Efficacy and safety of first-line regimens for advanced HER2-positive breast cancer: A Bayesian network meta-analysis.

Background: The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first-line therapy. However, with the development of newer treatment regimens, there is a lack of evidence regarding which is the optimal treatment strategy. The aim of this network meta-analysis was to evaluate the efficacy and safety of first-line regimens for advanced HER2-positive breast cancer by indirect comparisons. Methods: A systematic review and Bayesian network meta-analysis were conducted. The PubMed, EMBASE, and Cochrane Library databases were searched for relevant articles published through to December 2023. The hazard ratio (HR) and 95% credible interval (CrI) were used to compare progression-free survival (PFS) between treatments, and the odds ratio and 95% CrI were used to compare the objective response rate (ORR) and safety. Results: Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed. Compared with the traditional trastuzumab and docetaxel regimen, PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen (HR: 0.41, 95% CrI: 0.22-0.75) and the pertuzumab and trastuzumab plus docetaxel regimen (HR: 0.65, 95% CrI: 0.43-0.98). Consistent with the results for PFS, the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen. The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR. Comparable results were found for grade ≥3 AE rates of ≥10%. Conclusions: Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first-line therapy for patients with HER2-positive breast cancer.

Integrative analyses identified gap junction beta-2 as a prognostic biomarker and therapeutic target for breast cancer.

Background: Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer. Methods: We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed. Results: Gap junction beta-2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta-2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta-2 are rare in breast cancer. The gap junction beta-2 transcription level in the p110α subunit of the phosphoinositide 3-kinase mutant subgroup was higher than that in the wild-type subgroup. Gap junction beta-2 was associated with the phosphoinositide 3-kinase-Akt signaling pathway, extracellular matrix-receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta-2 overexpression may be associated with phosphoinositide 3-kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells. Conclusions: Gap junction beta-2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.

The Therapeutic Potential of Hemp Seed Oil in D-Galactose-Induced Aging Rat Model Was Determined through the Combined Assessment of 1H NMR Metabolomics and 16S rRNA Gene Sequencing.

Aging is an irreversible process of natural degradation of bodily function. The increase in the aging population, as well as the rise in the incidence of aging-related diseases, poses one of the most pressing global challenges. Hemp seed oil, extracted from the seeds of hemp (Cannabis sativa L.), possesses significant nutritional and biological properties attributed to its unique composition of polyunsaturated fatty acids and various antioxidant compounds. However, there is limited knowledge regarding the anti-aging mechanism of hemp seed oil. This study aimed to evaluate the beneficial effects and potential mechanisms of hemp seed oil in a D-galactose (D-gal)-induced aging rat model through a combined analysis of metabolomics and 16S rRNA gene sequencing. Using nuclear magnetic resonance (NMR)-based metabolomics, significant alterations in serum and urine metabolic phenotypes were observed between the D-gal-induced aging rat model and the healthy control group. Eight and thirteen differentially expressed metabolites related to aging were identified in serum and urine, respectively. Treatment with hemp seed oil significantly restored four and ten potential biomarkers in serum and urine, respectively. The proposed pathways primarily included energy metabolism, amino acid metabolism, one-carbon metabolism, and lipid metabolism. Furthermore, 16S rRNA gene sequencing analysis revealed significant changes in the gut microbiota of aged rats. Compared to the model group, the hemp seed oil group exhibited significant alterations in the abundance of 21 bacterial taxa at the genus level. The results indicated that hemp seed oil suppressed the prevalence of pathogenic bacterial genera such as Streptococcus, Rothia, and Parabacteroides. Additionally, it facilitated the proliferation of the genera Lachnospirace_NK4B4_group and Lachnospirace_UCG_001, while also enhancing the relative abundance of the genus Butyricoccus; a producer of short-chain fatty acids (SCFAs). These findings provided new insights into the pathogenesis of aging and further supported the potential utility of hemp seed oil as an anti-aging therapeutic agent.

PP2A as a potential therapeutic target for breast cancer: Current insights and future perspectives.

