Utilizing a novel model of PANoptosis-related genes for enhanced prognosis and immune status prediction in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is the most common histopathologic type of renal cell carcinoma. PANoptosis, a cell death pathway that involves an interplay between pyroptosis, apoptosis and necroptosis, is associated with cancer immunity and development. However, the prognostic significance of PANoptosis in KIRC remains unclear. RNA-sequencing expression and mutational profiles from 532 KIRC samples and 72 normal samples with sufficient clinical data were retrieved from the Cancer Genome Atlas (TCGA) database. A prognostic model was constructed using differentially expressed genes (DEGs) related to PANoptosis in the TCGA cohort and was validated in a Gene Expression Omnibus (GEO) cohorts. Incorporating various clinical features, the risk model remained an independent prognostic factor in multivariate analysis, and it demonstrated superior performance compared to unsupervised clustering of the 21 PANoptosis-related genes alone. Further mutational analysis showed fewer VHL and more BAP1 alterations in the high-risk group, with alterations in both genes also associated with patient prognosis. The high-risk group was characterized by an unfavorable immune microenvironment, marked by reduced levels of CD4 + T cells and natural killer cells, but increased M2 macrophages and regulatory T cells. Finally, the risk model was predictive of response to immune checkpoint blockade, as well as sensitivity to sunitinib and paclitaxel. The PANoptosis-related risk model developed in this study enables accurate prognostic prediction in KIRC patients. Its associations with the tumor immune microenvironment and drug efficacy may offer potential therapeutic targets and inform clinical decisions.

Prolonged administration of the granisetron transdermal delivery system reduces capecitabine plus oxaliplatin regimen induced nausea and vomiting.

OBJECTIVE: To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy. DESIGN: Open-label, prospective, multi-center phase II trial. SETTING: Three institutions. PARTICIPANTS: Fifty-four patients scheduled to receive CapeOX chemotherapy. INTERVENTIONS: Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone. MAIN OUTCOME MEASURES: The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life. RESULTS: The complete control rate for delayed CINV over the entire period (25-480 h) was 72.7% (95% CI 0.57-0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69-0.95). No serious adverse events related to the antiemetic regimen were reported. CONCLUSION: Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX. TRIAL REGISTRATION: ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021.

Optimal therapy for concomitant EGFR and TP53 mutated non-small cell lung cancer: a real-world study.

BACKGROUND: Non-small cell cancer (NSCLC) patients with concomitant epidermal growth factor receptor (EGFR) and TP53 mutations have a poor prognosis with the treatment of tyrosine kinase inhibitors (TKIs), and may benefit from a combination regimen preferentially. The present study aims to compare the benefits of EGFR-TKIs and its combination with antiangiogenic drugs or chemotherapy in patients with NSCLC harboring EGFR and TP53 co-mutation in a real-life setting. METHODS: This retrospective analysis included 124 patients with advanced NSCLC having concomitant EGFR and TP53 mutations, who underwent next-generation sequencing prior to treatment. Patients were classified into the EGFR-TKI group and combination therapy group. The primary end point of this study was progression-free survival (PFS). The Kaplan-Meier (KM) curve was drawn to analyze PFS, and the differences between the groups were compared using the logarithmic rank test. Univariate and multivariate cox regression analysis was performed on the risk factors associated with survival. RESULTS: The combination group included 72 patients who received the regimen of EGFR-TKIs combined with antiangiogenic drugs or chemotherapy, while the EGFR-TKI monotherapy group included 52 patients treated with TKI only. The median PFS was significantly longer in the combination group than in the EGFR-TKI group (18.0 months; 95% confidence interval [CI]: 12.1-23.9 vs. 7.0 months; 95% CI: 6.1-7.9; p < 0.001) with greater PFS benefit in TP53 exon 4 or 7 mutations subgroup. Subgroup analysis showed a similar trend. The median duration of response was significantly longer in the combination group than in the EGFR-TKI group. Patients with 19 deletions or L858R mutations both achieved a significant PFS benefit with combination therapy versus EGFR-TKI alone. CONCLUSION: Combination therapy had a higher efficacy than EGFR-TKI alone for patients with NSCLC having concomitant EGFR and TP53 mutations. Future prospective clinical trials are needed to determine the role of combination therapy for this patient population.

