Adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC): a phase II trial.

Background: This phase II prospective trial aimed to investigate the efficacy and safety of adebrelimab (PD-L1 antibody) plus first-line chemotherapy followed by sequential thoracic radiotherapy (TRT) combined with adebrelimab in extensive-stage small-cell lung cancer (ES-SCLC). Biomarkers associated with potential therapeutic effects were also explored. Methods: Patients with previously untreated ES-SCLC were enrolled at Shandong Cancer Hospital and Institute (Jinan, China). Patients received 4-6 cycles of adebrelimab (20 mg/kg, D1, Q3W) combined with EP/EC (etoposide, 100 mg/m2, D1-3, Q3W and cisplatin, 75 mg/m2, D1, Q3W or carboplatin, AUC = 5, D1, Q3W). Then patients with response sequentially underwent consolidative TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation), and maintenance adebrelimab until disease progression or intolerable adverse events (AEs). The primary endpoint was overall survival (OS). Genomic and circulating tumour DNA (ctDNA) profiling were also analyzed with tumour tissues and peripheral blood. This trial was registered with ClinicalTrials.gov, NCT04562337. Findings: From October 2020 to April 2023, 67 patients diagnosed with ES-SCLC were enrolled and received at least one dose of study treatment. All patients were included in the efficacy and safety analyses. 45 patients received sequential TRT as planned. The median OS and progression-free survival (PFS) was 21.4 months (95% CI: 17.2-not reached months) and 10.1 months (95% CI: 6.9-15.5 months), respectively. The confirmed objective response rate was 71.6% (48/67, 95% CI: 59.3-82.0%) and disease control rate was 89.6% (60/67, 95% CI: 79.7-95.7%). There were no treatment-related deaths. The most common grade 3 or higher treatment-related adverse events (TRAEs) were hematological toxicities. The incidence of any grade and G3+ pneumonitis was 25% (17/67) and 6% (4/67), respectively. No unexpected adverse events were observed. Patients without co-mutations of TP53/RB1 in both tissue and peripheral blood displayed longer PFS (tissue, P = 0.071; ctDNA, P = 0.060) and OS (tissue, P = 0.032; ctDNA, P = 0.031). Interpretation: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. Funding: This study was funded by the National Natural Science Foundation of China (82172865), Jiangsu Hengrui Pharmaceuticals Co., Ltd. and Amoy Diagnostics Co., Ltd.

The AST/ALT ratio predicts survival and improves oncological therapy decisions in patients with non-small cell lung cancer receiving immunotherapy with or without radiotherapy.

Background and purpose: Immunotherapy, with or without radiotherapy (iRT or ICIs-nonRT), is the standard treatment for non-small cell lung cancer (NSCLC). Nonetheless, the response to the treatment varies among patients. Given the established role of aspartate aminotransferase/alanine transaminase (AST/ALT) ratio in predicting cancer prognosis, we sought to identify whether the pre-treatment AST/ALT ratio has the potential to serve as a prognostic factor for NSCLC patients receiving ICIs-nonRT and iRT. Materials and methods: We retrospectively analyzed NSCLC patients who received immunotherapy between April 2018 and March 2021. Patients were classified into iRT group and ICIs-nonRT group and further classified based on AST/ALT ratio cut-off values. The Kaplan-Meier (KM) method estimated the time-to-event endpoints (progression-free survival (PFS) and overall survival (OS). Results: Of the cohort, 239 underwent ICIs-nonRT and 155 received iRT. Higher AST/ALT ratios correlated with worse outcomes in the ICIs-nonRT group but indicated better outcomes in those who received iRT. Multivariate analysis validated AST/ALT ratio as an independent prognostic factor. For AST/ALT ratios between 0.67-1.7, both ICIs-nonRT and iRT yielded similar treatment outcomes; with AST/ALT ratios greater than 1.7, iRT could be a more favorable treatment option (P=0.038). Conversely, for ratios less than 0.67, ICIs-nonRT could be a more favorable treatment option (P=0.073). Conclusions: The pre-treatment AST/ALT ratio demonstrates potential as a prognostic marker for treatment outcomes in NSCLC patients receiving either ICIs-nonRT or iRT. This finding could help guide clinicians in selecting more effective treatment protocols, thereby enhancing patient prognosis.

