Phase I/II clinical trial of efficacy and safety of EGCG oxygen nebulization inhalation in the treatment of COVID-19 pneumonia patients with cancer.

BACKGROUND: The antiviral drug Nirmatrelvir was found to be a key drug in controlling the progression of pneumonia during the infectious phase of COVID-19. However, there are very few options for effective treatment for cancer patients who have viral pneumonia. Glucocorticoids is one of the effective means to control pneumonia, but there are many adverse events. EGCG is a natural low toxic compound with anti-inflammatory function. Thus, this study was designed to investigate the safety and efficacy of epigallocatechin-3-gallate (EGCG) aerosol to control COVID-19 pneumonia in cancer populations. METHODS: The study was designed as a prospective, single-arm, open-label phase I/II trial at Shandong Cancer Hospital and Institute, between January 5, 2023 to March 31,2023 with viral pneumonia on radiographic signs after confirmed novel coronavirus infection. These patients were treated with EGCG nebulization 10 ml three times daily for at least seven days. EGCG concentrations were increased from 1760-8817umol/L to 4 levels with dose escalation following a standard Phase I design of 3-6 patients per level. Any grade adverse event caused by EGCG was considered a dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) is defined as the highest dose with less than one-third of patients experiencing dose limiting toxicity (DLT) due to EGCG. The primary end points were the toxicity of EGCG and CT findings, and the former was graded by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. The secondary end point was the laboratory parameters before and after treatment. RESULT: A total of 60 patients with high risk factors for severe COVID-19 pneumonia (factors such as old age, smoking and combined complications)were included in this phase I-II study. The 54 patients in the final analysis were pathologically confirmed to have tumor burden and completed the whole course of treatment. A patient with bucking at a level of 1760 umol/L and no acute toxicity associated with EGCG has been reported at the second or third dose gradients. At dose escalation to 8817umol/L, Grade 1 adverse events of nausea and stomach discomfort occurred in two patients, which resolved spontaneously within 1 hour. After one week of treatment, CT showed that the incidence of non-progression of pneumonia was 82% (32/39), and the improvement rate of pneumonia was 56.4% (22/39). There was no significant difference in inflammation-related laboratory parameters (white blood cell count, lymphocyte count, IL-6, ferritin, C-reactive protein and lactate dehydrogenase) before and after treatment. CONCLUSION: Aerosol inhalation of EGCG is well tolerated, and preliminary investigation in cancer population suggests that EGCG may be effective in COVID-19-induced pneumonia, which can promote the improvement of patients with moderate pneumonia or prevent them from developing into severe pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05758571. Date of registration: 8 February 2023.

Is there role of adjuvant radiotherapy after complete resection of locally advanced nonsmall cell lung cancer?

PURPOSE OF REVIEW: This review aims to provide a timely and relevant overview of the role of postoperative radiotherapy (PORT) in completely resected stage IIIA-N2 nonsmall cell lung cancer (NSCLC). Given the controversy surrounding the use of PORT and the emergence of advanced radiation techniques and therapies, this review provides valuable insight into current and potential treatment strategies. RECENT FINDINGS: The Lung ART and PORT-C trials have provided valuable insights into the efficacy of PORT in stage IIIA-N2 NSCLC. While the results have been mixed, studies have shown that advanced radiation techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy, can reduce cardiopulmonary toxicities associated with PORT. Molecular targeted therapies and immunotherapies have also shown potential in improving NSCLC treatment outcomes. SUMMARY: The role of radiotherapy becomes smaller and smaller in new era. However, it is too early to abolish radiotherapy for all the patients after complete resection of locally advanced NSCLC. Nowadays, it is recommended to adopt individualized treatment approaches guided by multidisciplinary team consultations. The integration of IMRT, proton therapy, and emerging therapies offers the potential to enhance treatment efficacy while minimizing toxicity. Further research is needed to optimize the use of PORT and explore the method to identify the patients who can really benefit from PORT.