Epifriedelinol Ameliorates DMBA-Induced Breast Cancer in Albino Rats by Regulating the PI3K/AKT Pathway.

We evaluated the protective effect of epifriedelinol against breast cancer and postulated an underlying mechanism. Breast cancer was induced by a single dose of 50 mg/kg 7,12-Dimethylbenanthracene (DMBA), and rats were treated with 100 or 200 mg/kg (i.p.) epifriedelinol for 4 weeks. We then evaluated the effect of epifriedelinol on tumor growth, oxidative stress and serum inflammatory cytokine levels in DMBA-induced breast cancer. Protein and mRNA levels were determined using western blotting and quantitative reverse transcription polymerase chain reaction, respectively. The tumor volume and weight were significantly (p < 0.01) decreased in the epifriedelinol-treated group compared to the negative control group. Epifriedelinol decreased the altered levels of oxidative stress and serum inflammatory cytokines in rats with DMBA-induced breast cancer. Protein levels of PI3K, AKT and mTOR and mRNA levels of PI3K, AKT, Map3k1, Erbb2 and Pdk1 were decreased in the mammary tissue of epifriedelinol-treated rats with DMBA-induced breast cancer. Apoptosis was significantly induced in the epifriedelinol-treated group compared to the negative control group. In conclusion, epifriedelinol ameliorates DMBA-induced breast cancer by regulating the PI3K/AKT pathway.

Safety and Efficacy of Apatinib Monotherapy for Unresectable, Metastatic Esophageal Cancer: A Single-Arm, Open-Label, Phase II Study.

LESSONS LEARNED: Patient compliance with the oral dosage treatment was good, with no need for hospitalization. Patients with tracheal and esophageal fistulas can take crushed apatinib by nutrient tube, with the same bioavailability and efficacy. Apatinib may be an effective and safe second- or further-line treatment for advanced esophageal cancer. BACKGROUND: Apatinib is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2), which is thought to play a role in esophageal cancer progression. Our goal was to evaluate the efficacy and safety of apatinib in patients with unresectable esophageal cancer and to examine whether VEGFR2 expression influenced the clinical response. METHODS: This single-arm, open-label, investigator-initiated phase II study enrolled patients with advanced squamous cell carcinoma (SCC) or adenocarcinoma of the esophagus or esophagogastric junction who were admitted to Tianjin Medical University Cancer Institute and Hospital between August 2017 and January 2019. Apatinib monotherapy (500 mg/day) was given orally or via an enteral tube until disease progression, unacceptable toxicity, withdrawal, or death. Patients were followed until treatment was discontinued or death. The main endpoints were tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs). RESULTS: Among 32 patients screened for inclusion, 30 were included in the safety and survival analyses (i.e., received apatinib), and 26 were included in the efficacy analysis (at least one imaging follow-up). Median follow-up time and exposure to apatinib were 5.34 months and 72 days, respectively. Among 26 patients included in the efficacy analysis, 2 had a partial response (PR; 7.7%) and 14 had stable disease (SD; 53.8%). The overall response rate (ORR) was 7.7%, and the disease control rate (DCR) was 61.5%. Median PFS and OS were 4.63 months (95% confidence interval, 2.11-7.16 months) and 6.57 months (4.90 months to not estimable), respectively. Fifteen patients (50.0%) experienced treatment-related AEs, most commonly hypertension (26.7%), diarrhea (20.0%), and hand-foot-skin reaction (10.0%). No patients had grade ≥4 treatment-related AEs. CONCLUSION: Apatinib was effective as second- or further-line treatment for advanced esophageal cancer.

Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer.

