Targeting the PI3K/AKT/mTOR pathway offer a promising therapeutic strategy for cholangiocarcinoma patients with high doublecortin-like kinase 1 expression.

BACKGROUND: Cholangiocarcinoma (CCA), characterized by high heterogeneity and extreme malignancy, has a poor prognosis. Doublecortin-like kinase 1 (DCLK1) promotes a variety of malignant cancers in their progression. Targeting DCLK1 or its associated regulatory pathways can prevent the generation and deterioration of several malignancies. However, the role of DCLK1 in CCA progression and its molecular mechanisms remain unknown. Therefore, we aimed to investigate whether and how DCLK1 contributes to CCA progression. METHODS: The expression of DCLK1 in CCA patients was detected using Immunohistochemistry (IHC). We established DCLK1 knockout and DCLK1 overexpression cell lines for Colony Formation Assay and Transwell experiments to explore the tumor-promoting role of DCLK1. RT-PCR, Western blot and multiple fluorescent staining were used to assess the association between DCLK1 and epithelial-mesenchymal transition (EMT) markers. RNA sequencing and bioinformatics analysis were performed to identify the underlying mechanisms by which DCLK1 regulates CCA progression and the EMT program. RESULTS: DCLK1 was overexpressed in CCA tissues and was associated with poor prognosis. DCLK1 overexpression facilitated CCA cell invasion, migration, and proliferation, whereas DCLK1 knockdown reversed the malignant tendencies of CCA cells, which had been confirmed both in vivo and in vitro. Furthermore, we demonstrated that DCLK1 was substantially linked to the advancement of the EMT program, which included the overexpression of mesenchymal markers and the downregulation of epithelial markers. For the underlying mechanism, we proposed that the PI3K/AKT/mTOR pathway is the key process for the role of DCLK1 in tumor progression and the occurrence of the EMT program. When administered with LY294002, an inhibitor of the PI3K/AKT/mTOR pathway, the tumor's ability to proliferate, migrate, and invade was greatly suppressed, and the EMT process was generally reversed. CONCLUSIONS: DCLK1 facilitates the malignant biological behavior of CCA cells through the PI3K/AKT/mTOR pathway. In individuals with cholangiocarcinoma who express DCLK1 at high levels, inhibitors of the PI3K/AKT/mTOR signaling pathway may be an effective therapeutic approach.

Risk Factors of Distant Metastatic Parathyroid Carcinoma and Insights into Therapeutic Perspectives.

BACKGROUND: Distant metastatic parathyroid carcinoma (DM-PC) is a rare but often lethal entity with limited data about prognostic indicators. We sought to investigate the risk factors, patterns, and outcomes of DM-PC. METHODS: In this observational cohort study, 126 patients who underwent surgery for PC at a tertiary referral center from 2010 to 2023 were enrolled, among whom 38 had DMs. Univariate and multivariate Cox regression analyses were used to assess the effects of prognostic factors on DM. RESULTS: The cumulative incidence of DM was 14.1%, 33.8%, and 66.9% at 5, 10, and 20 years in the duration of disease course, respectively. DM-PC patients suffered a worse 5-year overall survival of 37.1% compared with 89.8% in the non-DM patients (p < 0.001). DM-PC patients also suffered more previous operations (p < 0.001), higher preoperative serum calcium (p<0.001) and parathyroid hormone (PTH) levels (p < 0.001), lower frequencies of R0 resection (p < 0.001), higher rates of pathological vascular invasion (p = 0.020), thyroid infiltration (p = 0.027), extraglandular extension (p = 0.001), upper aerodigestive tract (UAT) invasion (p < 0.001), and lymph node metastasis (p < 0.001). Multivariate Cox regression revealed that non-R0 resection (HR 6.144, 95% CI 2.881-13.106, p < 0.001), UAT invasion (HR 3.718, 95% CI 1.782-7.756, p < 0.001), and higher preoperative PTH levels (HR 1.001, 95% CI 1.000-1.001, p = 0.012) were independent risk factors of DM. CONCLUSIONS: Upper aerodigestive tract invasion and higher preoperative PTH levels might be risk factors for possible metastatic involvement of PC. R0 resection and closer surveillance should be considered in such cases to minimize the risk of DM and to optimize patient care.

GGT5: a potential immunotherapy response inhibitor in gastric cancer by modulating GSH metabolism and sustaining memory CD8+ T cell infiltration.

