Genomic Alterations and Clinical Characterization in Chinese Patients with Metastatic Colorectal Cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) is increasingly characterized by myriad genomic alterations beyond the well-known factors such as RAS, BRAF, and microsatellite instability (MSI). Novel genomic changes, including ERBB2 amplifications, mutations, and gene fusions, are now recognized as potential targets for precision therapy. This study aims to explore the genomic landscape of a Chinese cohort with mCRC to identify potentially targetable genetic alterations for personalized treatment strategies. METHODS: A total of 500 mCRC patients in China were enrolled, based on which genomic profiling was performed using capture-based targeted sequencing across a panel of 520 genes on tumor tissues to identify prevalent genomic alterations. The mutations were analyzed by optimized proprietary algorithms. MSI and mismatch repair deficiency status were analyzed using the read-count-distribution approach. Besides, the overall survival (OS) related to these molecular changes was estimated. RESULTS: The cohort's genomic profiling revealed TP53 mutations in 78%, APC in 60%, and KRAS in 47% of the patients. MSI-High status was confirmed in 5.8% of cases via a next-generation sequencing (NGS)-based algorithm. ERBB2/HER2 amplifications were found in 12% (60/500) of patients, with potential therapeutic implications for those without concurrent KRAS mutations. A subset of patients (1.2%; 6/500) showed fusions and DNA damage response (DDR) gene mutations (except TP53) that could be targeted therapeutically. The KRAS (G12C) variant was detected in 14 patients (2.8%), and 61 (12.2%) had a BRAF V600E mutation. Notably, survival analysis showed no significant differences in OS between KRAS mutant loci and NRAS mutations (p = 0.436). However, BRAF V600E mutations were associated with a poorer prognosis than BRAF wild-type and non-V600E mutations (16.3 months vs. 29.5 and 31.1 months, respectively; p < 0.001). CONCLUSIONS: This study validates the feasibility of using NGS to detect prognostic and therapeutically actionable genetic variants in Chinese mCRC patients, contributing to understanding the genomic variation within this population and highlighting the potential for personalized medicine in managing mCRC.

Pyridine-borane complex-catalysed thioesterification: the direct conversion of carboxylic acids to thioesters.

Thioesters are a common class of biologically active fragments and synthetically useful building blocks. An attractive synthetic approach would be to use simple and bench-stable carboxylic acids as a coupling partner. Herein, we present a 4-bromo pyridine-borane complex as a catalyst for the direct coupling of carboxylic acids with thiols. A wide range of thioesters with good functional group compatibility could be prepared via this metal-free approach. The merit of this strategy is exemplified by the modification of carboxylic acid-containing drugs.

Impact of Skeletal Muscle Loss and Sarcopenia on Outcomes of Locally Advanced Esophageal Cancer during Neoadjuvant Chemoradiation.

BACKGROUND: The impact of changes in skeletal muscle and sarcopenia on outcomes during neoadjuvant chemoradiotherapy (NACR) for patients with esophageal cancer remains controversial. PATIENTS AND METHODS: We retrospectively analyzed the data of patients with locally advanced esophageal squamous cell cancer who received NACR followed by esophagectomy between June 2013 and December 2021. The images at third lumbar vertebra were analyzed to measure the cross-sectional area and calculate skeletal muscle index (SMI) before and after NACR. SMI less than 52.4 cm2/m2 for men and less than 38.5 cm2/m2 for women were defined as sarcopenia. The nonlinearity of the effect of percent changes in SMI (ΔSMI%) to survival outcomes was assessed by restricted cubic splines. RESULTS: Overall, data of 367 patients were analyzed. The survival outcomes between sarcopenia and non-sarcopenia groups had no significant differences before NACR. However, patients in post-NACR sarcopenia group showed poor overall survival (OS) benefit (P = 0.016) and poor disease-free survival (DFS) (P = 0.043). Severe postoperative complication rates were 11.9% in post-NACR sarcopenia group and 5.0% in post-NACR non-sarcopenia group (P = 0.019). There was a significant non-linear relationship between ΔSMI% and survival outcomes (P < 0.05 for non-linear). On the multivariable analysis of OS, ΔSMI% > 12% was the independent prognostic factor (HR 1.76, 95% CI 1.03-2.99, P = 0.039) and significant difference was also found on DFS analysis (P = 0.025). CONCLUSIONS: Patients with post-neoadjuvant chemoradiotherapy sarcopenia have worse survival and adverse short-term outcomes. Moreover, greater loss in SMI is associated with increased risks of death and disease progression during neoadjuvant chemoradiotherapy, with maximum impact noted with SMI loss greater than 12%.

Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation.

Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation's pure compound library of microbial origin, we identified elaiophylin as an autophagy inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

The comparisons of neoadjuvant chemoimmunotherapy versus chemoradiotherapy for oesophageal squamous cancer.

OBJECTIVES: The aim of this study was to evaluate the short-term outcomes of neoadjuvant chemoimmunotherapy (NACI) followed by oesophagectomy for locally advanced oesophageal squamous carcinoma. METHODS: Patients receiving NACI or chemoradiotherapy between September 2019 and September 2021 were identified. The primary outcomes were tumour response and survival. Secondary outcomes were toxic effects and postoperative complications. The propensity score matching for enrolled patients was performed. RESULTS: Data of 149 patients with clinical stage II-IV oesophageal squamous cancer, including 55 receiving NACI and 94 receiving neoadjuvant chemoradiotherapy (NACR), were analysed after propensity score matching. With regard to tumour response score, 24 (43.6%) and 59 (62.8%) patients were scored 0/1 in the NACI and NACR groups, respectively (P = 0.023). Of note, 17 (30.9%) patients in the NACI group achieved pathological complete response (CR) (ypT0N0), while 48 (51.1%) patients in NACR group achieved pathological CR (P = 0.026). NACR was associated with the higher risk of postoperative pneumonia (P = 0.034) and less lymph nodes and stations dissected (P ≤ 0.001). The 1-year cumulative overall survival rate was 94.5% and 86.2% in the NACI and NACR groups, respectively (P = 0.170). CONCLUSIONS: We found that NACI compared with NACR was associated with lower pneumonia rate and was safe and feasible for locally advanced oesophageal squamous cancer. However, the tumour regression score and the pathological CR rate of patients treated with neoadjuvant immunotherapy were lower than those of patients treated with NACR. The short-term follow-up results were comparable between 2 treatment modalities.

Application of stem cells and exosomes in the treatment of intracerebral hemorrhage: an update.

Non-traumatic intracerebral hemorrhage is a highly destructive intracranial disease with high mortality and morbidity rates. The main risk factors for cerebral hemorrhage include hypertension, amyloidosis, vasculitis, drug abuse, coagulation dysfunction, and genetic factors. Clinically, surviving patients with intracerebral hemorrhage exhibit different degrees of neurological deficits after discharge. In recent years, with the development of regenerative medicine, an increasing number of researchers have begun to pay attention to stem cell and exosome therapy as a new method for the treatment of intracerebral hemorrhage, owing to their intrinsic potential in neuroprotection and neurorestoration. Many animal studies have shown that stem cells can directly or indirectly participate in the treatment of intracerebral hemorrhage through regeneration, differentiation, or secretion. However, considering the uncertainty of its safety and efficacy, clinical studies are still lacking. This article reviews the treatment of intracerebral hemorrhage using stem cells and exosomes from both preclinical and clinical studies and summarizes the possible mechanisms of stem cell therapy. This review aims to provide a reference for future research and new strategies for clinical treatment.

Thrombotic thrombocytopenic purpura complicated with acute aortic dissection: A case report.

RATIONALE: Thrombotic thrombocytopenic purpura (TTP) is a critical thrombotic microangiopathy involving multiple organs. To the best of our knowledge, there are no reports of TTP complicated by acute aortic dissection. PATIENT CONCERNS: We herein described a 53-year-old male with TTP who did not have a significant medical history. After immediate plasma exchange and glucocorticoid therapy, the patient's clinical condition improved. However, the patient suddenly experienced chest pain with elevated blood pressure. DIAGNOSES: Computed tomography angiography suggested acute type B aortic dissection. INTERVENTIONS: The patient was immediately transferred to the cardiac aortic surgery department for thoracic aortic endovascular repair. OUTCOMES: The patient was discharged after successful thoracic aortic endovascular repair. Unfortunately, 3 months later, the patient experienced chest and back pain at home and died suddenly, possibly due to the recurrence of aortic dissection. LESSONS: Even if patients have no identifiable risk factors, physicians should be aware of this rare and life-threatening acute complication of TTP, which may have multiple causes, including preexisting connective tissue disease, abnormal blood pressure fluctuations, and increased risk of hemorrhage. Early identification and timely treatment of acute aortic dissection are critical for improving prognosis.

[Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria].

OBJECTIVE: To analyze the clinical efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for paroxysmal nocturnal hemoglobinuria (PNH), and preliminarily explore the role of an improved post-transplantation cyclophosphamide (PTCy) based conditioning regimen in PNH patients receiving transplantation. METHODS: Clinical related data of PNH sufferers receiving allo-HSCT in Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology were collected, and hematopoietic reconstitution, chimerism, PNH cloning, graft-versus-host disease (GVHD), infection, and survival were analyzed. RESULTS: Totally five PNH patients receiving allo-HSCT were enrolled, including 1 case with classic PNH, 3 cases with aplastic anemia-PNH syndrome, 1 case with myelodysplastic syndrome, three of them (case 1-3) received the improved PTCy based conditioning regimen before HSCT. All sufferers engrafted successfully within 28 days, the median time of neutrophil and platelet engraftment was 11 days and 12 days, respectively, no patient occurred acute or chronic GVHD, after a median follow-up of 16 months, all recipients survived and completely eliminated PNH cloning. CONCLUSION: Allo-HSCT can completely clear PNH cloning and restore hematopoietic function with controllable complications, and the improved PTCy based conditioning regimen is proved to be effective in PNH transplantation.

Disruption of MAP7D1 Gene Function Increases the Risk of Doxorubicin-Induced Cardiomyopathy and Heart Failure.

Doxorubicin is a cornerstone chemotherapeutic drug widely used to treat various cancers; its dose-dependent cardiomyopathy, however, is one of the leading causes of treatment-associated mortality in cancer survivors. Patients' threshold doses leading to doxorubicin-induced cardiomyopathy (DIC) and heart failure are highly variable, mostly due to genetic variations in individuals' genomes. However, genetic susceptibility to DIC remains largely unidentified. Here, we combined a genetic approach in the zebrafish (Danio rerio) animal model with a genome-wide association study (GWAS) in humans to identify genetic susceptibility to DIC and heart failure. We firstly reported the cardiac and skeletal muscle-specific expression and sarcomeric localization of the microtubule-associated protein 7 domain-containing protein 1b (Map7d1b) in zebrafish, followed by expression validation in mice. We then revealed that disruption of the map7d1b gene function exaggerated DIC effects in adult zebrafish. Mechanistically, the exacerbated DIC are likely conveyed by impaired autophagic degradation and elevated protein aggregation. Lastly, we identified 2 MAP7D1 gene variants associated with cardiac functional decline and heart failure in cancer patients who received doxorubicin therapy. Together, this study identifies MAP7D1 as a clinically relevant susceptibility gene to DIC and heart failure, providing useful information to stratify cancer patients with a high risk of incurring severe cardiomyopathy and heart failure after receiving chemotherapy.

Inherited Genetic Susceptibility to Nonimmunosuppressed Epstein-Barr Virus-associated T/NK-cell Lymphoproliferative Diseases in Chinese Patients.

Epstein-Barr virus (EBV) T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells, including chronic active EBV infection of T/NK-cell type (CAEBV+T/NK), EBV-associated hemophagocytic lymphohistiocytosis (EBV+HLH), extranodal NK/T-cell lymphoma of nasal type (ENKTL), and aggressive NK-cell leukemia (ANKL). However, the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown. A total of 171 nonimmunosuppressed patients with EBV+T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed. The 94 gene variants, mostly located in UNC13D, LYST, ITK, and PRF1 genes were detected, and mutations covered 28/50 (56.00%) of CAEBV-T/NK, 31/51 (60.78%) of EBV+HLH, 13/28 (46.42%) of ENKTL, and 13/48 (27.09%) of ANKL. Most mutations represented monoallelic and missense. Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations (P=0.0284, P=0.0137). Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV+T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.