BACKGROUND: Many anti-angiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy. Anlotinib has demonstrated anti-tumor efficacy in non-small cell lung cancer (NSCLC) in third-line clinical trials. However, its roles in immune regulation and potentially synergistic anti-tumor effect in combination with immune checkpoint inhibition remain unclear. METHODS: Here, based on a syngeneic lung cancer mouse model, the intratumoral immunological changes post-anlotinib treatment in the model were assessed. Furthermore, it was tested whether anlotinib could enhance the anti-tumor effect of αPD-1 in vivo. RESULTS: This study shows that anlotinib increased infiltration of the innate immune cells, including natural killer (NK) cells, and antigen-presenting cells (APC), which include M1-like tumor-associated macrophages (TAM) and dendritic cells (DC), whereas the percentage of M2-like TAM was dramatically reduced. Subsequently, when combined with PD-1/PD-L1 (programmed cell death 1/PD-1 ligand 1) blockade, anlotinib conferred significantly synergistic therapeutic benefits. CONCLUSIONS: Overall, these findings describe a role for anlotinib in the innate immune cells in the tumor microenvironment and a potentially synergistic anti-tumor combination with immune checkpoint inhibition.

Baicalin reverses radioresistance in nasopharyngeal carcinoma by downregulating autophagy.

BACKGROUND: Radiation resistance is the main cause of recurrence after radiotherapy, and increased autophagy after radiotherapy is related to radiotherapy resistance. This study aims to investigate the reversal effect of baicalin on radioresistance and its related mechanism. METHODS: CCK-8 and flow cytometry were used to detect the effect of proliferation and apoptosis by baicalin. Clone formation test was used to verify the effect of baicalin radiosensitization. Western blot analysis and electron microscopy were employed to observe the effect of baicalin on autophagy. RESULTS: Compared with the radiation therapy (RT) group, the RT combined baicalin (RT + BA) group showed a significantly low 2 Gy survival fraction of radiation therapy (P < 0.05). LC3-II protein expression in the RT group was significantly higher than which in the RT + BA group (P < 0.05). Electron microscopy showed that more autophagic vacuoles were observed in the RT group than those in the RT + BA group. CONCLUSIONS: Overall, baicalin can reverse the radioresistance of human nasopharyngeal carcinoma CNE-2R cells by downregulating RT-enhanced autophagy.

Systemic chemotherapy in combination with liver-directed therapy improves survival in patients with pancreatic adenocarcinoma and synchronous liver metastases.

OBJECTIVES: We investigated whether the combination of systemic chemotherapy (SCT) and liver-directed therapy (LDT) was superior to chemotherapy alone for patients with pancreatic adenocarcinoma and synchronous liver metastases (PACLM). METHODS: We reviewed the medical records of 184 patients treated with SCT ±â€¯LDT at Tianjin Medical University Cancer Hospital from 2001 to 2015. Overall survival (OS) was the primary end-point. The role of treatment modality and other clinical factors was evaluated by univariate and Cox regression analyses. RESULTS: Sixty-four (34.8%) patients in the SCT-LDT group and 120 (65.2%) patients in the SCT group were included in the analysis. Baseline clinical characteristics were similar between the groups (all P > 0.05). The median survival was 8.7 months in the SCT-LDT group and was 6.3 months in the SCT group. The 0.5-, 1-, 2- and 3-year survival rates were 67.2%, 33.4%, 13.3% and 8.9%, respectively, after SCT-LDT, and were 54.9%, 19.0%, 4.5% and 2.0%, respectively, after SCT (P = 0.01). Primary tumor size, ascites, and treatment modality (SCT + LDT vs. SCT) independently predicted survival (P < 0.05). The clinical efficacy congruously favored the SCT-LDT group across the majority of subgroups. CONCLUSIONS: SCT combined with LDT was well tolerated and may be effective to improve survival of patients with PACLM. Ascites and large primary tumor size were poor prognostic factors associated with survival.

Clinicopathological characteristics, staging classification, and survival outcomes of primary malignant melanoma of the esophagus.