TIGIT blockade enhances tumor response to radiotherapy via a CD103 + dendritic cell-dependent mechanism.

Blockade of the T cell immunoreceptor with the immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) can enhance innate and adaptive tumor immunity and radiotherapy (RT) can enhance anti-tumor immunity. However, our data suggest that TIGIT-mediated immune suppression may be an impediment to such goals. Herein, we report on the synergistic effects of RT combined with anti-TIGIT therapy and the mechanism of their interaction. Treatment efficacy was assessed by measuring primary and secondary tumor growth, survival, and immune memory capacity. The function of CD103 + dendritic cells (DCs) under the combined treatment was assessed in wild-type and BATF3-deficient (BATF3-/-) mice. FMS-like tyrosine kinase 3 ligand (Flt3L) was used to confirm the role of CD103 + DCs in RT combined with anti-TIGIT therapy. TIGIT was upregulated in immune cells following RT in both esophageal squamous cell carcinoma patients and mouse models. Administration of the anti-TIGIT antibody enhanced the efficacy of RT through a CD8 + T cell-dependent mechanism. It was observed that RT and the anti-TIGIT antibody synergistically enhanced the accumulation of tumor-infiltrating DCs, which activated CD8 + T cells. The efficacy of the combination therapy was negated in the BATF3-/- mouse model. CD103 + DCs were required to promote the anti-tumor effects of combination therapy. Additionally, Flt3L therapy enhanced tumor response to RT combined with TIGIT blockade. Our study demonstrated TIGIT blockade can synergistically enhance anti-tumor T cell responses to RT via CD8 + T cells (dependent on CD103 + DCs), suggesting the clinical potential of targeting the TIGIT pathway and expanding CD103 + DCs in RT.

Efficacy and safety of immune checkpoint inhibitors plus anlotinib in small cell lung cancer with brain metastases: a retrospective, multicentre study.

BACKGROUND: Previous studies showed that both immune checkpoint inhibitors (ICIs) and anlotinib have central nervous system (CNS) efficacy. This study aimed to evaluate the efficacy and safety of ICIs combined with anlotinib in small cell lung cancer (SCLC) patients with brain metastases (BMs). METHODS: We retrospectively reviewed SCLC patients with CNS metastases confirmed by brain magnetic resonance imaging (MRI). Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response assessment in neuro-oncology brain metastases (RANO-BM) were used to evaluate treatment response to ICIs plus anlotinib. Kaplan-Meier analysis and Cox regression analysis were performed to determine patient's prognosis. RESULTS: Sixty-six patients with baseline BMs were included. For patients with measurable intracranial lesions, the intracranial objective response rate (ORR) was 29.2% based on RECIST 1.1 criteria and was 27.1% based on RANO-BM criteria. The median intracranial progression-free survival (PFS) was 9.0 months (95% confidence interval [CI], 6.5-11.5 months). The median overall survival (OS) was 13.4 months (95% CI, 10.7-20.5 months). Multivariate Cox regression analysis showed that high disease burden (hazard ratio [HR] = 4.83, P < 0.001), multiple BMs (HR = 2.71, P = 0.036), and more than or equal to 3 prior lines of therapy (HR = 2.56, P = 0.023) were independent negative predictors of OS. The overall incidence of treatment-related adverse events (TRAEs) was 75.8%, and grade 3-4 TRAEs were reported in 19.7% of patients. CONCLUSIONS: Our results suggested that ICIs plus anlotinib had potent CNS efficacy with tolerable toxicity and could be a promising treatment option for SCLC patients with BMs.

TGIF1 plays a carcinogenic role in esophageal squamous cell carcinoma through the Wnt/ß­catenin and Akt/mTOR signaling pathways.