Breast cancer has become the most prevalent malignancy worldwide; however, therapeutic efficacy is far from satisfactory. To alleviate the burden of this disease, it is imperative to discover novel mechanisms and treatment strategies. Protein phosphatase 2 A (PP2A) comprises a family of mammalian serine/threonine phosphatases that regulate many cellular processes. PP2A is dysregulated in several human diseases, including oncological pathologies, and plays a pivotal role in the initiation and progression of tumours. The role of PP2A as a tumour suppressor has been extensively studied, and its regulation can serve as a target for anticancer therapy. Recent studies have shown that PP2A is a tumour promotor. PP2A-mediated anticancer therapy may involve two opposing mechanisms: activation and inhibition. In general, the contradictory roles of PP2A should not be overlooked, and more work is needed to determine the molecular mechanism by which PP2A affects in tumours. In this review, the literature on the role of PP2A in tumours, especially in breast cancer, was analysed. This review describes relevant targets of breast cancer, such as cell cycle control, DNA damage responses, epidermal growth factor receptor, immune modulation and cell death resistance, which may lead to effective therapeutic strategies or influence drug development in breast cancer.

Early-onset and late-onset Parkinson's disease exhibit a different profile of gait and posture features based on the Kinect.

INTRODUCTION: Gait and posture abnormalities are the common disabling motor symptoms in Parkinson's disease (PD). This study aims to investigate the differential characteristics of gait and posture in early-onset PD (EOPD) and late-onset PD (LOPD) using the Kinect depth camera. METHODS: Eighty-eight participants, including two subgroups of 22 PD patients and two subgroups of 22 healthy controls (HC) matched for age, sex, and height, were enrolled. Gait and posture features were quantitatively assessed using a Kinect-based system. A two-way analysis of variance was used to compare the difference between different subgroups. RESULTS: EOPD had a significantly higher Gait score than LOPD (p = 0.031). Specifically, decreased swing phase (p = 0.034) was observed in the EOPD group. Although the Posture score was similar between the two groups, LOPD was characterized by an increased forward flexion angle of the trunk at the thorax (p = 0.042) and a decreased forward flexion angle of the head relative to the trunk (p = 0.009). Additionally, age-independent features were observed in both PD subgroups, and post hoc tests revealed that EOPD generally performed worse gait features. In comparison, LOPD was characterized by worse performance in posture features. CONCLUSIONS: EOPD and LOPD exhibit different profiles of gait and posture features. The phenotype-specific characteristics likely reflect the distinct neurodegenerative processes between them.

Efficacy and safety of trastuzumab with or without a tyrosine kinase inhibitor for HER2-positive breast cancer: A systematic review and meta-analysis.

BACKGROUND: This study aimed to explore the efficacy and safety of trastuzumab plus tyrosine kinase inhibitors (TKIs) compared with those of trastuzumab monotherapy in patients with human epidermal growth factor receptor (HER2)-positive breast cancer. METHODS: The PubMed, Embase, Cochrane, and Web of Science databases were systematically searched for relevant articles from inception until September 2022. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were performed based on disease status, TKI type, and hormone receptor status. RESULTS: Sixteen studies were included in the current analysis. Trastuzumab plus TKI significantly improved OS and PFS compared to trastuzumab monotherapy. In the neoadjuvant setting, trastuzumab plus TKI significantly increased the pathologic complete response (pCR) rate compared to trastuzumab monotherapy. Moreover, a higher objective response rate (ORR) was observed with trastuzumab plus TKI. Patients who received the combination therapy had a higher incidence of discontinuation, all-grade diarrhea, and grade ≥ 3 diarrhea. CONCLUSIONS: Trastuzumab plus TKI was better than trastuzumab monotherapy for treating different stages of HER2-positive breast cancer. The safety of trastuzumab plus TKI anti-HER2 therapy was controllable. The different efficacies of TKIs combined with trastuzumab may be related to the mechanism of action of the different TKIs, needing further investigations.

The clinical significance for primary tumor surgery in metastatic head and neck adenoid cystic carcinoma.

