Bridging Gaps in Oncology Nutrition Education and Teaching: A Comprehensive Analysis of Resident Physicians in China.

Residents are actively involved in patient assessment and all aspects of patient care, and they are critical in providing nutritional support education and treatment for patients with cancer. This study aims to assess the nutritional knowledge and performance of resident physicians, providing insights into existing gaps in awareness and practices related to cancer nutrition. A total of 300 resident physicians undergoing standardized residency training in China participated in this study. An anonymous online questionnaire covering demographic characteristics, nutritional knowledge, clinical practice, and training requirements was designed and administered through the "Wenjuanxing" platform. Data were collected from June 1, 2023, to July 31, 2023. Among the participants, only 40.00% demonstrated adequate knowledge of cancer nutrition, and merely 32.00% exhibited proficient performance in nutritional care. Socio-demographic analysis revealed that residents without affiliations and those specializing in obstetrics and gynecology had superior knowledge, while surgery specialists showed significantly worse performance. Most participants expressed a lack of exposure to cancer nutrition education during academic and standardized residency training. The study highlights the demand for enhanced education and the preference for case-based teaching methods. The findings underscore an urgent need for comprehensive oncology nutrition education within China's standardized residency training. Targeted interventions and curriculum enhancements are essential to improve medical talent development and enhance patient care outcomes in oncology. The study emphasizes the critical role of practical, case-based teaching methods in addressing identified gaps in nutritional knowledge and practices among resident physicians.

Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases.

PURPOSE: To investigate the impact of radiotherapy (RT) and immune checkpoint inhibitor (ICI) sequence on the survival outcome in NSCLC patients with brain metastasis, and decide the best time to initiate RT. METHODS: Patients were managed with delayed RT (ICI delivered over 2 weeks prior to RT), concurrent RT (ICI delivered within 2 weeks prior to or after RT), or upfront RT (RT delivered over 2 weeks prior to ICI). Overall survival (OS), intracranial local progression-free survival (iLPFS), and intracranial distant progression-free survival (iDPFS) were assessed. A meta-analysis was performed to analyze the association between survival outcome and RT/ICI sequence. RESULTS: A total of 73 NSCLC patients were identified with a median follow-up of 13.9 months. Patients who receive delayed RT demonstrated shorter iLPFS (P = 0.0029), iDPFS (P = 0.016), and OS (P < 0.001). A meta-analysis was conducted and a total of 4 studies, 254 patients were included. The HR was 0.44 for iDPFS (P = 0.03), 0.41 for OS (P < 0.01) when compared concurrent with delayed RT, 0.21 for iDPFS (P < 0.01), 0.32 for OS (P < 0.01) when compared upfront with delayed RT, consistent with our conclusion that delayed RT brought with worst iDPFS and OS. More importantly, the best overall response rate (BOR) decreased in cases with longer RT and ICI intervals. Patients who receive intervals of RT and ICI within 7 days achieve the best median BOR of - 53%. CONCLUSIONS: Delayed RT brought poor survival outcomes including iLPFS, iDPFS, and OS in NSCLC patients. The shorter interval of RT and ICI is associated with better BOR.

Adjuvant therapy with gemcitabine and stereotactic body radiation therapy versus gemcitabine alone for resected stage II pancreatic cancer: a prospective, randomized, open-label, single center trial.

BACKGROUND: The role of adjuvant radiation in pancreatic adenocarcinoma (PDAC) remains unclear. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II PDAC. METHODS: In this single-center randomized controlled trial, patients with stage II PDAC that underwent margin-negative resection were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. RESULTS: Forty patients were randomly assigned to treatment between Sep 1, 2015 and Mar 31, 2018. Of these, 38 were included in the intention-to-treat analysis (20 in gemcitabine arm and 18 in gemcitabine plus SBRT arm). The median RFS and OS were 9.70, 28.0 months in the gemcitabine arm and 5.30, 15.0 months in the gemcitabine plus SBRT arm (RFS, P = 0.53; OS, P = 0.20), respectively. The median LRFS in both arms was unreached (P = 0.81). Grade 3 or 4 adverse events were all comparable between the two arms. Evaluation of data from the enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence-free survival. CONCLUSIONS: Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II PDAC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02461836 . Registered 03/06/2015.

Failure patterns after curative resection for intrahepatic cholangiocarcinoma: possible implications for postoperative radiotherapy.