PURPOSE: The variable responses to immunotherapy observed in gastric cancer (GC) patients can be attributed to the intricate nature of the tumor microenvironment. Glutathione (GSH) metabolism significantly influences the initiation and progression of gastric cancer. Consequently, targeting GSH metabolism holds promise for improving the effectiveness of Immune checkpoints inhibitors (ICIs). METHODS: We investigated 16 genes related to GSH metabolism, sourced from the MSigDB database, using pan-cancer datasets from TCGA. The most representative prognosis-related gene was identified for further analysis. ScRNA-sequencing analysis was used to explore the tumor heterogeneity of GC, and the results were confirmed by  Multiplex immunohistochemistry (mIHC). RESULTS: Through DEGs, LASSO, univariate and multivariate Cox regression analyses, and survival analysis, we identified GGT5 as the hub gene in GSH metabolism with the potential to promote GC. Combining CIBERSORT, ssGSEA, and scRNA analysis, we constructed the immune architecture of GC. The subpopulations of T cells were isolated, revealing a strong association between GGT5 and memory CD8+ T cells. Furthermore, specimens from 10 GC patients receiving immunotherapy were collected. mIHC was used to assess the expression levels of GGT5 and memory CD8+ T cell markers. Our results established a positive correlation between GGT5 expression, the enrichment of memory CD8+ T cells, and a suboptimal response to immunotherapy. CONCLUSIONS: Our study identifies GGT5, a hub gene in GSH metabolism, as a potential therapeutic target for inhibiting the response to immunotherapy in GC patients. These findings offer new insights into strategies for optimizing immunotherapy of GC.

Elemental diet preventative effects for adverse events during chemotherapy in patients with esophageal cancer - A systematic review and meta-analysis.

Introduction: The effectiveness of an elemental diet (ED) for preventing adverse events (AEs) during chemotherapy for patients with esophageal cancer (EC) remains unclear. The aim of this meta-analysis was to comprehensively assess the efficacy of ED for preventing AE in EC patients during chemotherapy. Medline (via PubMed), Embase, the Cochrane Library, and Web of Science were searched to retrieve prospective and randomized studies published before April 12, 2023. The odds ratio (OR) of each AE was calculated using Review Manger 5.4.1. The risk of bias was assessed, and a random effect model-based meta-analysis was used to analyze the available data. Four prospective and randomized studies involving 237 patients were identified after a systematic search. Regarding gastrointestinal toxicities, the findings indicated a trend toward a decrease in the risk of mucositis (OM) (OR = 0.54, 95 % CI: 0.25-1.14), constipation (OR = 0.87, 95 % CI: 0.49-1.53), and anorexia (OR = 0.99, 95 % CI: 0.32-3.05), as well as an increasing trend in the risk of diarrhea (OR = 1.48, 95 % CI: 0.79-2.79), among patients treated with ED. However, none of these reached statistical significance. For hematological toxicities, the risk of all-grade neutropenia (OR = 0.28, 95 % CI: 0.14-0.57), grade ≥ 2 leucopenia (OR = 0.43, 95 % CI: 0.22-0.84), grade ≥ 2 neutropenia (OR = 0.34, 95 % CI: 0.17-0.67), and grade ≥ 3 neutropenia (OR = 0.28, 95 % CI: 0.12-0.63) was significantly decreased. There is no firm evidence confirming the preventive effect of an ED against OM or diarrhea. However, an ED may potentially be helpful in preventing neutropenia and leucopenia.

