Development and validation of novel immune-inflammation-based clinical predictive nomograms in HER2-negative advanced gastric cancer.

Purpose: To explore the predictive value of multiple immune-inflammatory biomarkers including serum VEGFA and systemic immune-inflammation index (SII) in HER2-negative advanced gastric cancer (AGC) and establish nomograms for predicting the first-line chemotherapeutic efficacy, progression-free survival (PFS) and overall survival (OS) of patients with this fatal disease. Methods: From November 2017 to April 2022, 102 and 34 patients with a diagnosis of HER2-negative AGC at the First Affiliated Hospital of Bengbu Medical College were enrolled as development and validation cohorts, respectively. Univariate and multivariate analyses were performed to evaluate the clinical value of the candidate indicators. The variables were screened using LASSO regression analysis. Predictive models were developed using significant predictors and are displayed as nomograms. Results: Baseline VEGFA expression was significantly higher in HER2-negative AGC patients than in nonneoplastic patients and was associated with malignant serous effusion and therapeutic efficacy (all p<0.001). Multivariate analysis indicated that VEGFA was an independent predictor for first-line therapeutic efficacy and PFS (both p<0.01) and SII was an independent predictor for first-line PFS and OS (both p<0.05) in HER2-negative AGC patients. The therapeutic efficacy model had an R2 of 0.37, a Brier score of 0.15, and a Harrell's C-index of 0.82 in the development cohort and 0.90 in the validation cohort. The decision curve analysis indicated that the model added more net benefits than VEGFA assessment alone. The PFS/OS models had Harrell's C-indexes of 0.71/0.69 in the development cohort and 0.71/0.62 in the validation cohort. Conclusion: The established nomograms integrating serum VEGFA/SII and commonly available baseline characteristics provided satisfactory performance in predicting the therapeutic efficacy and prognosis of HER2-negative AGC patients.

The Roles of Myeloid Cells in Aging-related Liver Diseases.

Aging is a necessary process of life associated with various mechanisms, such as genomic instability, loss of proteostasis, deregulated nutrient sensing, and cellular senescence, causing progressive dysregulation of the microenvironment, organ homeostasis and biological functions. The hepatic microenvironment is essential for maintaining liver homeostasis, in which hepatocytes, sinusoidal endothelial cells, stellate cells and immune cells are closely associated with the development of aging-related liver diseases. There is increasing evidence that immunocytes, especially myeloid cells, are involved in aging-related liver diseases such as alcoholic liver disease, nonalcoholic liver disease, liver fibrosis or cirrhosis and liver cancer, becoming promising treatment targets of these diseases. This review summarizes the phenotypic and functional alterations associated with aging liver and myeloid cells, as well as the roles of myeloid cells in the progression of aging-related liver diseases.

Real-World Outcome and Prognostic Factors Among HER2-Positive Metastatic Breast Cancer Patients Receiving Pyrotinib-Based Therapy: A Multicenter Retrospective Analysis.

Purpose: To explore the efficacy, safety, and potential factors influencing efficacy and outcome of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in complex clinical practice. Methods: Real-world data for HER2-positive MBC patients treated with pyrotinib-based regimens from 6 hospitals in Northern Anhui, China, from September 2018 to February 2022, were retrospectively collected, and clinicopathological features, efficacy, prognosis, and safety were analyzed. Potential influencing factors including baseline serum vascular endothelial growth factor-A (VEGF-A) for evaluating pyrotinib's treatment response and outcome were also explored. Results: A total of 169 patients with HER2-positive MBC were enrolled. The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) of the overall cohort were 65.1%, 87.6%, and 12.4 months, respectively. Pyrotinib is highly beneficial as different treatment lines and appears to be a feasible strategy both in combination with chemotherapeutic drugs and alone. The mPFS values were 16.5 months, 12.4 months, and 9.3 months in the first, second, and third-or-higher lines of anti-HER2 therapy, respectively (P=0.027). The most common adverse event (AE) was diarrhea (88.2%), and patients with < grade 3 diarrhea achieved a longer mPFS than patients with ≥ grade 3 diarrhea (13.3 months vs 6.9 months, P=0.007). Among the patients with available baseline VEGF-A data, the ORR was 43.5% in patients with a high level of VEGF-A, compared to 81.5% in patients with a low level of VEGF-A (P=0.005). Moreover, patients in the VEGF-A-high group exhibited a shorter mPFS time than those in the VEGF-A-low group (7.8 months vs 19.1 months, P=0.004). Further analysis demonstrated AE of diarrhea and VEGF-A at baseline to be independent prognostic factors for PFS. Conclusion: Pyrotinib-based regimens showed promising efficacy, with manageable tolerance, and AE occurrence of severe diarrhea and baseline level of serum VEGF-A are helpful in predicting the treatment outcome of pyrotinib in HER2-positive MBC.