BACKGROUND: Primary malignant melanoma of esophagus (PMME) is a remarkably rare and highly aggressive tumor. Studies related with clinicopathological findings, staging classification, and clinical outcomes are lacking. METHODS: We reviewed 21 cases of PMME at the Tianjin Medical University Cancer Institute and Hospital from January 2002 to February 2017. RESULTS: Nineteen patients (90.48%) presented a history of dysphagia for months, and two (9.52%) experienced retrosternal pain. Histologically, tumors were composed of atypical melanocytes with melanocytosis surrounding the tumor. The overall survival was 1-40 months, with the median time of 10 months. The mucosal staging classification for upper aerodigestive tract showed better distribution of overall survival with different stages than that of the American Joint Commission on Cancer staging classification for esophagus, but without statistical difference. Both the clinical and pathological characteristics were not highly consistent with overall survival. CONCLUSIONS: PMME is a considerably aggressive tumor with poor prognosis. The staging classification of mucosal melanoma of the upper aerodigestive tract may be a good option for PMME patients.

Factors influencing survival of patients with pancreatic adenocarcinoma and synchronous liver metastases receiving palliative care.

BACKGROUND AND AIMS: Patients with pancreatic ductal adenocarcinoma and synchronous liver metastases (PACLM) have an extremely limited life expectancy. We performed a single-center analysis to explore the clinical results and prognostic factors of patients with PACLM receiving palliative care. METHODS: We retrospectively reviewed 189 patients undergoing palliative care at Tianjin Medical University Cancer Hospital over a 15-year period. Clinical characteristics, survival condition, and factors associated with survival were analyzed. Treatment methods included palliative bypass surgery, percutaneous transhepatic cholangiodrainage, drug analgesia, symptomatic treatment, and other nutritional or supportive measures. RESULTS: The overall survival (OS) was 3.6 months for all patients. Multivariate analysis for clinical features showed that Karnofsky performance score (KPS), ascites, cigarette smoking, primary tumor size, and lactate dehydrogenase (LDH) were prognostic variables with statistical significance (P < 0.05). The patients were classified into three groups of patients according to how many of these 5 risk factors were present: 0-1, 2, or 3-5 risk factors. The median OS of the 3 groups of patients were 5.0, 3.3, and 2.5 months, respectively, with a notable statistical significance (P < 0.0001). CONCLUSIONS: KPS<80, ascites, cigarette smoking, primary tumor size≥5 cm, and LDH≥250U/L are effective predictive factors of poor prognosis for patients with PACLM. The stratification of treatment outcome groups based on these factors facilitates evaluation of individual prognosis and can guide clinical decisions.

[A Retrospective Study of Chinese Herbal Medicine Combined with Systemic Chemotherapy and/or Regional Arterial Perfusion for Pancreatic Cancer with Liver Metastases].

OBJECTIVE: To evaluate the efficacy and safety of Chinese herbal medicine combined with systemic chemotherapy and/or regional arterial perfusion for pancreatic cancer with liver metastases (PCLM). METHODS: We retrospectively selected 292 patients with PCLM who were treated by Chinese herbal medicine combined with systemic chemotherapy and/or regional arterial perfusion at Tianjin Medical University Cancer Hospital from January 2001 to December 2010. All patients were assigned to the Western medicine treatment group (157 cases) and the integrative medicine treatment group (135 cases). Patients in the Western medicine treatment group were treated with gemcitabine (GEM)-based chemotherapy, and partial of them received regional arterial perfusion. Those in the integrative medicine treatment group additionally took Chinese herbs of clearing heat and eliminating mass for at least 4 weeks. The median survival time (MST) , adverse reactions and the incidence of complications were observed. RESULTS: There was no statistical significance in general data between the two groups (P > 0.05). There was statistical difference in MST between the two groups (4.8 months vs 5.5 months, P < 0.05). No death occurred during chemotherapy or regional arterial perfusion. All toxic or adverse reactions were tolerable. CONCLUSION: Chinese herbal medicine combined with systemic chemotherapy and/or regional arterial perfusion was effective and safe, and it could be optimally selected as palliative therapy for PCLM.

[Efficacy of lapatinib versus trastuzumab in neoadjuvant therapy of HER-2 positive breast cancer: a meta-analysis].