Anti-BCMA CAR-T Cell Therapy in Relapsed or Refractory Multiple Myeloma Patients with Impaired Renal Function.

Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy is effective and well-tolerated for refractory or relapsed multiple myeloma (RRMM). The purpose of the present study was to analyze efficacy in RRMM patients with renal impairment treated by anti-BCMA CAR-T cell therapy. A total of 59 RRMM patients were selected, and divided into impaired renal function (IRF) group [baseline estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 (n=18)] and normal renal function (NRF) group (baseline eGFR ≥ 90 mL/min/1.73 m2, n=41). For patients with IRF, eGFR at the 6th month post-CAR-T cells infusion was significantly higher than the baseline (P<0.05). The multivariate analysis showed that light chain type and beta-2 micro-globulin (beta-2M) were associated factors with the decrease of serum creatinine. Median progression-free survival (PFS) in the NRF group and IRF group was 266 days and 181 days respectively. Overall survival (OS) in the NRF group and IRF group was 877 days and 238 days respectively. There was no significant difference in the objective response rate (ORR) between the IRF group and the NRF group. It is suggested that CAR-T cells therapy could improve the renal function during the treatment of RRMM. The renal function could be more significantly improved in RRMM patients with light chain type than with other types.

Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Efficacy and Safety of Immune Checkpoint Inhibitor in Advanced Esophageal Squamous Cell Carcinoma: A Meta-Analysis.

BACKGROUND: The published evidence from several randomized controlled clinical trials of immunotherapy for advanced esophageal squamous cell carcinoma has shown promising results. This study aimed to investigate the efficacy and safety of immune checkpoint inhibitor treatment in esophageal squamous cell carcinoma. METHODS: PubMed, Web of Science, Cochrane Library, and Embase databases were searched for relevant articles published before December 30, 2020. The data for efficacy and safety of immune checkpoint inhibitor treatment were subjected to meta-analysis. RESULTS: Seven clinical trials comprising 1733 patients were included. The results showed that immune checkpoint inhibitor treatment as second- or later-line treatment was associated with an increased risk of the objective response rate (relative risk: 1.82, 95% confidence interval: 0.82-4.04; P=0.002) and median overall survival (hazard ratio: 0.75, 95% confidence interval: 0.67-0.85; P<0.001) compared with chemotherapy in locally advanced or metastatic esophageal squamous cell carcinoma. Moreover, immune checkpoint inhibitor treatment was associated with significant improvement in median overall survival (hazard ratio: 0.61, 95% confidence interval: 0.48-0.77, P<0.001) compared with chemotherapy in the programmed death-ligand 1 (PD-L1)-positive population. However, immune checkpoint inhibitor treatment was also effective in all patients independent of PD-L1 expression. The most common grade ≥3 treatment-related adverse events with immune checkpoint inhibitor therapy were anemia, asthenia, rash, fatigue, decreased appetite, diarrhea, pneumonia, decreased neutrophil count, and vomiting. Patients undergoing immune checkpoint inhibitor therapy was associated with a decreased risk of treatment-related adverse events (relative risk: 0.82, 95% confidence interval: 0.62-1.08; P<0.001) and grade ≥3 treatment-related adverse events (relative risk: 0.50, 95% confidence interval: 0.42-0.60; P<0.001) compared with those undergoing chemotherapy. CONCLUSIONS: Immune checkpoint inhibitors as second- or later-line therapy may improve overall response rate and overall survival but not all oncological outcomes for patients with locally advanced or metastatic esophageal squamous cell carcinoma. Patients treated with immune checkpoint inhibitors might experience fewer treatment-related adverse events of any grade, but specifically grade ≥3, compared with those treated with chemotherapy.