Selecting an Appropriate Experimental Animal Model for Cholangiocarcinoma Research.

Cholangiocarcinoma (CCA) is a highly aggressive biliary tree malignancy with intrahepatic and extra-hepatic subtypes that differ in molecular pathogeneses, epidemiology, clinical manifestations, treatment, and prognosis. The overall prognosis and patient survival remains poor because of lack of early diagnosis and effective treatments. Preclinical in vivo studies have become increasingly paramount as they are helpful not only for the study of the fundamental molecular mechanisms of CCA but also for developing novel and effective therapeutic approaches of this fatal cancer. Recent advancements in cell and molecular biology have made it possible to mimic the pathogenicity of human CCA in chemical-mechanical, infection-induced inflammatory, implantation, and genetically engineered animal models. This review is intended to help investigators understand the particular strengths and weaknesses of the currently used in vivo animal models of human CCA and their related modeling techniques to aid in the selection of the one that is the best for their research needs.

PHF5A Contributes to the Maintenance of the Cancer Stem-like Phenotype in Non-Small Cell Lung Cancer by Regulating Histone Deacetylase 8.

OBJECTIVE: Cancer stem-like cells (CSLCs) are closely associated with tumor recurrence, metastasis, and drug-resistance. PHD-finger domain protein 5A (PHF5A) is related to tumorigenesis and development of non-small cell lung cancer (NSCLC). The role and regulatory mechanism of PHF5A in CSLCs of NSCLC remain unclear. This study aimed to identify the biological characteristics of CSLCs and the role of PHF5A in maintaining stemness of NSCLC. METHODS: H1299-spheres and A549-spheres were obtained by oncosphere-forming assay and CSLCs by flow cytometry. Expression of CD133, aldehyde dehydrogenase isoform 1, E-cadherin, vimentin, PHF5A, and histone deacetylase 8 (HDAC8) was tested using immunofluorescence staining, qRT-PCR, and Western blotting. CCK-8 and Transwell assays were employed to determine proliferation, migration, and invasion ability of CSLCs and adherent monolayer cells in NSCLC. We regulated PHF5A expression and HDAC activity in CSLCs to explore the mechanism of PHF5A in stemness maintenance and analyzed expression of target proteins in NSCLC tissues. RESULTS: Compared with monolayer cells, CSLCs showed a decreased response to cisplatin-mediated inhibition of proliferation, increased migration and invasion, and high expression of PHF5A and HDAC8, accompanied by EMT marker alterations. Targeted knockdown of PHF5A in CSLCs of NSCLC resulted in diminished stemness phenotypes and HDAC8 expression, whereas inhibition of HDAC activity affected stemness maintenance. Moreover, the expression of target proteins showed consistent changes in NSCLC tissues. CONCLUSIONS: Compared with monolayer cells, cancer stem-like phenotype properties of NSCLC were altered, PHF5A was involved in stemness maintenance of CSLCs, and this process may be related to the activation of HDAC8.

A Comparative Study of Seminars Combined with Case-Based Learning versus Lecture-Based Learning for Cancer Pain Teaching in Medical Oncology Internship.