Introducción: La efectividad de una dieta elemental (DE) para prevenir eventos adversos (EA) durante la quimioterapia en pacientes con cáncer de esófago (CE) sigue sin estar clara. Este metaanálisis evalúa la eficacia de DE para prevenir EA en pacientes con CE durante quimioterapia. Se realizaron búsquedas en Medline (con PubMed), Embase, Biblioteca Cochrane y Web of Science para recuperar estudios prospectivos y aleatorios publicados antes del 12/04/2023. La razón de probabilidad (RP) de cada EA se calculó usando Review Manger 5.4.1. Se evaluó el riesgo de sesgo y se utilizó un metaanálisis basado en modelo de efectos aleatorios para analizar los datos disponibles. Después de una búsqueda sistemática, se identificaron cuatro estudios prospectivos y aleatorios con 237 pacientes. En cuanto a las toxicidades gastrointestinales, los hallazgos indicaron una tendencia hacia una disminución en el riesgo de mucositis (OM) (OR = 0,54, IC 95 %: 0,25-1,14), estreñimiento (OR = 0,87, IC 95 %: 0,49-1,53) y anorexia (OR = 0,99, IC 95 %: 0,32-3,05) y una tendencia creciente en el riesgo de diarrea (OR = 1,48, IC 95 %: 0,79-2,79) entre los pacientes tratados con DE. Sin embargo, no hubo muestras estadísticas significativas. Para toxicidades hematológicas, el riesgo de neutropenia de todos los grados (RP = 0,28; IC del 95 %: 0,14-0,57), leucopenia grado ≥ 2 (RP = 0,43; IC del 95 %: 0,22-0,84), neutropenia grado ≥ 2 (RP = 0,34; IC del 95 %: 0,17-0,67) y neutropenia grado ≥ 3 (RP = 0,28; IC del 95 %: 0,12-0,63) disminuyó significativamente. Ninguna evidencia firme confirmó el efecto preventivo de DE frente a OM o la diarrea. Una DE sería útil previniendo neutropenia y leucopenia.

Preventive Treatment with PD-1 Antibody Increases Tissue-resident Memory T Cells Infiltration and Delays Esophageal Carcinogenesis.

Numerous studies and clinical trials have shown that immune checkpoint inhibitors can effectively prevent tumor growth and metastasis in esophageal squamous cell carcinoma (ESCC) patients. In this study, we aimed to evaluate the anti-tumor effects of PD-1 antibody preventive treatment in patients with early stages ESCC as well as patients with high-grade intraepithelial neoplasia (HGIN). We first established an ESCC model using C57BL/6J mice treated with the chemical carcinogen 4- NQO and observed esophageal lesions at different time points. Second, we compared the antitumor efficacy of PD-1 antibody treatment in mice at the ESCC stage and PD-1 antibody preventive treatment in mice at the HGIN stage. The results showed that PD-1 antibody preventive treatment effectively impeded the progression of 4NQO-induced esophageal tumorigenesis. IHC analysis was performed to observe the infiltration of immune cells into the tumor microenvironment. It has been shown that active tissue-resident memory T cells can be induced and resided into the tumor microenvironment for a long period after treatment with PD-1 antibody. Reexposure to the oncogenic environment colonized by CD8+TRM cells can still exert antitumor effects. These results provide new strategies for the treatment of patients with early stage ESCC and HGIN. PREVENTION RELEVANCE: Immune checkpoint inhibitors have shown promising results in multiple tumor species. However, there is currently no clinical application to evaluate their therapeutic value in cancer preventive treatment. Prophylactic use of immune checkpoint inhibitors in the early stages of ESCC may provide long-term benefits to patients.

Construction of a novel immune response prediction signature to predict the efficacy of immune checkpoint inhibitors in clear cell renal cell carcinoma patients.

Background: Immune checkpoint inhibitor (ICI) treatment has enhanced survival outcomes in clear cell renal cell carcinoma (ccRCC) patients. Nevertheless, the effectiveness of immunotherapy in ccRCC patients is restricted and we intended to develop and characterize an immune response prediction signature (IRPS) to forecast the efficacy of immunotherapy. Methods: RNA-seq expression profile and clinicopathologic characteristics of 539 kidney cancer and 72 patients with normal specimens, were downloaded from the Cancer Genome Atlas (TCGA) database, while the Gene Expression Omnibus (GEO) database was used as the validation set, which included 24 ccRCC samples. Utilization of the TCGA data and immune genes databases (ImmPort and the InnateDB), we explored through Weighted Gene Co-expression Network Analysis (WGCNA), along with Least Absolute Shrinkage and Selection Operator method (LASSO), and constructed an IRPS for kidney cancer patients. GSEA and CIBERSORT were performed to declare the molecular and immunologic mechanism underlying the predictive value of IRPS. The Human Protein Atlas (HPA) was deployed to verify the protein expressions of IRPS genes. Tumor immune dysfunction and exclusion (TIDE) score and immunophenoscore (IPS) were computed to determine the risk of immune escape and value the discrimination of IRPS. A ccRCC cohort with anti-PD-1 therapy was obtained as an external validation data set to verify the predictive value of IRPS. Results: We constructed a 10 gene signature related to the prognosis and immune response of ccRCC patients. Considering the IRPS risk score, patients were split into high and low risk groups. Patients with high risk in the TCGA cohort tended towards advanced tumor stage and grade with poor prognosis (p < 0.001), which was validated in GEO database (p = 0.004). High-risk group tumors were related with lower PD-L1 expression, higher TMB, higher MSIsensor score, lower IPS, higher TIDE score, and enriched Treg cells, which might be the potential mechanism of immune dysfunction and exclusion. Patients in the IRPS low risk group had better PFS (HR:0.73; 95% CI: 0.54-1.0; P = 0.047). Conclusion: A novel biomarker of IRPS was constructed to predict the benefit of immunotherapy, which might lead to more individualized prognoses and tailored therapy for kidney cancer patients.