TGFB induced factor homeobox 1 (TGIF1), a transcriptional corepressor, has been reported to be involved in tumorigenesis and cancer development. However, the role of TGIF1 in the growth and metastasis of esophageal cancer is poorly studied. In the present study, it was found that TGIF1 was highly expressed in esophageal cancer tissues and cell lines. The silencing of TGIF1 by siRNA interference significantly inhibited the proliferation, migration, invasion and epithelial­mesenchymal transition (EMT) process of KYSE­150 esophageal cancer cells, and promoted cell apoptosis. Correspondingly, the upregulation of TGIF1 significantly promoted the proliferation and metastatic potential of Eca­109 cells, and reduced apoptosis. Furthermore, the data indicated that the Wnt/ß­catenin and Akt/mammalian target of rapamycin (mTOR) signaling pathways were inhibited by TGIF1 knockdown, and were promoted by the overexpression of TGIF1. It was also confirmed that TGIF1 knockdown reduced tumor growth, inhibited Wnt/ß­catenin and Akt/mTOR pathway activation, and reversed the TGF­ß1­mediated EMT process in a tumor xenograft model. Taken together, the data of the present study suggest that TGIF1 plays an oncogenic role in the progression of esophageal cancer. It may carry out this role by regulating the Wnt/ß­catenin and Akt/mTOR signaling pathways.

Perspective on treatment for unresectable locally advanced non-small cell lung cancer with oncogene-driven mutation: a narrative review.

The standard treatment of unresectable locally advanced non-small cell lung cancer (LA NSCLC) is concurrent chemoradiotherapy. With the addition of immunotherapy, patients with LA NSCLC received a significantly prolonged outcome, while patients with harboring epidermal growth factor receptor (EGFR) mutation benefited less. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of stage IV with harboring EGFR mutation and anaplastic lymphoma kinase rearrangement, but there are few recommendations indicating whether TKI treatment is effective in unresectable NSCLC. Preclinical studies have shown that TKIs could have a radiosensitizing effect, which provided a rationale to consider the application TKI with radiotherapy. In this review, we summarize the clinical studies that have used TKIs in LA-NSCLC as well as ongoing trials, and discuss recent progress in research related to the efficacy of TKI for unresectable LA NSCLC patients. Recent results of small studies evaluating TKI therapy for LA NSCLC patients in combination with radiation or chemoradiation demonstrated promising efficacy, improved outcomes with a tolerable toxicity profile. However, there is a lack of strong evidence for TKI treatment in unresectable LA NSCLC, because of unpowered statistics, lack of molecular selection, or lack of large randomized arms. We prospect the combination of TKI and radiation or chemoradiation therapy might eventually replace the current standard treatment for patients with LA NSCLC harboring oncogene-driven mutation.

Long non-coding RNAs as targets for immunosuppressive drug teriflunomide in anti-cancer potential for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Because of the relatively chemotherapy-refractory nature of HCC and significant potential poor hepatic reserve, chemotherapy has not been used consistently in the treatment of HCC. Effective new drugs for HCC are urgently needed. Teriflunomide, which was approved for the treatment of relapsing forms of multiple sclerosis (MS), has been identified as a potential antineoplastic drug. Long noncoding RNAs (lncRNAs) are a novel class of RNA molecules defined as transcripts longer than 200 nucleotides that lack protein coding potential. In this study, we investigated the ability of teriflunomide to act as an antineoplastic drug by examining the effects of teriflunomide treatment on HCC cells. Teriflunomide strongly inhibited the proliferation of HCC cells, induced cell apoptosis and induced cell accumulation in S phases of the cell cycle. LncRNA and mRNA expression profiles of HCC cells treated with teriflunomide compared with controls were performed by using microarray analysis. For comparison, the differentially expressed mRNAs were annotated by using gene ontology (GO) and pathway analyses. The microarray revealed that 2085 lncRNAs and 1561 mRNAs differed in the cells treated with teriflunomide compared with controls. Several GO terms including protein folding, mitochondrial outer membrane, transmembrane receptor protein phosphatase activity, negative regulation of cellular biosynthetic process, DNA packaging complex, and receptor signaling protein activity were enriched in gene lists, suggesting a potential correlation with the action mechanism of teriflunomide. Pathway analysis then demonstrated that JAK-STAT signaling pathway may play important roles in the cell apoptosis induced by teriflunomide. Co-expression network analysis indicated that a number of lncRNAs and mRNAs were included in the co-expression network, and p34710_v4 is the lncRNA with highest degree. Then the mRNAs associated with those differentially expressed lncRNAs were also annotated by using gene ontology (GO) and pathway analyses. The pathway analyses shows that teriflunomide significantly inhibited cell proliferation and promoted cell apoptosis partly by participating in Wnt signaling pathways. These findings suggest that teriflunomide could be a potential drug for chemotherapy and molecularly targeted therapies of HCC.