PURPOSE: To determine whether the teaching method of seminars combined with case-based learning (CBL) is superior to the traditional lecture-based learning (LBL) for teaching cancer pain in medical oncology internship. METHODS: Sixty medical and nursing interns in the medical oncology department of our hospital were selected between January 2019 and December 2020. Thirty students received traditional LBL instruction as the control group, and 30 students received combined seminars and CBL instruction as the observation group. The teaching evaluation and assessment was performed by theoretical and practical examinations and questionnaires. RESULTS: In the after-class examination, case analysis, clinical practice and overall scores of the observation group were higher than those of the control group (all p < 0.001). Theoretical knowledge scores did not differ significantly between the two groups (p = 0.470). In the questionnaire regarding attitudes towards opioid use, the observation group had better perceptions of using opioids than the control group (all p < 0.01). In the meantime, students in the observation group outperformed the control group in four aspects: self-learning (p < 0.001), analytical and problem-solving (p < 0.001), clinical thinking (p = 0.001), and clinical practice (p = 0.002) abilities all improved, while stimulating learning interest (p = 0.184) and enhancing theoretical knowledge mastery (p = 0.221) were not significantly different from those of the control group. Overall, students in the observation group were more satisfied with the teaching, teaching methods and teacher performances than the control group (all p < 0.001). CONCLUSION: Compared to the LBL, the combination of seminars and CBL is a more effective teaching method for cancer pain management, which is worth further study.

Evaluation of diagnostic and predictive values of the serum VEGF-A level and systemic immune-inflammation index in small cell lung cancer.

Purpose: To evaluate diagnostic and predictive values of the serum vascular endothelial growth factor-A (VEGF-A) level and systemic immune-inflammation index (SII) in small cell lung cancer (SCLC) patients. Methods: From January 2018 to April 2020, we prospectively enrolled 59 untreated SCLC patients in the study group and 50 non-neoplastic patients in the control group. Blood samples were collected at baseline, after the first two cycles of chemotherapy and at progression in the study group and at entry in the control group. Serum VEGF-A was measured by chemiluminescence, SII was calculated based on complete blood count results, and the relationship between the VEGF-A/SII and clinicopathological characteristics, chemotherapeutic efficacy and progression-free survival (PFS) of SCLC patients was analyzed. Results: Baseline serum VEGF-A was significantly higher in SCLC patients than in non-neoplastic patients (P<0.001), while baseline SII was not (P=0.114). There was no correlation between baseline VEGF-A and SII in SCLC patients (P=0.123); however, there was a significant correlation between baseline VEGF-A and disease stage and central nervous system (CNS) metastasis (P=0.021 and P=0.012, respectively), as well as between baseline SII and disease stage and liver metastasis (P=0.026 and P=0.018, respectively). Serum VEGF-A was significantly lower than the pretreatment level after 2 cycles of treatment (P=0.049) but was not different at progression (P=0.247). Baseline VEGF-A was correlated with the treatment response of first-line chemotherapy (P=0.001), while baseline SII was not (P=0.392). Kaplan-Meier survival analysis suggested that the PFS of first-line chemotherapy was significantly longer in the low-VEGF-A group at baseline than the high-VEGF-A group (11.37 vs. 6.17 months, P<0.001). There was a trend toward longer PFS of first-line chemotherapy in the low-SII group at baseline than the high-SII group, but the difference was not significant (12.10 vs. 9.10 months, P>0.050). Univariate and multivariate Cox regression analyses suggested that baseline VEGF-A (HR: 3.443, 95% CI: 1.330-8.908, P=0.011) was an independent prognostic factor for PFS in SCLC patients. Conclusions: Baseline serum VEGF-A and SII are associated with important clinicopathological characteristics of SCLC patients. VEGF-A, but not SII, has the ability of diagnosis and predicting first-line chemotherapeutic efficacy and prognosis in SCLC patients.

Molecular phenotype discordance between primary and synchronous metastatic lesions of breast cancer and its determinant role in guiding treatment decisions: a case report.

Molecular phenotype discordance between primary and metastatic tumors exists in a small proportion of breast cancer (BC) patients with accessible synchronous metastases. Reduced therapeutic effect and delays in treatment can occur when decisions on systemic therapy are determined by ignoring the differences in tumor type. Here we report a 54-year-old post-menopausal locally advanced BC patient, who showed no tumor response following routine treatment which included targeting anti-HER2, based on the phenotype of primary tumor (Luminal B, HER2-positive), during neoadjuvant therapy. However, following a secondary biopsy of the metastatic subclavian lymph node, a distinct pathological feature (Triple-negative) was revealed; chemotherapy was adjusted accordingly and resulted in a positive tumor response. Various subclones within primary and metastatic lesions were identified which might be attributed to tumor heterogeneity and in turn resulting in the phenotypic discordance in the receptor status. The patient died due to tumor progression related to triple-negative-featured lung metastasis, with overall survival time of 26.4 months. This study strengthens the value of concurrent biopsies of both primary and synchronous metastatic lesions in BC patients, and provides a reference for treating this kind of tumor when discordance in the molecular phenotype is observed.

