The treatment pattern of advanced HR-positive and HER2-negative breast cancer in central southern China: a hospital-based cross-sectional study.

AIMS: This investigation aims to elucidate the treatment status of advanced HR+/HER2- breast cancer patients in Hunan Province of Central Southern China from November 2021 to December 2022. METHODS: Data from 301 patients with advanced HR+/HER2- breast cancer were collected from the breast cancer investigation project in Hunan under the guidance of the Chinese Society of Clinical Oncolfogy (CSCO). The data included the clinical characteristics of patients and the status of first-line and second-line rescue treatment. RESULTS: First-line chemotherapy and endocrine therapy for mBC accounted for 40% (121/301) and 60% (180/301) of treatments, respectively. AI (21%), AI plus CDK4/6 inhibitor (28%), and fulvestrant (24%) or fulvestrant plus CDK4/6 inhibitor (18%) were the most common first-line endocrine therapies. Taxane-based chemotherapy was the most common first-line chemotherapy (59%). Second-line chemotherapy and endocrine therapy for mBC accounted for 43% (72/166) and 57% (94/166) of treatments, respectively. Fulvestrant (23%) or fulvestrant plus CDK4/6 inhibitor (29%) were the most common second-line endocrine therapies. The prevalences of AI and AI plus CDK4/6 inhibitor decreased to 19% and 11%, respectively. T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Third-line chemotherapy was more prevalent than endocrine therapy (57% vs. 41%). T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Fulvestrant plus CDK4/6 inhibitor was the most common endocrine therapy (33%). AI, AI plus CDK4/6 inhibitor, and fulvestrant accounted for 21%, 12% and 18% of third-line endocrine therapies, respectively. CONCLUSIONS: Compared to chemotherapy, endocrine therapy was a more favorable choice for first-line and second-line treatment for HR+/HER2- advanced breast cancer patients in Hunan Province.

Pyrotinib in combination with letrozole for hormone receptor-positive, human epidermal growth factor receptor 2-positive metastatic breast cancer (PLEHERM): a multicenter, single-arm, phase II trial.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) targeted therapy combined with endocrine therapy has been recommended as an alternative treatment strategy for patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (MBC). This study aimed to evaluate the role of pyrotinib, an oral pan-HER irreversible tyrosine kinase inhibitor, in combination with letrozole for patients with HR-positive, HER2-positive MBC. METHODS: In this multi-center, phase II trial, HR-positive and HER2-positive MBC patients who were not previously treated for metastasis disease were enrolled. Patients received daily oral pyrotinib 400 mg and letrozole 2.5 mg until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the clinical benefit rate (CBR) assessed by an investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: From November 2019 to December 2021, 53 patients were enrolled and received pyrotinib plus letrozole. As of August 2022, the median follow-up duration was 11.6 months (95% confidence interval [CI], 8.7-14.0 months). The CBR was 71.7% (95% CI, 57.7-83.2%), and the objective response rate was 64.2% (95% CI, 49.8-76.9%). The median progression-free survival was 13.7 months (95% CI, 10.7-18.7 months). The most common treatment-related adverse event of grade 3 or higher was diarrhea (18.9%). No treatment-related deaths were reported, and one patient experienced treatment discontinuation due to adverse event. CONCLUSIONS: Our preliminary results suggested that pyrotinib plus letrozole is feasible for the first-line treatment of patients with HR-positive and HER2-positive MBC, with manageable toxicities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04407988.

AisNet: A Universal Interatomic Potential Neural Network with Encoded Local Environment Features.

