Prior to pathological changes becoming apparent in any disease, the component and amount of intracellular proteins may undergo alteration. Thus, monitoring of proteins may be used to screen indicators in order to identify prognostic markers. The aim of this study was to investigate the feasibility of identification of serum biomarkers for lung cancer using protein mass spectrometry. Surface-enhanced laser desorption/ionization (SELDI) and weak cation exchange 2 (WCX2) protein chip array were employed for protein profiling of the sera of 17 healthy rabbits and 23 cancer‑bearing rabbits, of which 15 developed cancer in the lung (cancer group) and 8 developed lung cancer in the follow-up period (pre-cancer group). Data were obtained using a PBSII-C protein chip reader and analyzed using Biomarker Wizard and Proteinchip 3.1 software. Compared with the healthy rabbits, a total of 5 biomarkers were identified to be differentially expressed among 32 proteins screened from the sera in the cancer group and the pre-cancer group (P<0.05): 3 of the 5 biomarkers were upregulated and 2 were downregulated. Protein mass spectro-metry can be used to identify specific molecules closely correlated with the progression of lung cancer and, thus, this method may become an effective tool for the early diagnosis or prediction of lung cancer.
e14610 Background: The findings on the clinical effect of the therapy with anti-PD-1 Abs plus angiogenic receptor inhibitors in the treatment of MSS/pMMR mCRC have been inconsistent. The aim of this study was to evaluate the prognostic and predictive role of NLR and IFN-γ in mCRC treated with anti-PD-1 and angiogenic receptor inhibitors. Methods: A total number of 35 patients with MSS/pMMR colorectal cancer treated with anti-PD-1 and angiogenic receptor inhibitors at Shanghai Tenth People’s Hospital (Shanghai, China) between December 2019 and January 2023 were retrospectively evaluated. We reviewed the tumor response and progression-free survival (PFS), and evaluated the associations among neutrophil-to-lymphocyte ratio (NLR), cytokines, and outcomes in the treatment of MSS/pMMR mCRC. A cut-off value of 3 was adopted to discriminate patients with low (NLR < 3) versus high (NLR > 3) NLR. A cut-off value of 2.7 was employed to discriminate patients with low (IFN-γ < 2.7) versus high (IFN-γ > 2.7) IFN-γ. Tissue samples from the mCRC patients were stained with CD4, CD8 to establish the immune status. Results: Of the remaining 25 mCRC patients, 14 received sintilimab and fruquintinib, 3 received sintilimab and regorafenib, 6 received camrelizumab and fruquintinib, and 2 received raltizumab and fruquintinib. Two patients were treated with PEG-rhG-CSF, and one patient had myelosuppression after previous chemotherapy. Thus, the NLR ratio could not be calculated in these three patients. Meanwhile, among the 25 patients, 4 patients no cytokine test had been performed before the treatment with anti-PD-1 and VEGF inhibitors. Thus, cytokine analyses were conducted only in the remaining 21 patients. Partial response and stable disease were found in 5 (20%) and 8 (32%) patients, respectively. The disease control rate was 52%. The pretreatment NLR ratio and IFN-γ level of the responder and stable patients were higher than those in progressive patients ( P = 0.0010, n = 22; P = 0.0267, n = 21, respectively). Higher baseline levels of NLR ratio and IFN-γ was associated with longer progression-free survival in mCRC patients receiving anti-PD-1 and angiogenic receptor inhibitors. NLR and IFN-γ were also positively correlated with PFS (R 2 = 0.3334, P = 0.0049; R 2 = 0.4063, P = 0.0019) respectively. Patients getting clinical benefits (PR+SD) were found CD4+ T cells infiltrated (P = 0.0074). Conclusions: Higher NLR ratio and IFN-γ level are prognostic factors associated with longer progression-free survival and better response of MSS/pMMR mCRC patients to anti-PD-1 and angiogenic receptor inhibitors. NLR ratio and IFN-γ level pretreatment could be predictive factors of the response to anti-PD-1 and angiogenic receptor inhibitors in MSS/pMMR mCRC patients. Clinical trial information: ChiCTR2300067767 .
According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC.In this study, the use of poly(L-Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects-enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models.We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment.
For patients with chronic myeloid leukemia (CML) failing imatinib therapy, second-generation tyrosine kinase inhibitors (TKIs) are recommended. Here, we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib, but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullary toxicity. Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.