Clinical multi-dimensional prognostic nomogram for predicting the efficacy of immunotherapy in NSCLC.

The advent of immunotherapy has greatly improved the prognosis of non-small cell lung (NSCLC) patients. However, given its low response rate and high cost of treatment, the search for valuable predictive markers of treatment efficacy is necessary. Considering the complexity and heterogeneity of the tumour and tumour microenvironment, the construction of a multi-dimensional prediction model is necessary. Therefore, we aimed to integrate clinical parameters, radiomic features, and immune signature data from NSCLC patients receiving immunotherapy to construct a multi-dimensional prediction model to better predict the efficacy of immunotherapy. The current study enrolled 137 NSCLC patients who received immunotherapy. We collected baseline clinical information, CT images, and tumour tissue specimens. Using 3D-Slicer software, radiomic features were extracted from patient CT images, and tumor tissue samples obtained before immunotherapy were subjected to immunohistochemical staining. Then, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to downscale the data, and the radiomic features and immune signatures associated with the prognosis of immunotherapy patients were identified. The modified lung immune predictive index (mLIPI), radiomics score (Radioscore), immune score and multi-dimensional model nomogram were constructed. The C-index and area under the curve (AUC) were applied to evaluate the predictive efficacy of the models. Three radiomic features and three immune signatures that could predict the efficacy of immunotherapy were eventually screened. Multivariate analysis showed that the mLIPI, Radioscore, and immune score were independent predictive factors for PFS and OS (P < 0.05 for all models). The multi-dimensional model combining the three models showed better predictive efficacy than the mLIPI, Radioscore, and immune score (PFS: 0.721 vs. 0.662 vs. 0.610 vs. 0.610; OS: 0.727 vs. 0.661 vs. 0.601 vs. 0.602 respectively). The multi-dimensional model showed the best predictive efficacy, with C-index for PFS and OS higher than mLIPI, radioscore and immune score: 0.721 vs. 0.662 vs. 0.610 vs. 0.610 for PFS and 0.727 vs. 0.661 vs. 0.601 vs. 0.602 for OS, respectively. The AUC for the multi-dimensional model also performed better than those of the individual models: 0.771 vs. 0.684 vs. 0.715 vs. 0.711 for PFS and 0.768 vs. 0.662 vs. 0.661 vs. 0.658 for OS, respectively. The multi-dimensional model combining the three models had better predictive efficacy than any single model and was more likely to help provide patients personalized and precision medicine.

Progressive Disease with Mixed Response After Immunotherapy in Non-Small Cell Lung Cancer.

Purpose: There exists a dearth of research concerning non-small cell lung cancer (NSCLC) patients experiencing overall progressive disease concomitant with shrinking lesions after immunotherapy. This is a special type of mixed response. We aim to evaluate the clinical characteristics and treatment options of these patients during immunotherapy. Patients and Methods: We categorized patients into two groups: Progressive Disease with Mixed Responses (PDMR) (n = 31) and Progressive Disease with None Mixed Responses (PDNMR) (n = 144), depending on whether at least one target lesion had shrunk by ≥30% at the point of overall progression. Computed tomography scans and magnetic resonance imaging were utilized to evaluate the clinicopathological significance of these patients, and a multivariate analysis was conducted to scrutinize the clinical characteristics and prognosis-influencing factors in these patients. Results: Patients in the PDMR group had worse staging and a greater proportion of previous radiotherapy. The median overall survival (mOS 22 vs 36.4 months; P = 0.019) and median progression-free survival (mPFS 5.83 vs 9.03 months; P = 0.031) of the PDMR group were shorter than PDNMR group. Longer subsequent OS with continued immunotherapy after PDMR compared with patients who do not continue with immunization after PDMR (mOS 23.9 vs 6.5 months; P = 0.024). Conclusion: PDMR was primarily observed in stage IV patients and previously irradiated patients. OS and PFS were inferior in patients with PDMR compared to patients with PDNMR. The continuation of immunotherapy in PDMR patients could extend their survival.

Case report: Bridging radiation therapy before chimeric antigen receptor T-cell therapy induces sustained remission in patients with relapsed/refractory double-expressor diffuse large B-cell lymphoma with localized compressive symptoms.