This paper proposes a new interatomic potential energy neural network, AisNet, which can efficiently predict atomic energies and forces covering different molecular and crystalline materials by encoding universal local environment features, such as elements and atomic positions. Inspired by the framework of SchNet, AisNet consists of an encoding module combining autoencoder with embedding, the triplet loss function and an atomic central symmetry function (ACSF), an interaction module with a periodic boundary condition (PBC), and a prediction module. In molecules, the prediction accuracy of AisNet is comparabel with SchNet on the MD17 dataset, mainly attributed to the effective capture of chemical functional groups through the interaction module. In selected metal and ceramic material datasets, the introduction of ACSF improves the overall accuracy of AisNet by an average of 16.8% for energy and 28.6% for force. Furthermore, a close relationship is found between the feature ratio (i.e., ACSF and embedding) and the force prediction errors, exhibiting similar spoon-shaped curves in the datasets of Cu and HfO2. AisNet produces highly accurate predictions in single-commponent alloys with little data, suggesting the encoding process reduces dependence on the number and richness of datasets. Especially for force prediction, AisNet exceeds SchNet by 19.8% for Al and even 81.2% higher than DeepMD on a ternary FeCrAl alloy. Capable of processing multivariate features, our model is likely to be applied to a wider range of material systems by incorporating more atomic descriptions.

Nomogram for Predicting Chemotherapy-Induced Nausea and Vomiting for Breast Cancer Patients.

Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of cancer treatment. The factors influencing CINV in breast cancer patients remain unclear. In this study, we developed a nomogram for predicting the occurrence of CINV in this group using prospective clinical data. We pooled data from multiple studies which focused on the emetogenic chemotherapy. Then, we collected 334 breast cancer patients at Hunan Cancer Hospital (training set) to analyze the demographic and clinical variables. Using multivariate logistic regression, we identified the five significant factors that were associated with CINV: history of CINV, chemotherapy regimen, chemotherapy cycle, metastasis, and symptoms of distress. Then, we construct a prediction nomogram. The external validation set comprised an additional 66 patients. The reliability of the nomogram was assessed by bootstrap resampling. The C-index was 0.78 (95% confidence interval [CI], 0.73-0.85) for the training set and 0.74 (95% CI, 0.62-0.85) for the validation set. Calibration curves showed good concordance between predicted and actual occurrence of CINV. In conclusions, our nomogram model can reliably predict the occurrence of CINV in breast cancer patients based on five significant variables, which might be useful in clinical decision-making.

Skp2 modulates proliferation, senescence and tumorigenesis of glioma.

BACKGROUND: Gliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. Surgery followed by radiotherapy and chemotherapy has been used as a standard strategy but yielded unsatisfactory improvements in patient survival outcomes. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. In this study, we investigated the function of Skp2 in the proliferation, stem cell maintenance, and drug sensitivity to temozolomide (TMZ) of glioma. METHODS: To investigate the role of Skp2 in the prognosis of patients with glioma, we first analyzed data in databases TCGA and GTEx. To further clarify the effect of Skp2 on glioma cell proliferation, we suppressed its level in glioblastoma (GBM) cell lines through knockdown and small molecule inhibitors (lovastatin and SZL-P1-41). We then detected cell growth, colony formation, sphere formation, drug sensitivity, and in vivo tumor formation in xenograft mice model. RESULTS: Skp2 mRNA level was higher in both low-grade glioma and GBM than normal brain tissues. The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis. In addition, Skp2 level was found increased upon stem cells enriching, while the knockdown of Skp2 led to reduced sphere numbers. Downregulation of Skp2 also induced senescence. Repurposing of lovastatin and novel compound SZL-P1-41 suppressed Skp2 effectively, and enhanced glioma cell sensitivity to TMZ in vitro and in vivo. CONCLUSION: Our data demonstrated that Skp2 modulated glioma cell proliferation in vitro and in vivo, stem cell maintenance, and cell sensitivity to TMZ, which indicated that Skp2 could be a potential target for long-term treatment.

From community-acquired pneumonia to COVID-19: a deep learning-based method for quantitative analysis of COVID-19 on thick-section CT scans.