BACKGROUND: To explore the patterns of failures and areas at highest risk of recurrence for postoperative intrahepatic cholangiocarcinoma (IHCC), with the aim to guide IHCC adjuvant radiotherapy. METHODS: Patients with IHCC who had undergone radical surgery at our institution from July 2010 to August 2017 were retrospectively analyzed. The survival and prognostic factors were analyzed by univariate and multivariate analysis. All sites of recurrence were found out and classified as the surgical margin, regional lymph nodes, liver remnant and distant metastasis. According to the recurring area at highest risk, the target volume of adjuvant radiotherapy was proposed. RESULTS: The median follow-up time was 23.5 months (2-85 months). The median recurrence free survival (RFS) and overall survival (OS) were 12.1 months and 24.8 months, respectively. Seventy-three (73/127, 57.5%) IHCC patients developed tumor recurrence. Initial recurrences occurred in the potential postoperative radiotherapy (PORT) volume, remnant liver and distant sits were 46 (46/73, 63.0%), 36 (36/73, 49.3%) and 22 (22/73, 30.1%) cases, respectively. Of the 46 patients whose initial recurrence inside the potential PORT volume, 29 (29/73, 39.7%) developed recurrence only inside the potential PORT volume, including 13 tumor bed recurrences, 7 lymph node metastases, and 9 with both tumor bed recurrences and lymph node metastases. The most common lymph node metastases sites were nodes around the abdominal aorta, followed by lymph nodes along the celiac artery, the common hepatic artery, and in the hepatoduodenal ligament. CONCLUSIONS: High proportion of the recurrences occurred only inside the potential PORT volume, implying adjuvant radiotherapy might improve the local-regional control. Surgical margins and lymph node stations No.16a2, 9, 8, 12, 13, and 14 are suggested to be included in the radiation volume.

Glioma SOX2 expression decreased after adjuvant therapy.

BACKGROUND: SOX2 is regarded as an important marker in stem cell. The change of SOX2 expression after adjuvant therapy in high grade glioma (HGG) remains unknown so far. Few patients with recurrent glioma have opportunity to undergo operation once again, so the recurrent glioma samples are scarce. This study tries to analyze SOX2 expression in paired primary and recurrent HGG, aims to better understand the transformation law of SOX2 after adjuvant therapy in HGG. METHODS: Twenty-four recurrent HGG patients who undergone a second resection were included. 16 patients received adjuvant therapy, the remaining 8 patients didn't receive any adjuvant therapy at all. The protein expression of SOX2 in paired primary and recurrent HGG was tested by immunohistochemistry. The statistical analysis was conducted by IBM SPSS Statistics 19.0. RESULTS: In primary HGG, SOX2 expression of 3 + , 2 + , 1+ and 0+ were seen in 20 (83.3%), 1 (4.2%), 1 (4.2%) and 2 cases (8.3%), respectively. The expression of SOX2 was decreased in recurrent HGG compared to the paired primary sample (p = 0.001). The decrease of SOX2 was often seen in patients received chemotherapy, radiotherapy or both (p = 0.003). Patients with SOX2 high expression in primary glioma had a longer median PFS than those with SOX2 low expression with marginal statistic significance (12.7 vs. 5.4 months, p = 0.083). For cases with SOX2 high expression in the primary glioma, those had SOX2 low expression after recurrence seemed to have worse prognosis as compared to patients with stable SOX2 high expression (PFS: 10.4 vs. 14.9 months, p = 0.036; OS: 27.0 vs 49.5 months, p = 0.005). CONCLUSIONS: This is the first study comparing the protein expression of SOX2 in recurrent HGG and its paired primary tumor. SOX2 high expression is common in brain HGG, a tendency of decreased SOX2 expression in recurrent gliomas was evidenced. Lower SOX2 expression was seen in those patients who received adjuvant chemotherapy and/or radiotherapy. Patients with low SOX2 expression in primary HGG usually have poorer prognosis, those with SOX2 expression decreased in recurrent HGG had worse outcome.