OBJECTIVE: To compare the efficacy of lapatinib or lapatinib plus trastuzumab versus trastuzumab in the neoadjuvant therapy of human epidermal growth factor receptor 2 (HER-2) positive breast cancer. METHODS: MEDLINE database, American Society of Clinical Oncology (ASCO), San Antonio Breast Cancer Symposium (SABCS), European Society for Medical Oncology (ESMO) proceedings and China Biomedical Database were searched for literatures of trastuzumab or lapatinib in neoadjuvant therapy for breast cancer. There was no limit of language or time. A meta-analysis was performed for retrieved literatures meeting the inclusion criteria. RESULTS: A total of 1 794 breast cancer patients from 5 clinical trials were included. And the regimens were lapatinib plus neoadjuvant chemotherapy (n = 719), trastuzumab plus neoadjuvant chemotherapy (n = 714) and both drugs plus neoadjuvant chemotherapy (n = 361). The rate of pathological complete remission (pCR) was lower in lapatinib group than that in trastuzumab group (28.2% vs 35.4%). And the difference was statistically significant (P = 0.004). The pCR rate was significantly higher in lapatinib plus trastuzumab therapy group than that in trastuzumab group (53.2% vs 38.1%, P < 0.001). CONCLUSIONS: Lapatinib can not replace trastuzumab as a first-choice agent in neoadjuvant therapy of HER-2 positive breast cancer. Lapatinib plus trastuzumab achieves better pCR than trastuzumab so that it and may become a first-choice of neoadjuvant therapy for HER-2 positive breast cancer regardless of economic affordability for patients.

Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study.

Background: In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. Methods: From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. Findings: As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P = 0.0170), pain (-2.24, 95% CI: -4.30 to -0.17; P = 0.0337), fatigue (-2.24, 95% CI: -4.46 to -0.02; P = 0.0479), constipation (-3.27, 95% CI -5.49 to -1.05; P = 0.0039), QLQ-OES18 pain (-1.77, 95% CI -3.11 to -0.43; P = 0.0097), trouble swallowing saliva (-2.09, 95% CI: -3.77 to -0.42; P = 0.0146), and choked when swallowing (-3.23, 95% CI: -5.60 to -0.86; P = 0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61-0.94, P = 0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35-0.67, P < 0.0001). Improved OS were observed in patients with better performance in several functioning and symptom scales of QLQ-C30 and QLQ-QES18. Interpretation: The statistically significant differences of several HRQoL scales and improvements in delayed deterioration observed in our study further support the use of sintilimab plus chemotherapy as first-line treatment for advanced ESCC. Funding: This study was funded by Innovent Biologics and was co-funded by Eli Lilly.

Quercetin: A promising drug candidate against the potential SARS-CoV-2-Spike mutants with high viral infectivity.

The emergence of SARS-CoV-2-Spike mutants not only enhances viral infectivity but also lead to treatment failure. Gaining a comprehensive understanding of the molecular binding mode between the mutant SARS-CoV-2-Spike and human ACE2 receptor is crucial for therapeutic development against this virus. Building upon our previous predictions and verifications regarding heightened viral infectivity of six potential SARS-CoV-2-Spike mutants, this study aims to further investigate the potential disruption of the interaction between these mutants and ACE2 by quercetin, a Chinese herbal compound. Molecular docking and dynamics simulations results reveal that the binding sites of quercetin particularly enriched around a specific "cavity" at the interface of Spike/ACE2 complex, indicating a favorable region for quercetin to interfere with Spike/ACE2 interaction. Virus infection assay confirms that quercetin not only attenuates wild-type virus infectivity but also suppresses the infectivity of all six tested SARS-CoV-2-Spike mutants. Therefore, quercetin represents a promising therapeutic candidate against both wild-type and potential future variants of SARS-CoV-2 exhibiting high viral infectivity.

Nomogram based on multiparametric analysis of early-stage breast cancer: Prediction of high burden metastatic axillary lymph nodes.