PURPOSE: This study aimed to determine the prognostic significance and optimal candidates for primary tumor surgery (PTS) among patients with metastatic head and neck adenoid cystic carcinoma (HNACC). METHODS: The data were retrieved from Surveillance, Epidemiology, and End Results (SEER) database. Patients with metastatic HNACC at the initial diagnosis were included in this study. Univariate survival analysis was performed using the Kaplan-Meier method, and the difference in survival curves between PTS and non-PTS groups was estimated using the log-rank test. Multivariate analysis was performed to evaluate the independent prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS). RESULTS: Overall, 155 patients were eligible, of whom 93 underwent palliative PTS. Patients with lung metastasis alone were more likely to undergo PTS. PTS was associated with significantly improved OS and CSS compared with non-PTS. In the multivariate model, patients who underwent PTS had better OS than those who did not undergo PTS; however, no improvement was observed in the CSS. Subgroup analyses further revealed that patients aged < 60 years with T3-4 or N0 classification might benefit from PTS. CONCLUSION: PTS significantly improved the OS of patients with metastatic HNACC. PTS had a favorable prognostic impact on highly selected patients, namely, those aged < 60 years with T3-4 and N0 classification, which could be adopted in future clinical practice.

Risk factors and prognostic models of lymph node metastatic hypopharyngeal squamous cell carcinoma.

PURPOSE: To explore the risk factors for lymph node metastasis (LNM) and establish nomograms for predicting survival outcomes and assessing individual risk in patients with LNM and hypopharyngeal squamous carcinoma (HSCC). METHODS: Clinical data of patients with HSCC were retrospectively reviewed. The study's primary endpoints were overall survival (OS) and disease-specific survival (DSS). Nomograms were established based on Cox regression analyses. The accuracy and calibration ability of the nomograms were evaluated using the C-index, area under the curve, calibration curves, and decision curve analysis. RESULTS: Overall, 2888 patients were enrolled, and the LNM rate was 74.2%. Age ≤ 60 years, male sex, unmarried status, pyriform sinus location, grade III-IV, tumor larger than 4 cm, and advanced T stage increased the risk of LNM. In addition, LNM was a negative prognostic factor for OS and DSS. Ten variables were identified and incorporated into nomograms to estimate OS and DSS. Our nomograms outperformed the traditional staging system in training and validation cohorts. Patients were stratified into risk subgroups based on the OS- and DSS-nomogram scores. Patients in the high-risk subgroup had a higher risk of death and disease-specific mortality than those in the low- and intermediate-risk subgroups. CONCLUSIONS: LNM worsens the prognosis of HSCC. This study identified the independent prognostic factors for HSCC with LNM and developed satisfactory OS- and DSS-monogram to provide individual prediction and risk classification for patients with this diagnosis.

The association between CTSZ methylation in peripheral blood and breast cancer in Chinese women.

Purpose: Previous studies have shown that DNA methylation in peripheral blood may be associated with breast cancer (BC). To explore the association between the methylation level of the Cathepsin Z (CTSZ) gene in peripheral blood and BC, we conducted a case-control study in the Chinese population. Methods: Peripheral blood samples were collected from 567 BC cases, 635 healthy controls, and 303 benign breast disease (BBD) cases. DNA extraction and bisulfite-specific PCR amplification were performed for all samples. The methylation levels of seven sites of the CTSZ gene were quantitatively determined by Mass spectrometry. The odds ratios (ORs) of CpG sites were evaluated for BC risk using per 10% reduction and quartiles analyses by logistic regression. Results: Our analysis showed that five out of the seven CpG sites exhibited significant associations with hypomethylation of CTSZ and BC, compared to healthy controls. The highest OR was for Q2 of CTSZ_CpG_1 (OR: 1.62, P=0.006), particularly for early-stage breast cancer in the case of per 10% reduction of CTSZ_CpG_1 (OR: 1.20, P=0.003). We also found that per 10% reduction of CTSZ_CpG_5 (OR: 1.39, P=0.004) and CTSZ_CpG_7,8 (OR: 1.35, P=0.005) were associated with increased BC risk. Our study also revealed that four out of seven CpG sites were linked to increased BC risk in women under 50 years of age, compared to healthy controls. The highest OR was for per 10% reduction of CTSZ_CpG_1 (OR: 1.47, P<0.001). Additionally, we found that BC exhibited lower methylation levels than BBD at CTSZ_CpG_4 (OR for Q1: 2.18, P<0.001) and CTSZ_CpG_7,8 (OR for Q1: 2.01, P=0.001). Furthermore, we observed a correlation between methylation levels and tumor stage, ER, and HER2 status in BC patients. Conclusion: Overall, our findings suggest that altered CTSZ methylation levels in peripheral blood may be associated with breast cancer, particularly in young women, and may serve as a potential biomarker for early-stage BC.