DCLK1 Drives EGFR-TKI-Acquired Resistance in Lung Adenocarcinoma by Remodeling the Epithelial-Mesenchymal Transition Status.

OBJECTIVE: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a first-line treatment for lung adenocarcinoma with EGFR-sensitive mutations, but acquired resistance to EGFR-TKIs remains a problem in clinical practice. The development of epithelial-mesenchymal transition (EMT) is a critical mechanism that induces acquired resistance to TKIs. Reversing acquired resistance to EGFR-TKIs through targeting the key molecules driving EMT provides an alternative choice for patients. We, therefore, aimed to explore the role of doublecortin-like kinase 1 (DCLK1) as an EMT driver gene in the acquired resistance of lung adenocarcinoma to EGFR-TKIs. METHODS: The IC50 of Gefitinib or Osimertinib in PC9/HCC827 cells was measured using a cell counting kit-8 (CCK8) assay. The expression levels of EMT-related genes in PC9 and HCC827 cells were detected using RT-PCR and Western blot. Cell migration and invasion abilities were assessed via a transwell assay. For the in vivo experiments, PC9 cells were subcutaneously injected into BALB/c nude mice to form tumors. Upon harvesting, tumor tissues were retained for RT-PCR, Western blot, and polychromatic fluorescence staining to detect biomarker changes in the EMT process. RESULTS: Gefitinib-resistant PC9 (PC9/GR) and Osimertinib-resistant HCC827 (HCC827/OR) cells showed remarkable activation of EMT and enhanced migration and invasion abilities compared to TKI-sensitive cells. In addition, DCLK1 expression was markedly increased in EGFR-TKI-resistant lung adenocarcinoma cells. The targeted knockout of DCLK1 effectively reversed the EMT phenotype in TKI-resistant cells and improved EGFR-TKI sensitivity, which was further validated by the in vivo experiments. CONCLUSIONS: DCLK1 facilitates acquired resistance to EGFR-TKI in lung adenocarcinoma by inducting EMT and accelerating the migration and invasion abilities of TKI-resistant cells.

Targeting DCLK1 attenuates tumor stemness and evokes antitumor immunity in triple-negative breast cancer by inhibiting IL-6/STAT3 signaling.

Triple-negative breast cancer (TNBC) exhibits the poorest outcomes among breast cancer subtypes due to the high heterogeneity and a lasting scarcity of effectual treatments. Targeted therapies based on molecular subtypes of TNBC are critical step toward tailoring treatments to improve clinical outcomes. Gastrointestinal cancer stem cell (CSC) marker DCLK1 was reported to be highly expressed in stem cell-rich subtype of TNBC. Here, we firstly explored the impacts of DCLK1 on tumor cells as well as their immune microenvironment in TNBC and potential therapeutic strategies for TNBC patients with high DCLK1 expression. Our results disclosed that DCLK1 overexpression promoted, while knockout of DCLK1 suppressed the CSC-like traits of TNBC cells and resistance to chemotherapeutics. Besides, DCLK1 supported immune escape by inhibiting intratumoral cytotoxic T cell infiltration in TNBC and hence limited immune checkpoint inhibitors efficacy. Mechanistically, bioinformatics analysis revealed that IL-6/STAT3 signaling was significantly enriched in high DCLK1-expressing patients, and our results further revealed that DCLK1 enhanced IL-6 expression and STAT3 activation in TNBC cells, which finally gave rise to upregulated CSC traits and suppressed CD8+ T-cell activity. Inhibiting IL-6/STAT3 pathway by IL-6R antagonist, Tocilizumab or STAT3 inhibitor, S31-201 could abolish DCLK1-promoted malignant phenotypes of TNBC cells. Finally, DCLK1 was identified to be specifically and highly expressed in the mesenchymal-like subtype of TNBC and targeting DCLK1 could improve chemotherapy efficacy and activate antitumor immunity. Overall, our study revealed the potential clinical benefits of targeting DCLK1 in TNBC treatment.