Metastatic brain tumors respond favorably to pyrotinib in a HER2-positive breast cancer following failure using trastuzumab.

Treatment of breast cancer (BC) with overexpression of human epidermal growth factor receptor 2 (HER2) has undergone a prosperous development with the advent of emerging small molecule tyrosine kinase inhibitors (TKIs). However, their efficacy in brain metastases (BMs) requires further investigation in both clinical trials and practice by specifically targeting this population. We herein reported a HER2-positive metastatic bilateral BC case with symptomatic diffusion of parenchymal BM after first-line treatment with trastuzumab-based regimen. She then received pyrotinib (with a disease-free survival of 5.7 months) followed by whole brain radiotherapy. Unexpectedly, under satisfactory control of intracranial parenchymal lesions, the patient based on clinical manifestations, auxiliary examinations and exclusive diagnosis was diagnosed with meningeal progression, and soon died of tumor progression. Thus, pyrotinib response differed from meningeal to parenchymal BM in BC patients, and the need of comprehensive and systematic evaluation of TKIs in some particular clinical scenarios has become a critical issue.

Clinical and molecular characteristics of secondary breast metastases from primary lung cancer: a study of 22 Chinese cases.

BACKGROUND: To analyze the clinical and molecular characteristics, as well as pathologic diagnosis and treatment of lung tumors that spread to the breast in 22 Chinese patients. MATERIALS AND METHODS: A systematic literature search of PubMed, Embase, ScienceDirect, Chinese National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journal Database and Wanfang Databases was conducted to identify the related studies published before March 31, 2020. A case of a 64-year-old man who underwent pneumonectomy and who was eventually diagnosed with a breast lump 5 years after surgery at our hospital, was also included in the present study. We analyzed the clinical and immunohistochemical characteristics from these case reports. RESULTS: The analysis totally incorporates 21 case reports and our own case, covering 22 subjects. Among all cases we found 11 adenocarcinomas, 7 small-cell carcinomas, and 4 squamous carcinomas. In addition, most of metastatic breast masses were located below or near the nipple, rather than in the outer quadrant. The results of immunohistochemistry mostly showed triple negative breast cancers. CONCLUSION: A lung cancer patient with a breast tumor should suggest the possibility of metastasis. It is extremely difficult to distinguish secondary breast cancer from primary simply through medical observation and pathologic testing. Additional immunohistochemical examinations are necessary to avoid delays in diagnosis and treatment.

High STRN Expression Promotes HCC Invasion and Migration but Not Cell Proliferation or Apoptosis through Facilitating Epithelial-Mesenchymal Transition.

A STRN-ALK fusion protein has been recently identified as a potential therapeutic target in multiple cancers; however, the role of STRN alone in regulating the biological function of hepatocellular carcinoma (HCC) remains unclear. In this study, we firstly detected an overexpression of STRN in HCC tissues compared to that in adjacent nontumour (ANT) tissues through IHC analysis, and the expression level of this protein was positively correlated with lymph node metastasis and TNM stage. In vitro, high expression of STRN was also confirmed in different HCC cell lines, and regulation of STRN expression in Huh7 cells did not significantly affect tumour cell proliferation or apoptosis but was positively correlated with tumour cell invasion and migration capacities. Moreover, both the knockdown and overexpression of STRN in Huh7 cells can lead to cell morphological changes that are accompanied with an alteration of epithelial-mesenchymal transition (EMT) molecular markers E-cadherin and Vimentin. Finally, STRN was further proved to be negatively related to E-cadherin expression but positively related to Vimentin expression in human HCC tissue samples. Taken together, STRN is upregulated in HCC and acts as a tumour promoter regulating cell invasion and migration through facilitating the EMT process.

Complete response to crizotinib in a metastatic adenocarcinoma of unknown primary harboring MET amplification and NTRK1 co-occurring mutation.