OBJECTIVE: To develop a fully automated AI system to quantitatively assess the disease severity and disease progression of COVID-19 using thick-section chest CT images. METHODS: In this retrospective study, an AI system was developed to automatically segment and quantify the COVID-19-infected lung regions on thick-section chest CT images. Five hundred thirty-one CT scans from 204 COVID-19 patients were collected from one appointed COVID-19 hospital. The automatically segmented lung abnormalities were compared with manual segmentation of two experienced radiologists using the Dice coefficient on a randomly selected subset (30 CT scans). Two imaging biomarkers were automatically computed, i.e., the portion of infection (POI) and the average infection HU (iHU), to assess disease severity and disease progression. The assessments were compared with patient status of diagnosis reports and key phrases extracted from radiology reports using the area under the receiver operating characteristic curve (AUC) and Cohen's kappa, respectively. RESULTS: The dice coefficient between the segmentation of the AI system and two experienced radiologists for the COVID-19-infected lung abnormalities was 0.74 ± 0.28 and 0.76 ± 0.29, respectively, which were close to the inter-observer agreement (0.79 ± 0.25). The computed two imaging biomarkers can distinguish between the severe and non-severe stages with an AUC of 0.97 (p value < 0.001). Very good agreement (κ = 0.8220) between the AI system and the radiologists was achieved on evaluating the changes in infection volumes. CONCLUSIONS: A deep learning-based AI system built on the thick-section CT imaging can accurately quantify the COVID-19-associated lung abnormalities and assess the disease severity and its progressions. KEY POINTS: • A deep learning-based AI system was able to accurately segment the infected lung regions by COVID-19 using the thick-section CT scans (Dice coefficient ≥ 0.74). • The computed imaging biomarkers were able to distinguish between the non-severe and severe COVID-19 stages (area under the receiver operating characteristic curve 0.97). • The infection volume changes computed by the AI system were able to assess the COVID-19 progression (Cohen's kappa 0.8220).

Clinical and genetic risk factors for Fulvestrant treatment in post-menopause ER-positive advanced breast cancer patients.

BACKGROUND: Among breast cancer (BC) patients, near 40% are post-menopause, and 70%-80% are hormone receptor (HR)-positive. About 30%-40% BC patients who are diagnosed as invasive carcinoma HR-positive BC would eventually develop metastatic breast cancers. In 2016, FALCON trial proves Fulvestrant as an effective first-line endocrine therapy for post-menopause HR-positive advanced BC (ABC) patients. But even after FALCON published, Fulvestrant is rarely used as first-line in real world ABC patients in China. METHOD: In this study, 136 Fulvestrant users were enrolled from 2015. To investigate the clinical and genetic risk factors for Fulvestrant treatment response in real world data, biostatistic and bioinformatic analysis tools were adopted. RESULT: KM curves showed that Fulvestrant first-line users had a median progression-free survival (mPFS) of 15.67 months, which was longer than the second-line users and third (or higher)-line users (mPFS = 7.47 and 5.43 months, respectively). 16 s (or higher)-line users were voluntarily received circulating tumor DNA (ctDNA) testing after progression. ctDNA testing results showed that compared to patients with PFS longer than 6 months, Fulvestrant users with PFS less than 6 months had a significantly higher mutation rate of ESR1 or ERBB2 gene (0/6 vs 6/10, Fisher's Exact p-value = 0.03). Multivariate COX regression analysis showed that clinical features, including lymph node metastasis and HER-2 positive, were significant risk factors for poor PFS [hazard ratio (HR) = 2.396 and 2.863, respectively]; high portion of estrogen receptor-positive cells was significant protective factor (HR = 0.663). Propensity-score matching (PMS) analysis suggested that visceral metastasis, prior palliative chemotherapy, and old age at Fulvestrant usage were not significant influential factor for PFS. CONCLUSION: First-line Fulvestrant usage could guarantee a better prognosis than higher-line usage. ESR1 or ERBB2 mutation was found to be related to poor PFS in higher-line Fulvestrant users.

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis.