Nimotuzumab, an EGFR­targeted antibody, promotes radiosensitivity of recurrent esophageal squamous cell carcinoma.

Local tumor recurrence is one of the main causes for the failure of esophageal cancer treatment following radiotherapy. Previous studies have demonstrated that epidermal growth factor receptor (EGFR)­targeted therapy combined with radiotherapy is expected to become an effective means to control tumor recurrence. The aim of the present study was to investigate the effect and mechanism of nimotuzumab (an EGFR­targeted antibody) in the treatment of recurrent esophageal carcinoma. The radiation responses of two esophageal squamous carcinoma cell lines, EC109 and TE­1, with or without nimotuzumab, were first evaluated by CCK­8 assay. Colony formation and apoptosis were used to measure anti­proliferation effects. It was demonstrated that nimotuzumab arrested the cell cycle at the G2 phase in vitro. Western blotting and immunofluorescence analysis were used to determine signaling pathway changes. It was observed that nimotuzumab inhibited phosphorylation of EGFR in EC109 cells. Furthermore, recurrent tumor models were established and it was identified that the degree of tumor hypoxia was positively associated with EGFR overexpression. In EC109 cell xenografts, nimotuzumab combined with radiation led to a significant delay in recurrent tumor growth compared with that of radiation alone (P<0.001 for 0 Gy pre­irradiation, P=0.005 for 20 Gy pre­irradiation, P=0.005 for 10 Gy pre­irradiation). These results suggest that nimotuzumab combined with radiation may be an effective means to control recurrent esophageal squamous cell carcinoma with EGFR overexpression.

R-spondin family members as novel biomarkers and prognostic factors in lung cancer.

The R-spondin (RSPO) family of secreted proteins consists of four members that have critical roles in embryonic development and organogenesis. However, the expression patterns and the exact roles of the individual RSPO family members in tumorigenesis and progression of lung cancer are unknown, particularly in non-small cell lung cancer, which accounts for 85% of all lung cancer cases. In the present study, data from the ONCOMINE database was used to compare the RNA expression levels of RSPOs in multiple different types of cancer with normal controls. The expression profiles of RSPOs in various types of cancer cell lines were subsequently compared based on data from the Broad Institute Cancer Cell Line Encyclopedia. Using the Kaplan-Meier plotter, the prognostic value of expression of the different RSPOs members was determined for different pathological subtypes of lung cancer. When compared with normal tissues, expression of RSPO1, RSPO2 and RSPO3 was significantly lower in patients with lung cancer. In the survival analysis, increased mRNA expression levels of RSPO1, RSPO2 and RSPO3 were associated with increased survival in patients with lung adenocarcinomas. These results suggest that RSPO1, RSPO2 and RSPO3 may serve as distinct biomarkers and prognostic factors in patients with lung cancer.

Ten-Year Outcomes Of Intensity-Modulated Radiotherapy (IMRT) Combine With Chemotherapy Versus IMRT Alone For Stage II Nasopharyngeal Carcinoma In The Real-World Study (RWD).