Background: High-risk double-expressor diffuse large B-cell lymphoma has an inferior prognosis following standard first-line therapy. After failure of second-line therapy, treatment options are limited if accompanied by localized compressive symptoms. Chimeric Antigen Receptor T cell (CAR-T) therapy preceded by bridging radiotherapy may be an effective emerging therapy. Case presentation: We report a 66-year-old female patient diagnosed with stage IV double-expressor diffuse large B-cell lymphoma. The patient achieved progressive disease after two cycles of rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone and continued to develop cervical lymph node recurrence after second-line therapy. The patient was infused with CAR-T cells after receiving focal bridging radiotherapy and remained in complete response more than 9 months after treatment. In addition, the patients did not experience serious adverse reactions related to radiotherapy as well as CAR-T cell therapy. Conclusions: In this article, we describe a patient with double-expressor diffuse large B-cell lymphoma with localized compression symptoms after second-line treatment failure who benefited from CAR-T combined with focal bridging radiotherapy.

Suppressive immune microenvironment and CART therapy for glioblastoma: Future prospects and challenges.

Glioblastoma, a highly malignant intracranial tumor, has acquired slow progress in treatment. Previous clinical trials involving targeted therapy and immune checkpoint inhibitors have shown no significant benefits in treating glioblastoma. This ineffectiveness is largely due to the complex immunosuppressive environment of glioblastoma. Glioblastoma cells exhibit low immunogenicity and strong heterogeneity and the immune microenvironment is replete with inhibitory cytokines, numerous immunosuppressive cells, and insufficient effective T cells. Fortunately, recent Phase I clinical trials of CART therapy for glioblastoma have confirmed its safety, with a small subset of patients achieving survival benefits. However, CART therapy continues to face challenges, including blood-brain barrier obstruction, antigen loss, and an immunosuppressive tumor microenvironment (TME). This article provides a detailed examination of glioblastoma's immune microenvironment, both from intrinsic and extrinsic tumor cell factors, reviews current clinical and basic research on multi-targets CART treatment, and concludes by outlining the key challenges in using CART cells for glioblastoma therapy.

Cd39 and P2rx7-Wnt signaling enhance blast pathogenicity in an experimental model of acute myeloid leukemia.

Not available.

Exploring the value of FAP-targeted PET/CT in differentiating breast cancer molecular subtypes: a preliminary study.

PURPOSE: This prospective study aims to evaluate the value of [18F]AlF-NOTA-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography-computed tomography (PET/CT) in predicting molecular subtypes of breast cancer. METHODS: The study consecutively recruited patients suspected of having breast cancer from a single center who were prospectively enrolled from July 2023 to May 2024 and underwent [18F]AlF-NOTA-FAPI-04 PET/CT. This study compared the differences in tracer uptake among breast cancers with different adverse prognostic factors and molecular subtypes. The classification performance for each molecular subtype of breast cancer was assessed using a receiver operating characteristic (ROC) curve. RESULTS: Fifty-three participants (mean age, 51 ± 11 years; 52 females) were evaluated. Breast cancer lesions with adverse prognostic factors showed higher tracer uptake. The five different molecular subtypes exhibited varying levels of uptake. The luminal A and luminal B (HER2-negative) subtypes had relatively low uptake, while the luminal B (HER2-positive), HER2-positive, and triple-negative subtypes had relatively high uptake. ROC analysis identified the max standardized uptake value (SUVmax) as a significant classifier (AUC = 0.912, P = 0.0005) for the luminal A subtype, with 100% sensitivity and 83% specificity. For predicting the luminal B (HER2-negative) subtype, SUVmax had an AUC of 0.770 (P = 0.0015). SUVmax, with an AUC of 0.781 (P = 0.003), was used to identify the triple-negative subtype tumors, resulting in a sensitivity of 100% and specificity of 51%. Lastly, the ROC curve showed the cut-off 15.40 (AUC = 0.921, P < 0.0001) could classify luminal A & luminal B (HER2-negative), and luminal B (HER2-positive) & HER2-positive & triple-negative, yielding a sensitivity of 94% and specificity of 79%. CONCLUSION: The uptake of [18F]AlF-NOTA-FAPI-04 is significantly correlated with the molecular subtypes of breast cancer, and [18F]AlF-NOTA-FAPI-04 PET/CT is a potential tool for noninvasive identification of luminal A subtypes and guidance of FAP-targeted therapies.