PD-1 high expression predicts lower local disease control in stage IV M0 nasopharyngeal carcinoma.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) play a critical role in tumor immune surveillance and immune suppression. Understanding tumor infiltrating T cell subset density, location and PD-1/PD-L1 expression might provide insight for the prediction of tumor therapeutic response and clinical outcome. The purpose of this study was to evaluate the expression and localization of CD8, FoxP3, PD-1, and PD-L1 in primary tumor tissues and their effects on prognosis of stage IV M0 locally advanced nasopharyngeal carcinoma (NPC) patients. METHODS: Sixty NPC patients with stage IV M0 locally advanced disease were treated with definitive chemoradiation. Tumor biopsies from primary lesion were analyzed for the expression and localization of CD8, FoxP3, PD-1, and PD-L1 by immunohistochemistry. Their associations with local disease control and survival of NPC were analyzed. RESULTS: The average follow-up time was 43 months (range from 14 to 61 months). High expression of CD8+, FoxP3+, PD-1+ and PD-L1+ was observed in 60, 86.7, 56.7, and 91.7% of patients, respectively. There was no correlation between clinicopathological features and the expression of these immune markers. High PD-1 expression was found to be associated with lower local disease control (5-year LRFS 23.2% vs 96.8%, p < 0.001) and unfavorable clinical outcome (5-year OS 47.4% vs 73.3%, p = 0.014). In multivariate analysis, PD-1 expression was also an adverse prognostic factor for 5-year OS (HR: 3.68, P = 0.023) and LRFS (HR: 16.89, 1.27-11.84, P = 0.007). Those with PD-1 distribution in both stroma and tumor region had the poorest prognosis. However, PD-1 expression has no significant correlation with 5-year RRFS (p = 0.980) and DMFS (p = 0.865). Patients with both PD-1 and PD-L1 high expression had significant poor local disease control (5-year LRFS 96.0% vs 43.0%, p < 0.001) and overall survival (5-year OS 80.8% vs 45.1%, p < 0.001) compared with the others. Other immune markers were not found having corrections with disease control and survival. CONCLUSIONS: PD-1 high expression, especially with PD-L1 co-expression, is associated with high local recurrence and unfavorable clinical outcome for stage IV M0 NPC patients, and might be a potential target for immunotherapy.

Breast cancer primary tumor ER expression pattern predicts its expression concordance in matched synchronous lymph node metastases.

BACKGROUND: Estrogen receptor (ER) expression is important for treatment selection and prognostication of breast cancer patients. Although the metastases are the main targets of endocrine therapy, ER status is often based on the primary tumor. However, ER expression in breast cancer primary lesion may not match with its synchronous metastatic lesions in some cases. In this study, we analyzed ER expression concordance between breast cancer primary tumor and metastatic lesions. METHODS: Paraffin blocks of 100 primary breast invasive ductal carcinoma cases with axillary lymph node metastases were collected. Five tissue cores were punched out from individual primary breast cancer, and one tissue core from each lymph node metastases to assemble tissue microarrays for ER staining. Samples were then scored as 0, 1+, 2+, and 3+ according to the number and intensity of ER stained tumor cells. RESULTS: For cases with ER 3+ (strong expression) in all cores of primary lesions (n = 38), ER expression in metastatic lymph node was found in 94.7% of the patients. 91.0% of the metastatic lymph nodes were ER positive, and 84.3% of them to be 3+. Among the 46 cases of ER negative expression in all cores of primary lesions, 39 of them had all the metastatic nodes being ER negative, and ER negative nodes were seen in 95.7% of the metastases. As for 16 cases of ER inconsistent expression in primary lesions, 4 cases showed negative ER expression in all metastatic nodes, 2 cases displayed diffuse consistent ER 3+ expression, and 10 cases displayed variant ER expression. CONCLUSIONS: The findings suggest that ER expression concordance between breast cancer primary lesion and its matched metastatic lesions could be estimated by primary tumor ER expression pattern.

Impact of Postoperative Radiotherapy on the Prognosis of Early-Stage (pT1-2N0M0) Oral Tongue Squamous Cell Carcinoma.