Lymph node ratio-based prognostic model for risk stratification and individualized adjuvant therapy for postoperative major salivary duct carcinoma.

BACKGROUND: To investigate the value of lymph node ratio (LNR) for postoperative major salivary duct carcinoma (MSDC) and to establish a model for prognosis assessment and treatment optimization. METHODS: Data of MSDC were retrieved in public database, and prognostic factors were identified by univariate and multivariate analyses. A nomogram and risk stratification system were constructed. RESULTS: Four hundred and eleven eligible patients were included (training cohort vs. validation cohort: 287: 124). LNR ≥0.09 was associated with worse overall survival (OS). Age at diagnosis, sex, T stage, and LNR were identified as prognostic factors and integrated into nomogram. Low-risk patients were found to have better OS than high-risk patients. Furthermore, postoperative radiotherapy (PORT) significantly improved OS in the high-risk subgroup, but chemotherapy did not confer a long-term survival benefit. CONCLUSIONS: A nomogram model integrating LNR could better assess postoperative prognosis and risk stratification in MSDC, and identify patients who might benefit from PORT to avoid overtreatment.

Integration of transcriptomics and metabonomics revealed the protective effects of hemp seed oil against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis in mice.

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with few therapeutic options available currently. Hemp seed oil extracted from the seeds of hemp (Cannabis sativa L.) has significant nutritional and biological properties due to the unique composition of polyunsaturated fatty acids and various antioxidant compounds. However, little is known about the beneficial effects and molecular mechanisms of hemp seed oil on NASH. Here, the hepatoprotective effects of hemp seed oil on methionine-choline-deficient (MCD) diet-induced NASH in C57BL/6 mice were explored via integration of transcriptomics and metabolomics. Hemp seed oil could improve hepatic steatosis, inflammation and fibrosis in mice with MCD diet-induced NASH. In a nuclear magnetic resonance (NMR)-based metabonomic study, the hepatic and urinary metabolic profiles of mice supplemented with hemp seed oil showed a tendency to recover to healthy controls compared to those of NASH mice. Eight potential biomarkers associated with NASH in both liver tissue and urine were restored to near normal levels by administration of hemp seed oil. The proposed pathways were mainly involved in pyrimidine metabolism, one-carbon metabolism, amino acid metabolism, glycolysis and the tricarboxylic acid (TCA) cycle. Hepatic transcriptomics based on Illumina RNA-Seq sequencing showed that hemp seed oil exerted anti-NASH activities by regulating multiple signaling pathways, e.g., downregulation of the TNF signaling pathway, the IL-17 signaling pathway, the MAPK signaling pathway and the NF-κB signaling pathway, which played a pivotal role in the pathogenesis of NASH. In particular, integration of metabonomic and transcriptomic results suggested that hemp seed oil could attenuate NASH-related liver fibrosis by inhibition of glutaminolysis. These results provided new insights into the hepatoprotective effects of hemp seed oil against MCD diet-induced NASH and hemp seed oil might have potential as an effective therapy for NASH.

Development, validation, and evaluation of a deep learning model to screen cyclin-dependent kinase 12 inhibitors in cancers.

Deep learning-based in silico alternatives have been demonstrated to be of significant importance in the acceleration of the drug discovery process and enhancement of success rates. Cyclin-dependent kinase 12 (CDK12) is a transcription-related cyclin-dependent kinase that may act as a biomarker and therapeutic target for cancers. However, currently, there is no high selective CDK12 inhibitor in clinical development and the identification of new specific CDK12 inhibitors has become increasingly challenging due to their similarity with CDK13. In this study, we developed a virtual screening workflow that combines deep learning with virtual screening tools and can be applied rapidly to millions of molecules. We designed a Transformer architecture Drug-Target Interaction (DTI) model with dual-branched self-supervised pre-trained molecular graph models and protein sequence models. Our predictive model produced satisfactory predictions for various targets, including CDK12, with several novel hits. We screened a large compound library consisting of 4.5 million drug-like molecules and recommended a list of potential CDK12 inhibitors for further experimental testing. In kinase assay, compared to the positive CDK12 inhibitor THZ531, the compounds CICAMPA-01, 02, 03 displayed more effective inhibition of CDK12, up to three times as much as THZ531. The compounds CICAMPA-03, 05, 04, 07 showed less inhibition of CDK13 compare to THZ531. In vitro, the IC50 of CICAMPA-01, 04, 05, 06, 09 was less than 3 µM in the HER2 positive CDK12 amplification breast cancer cell line BT-474. Overall, this study provides a highly efficient and end-to-end deep learning protocol, in conjunction with molecular docking, for discovering CDK12 inhibitors in cancers. Additionally, we disclose five novel CDK12 inhibitors. These results may accelerate the discovery of novel chemical-class drugs for cancer treatment.