BACKGROUND/AIMS: Hypoxia can induce cell injury in cardiomyocytes and further lead to cardiovascular diseases. Genistein (Gen), the predominant isoflavone found in soy products, has shown protective effects on cardiovascular system. The aim of the present study was to investigate the cardioprotective effect of Gen against chemical hypoxia-induced injury. METHODS: Cobalt chloride (CoCl2) was administrated to trigger chemical hypoxia in H9c2 cardiomyocytes. Cell proliferation was detected by using MTT assay. The expression level of hypoxia-related proteins (hypoxia-inducible factor [HIF]-1α and Notch-1) and apoptosis-related proteins (B cell lymphoma [Bcl]-2, Bax, and caspase-3) were evaluated by Western blot analysis. RESULTS: In response to hypoxia, cell viability was reduced dramatically, whereas the expression of HIF-1α was upregulated. Hypoxia also induced cardiomyocytes apoptosis by reducing the ratio of Bcl-2/Bax and increasing expression of caspase-3. Interestingly, Gen attenuated CoCl2-induced cell death and suppressed HIF-1α expression, as well as upregulated the expression of Notch-1. Furthermore, Gen could antagonize CoCl2-induced apoptosis through upregulating Bcl-2/Bax ratio and inhibiting caspase-3 expression. CONCLUSIONS: Gen prevents chemical hypoxia-induced cell apoptosis through inhibition of the mitochondrial apoptotic pathway, exerting protective effects on H9c2 cardiomyocytes.

Transesophageal echocardiography measures left atrial appendage volume and function and predicts recurrence of paroxysmal atrial fibrillation after radiofrequency catheter ablation.

AIMS: Paroxysmal atrial fibrillation (PAF) commonly recurs after radiofrequency catheter ablation (RFCA). This study aimed to assess left atrial appendage (LAA) volume and function by transesophageal echocardiography (TEE) and to explore its value in predicting PAF recurrence after RFCA. METHODS: Eighty patients with PAF were recruited. The left atrial (LA) and LAA volume and function were measured by transthoracic echocardiography (TTE) and TEE before ablation. Patients were followed up for 12 months after RFCA, and recurrence was recorded. Odds ratios of candidate risk indicators were determined by logistic regression analysis. Prediction model was constructed using logistic regression with backward selection. Receiver operating characteristic (ROC) curve with area under curve (AUC) was performed to evaluate the prediction efficiency. RESULTS: Twenty-four (30%) PAF patients had recurrence (R group), and 56 (70%) patients had no recurrence (NR group). Compared to NR group, LA dimension (LAD), LA volume index (LAVI), LAA maximum volume (LAAVmax), and LAA minimum volume (LAAVmin) were significantly higher in R group, while LAA peak emptying flow velocity (LAAeV), LAA peak filling flow velocity (LAAfV), and LAA ejection fraction (LAAEF) significantly declined in R group. According to multivariate analysis and backward selection, LAVI, LAAEF, and LAAeV were significant risk factors for PAF recurrence. The LAVI + LAAEF + LAAeV joint model could effectively predict PAF recurrence with AUC of 0.893 (95% confidence interval = 0.816, 0.970), sensitivity of 0.75, and specificity of 0.929. CONCLUSIONS: This study demonstrated that LAVI, LAAEF, and LAAeV were significant predictors of PAF recurrence after RFCA.

Diagnostic Efficiency of Quantitative Contrast-Enhanced Ultrasound Indicators for Discriminating Benign From Malignant Solid Thyroid Nodules.

OBJECTIVES: We aimed to determine the most efficient quantitative parameters to establish a contrast-enhanced ultrasound (US) assessment system for distinguishing between benign and malignant thyroid nodules. METHODS: A total of 167 patients with thyroid solitary nodules had the diagnosis confirmed by surgery or fine-needle aspiration. Quantitative contrast-enhanced US indicators (time to peak, time from peak to one-half, ascend slope, descend slope, peak intensity, and area under the curve [AUC]) were gathered in nodule and perinodule areas. Univariate and multivariate logistic regression analyses were performed. Receiver operating characteristic curves were generated. Sensitivities, specificities, and positive and negative predictive values were calculated to identify the best cutoff value. RESULTS: The univariate logistic regression model showed that the peak intensity, ascend slope, descend slope, and AUC were significant indicators for discriminating benign from malignant nodules under contrast-enhanced US (P < .0001). For thyroid nodules, low peak intensity, ascend slope, and AUC and high descend slope values were significant indicators of malignancy. However, in perinodule areas, high peak intensity, ascend slope, and AUC and low descend slope values were significantly associated with malignancies. The cutoff values for the nodule peak intensity, ascend slope, descend slope, and AUC were 20.75, 0.91, -0.2, and 1818.23, respectively. The cutoff values for the ratios of the nodule versus perinodule peak intensity, ascend slope, descend slope, and AUC were 0.90, 0.95, 0.96, and 0.96. The nodule-to-perinodule peak intensity ratio showed the best diagnostic efficiency, with 80.41% sensitivity and 80.00% specificity. CONCLUSIONS: Quantitative contrast-enhanced US indicators help discriminate benign from malignant thyroid nodules. The nodule-to-perinodule peak intensity ratio showed the best diagnostic efficiency.