PURPOSE: To identify subgroups of patients with early-stage (pT1-2N0M0) oral tongue squamous cell carcinoma (OTSCC) who may benefit from postoperative radiotherapy (PORT). PATIENTS AND METHODS: This retrospective cohort study included 528 patients diagnosed between October 2009 and December 2021. Clinicopathological characteristics and treatments with or without PORT were analyzed for their impact on outcomes. RESULTS: Among 528 patients who underwent radical surgery (median age, 62 years [IQR, 52-69]), 145 (27.5%) also underwent PORT. Multivariate analyses revealed that PORT was associated with improved survival outcomes, whereas moderate-to-poor differentiation, perineural infiltration (PNI), lymphovascular invasion (LVI), and increasing depth of invasion (DOI) were associated with poorer survival outcomes. For patients with moderate-to-poor differentiation, the surgery + PORT group showed improved outcomes compared with the surgery-alone group. After propensity score matching, the results were as follows: overall survival (OS), 97% versus 69%, P = .003; disease-free survival (DFS), 88% versus 50%, P = .001. After excluding cases with PNI/LVI, the differences persisted: OS, 97% versus 82%, P = .040; DFS, 87% versus 64%, P = .012. Similar survival benefits were observed in 104 patients with PNI and/or LVI (OS, 81% v 58%; P = .022; DFS, 76% v 47%; P = .002). In subgroups with DOI >5 mm or close margins, PORT contributed to improved DFS (80% v 64%; P = .006; 92% v 66%; P = .049) but did not significantly affect OS. CONCLUSION: Patients with moderately-to-poorly differentiated pT1-2N0M0 OTSCC benefited from PORT. Our study provided evidence that patients with PNI and/or LVI who underwent PORT had improved survival. PORT also offered DFS benefit among patients with DOI >5 mm.

Novel insights into the progression and prognosis of the calpain family members in hepatocellular carcinoma: a comprehensive integrated analysis.

Objectives: The goal of our bioinformatics study was to comprehensively analyze the association between the whole calpain family members and the progression and prognosis of hepatocellular carcinoma (HCC). Methods: The data were collected from The Cancer Genome Atlas (TCGA). The landscape of the gene expression, copy number variation (CNV), mutation, and DNA methylation of calpain members were analyzed. Clustering analysis was performed to stratify the calpain-related groups. The least absolute shrinkage and selection operator (LASSO)-based Cox model was used to select hub survival genes. Results: We found 14 out of 16 calpain members expressed differently between tumor and normal tissues of HCC. The clustering analyses revealed high- and low-risk calpain groups which had prognostic difference. We found the high-risk calpain group had higher B cell infiltration and higher expression of immune checkpoint genes HAVCR2, PDCD1, and TIGHT. The CMap analysis found that the histone deacetylase (HDAC) inhibitor trichostatin A and the PI3K-AKT-mTOR pathway inhibitors LY-294002 and wortmannin might have a therapeutic effect on the high-risk calpain group. The DEGs between calpain groups were identified. Subsequent univariate Cox analysis of each DEG and LASSO-based Cox model obtained a calpain-related prognostic signature. The risk score model of this signature showed good ability to predict the overall survival of HCC patients in TCGA datasets and external validation datasets from the Gene Expression Omnibus database and the International Cancer Genome Consortium database. Conclusion: We found that calpain family members were associated with the progression, prognosis, and drug response of HCC. Our results require further studies to confirm.

Postoperative recurrent patterns of gallbladder cancer: possible implications for adjuvant therapy.

BACKGROUND: Gallbladder cancer (GBC) is an uncommon malignancy with high recurrent rate and poor prognosis. This study investigates the recurrent patterns of postoperative GBC, with the aim to guide the adjuvant treatments, including the radiotherapy. METHODS: Retrospectively analyzed the 109 GBC patients who underwent surgery in our institution from January 2013 to 2018. Clinical follow-up revealed 54 recurrent cases, of which 40 had detailed locations of recurrence. The sites of recurrence were recorded and divided into the tumor bed, corresponding lymphatic drainage area, intrahepatic recurrence, and the other distant metastasis. RESULTS: The median follow-up time is 34 months (IQR: 11-64). The median disease-free survival (DFS) and overall survival (OS) were 48.8 months and 53.7 months, respectively. Through univariate analysis, risk factors for DFS and OS include tumor markers (CA199 and CEA), hepatic invasion, perineural invasion, lymphovascular invasion, TNM staging and tumor differentiation. Through multivariate analysis, risk factors for DFS include hepatic invasion and TNM staging, and for OS is TNM staging only. Of the 40 cases with specific recurrent sites, 29 patients (29/40, 72.5%) had recurrence in the potential target volume of postoperative radiotherapy (PORT), which include tumor bed and corresponding lymphatic drainage area. The common recurrent lymph node groups included abdominal para-aortic lymph node (No.16, 15/29), hepatoduodenal ligament lymph node (No.12, 8/29), retro-pancreatic head lymph node (No.13, 7/29) and celiac axis lymph node (No.9, 4/29). Twenty cases with recurrences inside the potential PORT target volume were accompanied by distant metastasis. Another 11 cases had distant metastasis alone, so totally 31 cases developed distant metastasis (31/40, 77.5%), including 18 cases with hepatic metastasis. CONCLUSION: The recurrence and metastasis rates are high in GBC and adjuvant therapy is needed. Up to 75% of the recurrent cases occurred in the potential target volume of postoperative radiotherapy, suggesting that postoperative radiotherapy has the possible value of improving local-regional control. The potential target volume of radiotherapy should include the tumor bed, No.8, No.9, No.11, No.12, No.13, No.14, No. 16a2, No. 16b1 lymph node groups.