Genetic spectrum and clinical features in a cohort of Chinese patients with isolated dystonia.

Dystonia is a genetically and phenotypically heterogeneous disorder that occurs in isolation (isolated dystonia) or in combination with other movement disorders. To determine the genetic spectrum in isolated dystonia, we enrolled 88 patients with isolated dystonia for whole-exome sequencing (WES). Seventeen mutations, including nine novel ones, were identified in 19 of the 88 patients, providing a 21.59% positive molecular diagnostic rate. Eleven distinct genes were involved, of which TOR1A and THAP1 accounted for 47.37% (9/19) of the positive cases. A novel missense variant, p.S225R in TOR1A, was found in a patient with adolescence-onset generalized dystonia. Cellular experiments revealed that p.S255R results in the abnormal aggregation of Torsin-1A encoding by TOR1A. In addition, we reviewed the clinical and genetic features of the isolated dystonia patients carrying TOR1A, THAP1, ANO3, and GNAL mutations in the Chinese population. Our results expand the genetic spectrum and clinical profiles of patients with isolated dystonia and demonstrate WES as an effective strategy for the molecular diagnosis of isolated dystonia.

Prognostic models for estimating survival of salivary duct carcinoma: a population-based study.

PURPOSE: In a large salivary duct carcinoma (SDC) cohort, we aimed to investigate the clinical factors influencing their survival outcomes and to further establish prognostic models. METHODS: Data of patients with SDC were extracted from the Surveillance, Epidemiology, and End Results database (1975-2019). A retrospective analysis was conducted to explore the prognostic factors on overall survival (OS) and disease-specific survival (DSS), and corresponding nomograms were established. RESULTS: A steady upward trend in the incidence of SDC was observed over the past four decades. Totally, 399 patients (280 in the training set and 199 in the testing set) were enrolled. Advanced T stage, lymph node metastasis, distant metastasis, and surgery were associated with favorable OS and DSS. Besides, age > 80 years exhibited worse OS. The selected variables above were used to construct nomograms and online web calculators that could accurately predict patient survival. In addition, risk stratification systems were generated to identify low- and high-risk patients. As the risk level increased, the risk of both patient mortality and disease-specific mortality increased. CONCLUSIONS: The SDC incidence was low, but steadily increasing. The proposed prognostic models provided a robust and efficient approach to predict survival and risk stratification in SDC patients.

Clinical value of adjuvant therapy on the prognosis of ductal carcinoma of the major salivary gland: a large-scale cohort study.

PURPOSE: To explore the clinical characteristics, prognostic factors, and value of adjuvant therapy for major salivary duct carcinoma (SDC). METHODS: Data of SDC patients who received surgery was obtained from Surveillance, Epidemiology, and End Results (SEER) database (2004-2016). Kaplan-Meier and Cox regression analyses were performed to assess prognostic factors. Propensity score matching (PSM) was done to evaluate the clinical value of adjuvant therapy. RESULTS: A total of 287 patients were enrolled. The 5-year overall survival (OS) and disease-specific survival (DSS) rates were 53.8% and 70.8%, respectively. In the univariate analysis, tumor size, T, N, TNM staging, SEER combined staging, number of regional lymph nodes examined, and number of positive lymph nodes were associated with OS and DSS. Age and primary surgical methods were also related to OS. Among patients with negative lymph nodes, patients with tumor size > 4 cm had significantly worse prognosis (P = 0.009). Multivariate analysis showed that age > 75 years, T3-4, and positive lymph nodes were independent risk factors for SDC. After PSM, the prognostic factors were age, tumor site, and T and N stage. Postoperative radiotherapy could improve OS in patients with tumor size > 4 cm (P = 0.049). CONCLUSIONS: Advanced age, submandibular gland lesions, T3-4 stage, and lymph node involvement were independent prognostic factors for SDC. In patients with tumors > 4 cm, adjuvant radiotherapy improved the OS of SDC patients.