Organ-specific immune checkpoint inhibitor treatment in lung cancer: a systematic review and meta-analysis.

OBJECTIVES: Based on the acknowledged organ-specific immune microenvironment, little is known regarding the efficacy of immunotherapy in patients with lung cancer according to metastatic sites. This meta-analysis aimed to explore the efficacy of immune checkpoint inhibitors (ICIs) vs chemotherapy in patients with lung cancer with liver metastases (LM) or brain metastases (BM). DESIGN: Meta-analysis and systematic review. DATA SOURCES: We systematically searched in electronic databases (PubMed, EMBASE, Cochrane Library and Web of Science), up to 31 January 2022. We also reviewed the abstracts from major international conferences. Eligibility criteria were randomised controlled phase II or III trials reporting the overall survival (OS) or progression-free survival (PFS) of LM or BM subsets. DATA EXTRACTION AND SYNTHESIS: Hazard ratios (HRs) with 95% CIs for OS and PFS were extracted and aggregated using a random-effects model. RESULTS: Twenty-four randomised controlled trials with available outcomes for patients with BMs or LMs were identified. A total of 1124 patients with BM and 2077 patients with LM were included in the analysis. The pooled OS HR of patients with LMs was 0.83 (95% CI 0.72 to 0.95), and that of patients without LM 0.73 (95% CI 0.69 to 0.79). LM was associated with less benefits from ICIs. In patients with BM treated with ICIs, the pooled OS HR compared with the control arms was 0.71 (95% CI 0.53 to 0.94). Subgroup analyses by histology suggested that only patients with non-small cell lung cancer (NSCLC) with BM could gain benefit from ICIs (HR 0.53, 95% CI 0.41 to 0.68). BM negatively influenced efficacy of immunotherapy in patients with small cell lung cancer. CONCLUSIONS: Our results showed immunotherapy demonstrated efficacy in patients with lung cancer with LM and BM, survival benefits dominantly favoured patients with NSCLC. Patients with lung cancer with LM obtained less benefits from ICIs than those without. Therefore, organ-specific immunotherapeutic approaches should be considered. PROSPERO REGISTRATION NUMBER: CRD42020212797.

Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial.

INTRODUCTION: In CameL phase 3 study (ClinicalTrials.gov: NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in patients with stages IIIB to IV nonsquamous NSCLC. Here, we present outcomes after a minimum follow-up of 43.9 months since last patient randomization. METHODS: Eligible patients were randomized 1:1 to 4 to 6 cycles of camrelizumab plus carboplatin and pemetrexed or chemotherapy alone every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only (n = 205 and 207, respectively). Total camrelizumab exposure was up to 2 years. RESULTS: As of January 31, 2022, camrelizumab plus chemotherapy exhibited substantially improved overall survival over chemotherapy alone (median, 27.1 versus 19.8 mo; hazard ratio = 0.72 [95% confidence interval: 0.57-0.92]). In the chemotherapy-alone group, 95 patients (45.9%) crossed over to camrelizumab monotherapy. After adjustment for crossover, the survival benefit with camrelizumab plus chemotherapy was more pronounced (adjusted hazard ratio = 0.55 [95% confidence interval: 0.42-0.71]). In camrelizumab plus chemotherapy group, 33 patients completed 2 years of camrelizumab. Objective response rate was 97.0%, with ongoing responses in 17 of the 32 responses (53.1%), and 93.9% (31 of 33) of the patients were alive at data cutoff. Safety profiles were consistent with the previous report, and no obvious evidence of cumulative toxicity was found with long exposure to camrelizumab. CONCLUSIONS: Camrelizumab plus carboplatin and pemetrexed provides long-term survival benefit over chemotherapy, with manageable toxicity and remarkable and durable response in patients receiving 2 years of camrelizumab, further supporting camrelizumab combination as first-line treatment for advanced nonsquamous NSCLC.

DCLK1 Suppresses Tumor-Specific Cytotoxic T Lymphocyte Function Through Recruitment of MDSCs via the CXCL1-CXCR2 Axis.