The impact of radiation induced lymphopenia in the prognosis of head and neck cancer: A systematic review and meta-analysis.

OBJECTIVES: Radiotherapy is a key part of head and neck cancer (HNC) treatment. Radiation induced lymphopenia (RIL) is a severe complication of radiotherapy. The aim of this study was to evaluate the prognostic role of RIL in HNC patients. METHOD: We conducted a PRISMA guideline based systematic review and meta-analysis. The studies were identified on the PubMed, Embase and Cochrane Library from 2007 to October 2021. The quality of each study was assessed by Newcastle-Ottawa Quality Assessment Form for Cohort Studies (NOS). RESULTS: There were 8 studies with 2,733 samples finally included in current study. The meta-analysis showed that the odds ratio of developing grade 3-4 RIL was 13.49 (95%CI = 7.03-25.89, I2 = 94%). The incidence rate of grade 3-4 RIL ranged from 73%-88%. Multivariate meta-analysis found that the RIL significantly decreased the overall survival (HR = 2.94, 95%CI = 1.83-4.74, I2 = 0%) and distant metastasis free survival of HNC (HR = 3.79, 95%CI = 2.06-6.97, I2 = 0%). After sensitivity analysis and excluding a potential study that caused heterogeneity, the new pooled multivariate meta-analysis showed RIL was a risk factor to the progression free survival of HNC patients (HR = 3.16, 95%CI = 1.77-5.63, I2 = 0%). CONCLUSION: This is the first meta-analysis which showed severe RIL decreased the overall survival and promoted the progression of HNC patients. Future large-scale prospective studies are required to evaluate the association between severe RIL and the prognosis of HNC.

A Comprehensive Analysis of the Effects of Key Mitophagy Genes on the Progression and Prognosis of Lung Adenocarcinoma.

The aim of our study was to perform a comprehensive analysis of the gene expression, copy number variation (CNV) and mutation of key mitophagy genes in the progression and prognosis of lung adenocarcinoma (LUAD). We obtained the data from The Cancer Genome Atlas (TCGA). Clustering analysis was performed to stratify the mitophagy related groups. The least absolute shrinkage and selection operator (LASSO) based cox model was used to select hub survival genes. An independent validation cohort was retrieved from Gene Expression Omnibus database. We found 24 out of 27 mitophagy genes were aberrantly expressed between tumor and normal samples. CNV gains were associated with higher expression of mitophagy genes in 23 of 27 mitophagy genes. The clustering analysis identified high and low risk mitophagy groups with distinct survival differences. The high risk mitophagy groups had higher tumor mutation burden, stemness phenotype, total CNVs and lower CD4+ T cells infiltration. Drugs targeted to high risk mitophagy groups were identified including the PI3K/AKT/mTOR inhibitor, HDAC inhibitor and chemotherapy agents such as cisplatin and gemcitabine. In addition, the differentially expressed genes (DEGs) were identified between mitophagy groups. Further univariate Cox analysis of each DEG and subsequent LASSO-based Cox model revealed a mitophagy-related prognostic signature. The risk score model of this signature showed a strong ability to predict the overall survival of LUAD patients in training and validation datasets. In conclusion, the mitophagy genes played an important role in the progression and prognosis of LUAD, which might provide useful information for the treatment of LUAD.

Severe Radiation-Induced Lymphopenia Affects the Outcomes of Esophageal Cancer: A Comprehensive Systematic Review and Meta-Analysis.