Dystonia and the pedunculopontine nucleus: Current evidences and potential mechanisms.

Being a major component of the midbrain locomotion region, the pedunculopontine nucleus (PPN) is known to have various connections with the basal ganglia, the cerebral cortex, thalamus, and motor regions of the brainstem and spinal cord. Functionally, the PPN is associated with muscle tone control and locomotion modulation, including motor initiation, rhythm and speed. In addition to its motor functions, the PPN also contribute to level of arousal, attention, memory and learning. Recent studies have revealed neuropathologic deficits in the PPN in both patients and animal models of dystonia, and deep brain stimulation of the PPN also showed alleviation of axial dystonia in patients of Parkinson's disease. These findings indicate that the PPN might play an important role in the development of dystonia. Moreover, with increasing preclinical evidences showed presence of dystonia-like behaviors, muscle tone changes, impaired cognitive functions and sleep following lesion or neuromodulation of the PPN, it is assumed that the pathological changes of the PPN might contribute to both motor and non-motor manifestations of dystonia. In this review, we aim to summarize the involvement of the PPN in dystonia based on the current preclinical and clinical evidences. Moreover, potential mechanisms for its contributions to the manifestation of dystonia is also discussed base on the dystonia-related basal ganglia-cerebello-thalamo-cortical circuit, providing fundamental insight into the targeting of the PPN for the treatment of dystonia in the future.

Prognostic Factors and a Model for Occult Breast Cancer: A Population-Based Cohort Study.

Occult breast cancer (OBC) is a special type of breast cancer of an unknown primary origin. Early stage OBC is treated as stage II−III breast cancer. Currently, there are no models for predicting the survival outcomes. Hence, we aimed to evaluate the role of the positive lymph node ratio (PLNR) in OBC and further establish and validate a prognostic nomogram. Patients with stage T0N+M0 breast cancer were enrolled from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox analyses were used to evaluate the effects of prognostic factors on breast-cancer-specific survival (BCSS), and a nomogram was established and validated for OBC. Overall, 843 patients were included, and the 5-year BCSS rate was 92.4%. Patients with a PLNR < 0.54 had better BCSS rates than those with a PLNR ≥ 0.54. The nomogram combined clinicopathological parameters, including the PLNR, pN stage, and estrogen receptor status, and showed a higher accuracy than the TNM staging system in predicting the BCSS. The patients could be stratified into different risk groups based on their prognostic scores. Patients in the low-risk subgroup showed an improved BCSS compared those in the high-risk subgroup. In conclusion, the PLNR is an independent prognostic factor for OBC. The PLNR-based nomogram has a better predictive ability than the TNM staging system and could be of great value for the treatment of OBC and prediction of its prognosis.

Prognostic Value of the Serum HER2 Extracellular Domain Level in Breast Cancer: A Systematic Review and Meta-Analysis.

An elevated serum HER2 extracellular domain is associated with poor prognosis in breast cancer, but the relationship between sHER2 and the efficacy of different modalities remains controversial. Herein, we aimed to evaluate the prognostic value of serum HER2 extracellular domain (sHER2 ECD) in breast cancer and to identify its correlation with the efficacy of different treatment regimens. A systematic search of the PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases was conducted to identify studies exploring the association between HER2 ECD level and clinical outcomes among patients with breast cancer. Using the random effects models, pooled hazard ratios (HRs), and odds ratios (ORs) with 95% confidence intervals (CI), were calculated for progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), and the objective response rate (ORR). Heterogeneity was further evaluated by subgroup and sensitivity analysis. Overall, 40 studies comprising 12,229 patients were included in this systematic review and meta-analysis. Elevated HER2 ECD levels were associated with worse PFS (HR 1.74, 95% CI 1.40−2.17; p < 0.001), and this effect was observed in patients treated with chemotherapy (HR 1.81, 95% CI 1.37−2.39; p < 0.001), endocrine therapy (HR 1.91, 95% CI 1.57−2.32; p < 0.001), and trastuzumab (HR 1.74, 95% CI 1.31−2.30; p < 0.001). However, this association was not present in patients treated with tyrosine kinase inhibitors (TKIs) (HR 1.44, 95% CI 0.85−2.43, p = 0.17). The HRs/ORs for an elevated HER2 ECD level for DFS, OS, and ORR were 2.73 (95% CI 2.17−3.42; p < 0.001), 2.13 (95% CI 1.77−2.57; p < 0.001), and 0.80 (95% CI 0.49−1.31; p = 0.381), respectively. An elevated sHER2 ECD was an unfavorable prognostic factor in breast cancer but did not affect the efficacy of tyrosine kinase inhibitors such as lapatinib. Detection of sHER2 ECD may be helpful for clinicians selecting the appropriate anti-HER2 therapy for patients with HER2-positive breast cancer.