Benefits of local tumor excision and pharyngectomy on the survival of nasopharyngeal carcinoma patients: a retrospective observational study based on SEER database.

BACKGROUND: There is ongoing debate about surgery of primary site in nasopharyngeal carcinoma patients. METHODS: 3919 patients with nasopharyngeal carcinoma identified in the SEER registry between 2004 and 2013. The benefit of surgery of primary nasopharynx tumor site on overall and cancer-specific survival was assessed by risk-adjusted multivariate Cox proportional hazard regression and propensity score matching modeling. RESULTS: Surgery was marginally associated with better overall survival (hazard ratio (HR) = 0.816, 95% CI 0.656-1.015, p = 0.07) and cancer-specific survival (HR = 0.749, 95% CI 0.552-1.018, p = 0.06) in the propensity score model. Among 398 cases who underwent primary site surgery, 282 (70.85%) received local tumor excision and 79 (20.31%) received pharyngectomy. Local tumor excision and pharyngectomy had almost the same effect on survival in propensity score matching analysis. The benefit was significant in subgroups of white, age <60 year, and patients with T3, N1, M0, AJCC stage III, or moderately differentiated tumors. Further survival analysis showed surgery to promote survival in both radiotherapy and non-radiotherapy patients. CONCLUSION: This is the first population-based analysis using propensity score model to provide evidence of a positive impact of surgery on survival in nasopharyngeal carcinoma. Moreover, surgery demonstrated the significant benefit in subgroups of patients with specific clinical characteristics.

Case report: Pilomatrix carcinoma with PDL1 expression and CDKN2A aberrant.

Case report: A 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed. Conclusion: Chemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma.

c-Rel is a Novel Oncogene in Lung Squamous Cell Carcinoma Regulating Cell Proliferation and Migration.

Lung squamous cell carcinoma (LUSC) accounts for approximately 25% to 30% of lung cancers, but largely no targeted therapy is available against it, calling for identification of new oncogenes in LUSC growth for new therapeutic targets. In this study, REL was identified through a screening for oncogenes that are highly amplified in human LUSC. Its expression was associated with poor prognosis in LUSC patients. Furthermore, knockdown of c-Rel in LUSC cell lines lead to significant decrease in cell proliferation and migration. Mechanistically, c-Rel knockdown suppressed NFκB pathway by blocking phosphorylation of IκB. Consistently, pharmaceutic inhibition of c-Rel also. In orthotopic xenograft lung cancer mouse model, c-Rel knockdown inhibited the tumor growth. Cancer cell proliferation and epithelial-mesenchymal-transition (EMT) of the tumors were impaired by c-Rel knockdown. Finally, it's confirmed in precision-cut tumor slices of LUSC that deletion of c-Rel inhibits the NFκB pathway and cancer cell growth. Accordingly, we hypothesize that c-Rel promotes the activation of the NFκB pathway by promoting the phosphorylation of IκB in LUSC. Our study reveals REL as a novel LUSC oncogene and provides new insights into the molecular regulation of LUSC, which will provide new therapeutic targets for the treatment of squamous lung cancer.

Beyond clinical trials: CDK4/6 inhibitor efficacy predictors and nomogram model from real-world evidence in metastatic breast cancer.