Comparison of proton therapy and photon therapy for early-stage non-small cell lung cancer: a meta-analysis.

The use of proton therapy (PT) in early-stage non-small cell lung cancer (ES-NSCLC) remains controversial, with insufficient evidence to determine its superiority over photon therapy (XRT). We conducted a systematic review of PT trials in ES-NSCLC, analyzing dosimetry, efficacy, and safety across to inform clinical decision-making. Our study showed that PT reduced lung and heart dosimetric parameters compared to XRT, with significant differences in lung V5, lung V10 and mean heart dose (MHD). In terms of efficacy, there were no significant differences in 1-year OS, 3-year OS and 3-year PFS between PT and XRT. For toxicity, no significant difference was observed in treatment-related adverse events (TRAEs) and radiation pneumonitis (RP). Single-arm analysis of PT found that V5, V10, V20 of lung and heart V5 were 13.4%, 11.3%, 7.9% and 0.7%, respectively. The mean lung dose and MHD were 4.15 Gy and 0.17 Gy, respectively. The single-arm pooled 1-, 2-, 3- and 5-year OS rates for PT were 95.3%, 82.5%, 81.3% and 69.3%, respectively. PFS rate and local control rate at 3 years were 68.1% and 91.2%, respectively. The rates of TRAEs of grade ≥ 3 and grade ≥ 2 were 2.8% and 19.8%, respectively. The grade ≥ 2 RP occurred at a rate of 8.7%. In conclusion, PT had acceptable efficacy and safety, and was better at protecting organs at risk than XRT in ES-NSCLC. However, the survival and safety benefit of PT was not significant compared to XRT.

Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression.

Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.

Irradiated tumor cell-released microparticles enhance the therapeutic efficacy of PD-1 inhibitors by promoting M1-TAMs polarization in NSCLC brain metastases.

Brain metastases (BMs) are the most common sites of metastasis in patients with non-small cell lung cancer (NSCLC). However, BMs are not responsive to immunotherapy because of the blood-brain barrier. This is because intracranial immune cells such as M2 tumor-associated macrophages (TAMs) accumulate, creating an immunosuppressive tumor microenvironment. In this study, we focused on irradiated tumor cell-released microparticles (RT-MPs) that can cross the blood-brain barrier and influence the intracranial immune microenvironment. Using animal models of BMs, we observed that RT-MPs could penetrate the blood-brain barrier and be swallowed by TAMs. Then the microenvironment of TAMs is shifted from the M2 phenotype to the M1 phenotype, thereby modulating the interactions between TAMs and tumor cells. Single-cell sequencing analysis demonstrated that TAMs, after internalizing RT-MPs, active chemokine signaling pathways and secrete more chemokines, such as CCL5, CXCL2, CXCL1, CCL3, CCL4, and CCL22, attracting more CD4+ T cells and CD8+ T cells, improving immune-mediated killing, and enhancing subsequent combination anti-PD-1 therapy. These findings provide a preclinical foundation for exploring alternative treatments for patients with immunoresistant NSCLC BMs.

Sex-specific Difference for Small Cell Lung Cancer from Immunotherapy Advancement.

BACKGROUND: The treatment of lung cancer has witnessed significant progress, leading to improved survival rates among patients. It is important to assess the individual contributions of non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) to overall lung-cancer incidence and mortality trends based population, especially sex difference. METHODS: We analyzed lung cancer mortality based on subtype, gender, and calendar year. The Joinpoint software was used to identify any changes in incidence and trends in mortality. RESULTS: Incidence and incidence-based mortality declined from 2001 to 2019 both NSCLC and SCLC annually. The most significant decrease occurred between 2016 and 2019 with annual percent change of 5.71%. From 2012 to 2016, the incidence-based mortality of SCLC in women changed by 2.7% in tandem with incidence decreased 2.84%. Remarkably, the incidence-based mortality for women declined notably by 5.23% between 2016 and 2019, even as the incidence showed a less extent of decreasing (-2.59%). The survival rate for women was 15.2% in 2001, 19.3% in 2016, it had increased to 21.3% in 2018 but similar trends not in men. The survival curve showed the change in survival outcomes over time among men and women (median overall survival: 13 vs 23months) receiving immunotherapy for SCLC. CONCLUSION: Population-level mortality from NSCLC and SCLC in the United States fell sharply from 2016 to 2019 as incidence deceased, and survival improved substantially. Our analysis suggests that approval for and use of immunotherapy may explain the mortality reduction observed during this period, with significant benefits especially for SCLC patient in women.