Clinical value of next-generation sequencing in guiding decisions regarding endocrine therapy for advanced HR-positive/HER-2-negative breast cancer.

Objective: The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor (HR)-positive advanced breast cancer. Circulating tumor DNA (ctDNA) has been allowed for the assessment of the genomic profiles of patients with advanced cancer. We performed this study to search for molecular markers of endocrine therapy efficacy and to explore the clinical value of ctDNA to guide precise endocrine therapy for HR-positive/human epidermal growth factor receptor-2 (HER-2)-negative metastatic breast cancer patients. Methods: In this open-label, multicohort, prospective study, patients were assigned to four parallel cohorts and matched according to mutations identified in ctDNA: 1) activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway preferred mTOR inhibitor combined with endocrine therapy; 2) estrogen receptor 1 (ESR1) mutation preferred fulvestrant; 3) HER-2 mutations preferred pyrotinib; and 4) no actionable mutations received treatment according to the clinical situation. In all cohorts, patients were divided into compliance group and violation group. The primary outcome measure was progression-free survival (PFS), and the secondary outcome measure was overall survival (OS). Results: In all cohorts, the combined median PFS was 4.9 months, and median PFS for the compliance and violation groups was 6.0 and 3.0 months, respectively [P=0.022, hazard ratio (HR)=0.57]. Multivariate Cox regression model showed the risk of disease progression was lower in compliance group than in violation group (P=0.023, HR=0.55). Among the patients with HER-2 mutations, the median PFS was 11.1 months in the compliance group and 2.2 months in the violation group (P=0.011, HR=0.20). There was no significant difference in the median PFS between patients who did and did not comply with the treatment protocol in patients with activation of the PI3K/AKT/mTOR or ESR1 mutation. Conclusions: The results suggest that ctDNA may help to guide the optimal endocrine therapy strategy for metastatic breast cancer patients and to achieve a better PFS. Next-generation sequencing (NGS) detection could aid in distinguishing patients with HER-2 mutation and developing new treatment strategies.

Prognostic Nomogram for Postoperative Hypopharyngeal Squamous Cell Carcinoma to Assist Decision Making for Adjuvant Chemotherapy.

We aimed to investigate the effect of lymph node parameters on postoperative hypopharyngeal squamous cell carcinoma (HSCC) and to establish a nomogram to predict its prognosis and assist in adjuvant chemotherapy decisions. A retrospective analysis of postoperative HSCC in the Surveillance, Epidemiology, and End Results database (2004-2019) was performed. Cutoff points for continuous variables were determined by X-tile software. Univariate and multivariate analyses were performed to identify prognostic factors on overall survival (OS), and these variables were used to construct a nomogram. The nomogram's accuracy was internally validated using concordance index, area under the curve, calibration plot, and decision curve analyses. Furthermore, the value of chemotherapy in each risk subgroup was assessed separately based on individualized scores from the nomogram. In total, 404 patients were eligible for analysis, and the median OS was 39 months. Age, origin, primary site, T stage, number of lymph nodes examined, lymph node ratio, and radiotherapy were identified as prognostic factors for OS and incorporated into the nomogram. In both the training and validation cohorts, favorable performance was exhibited compared with the other stage systems, and patients could be classified into low-, intermediate-, and high-risk subgroups. Chemotherapy significantly improved the OS in the high-risk subgroup, whereas chemotherapy did not confer a survival benefit in the low- or intermediate-risk groups. The lymph node parameter-based nomogram model can better stratify the prognosis of HSCC patients and screen out patients who would benefit from chemotherapy, suggesting that the model could be used as a reference for clinical decision making and to avoid overtreatment.