Background: CDK4/6 inhibitors (CDK4/6i) have shown promising results in the treatment of hormone receptor-positive (HR+) metastatic breast cancer (MBC) when combined with endocrine therapy (ET). It is crucial to evaluate the actual effectiveness and safety of CDK4/6i in clinical practice, as well as to analyze the factors that can predict their outcomes. Methods: Patients with HR+ MBC who received CDK4/6i-based therapy between May 2016 and May 2023 at Hunan Cancer Hospital were evaluated for progression-free survival (PFS). Adverse reactions were assessed based on the National Cancer Institute Common Toxicity Criteria (version 5.0). Results: This study included 344 patients, with a median PFS (mPFS) of 12.8 months (range: 10.4-15.2 months). After adjustment, Cox multivariate regression analysis revealed that visceral metastasis (specifically liver and brain metastases), Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 1, estrogen receptor ≤ 80%, progesterone receptor ≤ 10%, Ki-67 > 30%, and treatment in later stages were significant factors associated with reduced PFS. Based on this, we created a prognostic nomogram and validated its performance, obtaining a C-index of 0.714 (95% confidence interval: 0.640-0.787) as well as reliable calibration and clinical impact. The mPFS of CDK4/6i rechallenge was 7.7 months; for patients who initially discontinued CDK4/6i for reasons other than disease progression, CDK4/6i rechallenge still provided a mPFS of 11.4 months. The tolerability and safety of combining CDK4/6is with ET were manageable. Adverse events led to treatment discontinuation in 3.8% of patients. Neutropenia (29.1%), leukopenia (13.7%), and anemia (4.1%) were the primary grade 3/4 adverse reactions. Conclusions: This real-world study highlights the ample efficacy and reasonable safety of combined CDK4/6i and ET in patients with HR+ MBC. Individualized treatment decisions and ongoing safety monitoring are important to optimize the therapeutic benefit of CDK4/6i treatment.

Associations of Workplace Violence With Cardiovascular Disease Among United States Workers: Findings From a National Survey.

OBJECTIVES: Recent research indicates a potential association between workplace violence and an increased risk of cardiovascular disease (CVD) in the working-age population. However, the relevant evidence in the United States is sparse. Thus, this study was conducted to explore the possible relationship between workplace violence and CVD among United States workers. METHODS: We utilized cross-sectional data from the 2015 National Health Interview Survey, which included a representative sample of 18 380 workers, to investigate the associations between workplace violence and the prevalence of CVD using logistic regression. Workplace violence was determined based on self-reported threats, bullying, or harassment at work over the past 12 months, supplemented with additional information regarding frequency. CVD included all forms of heart disease and stroke. RESULTS: A total of 1334 workers reported experiences of workplace violence, and 1336 workers were diagnosed with CVD. After adjustment for covariates, participants who reported any instance of workplace violence had significantly higher odds of having CVD (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.35 to 2.30) than those who reported no such violence. Furthermore, the highest odds of CVD (OR, 1.80; 95% CI, 1.23 to 2.63) were observed among those frequently exposed to workplace violence. Even occasional exposure to workplace violence was associated with 74% excess odds of CVD. CONCLUSIONS: Our study indicates an association between workplace violence and CVD in United States workers, exhibiting a dose-response pattern.

LncRNA HHIP-AS1 suppresses lung squamous cell carcinoma by stabilizing HHIP mRNA.

AIMS: Lung squamous cell carcinoma (LUSC) causes over 400,000 deaths annually, yet it lacks targeted therapy. A major antagonist of Hedgehog pathway, HHIP (Hedgehog Interacting Protein) plays an important role in LUSC; however, the regulatory mechanism remains unclear. Long non-coding RNA HHIP-AS1 plays suppressive or promotive roles in different cancers, but its role in LUSC remains unknown. This manuscript is to investigate regulatory mechanism of HHIP and the role of HHIP-AS1 in LUSC. MAIN METHODS: Precision-cut lung slices (PCLS) from human LUSC samples are cultured to mimic LUSC growth. Overexpression and knockdown in multiple LUSC cell lines and PCLS are achieved by lentivirus infection. Transcriptome profile and lung cancer activity are evaluated by RNA-sequencing, immunostaining and CCK8 assay etc. KEY FINDINGS: HHIP is regulated independently of Hh pathway in LUSC. Additionally, downregulation of HHIP-AS1 is associated with poor prognosis. Consistently, HHIP-AS1 inhibits LUSC growth by suppressing cell proliferation and migration. Transcriptome profiling of HHIP-AS1 knockdown (KD) cells uncovered HHIP downregulation. Interestingly, a comparison between the transcriptomes of HHIP-AS1 KD or HHIP KD cells manifested high similarity. Subsequently it's confirmed that HHIP-AS1 regulates HHIP in LUSC cells. Notably, HHIP-AS1 regulation on LUSC growth is achieved through stabilizing HHIP mRNA rather than regulating MIR-153-3P/PCDHGA9 or MIR-425-5P/DNYC1I2. Finally, it's confirmed in PCLS from human LUSC samples that HHIP-AS1 suppresses LUSC via regulating HHIP mRNA. SIGNIFICANCE: This study uncovers HHIP-AS1 as a novel tumor suppressor in LUSC and provides new insights into the molecular regulation of LUSC, which will help developing new therapeutic strategies.