OBJECTIVES: The aim was to define the role of chemotherapy in stage II nasopharyngeal carcinoma (NPC) and to identify the toxicity of chemotherapy for these patients in the era of intensity-modulated radiotherapy (IMRT). METHODS: Between January 2002 and December 2013, 169 patients with stage II NPC were analyzed. Of these patients, 149 patients treated with chemotherapy were divided into three groups as follows: neoadjuvant chemotherapy followed by IMRT (NCT) group, concurrent chemotherapy with IMRT (CCRT) group, and neoadjuvant chemotherapy followed by CCRT (NC+CCRT) group. In addition, 20 patients received IMRT alone. We retrospectively assessed the 10-year survival and acute adverse effects in the patients using SPSS software. RESULTS: The median follow-up time was 93 months (2-160 months). The 10-year OS of the NCT, CCRT, NC+CCRT groups vs the IMRT alone group was 69.8%, 63.4%, 69.7% vs 72.4%, respectively (P=0.664, 0.940, and 0.998, respectively). Both univariable and multivariable analyses showed that the addition of chemotherapy to IMRT did not significantly improve the 10-year survival outcomes. The hematotoxicity and mucous reaction of patients with chemotherapy were more serious than those with IMRT alone (P=0.007 and 0.049). Distant metastasis for stage II NPC patients mostly occurred within 3 years, which is very different from patients with advanced NPC. CONCLUSION: Patients with stage II NPC who are treated with IMRT may obtain satisfactory long-term survival outcomes. The additional chemotherapy cannot significantly increase survival; however, it may remarkably increase treatment-associated acute toxic reactions.

Membrane-Binding Adhesive Particulates Enhance the Viability and Paracrine Function of Mesenchymal Cells for Cell-Based Therapy.

Understanding the fundamental cell-material interactions is essential to designing functional materials for biomedical applications. Although mesenchymal stromal cells (MSCs) are known to secrete cytokines and exosomes that are effective to treat degenerative diseases, the inherent property of biomaterials to modulate the therapeutic function of MSCs remains to be investigated. Here, a multivalent cell-membrane adhesive conjugate was generated through polyamindoamine (PAMAM) and an oligopeptide, IKVAV, and the conjugate was further complexed with hyaluronic acid (HA). The adhesive particulates were used to coat the surface of adipose-derived mesenchymal stromal cells (Ad-MSCs) and studied in the MSC spheroid culture. The analysis showed that the adhesive complexes formed via PAMAM conjugates and HA significantly promoted the proliferation and the gene expression of pro-angiogenesis cytokines in MSCs; the production of anti-inflammatory miRNAs in exosomes could also be elevated. The transplantation of the Ad-MSCs primed with PAMAM-IKVAV/HA composite particulates in a rat myocardial infarction model further demonstrated the beneficial effects of membrane-binding materials on improving the cell retention and tissue angiogenesis. The new function of membrane-binding adhesive materials potentially provides useful ways to improve cell-based therapy.

Proton beam therapy for cancer in the era of precision medicine.

Precision radiotherapy, which accurately delivers the dose on a tumor and confers little or no irradiation to the surrounding normal tissue and organs, results in maximum tumor control and decreases the toxicity to the utmost extent. Proton beam therapy (PBT) provides superior dose distributions and has a dosimetric advantage over photon beam therapy. Initially, the clinical practice and study of proton beam therapy focused on ocular tumor, skull base, paraspinal tumors (chondrosarcoma and chordoma), and unresectable sarcomas, which responded poorly when treated with photon radiotherapy. Then, it is widely regarded as an ideal mode for reirradiation and pediatrics due to reducing unwanted side effects by lessening the dose to normal tissue. During the past decade, the application of PBT has been rapidly increasing worldwide and gradually expanding for the treatment of various malignancies. However, to date, the role of PBT in clinical settings is still controversial, and there are considerable challenges in its application. We systematically review the latest advances of PBT and the challenges for patient treatment in the era of precision medicine.

Anti-inflammatory drug, leflunomide and its metabolite teriflunomide inhibit NSCLC proliferation in vivo and in vitro.

