Gut Roseburia is a protective marker for peritoneal metastasis of gastric cancer.

BACKGROUND: Gastric cancer (GC), particularly for advanced stage of GC, commonly undergoes peritoneal metastasis (PM), which is the leading cause of GC-related death. However, there currently has no reliable biomarker to predict the onset of GCPM. It is well known that the imbalance of gut microbiota contributes to the development and metastasis of gastrointestinal tumors. Unfortunately, little is known about how the alternation in gut microbiota is associated with the onset of GCPM. METHODS: Our current study analyzed structural characteristics and functional prediction of gut microbiota in GC patients with PM (PM group) and without PM (non-PM group). Fresh fecal samples were collected from a discovery cohort (PM = 38, non-PM = 54) and a validation cohort (PM = 15, non-PM = 21) of GC patients and their 16S ribosomal RNA (16s rRNA) gene amplicons were sequenced, followed by bioinformatics. RESULTS: The results indicated an increase in the biodiversity of gut microbiota in the non-PM group of the discovery cohort, compared with the PM group. Moreover, LEfSe analysis found 31 significantly different microorganisms, of which the Roseburia ranked the fifth in the random forest (RF) model. The characteristics of intestinal microbiota in GCPM patients were changed, and the abundance of Roseburia in gut microbiota from the GCPM patients was reduced and receiver operating characteristic (ROC) analysis revealed that the reduced abundance of gut Roseburia effectively predicted the onset of GCPM. CONCLUSION: This signature was also observed in the validation cohort. Therefore, Roseburia is a protective microbial marker and the reduced abundance of Roseburia in gut microbiota may help early diagnosis of GCPM.

Nab-paclitaxel plus S-1 versus nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer: a multicenter, randomized, phase II study.

BACKGROUND: Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). METHODS: In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. CONCLUSION: The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308).

Efficacy and safety of SBRT combined with sintilimab and IBI305 in patients with advanced HCC and previously failed immunotherapy: study protocol of a phase 2 clinical trial.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China. The combination of immune checkpoint inhibitors (ICIs) and antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors, has been recommended as first-line treatment for advanced HCC. However, two-thirds of patients did not benefit from this form of immunotherapy. Currently, data on the subsequent regimen for patients previously treated with ICIs are lacking. Studies have shown that the combination of radiotherapy (RT) and ICIs is a potentially effective second-line therapy for HCC. This study aims to assess the efficacy and safety of combined therapy with stereotactic body RT (SBRT), sintilimab and IBI305 (a biosimilar of bevacizumab) in patients with HCC following the progression of first-line ICI therapy. METHODS AND ANALYSIS: This study is an open-label, single-arm, single-centre, phase 2 trial of 21 patients with advanced HCC in whom previous ICI therapy has failed. Participants will receive approximately 30-40 Gy/5-8F SBRT, followed by 200 mg sintilimab and 15 mg/kg IBI305 intravenously every 3 weeks. Treatment will continue until the development of unacceptable toxicity or disease progression. We will use Simon's two-stage design, with the objective response rate (ORR) as the primary endpoint. Secondary endpoints include ORR of lesions without RT, disease control rate, progression-free survival, overall survival and safety. ETHICS AND DISSEMINATION: The study was authorised by the Medical Ethics Committee. Dissemination of results will occur via a peer-reviewed publication and other relevant media. TRIAL REGISTRATION NUMBER: ChiCTR2200056068.

Bone marrow lesion and 5-year incident joint surgery in patients with knee osteoarthritis: a retrospective cohort study.

BACKGROUND: It is beneficial for society to discover the risk factors associated with surgery and to carry out some early interventions for patients with these risk factors. Few studies specifically explored the relationship between bone marrow lesions (BMLs) and long-term incident joint surgery. OBJECTIVE: To investigate the association between BML severity observed in knee osteoarthritis (OA) patients' first MRI examination and incident knee surgery within 5 years. Additionally, to assess the predictive value of BMLs for the incident knee surgery. DESIGN: Retrospective cohort study. METHODS: We identified patients diagnosed with knee OA and treated at our institution between January 2015 and January 2018, and retrieved their baseline clinical data and first MRI examination films from the information system. Next, we proceeded to determine the Max BML grades, BML burden grades and Presence BML grades for the medial, lateral, patellofemoral, and total compartments, respectively. Multi-variable logistic regression models examined the association of the BML grades with 5-year incident knee surgery. Positive and negative predictive values (PPVs and NPVs) were determined for BML grades referring to 5-year incident knee surgery. RESULTS: Totally, 1011 participants (knees) were found eligible to form the study population. Within the 5 years, surgery was performed on 74 knees. Max BML grade 2 and grade 3 of medial, patellofemoral and total compartments were strongly and significantly associated with incident surgery. None of the BML grades from lateral compartment was associated with incident surgery. The PPV was low and NPV was high for BMLs. CONCLUSIONS: BMLs found in the first MRI examination were associated with 5-year incident joint surgery, except for those allocated in lateral compartments. The high NPVs imply that patients without BMLs have a low risk of requiring surgery within 5 years.

