidence intervals were used to evaluate the effect of SMAD4 mutations on overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS).Results Ten studies enrolling 4394 patients were eligible for inclusion. Data on OS were available from five studies. Comparing SMAD4-mutated CRC patients with SMAD4 wild-type CRC patients, the summary HR for OS was 1.46 (95% confidence interval [95% CI] 1.28–1.67, P=0.001), the summary HR for PFS/RFS was 1.59 (95% CI=1.14–2.22, P=0.006). In terms of clinicopathology parameters, SMAD4 mutations were associated with tumor location (odds ratio [OR]= 1.15, colon/rectum, 95% CI=1.01-1.31, P=0.042), TNM stage (OR=0.78, stage Ⅰ-Ⅲ/Ⅳ, [95% CI] 0.63-0.97, P=0.025), lymph node metastases (OR=1.42, N+/N0, 95% CI=1.20-1.67, PRAS wild-type/RAS mutation, 95% CI=0.30-0.73, P=0.001). No connection was found with age, gender, tumor grade, microsatellite instability (MSI) status and b-viral oncogene homolog B1(BRAF) status. Besides, publication bias was not observed in all studies.Conclusions This meta-analysis suggests that SMAD4 mutation was associated with OS, PFS/RFS, and clinicopathological parameters, including tumor site, disease stage, RAS status, lymph node metastases and tumor mucinous differentiation. It was indicated that SMAD4 mutations could predict the poor prognosis and aggressive clinicopathological characteristics of CRC. More large-sample cohort studies were needed to further confirm this conclusion. As SMAD4 mutation was found to be closely associated with RAS mutations, their relationship was worth further investigating.

Background: Multiple primary malignant tumors are two or more malignancies in an individual without any relationship between the neoplasms. In recent years, increasing number of cases have been reported. However, Synchronous double primary gastric cancer and pancreatic acinar cell carcinoma are relatively rare to be reported. Further, most pancreatic tumors are consistent with pancreatic ductal adenocarcinomas, and other histologies are rare. We present the first case of synchronous pancreatic acinar cell adenocarcinoma and gastric adenocarcinoma.Case presentation: A 69-year-old man came to our department with a history of vomiting, epigastric pain, and weight loss. Imaging revealed space-occupying lesions in the stomach and the tail of the pancreas, respectively. The patient underwent laparoscopic radical gastrectomy and pancreatectomy simultaneously. The pathologies of surgical specimens were completely different: the resected gastric specimen was a moderate to poorly differentiated adenocarcinoma, whereas the pancreatic tumor was consistent with acinar cell carcinoma. The patient was treated with six cycles of oxaliplatin and S-1 chemotherapy. As of March 2021, the patient was healthy without any recurrence or metastasis. After reviewing lots of literatures on simultaneous pancreatic and gastric cancers at home and abroad, we discuss the clinical characteristics of these rare synchronous double cancers. Most of the cases had undergone surgery and adjuvant chemotherapy, and all of the cases were pathologically confirmed by postoperative specimen. Conclusions: Synchronous pancreatic acinar cell and gastric adenocarcinoma can occur and should be considered when tumors are found in these organs.