Lung cancer causes more than 150000 deaths annually in the United States alone, of which non-small cell lung cancer (NSCLC) accounts for 80%. Our studies demonstrated that NSCLC cells were sensitive to leflunomide and its metabolite teriflunomide, a FDA approved drug, which was a well-known immunomodulatory drug for relapsing multiple sclerosis (MS). In the present studies, we found first time that they displayed anti-tumor activity of NSCLC in vitro and in vivo. Potent anti-cancer effects in NSCLC in vitro, including inhibiting NSCLC cells viability, arresting cell cycle at the G0/G1 phase, inducing cell apoptosis, delaying and suppressing NSCLC cells colony-forming ability and cell motility, could be achieved with this agent. Meanwhile, we provided evidence that these effects were applicable in vivo by using H460 cells xenograft model in nude mice. In addition, to comprehensively clarify the mechanisms of teriflunomide in NSCLC, we explored a genome-wide transcriptomic analysis, and found that teriflunomide was involved in multiple signaling pathways and cellular processes, such as cell cycle, apoptosis, MAPK and p53 signaling pathway. Taken together, the results of our studies provided insights into a novel anti-cancer effect of leflunomide and teriflunomide on NSCLC and might open new therapeutic avenues for the treatment of NSCLC.

Consolidative thoracic radiotherapy for extensive stage small cell lung cancer.

Extensive stage small cell lung cancer (ES-SCLC) represents approximately half of all diagnosed small cell lung cancer worldwide. It is notorious for a high risk of local recurrence although it's sensitive to chemotherapy. Nearly 90% of intrathoracic failures happen in the first year after diagnosis. The cornerstone of treatment for ES-SCLC is etoposide-platinum based chemotherapy. Consolidative radiotherapy to thorax has diminished the incidence of local relapse, therefore it should be offered to patients with excellent response to induction first-line chemotherapy. This review centers on the clinical evidence for the use of thoracic radiotherapy (TRT) and current modalities of TRT delivery, then tries to determine a feasible way to conduct TRT in a selective group of cases.

The paracrine effects of adipose-derived stem cells on neovascularization and biocompatibility of a macroencapsulation device.

The foreign-body response to biomaterials compromises the performance of many biomedical devices by severe fibrosis and limited neovascularization. Mesenchymal stem cells are known to secrete cytokines for treating inflammatory conditions. In this study, we aim to investigate whether the paracrine products of adipose-derived mesenchymal stem cells (ADSCs) can affect the microenvironment of biomaterials and improve tissue responses to biomaterial implants. A model system was built by loading ADSC spheroids into a macroencapsulation device composed of polytetrafluoroethylene (PTFE) filtration membranes. Soluble ADSC factors that diffused out of the device in vitro promoted the angiogenetic activity of endothelial cells and affected the secretion pattern of macrophages. In vivo study was carried out by subcutaneously embedding blank or ADSC-laden devices in rats. Following a 4 week implantation, the ADSC-laden devices were better vascularized and induced significantly less fibrotic tissue formation in comparison to the non-cellular controls. This study may facilitate our understanding of foreign-body responses and suggest new ways to improve the tissue reaction of biomedical devices for cell-based therapy.

Involved field irradiation for the treatment of esophageal cancer: is it better than elective nodal irradiation?

Esophageal cancer (EC) is an extremely aggressive and lethal malignancy with an increasing incidence worldwide. Currently, the combination of radiotherapy and concurrent chemotherapy is performed for nonsurgical EC. However, there is no clear consensus on the accurate definition of the clinical target volume. Still, elective nodal irradiation (ENI) is the conventional remedy adopted for EC patients, while severe radiotherapy-related toxicities would occur in at least half of patients. Involved field irradiation (IFI) is a selective way to decrease the irradiation volume and thereby to decline toxicities. This review centers on the modality of IFI and compares the treatment efficacy between IFI and ENI.