Targeting HIF-1α with Specific DNA Yokes for Effective Anticancer Therapy.

Hypoxia, a ubiquitous hallmark in cancer, underscores the significance of targeting HIF-1α, the principal transcriptional factor of hypoxic responses, for effective cancer therapy. Herein, DNA yokes, a novel class of DNA nanomaterials harboring specific HIF-1α binding sequences (hypoxia response elements, HREs), are introduced as nanopharmaceuticals for cancer treatment. Comprising a basal tetrahedral DNA nanostructure and four HRE-bearing overhanging chains, DNA yokes exhibit exceptional stability and prolonged intracellular retention. The investigation reveals their capacity to bind HIF-1α, thereby disrupting its interaction with the downstream genomic DNAs and impeding transcriptional activity. Moreover, DNA yokes facilitate HIF-1α degradation via the ubiquitination pathway, thereby sequestering it from downstream targets and ultimately promoting its degradation. In addition, DNA yokes attenuate cancer cell proliferation, migration, and invasion under hypoxic conditions, while also displaying preferential accumulation within tumors, thereby inhibiting tumor growth and metastasis in vivo. This study pioneers a novel approach to cancer therapy through the development of DNA-based drugs characterized by high stability and low toxicity to normal cells, positioning DNA yokes as promising candidates for cancer treatment.

Can rectal MRI and endorectal ultrasound accurately predict the complete response to neoadjuvant immunotherapy for rectal cancer?

Background: Standardized assessments of clinical complete response (cCR) to neoadjuvant chemoradiotherapy (nCRT) for rectal cancer have been established, but their utility and accuracy remain unclear. This study aimed to evaluate the clinical diagnostic value of rectal magnetic resonance imaging (MRI) and endorectal ultrasonography (ERUS) for the determination of cCRs after neoadjuvant immunotherapy and to investigate the concordance between cCR and pathological complete response (pCR). Methods: Ninety-four patients with rectal cancer treated with neoadjuvant radiotherapy with or without immunotherapy were included. The sensitivity, specificity, and accuracy of each evaluation method were calculated. Results: Combined MRI and ERUS assessments found cCR in seven of the 94 patients in our cohort. In the non-immunotherapy group, the sensitivity, specificity, and accuracy of MRI for diagnosing cCR were 50.0%, 85.2%, and 77.1%, respectively, whereas those of ERUS were 50.0%, 92.6%, and 82.9%, respectively; those of combined MRI and ERUS were 25.0%, 96.3%, and 87.5%, respectively. In the immunotherapy group, the sensitivity, specificity, and accuracy with which MRI identified CR were 51.7%, 76.7%, and 64.4%, respectively; those of ERUS were 13.8%, 90.0%, and 52.5%, respectively, and those of combined MRI and ERUS were 10.3%, 96.7%, and 54.2%, respectively. We also found that 32 of 37 patients with pCR did not meet the cCR evaluation criteria. Of these pCR patients, 78.4% (29/37) received immunotherapy. In the entire cohort, there were five pCRs among the seven cCRs. Of the four cCRs that occurred in the immunotherapy group, three were pCRs. Conclusions: Rectal MRI and/or ERUS did not provide sufficiently accurate assessments of cCR in patients with rectal cancer receiving neoadjuvant therapy, especially immunotherapy, and cCR did not predict pCR.

Significant response to pembrolizumab plus lenvatinib in Epstein-Barr-virus-associated intrahepatic cholangiocarcinoma: a case report.

BACKGROUND: The prognosis for advanced intrahepatic cholangiocarcinoma (iCCA) is poor, and there remains an urgent need to develop efficient systemic therapy. The efficacy of Pembrolizumab immunotherapy combined with lenvatinibin in iCCA is still unclear. The role of Epstein-Barr-virus (EBV) as a biomarker in iCCA for response to immunotherapy needs further exploration. CASE PRESENTATION: We report a case of a 60-year-old female with EBV-associated advanced iCCA (EBVaiCCA) who progressed after first-line therapy. She accomplished an available response to the combination therapy of pembrolizumab with lenvatinib, with overall survival of 20 months. CONCLUSIONS: As far as we know, this is the first case report about the application of Pembrolizumab with lenvatinib for EBVaiCCA patients. This case indicates that the combination of immunotherapy and antiangiogenic therapy provides a glimmer of hope for advanced EBVaiCCA patients.