BACKGROUND: The Z0011 and AMAROS trials found that axillary lymph node dissection (ALND) was no longer mandatory for early-stage breast cancer patients who had one or two metastatic axillary lymph nodes (mALNs). The aim of our study was to establish a nomogram which could be used to quantitatively predict the individual likelihood of high burden mALN (≥3 mALN). METHODS: We retrospectively analyzed 564 women with early breast cancer who had all undergone both ultrasound (US) and magnetic resonance imaging (MRI) to examine axillary lymph nodes before radical surgery. All the patients were divided into training (n = 452) and validation (n = 112) cohorts by computer-generated random numbers. Their clinicopathological features and preoperative imaging associated with high burden mALNs were evaluated by logistic regression analysis to develop a nomogram for predicting the probability of high burden mALNs. RESULTS: Multivariate analysis showed that high burden mALNs were significantly associated with replaced hilum and the shortest diameter >10 mm on MRI, with cortex thickness >3 mm on US (p < 0.05 each). These imaging criteria plus higher grade (grades II and III) and quadrant of breast tumor were used to develop a nomogram calculating the probability of high burden mALNs. The AUC of the nomogram was 0.853 (95% CI: 0.790-0.908) for the training set and 0.783 (95% CI: 0.638-0.929) for the validation set. Both internal and external validation evaluated the accuracy of nomogram to be good. CONCLUSION: A well-discriminated nomogram was developed to predict the high burden mALN in early-stage breast patients, which may assist the breast surgeon in choosing the appropriate surgical approach.

Is lung involvement a favorable prognostic factor for pancreatic ductal adenocarcinoma with synchronous liver metastases?-A propensity score analysis.

BACKGROUND: For advanced pancreatic cancer, pulmonary metastases (PM) have been considered favorable factors compared to metastases of other sites, but it remains unknown whether the prognosis of patients with synchronous liver and lung metastases is better than that of non-PM. METHODS: Data was derived from a two-decade cohort and included 932 cases of pancreatic adenocarcinoma with synchronous liver metastases (PACLM). Propensity score matching (PSM) was applied to balance 360 selected cases, grouped into PM (n = 90) and non-PM (n = 270). Overall survival (OS) and survival-related factors were analyzed. RESULTS: In PSM-adjusted data, the median OS was 7.3 and 5.8 months, for PM and non-PM, respectively (p = 0.16). Multivariate analysis revealed that male gender, poor performance status, higher hepatic tumor burden, ascites, elevated carbohydrate antigen 19-9, and lactate dehydrogenase were factors of poor survival (p < 0.05). Chemotherapy was the only independent significant factor of favorable prognosis (p < 0.05). CONCLUSION: Although lung involvement was indicated to be a favorable prognostic factor for patients with PACLM in the whole cohort, PM were not associated with better survivals in the subset of cases subjected to PSM adjustment.

A Randomized Phase III Study of Anlotinib Versus Bevacizumab in Combination With CAPEOX as First-Line Therapy for RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Clinical Trial Protocol.

Background: Chemotherapy combined with antivascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor monoclonal antibodies is the most promising approach to prolong survival and improve the quality of life of patients with unresectable metastatic colorectal cancer (mCRC). Anlotinib is an oral antiangiogenic tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, fibroblast growth factor receptors 1-4, and platelet-derived growth factor receptors a/ß. Since anlotinib combined with oxaliplatin and capecitabine (CAPEOX) as a first-line treatment was previously shown to be effective and safe for patients with RAS/BRAF wild-type (WT) mCRC, we designed this randomized, open-label, parallel-group, non-inferiority, phase III study to evaluate the efficacy and safety of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX in patients with RAS/BRAF WT mCRC. Methods/design: The primary inclusion criteria are Eastern Cooperative Oncology Group performance status 0/1, confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastases assessed by a multidisciplinary team. The main exclusion criteria are as follows: high microsatellite instability or deficient mismatch repair status, resectable or potentially resectable metastases, and previous systemic therapy for mCRC. A total of 698 patients will be randomized into the anlotinib and bevacizumab groups in a 1:1 ratio. Patients will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), followed by maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. Progression-free survival (PFS) assessed by an independent review committee is the primary endpoint, whereas investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, resection rate of liver metastases, quality of life, and safety are the secondary endpoints. Enrollment commenced in May 2021. Discussion: A prospective, randomized, phase III trial will provide a meaningful comparison of the efficacy and safety of anlotinib plus CAPEOX with standard treatment for patients with unresectable RAS/BRAF WT mCRC.