Carcinomas of unknown primary (CUPs) have poor prognosis due to the paucity of data on their clinical characteristics and laboratory features, and empirical chemotherapy still remains the critical management for this kind of disease. This study aimed to present the knowledge of treating an elderly man with metastatic adenocarcinoma of unknown primary and also with a history of long-term hypertension and renal cysts. He was identified to harbor mesenchymal-epithelial transition factor (MET) gene amplification and neurotrophic tyrosine receptor kinase 1 (NTRK1) gene co-occurring mutation by targeted next-generation sequencing analysis upon the progression of empirical chemotherapy. He was then treated with a standard dose of crizotinib (250 mg, twice daily), which exhibited a satisfactory complete response (CR) of the targeted lesions after 1 month of treatment. When the number of renal cysts increased and renal inadequacy occurred after treatment for 2 months, crizotinib was reduced to half-dose (250 mg, once daily), and still conferred maintenance of CR for another 6.5 months and good quality life of the patient. These results suggested that treatments based on driver genes rather than primary tumor types could be a promising manipulation for achieving better treatment outcome, and a half-dose of crizotinib might be both effective and tolerable for MET-overexpressed CUPs with underlying renal diseases.

Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT.

Background: Oxaliplatin (OXA)-based chemotherapy is critical in the management of advanced hepatocellular carcinoma (HCC); however, acquired drug resistance has largely restricted its clinical efficacy. This study aims to explore the key mechanisms and regulatory factors determining chemosensitivity in HCC. Methods: We developed OXA-resistant (OR) HCC cells and used multiple methods, including real-time RT-PCR, Western blot, immunofluorescence, transwell invasion assay, wound-healing assay, MTT assay, gene transfection, and immunohistochemistry to achieve our goals. Results: We found that OR HCC cells showed a typical epithelial-mesenchymal transition (EMT) phenotype. Meanwhile, the expression of Cx32, a major member of the liver connexin (Cx) family, was lowly expressed in OR HCC cells. Downregulation of Cx32 in parental HCC cells led to EMT induction and thereby reduced OXA cytotoxicity, while Cx32 upregulation in OR HCC cells could reverse the EMT phenotype and partially restore chemosensitivity to OXA. Finally, in human HCC tissue samples, Cx32 was positively correlated with the expression of the EMT marker E-cadherin and negatively correlated with the expression of Vimentin. Conclusion: Our findings demonstrated that downregulation of Cx32 may be an important determinant for HCC cells to acquire EMT-related acquired drug resistance to OXA, and targeting Cx32 could be a novel strategy to overcome OXA resistance in HCC.

HER2 positive bilateral metachronous primary breast carcinoma: A case report.

Human epidermal growth factor receptor 2 (HER2) positive is a unique molecular subtype of breast cancer (BC) characterized by high malignancy and poor prognosis. Bilateral primary breast cancer (BPBC) harboring HER2 gene amplification is available to be detected among the BC survivors due to the increasing use of anti-HER2 adjuvant therapy. However, owing to the paucity of cases reported, knowledge of treating HER2-positive BPBC patients including the clinical behavior, histopathologic characteristics, anti-HER2 therapeutic response and disease outcome are not fully understood. Here we report a case of its kind receiving nonstandardized treatment during adjuvant stage. Upon tumor recurrence with liver metastasis, she received trastuzumab combined with chemotherapy and reached a PFS of 14.5 months in first-line treatment. While maintained trastuzumab plus carboplatin as second-line treatment progressed promptly, re-treatment of trastuzumab after lapatinib administration in third line can still benefit the patient. The present case report delineates an anti-HER2 path for a particular characterized patient, and also provides new evidence of trastuzumab re-usage after disease progression of prior anti-HER2 therapy.

First-line treatment of apatinib in elderly patient of advanced gastric carcinoma: A case report of NGS-driven targeted therapy.

Gastric carcinoma (GC) is a common gastrointestinal malignancy with high incidence and mortality worldwide, and most patients are diagnosed in the late stages of disease. Palliative chemotherapy provides a survival benefit for patients with inoperable advanced GC. However, elderly patients who are unable to tolerate chemotherapy had worse prognosis due to lack of effective treatment. Herein we reported a Chinese elderly GC patient using next generation sequencing (NGS)-based tumor DNA analysis. Valuable gene variants of vascular endothelial growth factor (VEGF) A gene amplification were detected. Additionally, a novel NOTCH1-BPHL fusion has been identified. He received antiangiogenic drug apatinib and showed both good clinical and radiographic response, but eventually died of non-cancer related cause, with progression free survival time (PFS) and overall survival time (OS) up to 9.53 months. This was the first GC case with apatinib usage as first-line treatment under the guidance of NGS gene profiling.