Catalase-like pleated niobium carbide MXene loaded with polythiophene for oxygenated sonodynamic therapy in solid tumor.

Sonodynamic therapy (SDT), an emerging treatment for solid tumors, has the advantages of deep tissue penetration, non-invasiveness, low side effects, and negligible drug resistance. However, the hypoxic environment of deep solid tumors can discount the efficacy of oxygenated dependent SDT. Here, we synthesized a polythiophene-based sonosensitizer (PT2) and a two-dimensional pleated niobium carbide (Nb2C) Mxene. PT2 was loaded onto the surface of poly(vinylpyrrolidone) (PVP)-coated Nb2C MXene through electrostatic interaction to obtain Nb2C-PVP-PT2 nanosheets (NSs) with a high loading efficiency of 153.7%. Nb2C MXene exhibited catalase-like activity, which could catalyze hydrogen peroxide (H2O2) to produce O2, in turn alleviating tumor hypoxia and enhancing the efficacy of SDT. The depletion of H2O2 further results in abnormal cellular H2O2 levels and reduced tumor cell activity. Moreover, the decomposed NSs led to the release of the sonosensitizer PT2 that can efficiently generate both singlet oxygen and superoxide anions under ultrasound irradiation. These events led to the inhibition of DNA replication of tumor cells, causing tumor cell death, allowing for enhanced SDT efficacy.

Exploring the clinical outcomes and safety profile of inetetamab treatment in metastatic breast cancer patients: A multicenter assessment of a Chinese-origin recombinant Anti-HER2 monoclonal antibody.

BACKGROUND: Inetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody. This study aimed to evaluate the efficacy and safety of inetetamab and predictive factors for response in HER2-positive metastatic breast cancer (MBC) patients. METHODS: A cohort of HER2-positive MBC patients who received inetetamab-based therapy between June 2020 and August 2021 was evaluated. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 141 patients were included in the final analysis. The median PFS of the entire cohort was 7.1 months. The median number of treatment lines administered was three. The ORR was 36.9 %, and the DCR was 80.9 %. The most frequently employed treatment strategy was inetetamab + chemotherapy (49/141, 34.8 %), followed by inetetamab + HER2-tyrosine kinase inhibitors (HER2-TKIs) + chemotherapy, inetetamab + pertuzumab + chemotherapy, inetetamab + endocrine treatment and inetetamab + HER2-TKIs. Cox multivariate analysis revealed that PFS was associated with liver metastasis (hazard ratio [HR] 2.112, 95 % confidence interval [CI] 1.334-3.343, p = 0.001), previous HER2-TKI treatment (HR 2.019, 95 % CI 1.133-3.597, p = 0.017) and estrogen receptor positivity (HR 0.587, 95 % CI 0.370-0.934, p = 0.024). The toxicity was tolerable, with neutropenia being the most common treatment-related grade 3/4 AE (14.9 %). CONCLUSION: Inetetamab demonstrates effectiveness with a manageable safety profile, offering a promising therapeutic option for HER2-positive breast cancer patients who have shown resistance to prior anti-HER2 treatments.