Abstract Background Programmed cell death-1 (PD-1) blockade immunotherapies have demonstrated excellent clinical benefits in multiple cancers, but < 20% of melanoma patients respond to these treatments. Thus, it is crucial to understand for getting awareness of the dynamic changes vibrant transformations in the tumor microenvironment (TME) after PD-1 blockade, in exploring novel intervention targets as a potential therapy, for developing immunotherapy efficacy. MethodsTo ascertain the differentially expressed between PDCD1 low and PDCD1 high subsets and further PDCD1 related genes in skin cutaneous melanoma (SKCM) patients, a genomic analysis was conducted by The Cancer Genome Atlas (TCGA) datasets and web platform TIMER2.0 datasets. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells and B16F10 melanoma mouse were used as models. The cellular and molecular characteristics and mechanisms of Treg cells in melanoma were assessed by performing gene expression studies, immunohistochemistry, RNA sequencing, and flow cytometry.ResultsHere, we evaluate the countenance of T cell immunoglobulin and mucin-domain containing-3 (Tim-3), various immunosuppressive factors within tumor infiltrated regulatory T (Treg) cells after treated with anti-PD-1 or the indicator transduction and activator of transcription 3 (STAT3) inhibitors. Tim-3 gene is expressed differentially between PD-1 low and PD-1 high subsets from TCGA datasets and melanoma patients’ biopsies. Increased expression of Tim-3 is markedly observed within the tissues of the PD-1 blockade resistance of melanoma patients. Targeting STAT3 significantly boosts the response of resistant-PD-1 therapy within the melanoma mouse model. Mechanistically, the manifestation of STAT3 decreases the expression of Tim-3 and various cytokines in the purified Treg cells from individual peripheral blood mononuclear cells (PBMCs) and murine melanoma model, limiting the immunosuppression of Treg cells. ConclusionsOur findings indicate that Tim-3 expression on Treg cells within the TME is STAT3-dependent, providing support to STAT3 as a target and enhancing the immunotherapy for patients suffering from melanoma.
This study investigated the characteristics of oxaliplatin-induced hypersensitivity reactions (HSRs) and evaluated the efficacy of premedication for controlling HSRs among colorectal cancer patients. A retrospective study was performed on the clinical records of 291 patients with colorectal cancer in The Tenth People's Hospital of Shanghai from January 2008 to January 2016. Patients who experienced HSRs to oxaliplatin were compared with those who did not. A total of 291 colorectal cancer patients received oxaliplatin, with 39 (13.40%) experiencing HSRs. Oxaliplatin-free interval and premedication with dexamethasone and antihistamine were independent variables for oxaliplatin-related HSRs. Rechallenging patients with premedication was successful in 72.2% of the patients who successfully completed their treatment. Attention should be paid to patients with any prior exposure to oxaliplatin. Patients with grades 1 and 2 HSRs can successfully rechallenge with oxaliplatin and complete their treatment by premedication with dexamethasone and antihistamine.
Small bowel adenocarcinoma (SBA) is a rare cancer. Optimal treatment regimens have not been established for SBA. This is due in part to the low disease incidence and subsequently, the lack of large, properly designed, randomized clinical trials. In this study, we present a case of an advanced small bowel adenocarcinoma patient with a prolonged progression-free survival of more than 3 years. Genetic profiling of this patient was used to predict prognosis and guide clinical management of the disease. The patient was treated with bevacizumab in combination with XELOX based on her genetic background and our experience in treating colorectal cancer. This treatment strategy, which was tolerable and effective, may be considered as a viable therapeutic strategy for the treatment of metastatic SBA.
3605 Background: Recombinant human adenovirus serotype 5 injection (H101), obtained through genetic engineering to delete the E1B domain and part of the E3 domain and then selectively replicated in tumor cells, has been approved in 2005 for the local treatment of nasopharyngeal carcinoma and head and neck cancers. This trial aimed to evaluate the safety and the preliminary treatment efficacy of H101 combined with standard treatments in patients with liver metastases from colorectal cancer. Methods: In this phase 1, dose-escalation trial (ChiCTR1900027922), 17-75 years old colorectal cancer patients with unresectable liver metastases that failed to first-line therapy were included at The Tenth People's Hospital Affiliated to Tongji University between 2018.9 and 2020.12. All patients received H101 combined with standard therapy (bevacizumab + mFOLFOX6/FOLFIRI). Ultrasound-guided injection of H101 into the liver metastases was performed for all patients, with one of the following doses: 5×10 11 vp/injection for the low, 1×10 12 vp/injection for the moderate, 2×10 12 vp/injection for the moderate-high, and 3×10 12 vp/injection for the high dose groups. Intravenous infusion of bevacizumab (5 mg/kg) and administration of standard-dose mFOLFOX6 or FOLFIRI within 48 h after the intratumor injection was performed. The primary endpoint of the trial was the maximum tolerated dose (MTD). The secondary endpoints included safety, tumor responses, and tumor marker CEA. The adverse events (AEs) were monitored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) and evaluated within 1 week after injection. Imaging examinations were performed for all patients to evaluate the tumor responses, according to the irRECIST. Results: Finally, 8 patients were included; the numbers of patients in the 4 groups were 1, 3, 3, and 1, respectively. MTD was not observed in this study. No grade >4 AEs were observed. The major AE included fatigue (5/8), fever (4/8), shiver (3/8), abdominal pain (3/8), and night sweat (3/8). The tumor responses included partial response in one patient (moderate dose group), stable disease in 6 patients (1, 1, 3, and 1 in the low, moderate, moderate-high, and high dose groups, respectively), and progressive disease in 1 patient (moderate group). No dose-effect response was found. The tumor marker CEA was reduced in 6 of the 8 patients, including 1 (1/1), 3 (3/3), 2 (2/3), and 0 patients in the low, moderate, moderate-high, and high-dose groups, respectively. Conclusions: The safety of H101 combined with standard therapy for liver metastases from colorectal cancer is acceptable, which also shows certain preliminary efficacy. The phase 2 trial is now ongoing. Clinical trial information: ChiCTR1900027922. [Table: see text]
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