The aim of the current study was to evaluate the influence of severe radiation-induced lymphopenia (RIL) on the outcomes of esophageal cancer (EC). A systematic review and meta-analysis was performed through the PRISMA guideline. Seventeen studies were included in the current systematic review, with eight included in the meta-analyses. Meta-analyses found that severe RIL was associated with lower pathologic complete response (pCR) rate (odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.30-0.66, I2 = 0%), inferior overall survival (OS) (hazard ratio (HR) = 1.50, 95% CI = 1.29-1.75, I2 = 6%), and worse progression-free survival (PFS) (HR = 1.70, 95% CI = 1.39-2.07, I2 = 0%) of EC patients. The lymphocyte nadir was found during 4-6 weeks after the start of radiotherapy. The leading dosimetric factors associated with severe RIL included larger PTV, higher dose to heart and body, and higher effective dose to the immune cells (EDIC). Clinical risk factors for RIL mainly comprised lower baseline ALC, higher tumor length and clinical stage, and distal EC. In conclusion, severe RIL might be associated with a lower pCR rate and worse OS and PFS of EC patients. Minimizing the dosimetric risk factors, especially in patients with clinical risk factors, might benefit their outcomes.

Implications of m6A-associated snRNAs in the prognosis and immunotherapeutic responses of hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the most prevalent pathological type of liver cancer worldwide with high mortality and poor prognosis. N6-methyladenosine (m6A) can modify RNAs such as mRNA, lncRNA, miRNA, and tRNA, thereby playing a critical role in the pathogenesis of HCC. However, the role of m6A-associated small nuclear RNA (snRNA) in the prognostic value and immunotherapeutic response in HCC remains unclear. Materials and methods: In this study, snRNA expression data, gene mutation data, and clinical data of HCC patients were acquired from The Cancer Genome Atlas (TCGA) database. We used the least absolute shrinkage and selection operator (LASSO) Cox regression analysis to identify significant prognostic m6A-associated snRNAs, and then developed a multivariate Cox model based on the selected snRNAs. HCC patients were split into low- and high-risk groups based on the median risk score. We subsequently performed Kaplan-Meier curve analysis to estimate overall survival (OS) by clinicopathological characteristics and tumor mutational burden (TMB) status in low- and high-risk HCC patients. Finally, we compared the immunotherapeutic response as represented by tumor immune dysfunction and exclusion (TIDE) scores between the two risk groups. Results: Eight m6A-associated snRNAs were selected as independent predictors to develop the risk model. Our results revealed that the OS of HCC patients in the high-risk group was significantly worse than that in the low-risk group on clinicopathologic characteristics, including age (≤65 years and >65 years), gender (male), grade (G I-II and G III-IV) and TNM staging (Stage I-II and Stage III-IV). In addition, the OS of low-TMB and low-risk group was longer than that of high-TMB and high-risk group. The TIDE score indicated that HCC patients in the high-risk group were more susceptible to immunotherapy. Conclusion: Our study suggests that m6A-associated snRNAs may be useful biomarkers for the prognosis of HCC and that m6A-associated snRNA models can predict the effect of immunotherapy in HCC patients.

Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune-related adverse events (irAEs) remain poorly understood, especially in a real-world setting. METHODS: A multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD-L1) monotherapy, anticytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy. RESULTS: In total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28-87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3-5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0-1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD-L1 expression (≥1%) and who received first-line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001). CONCLUSIONS: The incidence rate of irAEs was 26.9% in a real-world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma.

AIM: Immune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA). METHODS: Immune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC. RESULTS: We selected 255 patients with SARC for our analysis. The Kaplan-Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p < 0.05, fold change >4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p < 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC. CONCLUSION: The current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.

Combination of Radiosensitivity Gene Signature and PD-L1 Status Predicts Clinical Outcome of Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma: A Study Based on The Cancer Genome Atlas Dataset.