LILRB2 inhibition enhances radiation sensitivity in non-small cell lung cancer by attenuating radiation-induced senescence.

Radiotherapy (RT) in non-small cell lung cancer (NSCLC) triggers cellular senescence, complicating tumor microenvironments and affecting treatment outcomes. This study examines the role of lymphocyte immunoglobulin-like receptor B2 (LILRB2) in modulating RT-induced senescence and radiosensitivity in NSCLC. Through methodologies including irradiation, lentivirus transfection, and various molecular assays, we assessed LILRB2's expression and its impact on cellular senescence levels and tumor cell behaviors. Our findings reveal that RT upregulates LILRB2, facilitating senescence and a senescence-associated secretory phenotype (SASP), which in turn enhances tumor proliferation and resistance to radiation. Importantly, LILRB2 silencing attenuates these effects by inhibiting the JAK2/STAT3 pathway, significantly increasing radiosensitivity in NSCLC models. Clinical data correlate high LILRB2 expression with reduced RT response and poorer prognosis, suggesting LILRB2's pivotal role in RT-induced senescence and its potential as a therapeutic target to improve NSCLC radiosensitivity.

Assessment of bidirectional relationships between hypothyroidism and endometrial cancer: a two-sample Mendelian randomization study.

Objective: Hypothyroidism, characterized by reduced thyroid hormone levels, and endometrial cancer, a prevalent gynecological malignancy, have been suggested to have a potential association in previous observational studies. However, the causal relationship between them remains uncertain. This study aimed to investigate the causal relationship between hypothyroidism and endometrial cancer using a bilateral Mendelian randomization approach. Methods: A bidirectional two-sample Mendelian randomization study was conducted using summary statistics from genome-wide association studies to identify genetic variants associated with hypothyroidism and endometrial cancer. The inverse variance weighting method was used as the main analysis, and sensitivity analyses were conducted to validate the MR results. Results: The results of our analysis did not support a causal effect of hypothyroidism (OR: 0.93, p=0.08) or autoimmune hypothyroidism (OR: 0.98, p=0.39) on endometrial cancer risk. In the reverse MR analysis, we did not find a significant causal effect of endometrial cancer on hypothyroidism (OR: 0.96, p=0.75) or autoimmune hypothyroidism (OR: 0.92, p=0.50). Based on subgroup analysis by pathological subtypes of endometrial cancer, the above findings were further substantiated (all p-value >0.05). Conclusions: Our Mendelian randomization analysis suggests a lack of causal association between hypothyroidism and endometrial cancer. To gain a deeper understanding of this association, it is essential to conduct large-scale randomized controlled trials in the future to validate our findings.

Spatial interaction and functional status of CD68+SHP2+ macrophages in tumor microenvironment correlate with overall survival of NSCLC.