BACKGROUND & AIMS: Gastrointestinal cancer stem cell marker doublecortin-like kinase (DCLK1) is strongly associated with poor outcomes in colorectal cancer (CRC). Although DCLK1's regulatory effect on the tumor immune microenvironment has been hypothesized, its mode of action has not been shown previously in vivo, which hampers the potential intervention based on this molecule for clinical practice. METHODS: To define the immunomodulatory mechanisms of DCLK1 in vivo, we generated DCLK1-/- tumor cells by Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) and developed subcutaneous and intestinal orthotopic transplantation tumor models. Tumor tissues were harvested and subjected to immunofluorescence staining, flow cytometry analysis of tumor-infiltrating immune cell populations, tumor myeloid-derived suppressor cell (MDSC) sorting by isolation kit and then co-culture with spleen T cells, and RNA sequencing for transcriptomic analysis. RESULTS: We found that DCLK1-/- tumor cells lose their tumorigenicity under immune surveillance. Failed tumor establishment of DCLK1-/- was associated with an increase in infiltration of CD8+ T cells and effector CD4+ T cells, and reduced numbers of MDSCs in the tumor tissue. Furthermore, DCLK1 promoted the up-regulation of C-X-C motif ligand 1, which recruits MDSCs in CRC through chemokine C-X-C motif receptor 2. The ability of in vivo tumor growth of DCLK1-/- tumor cells was rescued by C-X-C motif ligand 1 overexpression. Collectively, we validated that DCLK1 promotes tumor growth in CRC through recruitment of T-cell-suppressive MDSCs. CONCLUSIONS: DCLK1-mediated immune suppression in tumor models allows escaping from the host's antitumor response. Because DCLK1 is one of the most common markers in gastrointestinal tumors, these results identify a precise therapeutic target for related clinical interventions.

Sintilimab versus docetaxel as second-line treatment in advanced or metastatic squamous non-small-cell lung cancer: an open-label, randomized controlled phase 3 trial (ORIENT-3).

BACKGROUND: Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC. METHODS: ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. RESULTS: Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001)，for sintilimab treatment. CONCLUSIONS: Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.

Molecular and clinicopathological characteristics of ERBB2 gene fusions in 32,131 Chinese patients with solid tumors.

ERBB2 amplification is one of the most important and mature targets for HER2-targeted drug therapy. Somatic mutations of ERBB2 in the tyrosine kinase domain have been studied extensively, and play a role in response to anti-HER2 therapy among different cancer types. However, ERBB2 fusion has not been got attention and its relevance to HER2-targeted therapy is unclear. We comprehensively characterized ERBB2 fusions from next-generation sequencing (NGS) data between May 2018 and October 2021 in 32,131 various solid tumors. Among the tumors, 0.28% harbored ERBB2 fusions, which occurred more commonly in gastroesophageal junction cancer (3.12%; 3/96), breast cancer (1.89%; 8/422), urothelial carcinoma (1.72%; 1/58), and gastric cancer (1.60%; 23/1,437). Our population presented with a median age of 65 years (range 28 to 88 years), a high proportion of men (55 men vs 34 women; 61.80%). Among the patients with ERBB2 fusions, TP53 (82%), APC (18%), and CDK4 (15%) were the top3 co-mutant genes. What's more, most patients with ERBB2 fusion also had ERBB2 amplification (75.28%; 67/89), which was similar to the data in the TCGA database (88.00%; 44/50). Furthermore, TCGA database shows that patients with ERBB2 fusions in pan-cancer had a worse prognosis than those without ERBB2 fusions, as well as in breast cancer. Besides, ERBB2 amplification combined with ERBB2 fusion had worse prognosis than those with only ERBB2 amplification. ERBB2 fusion may interfere the effect of anti-HER2-targeted antibody drugs and influence the prognosis of patients with ERBB2 amplification. Prospective clinical trials are warranted to confirm the results in the future.

Mn(II) Oxidation by Free Chlorine Catalyzed by the Hydrolytic Products of Ferric and Aluminum Species under Drinking Water Conditions.