Aim: The aim of our study was to investigate the potential predictive value of the combination of radiosensitivity gene signature and PD-L1 expression for the prognosis of locally advanced head and neck squamous cell carcinoma (HNSCC). Methods: The cohort was selected from The Cancer Genome Atlas (TCGA) and classified into the radiosensitive (RS) group and radioresistant (RR) group by a radiosensitivity-related gene signature. The cohort was also grouped as PD-L1-high or PD-L1-low based on PD-L1 mRNA expression. The least absolute shrinkage and selection operator (lasso)-based Cox model was used to select hub survival genes. An independent validation cohort was obtained from the Gene Expression Omnibus (GEO) database. Results: We selected 288 locally advanced HNSCC patients from TCGA. The Kaplan-Meier method found that the RR and PD-L1-high group had a worse survival than others (p = 0.033). The differentially expressed gene (DEG) analysis identified 553 upregulated genes and 486 downregulated genes (p < 0.05, fold change >2) between the RR and PD-L1-high group and others. The univariate Cox analysis of each DEG and subsequent lasso-based Cox model revealed five hub survival genes (POU4F1, IL34, HLF, CBS, and RNF165). A further hub survival gene-based risk score model was constructed, which was validated by an external cohort. We observed that a higher risk score predicted a worse prognosis (p = 0.0013). The area under the receiver operating characteristic curve (AUC) plots showed that this risk score model had good prediction value (1-year AUC = 0.684, 2-year AUC = 0.702, and 3-year AUC = 0.688). Five different deconvolution methods all showed that the B cells were lower in the RR and PD-L1-high group (p < 0.05). Finally, connectivity mapping analysis showed that the histone deacetylase (HDAC) inhibitor trichostatin A might have the potential to reverse the phenotype of RR and PD-L1-high in locally advanced HNSCC (p < 0.05, false discovery rate <0.1). Conclusion: The combination of 31-gene signature and the PD-L1 mRNA expression had a potential predictive value for the prognosis of locally advanced HNSCC who had RT. The B cells were lower in the RR and PD-L1-high group. The identified risk gene signature of locally advanced HNSCC and the potential therapeutic drug trichostatin A for the RR and PD-L1-high group are worth being further studied in a prospective homogenous cohort.

Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II-induced hypertension.

Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg-1min-1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCß3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCß3 impaired the effect of TMAO on Ca2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCß3 axis.

Knockdown of PLCB2 expression reduces melanoma cell viability and promotes melanoma cell apoptosis by altering Ras/Raf/MAPK signals.

Malignant melanoma has the highest malignancy rate among all skin cancer and is characterized by an insidious onset, high invasion and poor patient prognosis. Yet, the mechanisms involved remain unclear and warrant further investigation. Based on bioinformatic analysis, phospholipase C ß2 (PLCB2) has been found to be correlated with melanoma growth. The present study was the first to demonstrate that PLCB2 is a key factor affecting melanoma proliferation and apoptosis. Here, microarray datasets from the publicly available Gene Expression Omnibus (GEO) database were employed, and gene set enrichment analysis (GSEA) was introduced to identify candidate transcription factors. PLCB2 was identified as a crucial gene in the protein­protein interaction (PPI) network. The expression of PLCB2 mRNA in various cancer lines was analyzed by reverse transcription­polymerase chain reaction (RT­PCR). In addition, the proliferation ability and apoptosis rate in human melanoma cells overexpressing or not overexpressing PLCB2 were assessed using colony formation assay, flow cytometry and the Cell Counting Kit­8 (CCK­8) assay. Cell viability and apoptosis­related factors, such as p53, Bcl­2, Bax and caspase­3 were significantly regulated. Knockdown of PLCB2 suppressed the activation of the Ras/Raf/MAPK signaling pathway. In conclusion, knockdown of PLCB2 suppressed cell viability and promoted cell apoptosis by activating the Ras/Raf/MAPK pathway. Thus, PLCB2 may utilized as a potential therapeutic target in patients with melanoma.

Utility of Radiomics for Predicting Patient Survival in Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis Treated With Stereotactic Body Radiotherapy.

Introduction: This study aimed to develop and validate the combination of radiomic features and clinical characteristics that can predict patient survival in hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) treated with stereotactic body radiotherapy (SBRT). Materials and Methods: The prediction model was developed in a primary cohort of 70 patients with HCC and PVTT treated with SBRT, using data acquired between December 2015 and June 2017. The radiomic features were extracted from computed tomography (CT) scans. A least absolute shrinkage and selection operator regression model was used to build the model. Multivariate Cox-regression hazard models were created for analyzing survival outcomes and the radiomic features and clinical characteristics were presented with a nomogram. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the model. Participants were divided into a high-risk group and a low-risk group based on the radiomic features. Results: A total of four radiomic features and six clinical characteristics were extracted for survival analysis. A combination of the radiomic features and clinical characteristics resulted in better performance for the estimation of overall survival (OS) [area under the curve (AUC) = 0.859 (CI: 0.770-0.948)] than that with clinical characteristics alone [AUC = 0.761 (CI: 0.641-0.881)]. These patients were divided into high-risk and low-risk groups according to the radiomic features. Conclusion: This study demonstrated that a nomogram of combined radiomic features and clinical characteristics can be conveniently used to assess individualized preoperative prediction of OS in patients with HCC with PVTT before SBRT.