Background: Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and support resistance to therapy, constituting promising targets for the development of novel anticancer agents. Our previous results suggest that SHP2 plays a crucial role in reprogramming the phenotype of TAMs. Thus, we hypothesized that SHP2+ TAM may predict the treatment efficacy of non-small cell lung cancer NSCLC patients as a biomarker. Methods: We analyzed cancer tissue samples from 79 NSCLC patients using multiplex fluorescence (mIF) staining to visualize various SHP-2+ TAM subpopulations (CD68+SHP2+, CD68+CD86+, CD68 + 206+, CD68+ CD86+SHP2+, CD68+ CD206+SHP2+) and T cells (CD8+ Granzyme B +) of immune cells. The immune cells proportions were quantified in the tumor regions (Tumor) and stromal regions (Stroma), as well as in the overall tumor microenvironment (Tumor and Stroma, TME). The analysis endpoint was overall survival (OS), correlating them with levels of cell infiltration or effective density. Cox regression was used to evaluate the associations between immune cell subsets infiltration and OS. Correlations between different immune cell subsets were examined by Spearman's tests. Results: In NSCLC, the distribution of different macrophage subsets within the TME, tumor regions, and stroma regions exhibited inconsistency. The proportions of CD68+ SHP2+ TAMs (P < 0.05) were higher in tumor than in stroma. And the high infiltration of CD68+SHP2+ TAMs in tumor areas correlated with poor OS (P < 0.05). We found that the expression level of SHP2 was higher in M2-like macrophages than in M1-like macrophages. The CD68+SHP2+ subset proportion was positively correlated with the CD68+CD206+ subset within TME (P < 0.0001), tumor (P < 0.0001) and stroma (P < 0.0001). Conclusions: The high infiltration of CD68+SHP2+ TAMs predict poor OS in NSCLC. Targeting SHP2 is a potentially effective strategy to inhibit M2-phenotype polarization. And it provides a new thought for SHP2 targeted cancer immunotherapy.

Efficacy and safety of pyrotinib combined with albumin-bound paclitaxel as first-line treatment for HER2-positive metastatic breast cancer in patients previously treated with adjuvant and/or neoadjuvant trastuzumab therapy: The stage 1 results of a single-arm, phase 2 prospective clinical trial.

OBJECTIVE: It has been observed that the prognosis of patients with HER2-positive metastatic breast cancer has improved significantly with HER2-targeted agents. However, there is still a lack of evidence regarding first-line anti-HER2 treatment options for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, there are no reliable markers that can predict the efficacy of anti-HER2 treatment in these patients. METHODS: Patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer were enrolled. Pyrotinib plus albumin-bound paclitaxel were used as first-line treatment. The primary endpoint was the objective response rate (ORR). The safety profile was also assessed. In order to explore predictive biomarkers using Olink technology, blood samples were collected dynamically. RESULTS: From December 2019 to August 2023, the first stage of the study involved 27 eligible patients. It has not yet reached the median PFS despite the median follow-up being 17.8 months. Efficacy evaluation showed that the ORR was 92.6%, and the DCR was 100%. Adverse events of grade 3 or higher included diarrhoea (29.6%), leukopenia (11.1%), neutropenia (25.9%), oral mucositis (3.7%), and hand-foot syndrome (3.7%). Toll-like receptor 3 (TLR3) and Proto-oncogene tyrosine-protein kinase receptor (RET) were proteins with significant relevance to PFS in these patients. CONCLUSIONS: This study demonstrates that pyrotinib plus albumin-bound paclitaxel as a first-line treatment regimen shows good efficacy and manageable safety for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, a significant association was identified between the expression levels of TLR3 and RET and the PFS in patients.

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.

Prognostic effect of TCF1+ CD8+ T cell and TOX+ CD8+ T cell infiltration in lung adenocarcinoma.

Recent studies have highlighted the pivotal roles of T cell transcription factors TCF-1 and TOX in modulating the immune response in cancer, with TCF-1 maintaining CD8+ T cell stemness and TOX promoting T cell exhaustion. The prognostic significance of these factors in lung adenocarcinoma (LUAD) remains a critical area of investigation. The retrospective study included 191 patients with LUAD who underwent surgery, of whom 83% were in stages II and III. These patients were divided into exploratory (n = 135) and validation (n = 56) groups based on the time of diagnosis. Multiplex fluorescence immunohistochemistry was used to examine the infiltration levels of CD8+ T cells, TCF1+ CD8+ T cells, and TOX+ CD8+ T cells. The percentage of CD8+ T cells in tumor was markedly lower than that in stroma (p < 0.05). In tumor-draining lymph nodes (TDLNs) invaded by tumor, the proportion of stem-like TCF1+ CD8+ T cells was significantly decreased (p < 0.01). Importantly, higher infiltration levels of CD8+ T cells and TCF1+ CD8+ T cells were associated with improved disease-free survival (DFS) (p = 0.009 and p = 0.006, respectively) and overall survival (OS) (p = 0.018 and p = 0.010, respectively). This study underscores the potential of TCF1+ CD8+ T cells as prognostic biomarkers in LUAD, providing insights into the tumor immune microenvironment and guiding future therapeutic strategies.