Novel bioinformatic classification system for genetic signatures identification in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a spectrum of disease comprising more than 30% of non-Hodgkin lymphomas. Although studies have identified several molecular subgroups, the heterogeneous genetic background of DLBCL remains ambiguous. In this study we aimed to develop a novel approach and to provide a distinctive classification system to unravel its molecular features. METHOD: A cohort of 342 patient samples diagnosed with DLBCL in our hospital were retrospectively enrolled in this study. A total of 46 genes were included in next-generation sequencing panel. Non-mutually exclusive genetic signatures for the factorization of complex genomic patterns were generated by random forest algorithm. RESULTS: A total of four non-mutually exclusive signatures were generated, including those with MYC-translocation (MYC-trans) (n = 62), with BCL2-translocation (BCL2-trans) (n = 69), with BCL6-translocation (BCL6-trans) (n = 108), and those with MYD88 and/or CD79B mutations (MC) signatures (n = 115). Comparison analysis between our model and traditional mutually exclusive Schmitz's model demonstrated consistent classification pattern. And prognostic heterogeneity existed within EZB subgroup of de novo DLBCL patients. As for prognostic impact, MYC-trans signature was an independent unfavorable prognostic factor. Furthermore, tumors carrying three different signature markers exhibited significantly inferior prognoses compared with their counterparts with no genetic signature. CONCLUSION: Compared with traditional mutually exclusive molecular sub-classification, non-mutually exclusive genetic fingerprint model generated from our study provided novel insight into not only the complex genetic features, but also the prognostic heterogeneity of DLBCL patients.

Antithymocyte Globulin for Matched Sibling Donor Transplantation in Patients With Hematologic Malignancies: A Multicenter, Open-Label, Randomized Controlled Study.

PURPOSE: The role of antithymocyte globulin (ATG) in preventing acute graft-versus-host disease (aGVHD) after HLA-matched sibling donor transplantation (MSDT) is still controversial. PATIENTS AND METHODS: We performed a prospective, multicenter, open-label, randomized controlled trial (RCT) across 23 transplantation centers in China. Patients ages 40-60 years with standard-risk hematologic malignancies with an HLA-matched sibling donor were randomly assigned to an ATG group (4.5 mg/kg thymoglobulin plus cyclosporine [CsA], methotrexate [MTX], and mycophenolate mofetil [MMF]) and a control group (CsA, MTX, and MMF). The primary end point of this study was grade 2-4 aGVHD on day 100. RESULTS: From November 2013 to April 2018, 263 patients were enrolled. The cumulative incidence rate of grade 2-4 aGVHD was significantly reduced in the ATG group (13.7%; 95% CI, 13.5% to 13.9%) compared with the control group (27.0%; 95% CI, 26.7% to 27.3%; P = .007). The ATG group had significantly lower incidences of 2-year overall chronic GVHD (27.9% [95% CI, 27.6% to 28.2%] v 52.5% [95% CI, 52.1% to 52.9%]; P < .001) and 2-year extensive chronic GVHD (8.5% [95% CI, 8.4% to 8.6%] v 23.2% [95% CI, 22.9% to 23.5%]; P = .029) than the control group. There were no differences between the ATG and control groups with regard to cytomegalovirus reactivation, Epstein-Barr virus reactivation, 3-year nonrelapse mortality (NRM), 3-year cumulative incidence of relapse (CIR), 3-year overall survival, or 3-year leukemia-free survival. Three-year GVHD relapse-free survival was significantly improved in the ATG group (38.7%; 95% CI, 29.9% to 47.5%) compared with the control group (24.5%; 95% CI, 16.9% to 32.1%; P = .003). CONCLUSION: Our study is the first prospective RCT in our knowledge to demonstrate that ATG can effectively decrease the incidence of aGVHD after MSDT in the CsA era without affecting the CIR or NRM.

CAR T Cell Therapy for Hematological Malignancies.

As a rapidly progressing field in oncology, the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors (CARs) has shown striking efficacy in the management of hematological malignancies and has been reported in a number of clinical trials. Of note, CAR T cell therapy has shown extraordinary potential, especially in relapsed/refractory patients. However, there are still challenges regarding the further development of this strategy, spanning from engineering and manufacturing issues, to limited applications, to accompanying toxicities. In this review, we will summarize the general knowledge of this novel method, including receptor composition, applications, adverse events and challenges. Additionally, we will propose several comprehensive recommendations.