Apatinib and Ginsenoside-Rb1 Synergetically Control the Growth of Hypopharyngeal Carcinoma Cells.

BACKGROUND: Apatinib is an anticancer drug known to inhibit the vascular endothelial growth factor receptor-2 (VEGFR-2) through regulating tyrosine kinases. Drug resistance and reduced activity in various cancers is the matter of great concern; thus, researchers opt to use combination of the two or more drugs. So far, its gynergetic anticancer role with a traditional Chinese drug Ginsenoside-Rb1 (G-Rb1) has not been studied in cancers including hypopharyngeal carcinoma. OBJECTIVE: The current study is aimed at investigating the anticancer synergetic effects of G-Rb1 and apatinib in hypopharyngeal carcinoma. METHODS: The synergetic effects of both drugs on cell proliferation, wound healing and cell migration, and cell apoptosis were studied in hypopharyngeal carcinoma cells. Furthermore, the xenograft rat model was generated, and tumor inhibition was monitored after treating rats with both drugs as mono- and combination therapy. In addition, protein expression and localization were performed by western blotting and immunofluorescent staining, respectively. RESULTS: The analyses of the data showed that combination therapy of apatinib and G-Rb1 significantly inhibited the proliferation, migration, and wound healing capability of hypopharyngeal carcinoma cells. Moreover, the glycolysis rate of the cells in the combination therapy (apatinib and G-Rb1) group was significantly decreased as compared to that in the monotherapy group or no treatment group, suggesting that the glycolysis inhibition led to the inhibition of tumor growth. Moreover, the combination therapy on xenograft rats dramatically reduced the tumor size. Furthermore, combination therapy also exhibited an increased count of CD3+ and CD4+ T cells, as well as the ratio between CD4+ and CD8+ T cells. CONCLUSION: Interestingly, a combination of apatinib and G-Rb1 induced more tumor cell apoptosis and reduced cell proliferation than the individual drug treatment and promote antitumor immunity by enhancing immunomodulatory molecules. Thus, we believe that this study could serve as a valuable platform to assess the synergetic anticancer effects of the herbal as well as synthetic medicines.

Systematic Analysis of Molecular Subtypes and Immune Prediction Based on CD8 T Cell Pattern Genes Based on Head and Neck Cancer.

CD8+ T lymphocytes, also known as cytotoxic T lymphocytes, are the most powerful antitumour cells in the human body. Patients with head and neck squamous cell carcinoma (HNSCC) in whom CD8+ T lymphocyte infiltration is high have a better prognosis. However, the clinical significance and prognostic significance of CD8+ T cell-related regulatory genes in HNSCC remain unclear, and further research is required. In total, 446 CD8+ T cell-related genes were obtained using WGCNA. It was discovered that 111 genes included within the TCGA and GSE65858 datasets were intimately linked to the patient's prognosis. These genes were included in the subsequent analysis. According to consensus clustering analysis, HNSCC samples were classified into 3 subtypes (IC1, IC2, and IC3). There were substantial differences between the three subtypes in terms of immunological molecules, immune function, and the response to drug treatment. In addition, the 8-gene signature, which was generated premised on CD8+ T cell-related genes, exhibited stable prognostic prediction in the TCGA and GEO datasets and different HNSCC patient subgroups and independently served as a prognostic indicator for HNSCC. More importantly, the 8-gene signature effectively predicted immunotherapy response. We first constructed a molecular subtype of HNSCC based on CD8+ T cell-related genes. Between the three subtypes, there were significant differences in the prognosis, clinical features, immunological molecules, and drug treatment response. The 8-gene signature that was further constructed effectively predicted prognosis and immunotherapy response.