Colon-targeted hydroxyethyl starch-curcumin microspheres with high loading capacity ameliorate ulcerative colitis via alleviating oxidative stress, regulating inflammation, and modulating gut microbiota.

Curcumin (CUR) is a natural polyphenol that holds promise for treating ulcerative colitis (UC), yet oral administration of CUR exhibits limited bioavailability and existing formulations for oral delivery of CUR often suffer from unsatisfactory loading capacity. This study presents hydroxyethyl starch-curcumin microspheres (HC-MSs) with excellent CUR loading capacity (54.52 %), and the HC-MSs can further encapsulate anti-inflammatory drugs dexamethasone (DEX) to obtain a combination formulation (DHC-MSs) with high DEX loading capacity (19.91 %), for combination therapy of UC. The microspheres were successfully engineered, retaining the anti-oxidative and anti-inflammatory activities of parental CUR and demonstrating excellent biocompatibility and controlled release properties, notably triggered by α-amylase, facilitating targeted drug delivery to inflamed sites. In a mouse UC model induced by dextran sulfate sodium, the microspheres effectively accumulated in inflamed colons and both HC-MSs and DHC-MSs exhibited superior therapeutic efficacy in alleviating UC symptoms compared to free DEX. Moreover, mechanistic exploration uncovered the multifaceted therapeutic mechanisms of these formulations, encompassing anti-inflammatory actions, mitigation of spleen enlargement, and modulation of gut microbiota composition. These findings underscore the potential of HC-MSs and DHC-MSs as promising formulations for UC, with implications for advancing treatment modalities for various inflammatory bowel disorders.

Hybridization chain reaction assisted multicolor immunosensor for sensitively detection of human chorionic gonadotropin.

The level of human chorionic gonadotropin (HCG) is an important indicator for early pregnancy, pregnancy-related diseases trophoblastic diseases and even cancer diagnosis. Therefore, sensitive detection of HCG has crucial significance in clinical, especially in gynaecology and obstetrics. Herein, a hybridization chain reaction (HCR) assisted multicolor immunosensor have been developed for HCG analysis. The proposed method introduced HCR after the immunoreaction between antibody and HCG protein, and produced long double strand DNA (dsDNA) that contain biotin sites. The streptavidin-horseradish peroxidase was linked on the dsDNA by the interaction between biotin and streptavidin, and can further mediated gold nanobipyramids (Au NBPs) etching. The localized surface plasmon resonance absorption peaks of Au NBPs blue shift and accompanied a vivid color change after etching effect. Based on this color change, HCG could be qualitative and semi-quantitative detected. Because of the introduction of HCR and enzyme amplification technique, the proposed method exhibited high sensitivity with a linear range of 0.1-2000 pg/mL and limit of detection (LOD) of 0.1 pg/mL. Finally, the proposed immunosensor was used to detect clinical serum samples. The results show there are no significant differences between clinical results and the test results by this method, indicating the practicability of the proposed method.

Efficacy and safety of radiotherapy combined with anti-angiogenic therapy and immune checkpoint inhibitors in MSS/pMMR metastatic colorectal cancer.

PURPOSE: Several studies have demonstrated the effectiveness of anti-angiogenic drugs in combination with immune checkpoint inhibitors (ICIs) in patients with microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC). However, whether combination radiotherapy (RT) can further improve the prognosis of mCRC patients after second-line treatment remains to be explored. METHODS: Retrospective analysis of data from mCRC patients who received anti-angiogenic targeted therapy (TT) and immunotherapy (IT) with or without RT after the failure of standard therapy. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated. RESULTS: A total of 82 patients who received TT + IT were analyzed. For RT group (n = 42) versus NRT group (n = 40), ORR was 21.4% (9/42) versus 5.0% (2/40); DCR was 83.8% (35/42) versus 65.0% (26/40). Compared with NRT group, RT improved PFS (median: 5.0 vs. 3.6 months; p = 0.04) and OS (median: 15.2 vs. 7.2 months; p = 0.01). In addition, in the population receiving RT, the PFS of RT sequential/simultaneous TT + IT was superior to TT + IT sequential RT (median: 7.1 vs. 6.2 vs. 3.5 months, p = 0.004). Multivariate analysis suggested RT was an independent prognostic factor for PFS and OS. No treatment-related deaths were reported. CONCLUSIONS: Compared with TT + IT, RT combined with TT + IT improved survival outcomes in MSS/pMMR mCRC patients, with manageable toxicity. RT sequential/simultaneous TT + IT treatment is expected to be the optimal strategy for MSS/PMMR mCRC.