Mn(II) oxidation by free chlorine can be applied to remove Mn(II) at water treatment plants. This reaction also results in particulate MnOx formation and accumulation in drinking water distribution systems. This study investigated the effect of Fe(III) and Al(III) hydrolysis products (mainly precipitates) on Mn(II) oxidation by free chlorine under drinking water conditions. The results showed that Fe3+ added as FeCl3 and Al(III) added as polyaluminum chloride (PACl) at tens to hundreds of micrograms per liter dramatically catalyzed Mn(II) oxidation by free chlorine. Through hydrolytic precipitation at circumneutral pH, Fe3+ and Al13 (the dominant preformed Al species in PACl) generated Fe(OH)3-like particles and Al13 aggregates, respectively, which initiated heterogeneous Mn(II) oxidation. Kinetic modeling indicated that, once some MnOx was formed, MnOx and Fe(OH)3 catalyzed the subsequent Mn(II) oxidation to an equal extent. The particles (aggregates) formed from Al13 species exhibited a weaker catalytic capacity in comparison to MnOx and Fe(OH)3 at equivalent molar concentrations. Interestingly, unlike Al13 species in PACl, Al(III) added as AlCl3 had a negligible influence on Mn(II) oxidation, even when Al(OH)3(am) precipitates were formed. The catalytic effects of Fe3+ and Al13 hydrolysis products were confirmed by experiments with natural water and finished water, and the lower Mn(II) oxidation rate was mainly attributed to organic matter.

Inhibition of DCLK1 sensitizes resistant lung adenocarcinomas to EGFR-TKI through suppression of Wnt/ß-Catenin activity and cancer stemness.

Lung adenocarcinoma is the most common form of lung cancer, accounting for 60% of non-small cell lung cancer (NSCLC) cases in Asian patients. Importantly, nearly half of these patients have epithelial growth factor receptor (EGFR) mutations. Though EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as the first-line therapy for NSCLC patients, the development of resistance reduces their efficiency and limits their application. As the complicated and heterogeneous mechanism of acquired resistance among individuals, the efficiency of anti-angiogenesis therapy, immune checkpoint inhibitors, or chemo-radiotherapies is rather less promising. In this research, we investigated the role of the tumor stem cell marker DCLK1 in EGFR-TKI resistance of lung adenocarcinoma. We discovered that DCLK1 was critical in maintaining the stemness of tumor cells through the Wnt/ß-Catenin pathway, which was conducive to the development of EGFR-TKI resistance. Inhibiting DCLK1 activity restored the sensitivity of TKI-resistant tumor cells and organoids. Moreover, our study showed that DCLK1 inhibitor had a synergistic effect in controlling tumor growth when combined with EGFR-TKIs. Overall, our study provides new insights into EGFR-TKI resistant lung adenocarcinoma through inhibition of DCLK1 expression.

Establishment of a Competing Risk Nomogram in Patients with Pulmonary Sarcomatoid Carcinoma.

Background and aim: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of nonsmall cell lung cancer with a poor prognosis. This study aimed to analyze the clinicopathological characteristics and survival outcomes among patients with PSC, lung squamous cell cancer (SCC), and lung adenocarcinoma (LAC), and to construct a competing risk nomogram for patients with PSC. Method: Data of 3 groups of patients diagnosed with PSC, SCC, or LAC from the surveillance, epidemiology, and end results (SEER) database between 1988 and 2015 were retrospectively reviewed. A 1:1 propensity score matching (PSM) analysis was used to balance the baseline data of patients. Independent risk factors associated with survival outcomes were screened by the least absolute shrinkage and selection operator and further determined by univariate and multivariate Cox proportional risk regression analyses. The overall survival (OS) of patients was evaluated by Kaplan-Meier analysis and compared with a log-rank test. The cumulative incidence function was used to estimate the 5-year probabilities of the cancer-specific mortality of PSC. A nomogram was constructed to illustrate the competing risk model to predict the 3- and 5-year OS, and corresponding concordance indexes (C-indexes) and calibration curves were used to assess and validate the competing risk nomogram. Results: A total of 2285 patients with PSC were included in this study. Compared with SCC and LAC patients, the Kaplan-Meier analysis showed that patients with PSC had a worse prognosis, with a median survival of 5 months (95% confidence interval [CI]: 5-6 months) and a 5-year OS rate of 15.3% (95% CI: 13.9%-16.9%). Similar outcomes were demonstrated after 1:1 PSM. Moreover, the competing risk model showed that age, T stage, M stage, tumor size, lymph node ratio (LNR), surgery, and chemotherapy were associated with PSC-specific mortality. The 5-year C-index of the nomogram was 0.718. Calibration curves illustrated that the nomogram was well-validated and had great accuracy. Conclusions: Patients with PSC had a worse survival outcome compared with SCC or LAC patients. Age, T stage, M stage, tumor size, LNR, surgery, and chemotherapy were associated with PSC-specific mortality. The competing risk nomogram displayed excellent discrimination in predicting PSC-specific mortality.