The circulating tumor DNA (ctDNA) alteration level predicts therapeutic response in metastatic breast cancer: Novel prognostic indexes based on ctDNA.

PURPOSE: Circulating tumor DNA (ctDNA) has good clinical guiding value for metastatic breast cancer (MBC) patients. This study aimed to apply a novel genetic analysis approach for therapeutic prediction based on ctDNA alterations. METHOD: This nonrandomized, multicenter study recruited 223 MBC patients (NCT05079074). Plasma samples were collected for target-capture deep sequencing of ctDNA at baseline, after the 2nd cycle of treatment, and when progressive disease (PD) was evaluated. Samples were categorized into four levels according to the number of ctDNA alterations: level 1 (no alterations), level 2 (1-2 alterations), level 3 (3-4 alterations) and level 4 (≥5 alterations). According to ctDNA alteration level and variant allele frequency (VAF), a novel ctDNA-level Response Evaluation Criterion in Solid Tumors (ctle-RECIST) was established to assess treatment response and predict progression-free survival (PFS). RESULTS: The median PFS in level 1 (6.63 months) patients was significantly longer than that in level 2-4 patients (level 2: 5.70 months; level 3-4: 4.90 months, p < 0.05). After 2 cycles of treatment, based on ctle-RECIST, the median PFS of level-based disease control rate (lev-DCR) patients was significantly longer than that of level-based PD (lev-PD) patients [HR 2.42 (1.52-3.85), p < 0.001]. In addition, we found that ctDNA level assessment could be a good supplement to radiologic assessment. The median PFS in the dual-DCR group tended to be longer than that in the single-DCR group [HR 1.41 (0.93-2.13), p = 0.107]. CONCLUSION: The ctDNA alteration level and ctle-RECIST could be novel biomarkers of prognosis and could complement radiologic assessment in MBC.

The prognosis and risk factors for capecitabine maintenance treatment in metastatic breast cancer: a retrospective comparative cohort study.

Background: Maintenance treatment following efficient chemotherapy can improve the treatment outcomes of patients with metastatic breast cancer (MBC). However, there are no studies for identifying the prognostic factors for patients who could benefit from capecitabine maintenance. Therefore, this study aimed to investigate the prognosis and risk factors of capecitabine maintenance therapy and analysed the circulating tumour DNA (ctDNA) markers that may be related to the treatment response. Methods: This study recruited 482 consecutive patients with MBC who achieved clinical benefit from capecitabine-based chemotherapy from 2011 to 2019. A total of 256 patients received subsequent capecitabine maintenance therapy. The baseline clinical factors included age at diagnosis, menopause, neoadjuvant therapy, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and subtypes, prior treatment lines, and prior capecitabine-based treatment response. Treatment outcome (progression-free survival, PFS) was assessed by imaging tools according to RSCIST 1.1 standard during the first two treatment cycles and every 3 weeks thereafter. Univariate and multivariate Cox proportional hazards models were used to analysethe association between capecitabine maintenance treatment and prognosis. Results: The median PFS of patients receiving capecitabine maintenance treatment was 21.7 months [95% confidence interval (CI): 15.1-36.3 months]. Capecitabine maintenance showed similar effects as endocrine maintenance or anti-HER2 therapy in hormone receptor (HR)-positive or HER2-positive patients, with adjusted HR of 1.17 (95% CI: 0.81-1.71, P=0.40). In patients with triple-negative breast cancer (TNBC), capecitabine maintenance showed a marginal benefit in PFS. Compared to late-line (≥2) capecitabine maintenance, first-line capecitabine maintenance significantly prolonged median PFS. Compared to other HR/HER2 subtypes, patients with HR-positive and HER2-positive subtypes significantly benefited from capecitabine maintenance treatment. Analysis of ctDNA revealed that among patients receiving capecitabine maintenance, TP53 aberrations were concentrated in patients with short PFS. Conclusions: Capecitabine maintenance treatment is associated with longer PFS in patients with MBC, especially those receiving first-line capecitabine-based chemotherapy and those with HR positivity/HER2 positivity. TP53 aberrations may be responsible for the poor response to capecitabine maintenance treatment.