Synergistic anti-tumour effects of Clostridium butyricum in combination with apatinib in CT26 colorectal tumour-bearing mice.

To investigate the synergistic antitumour effect of Clostridium butyricum combined with apatinib on colorectal cancer in mice. Murine colorectal carcinoma cell line CT26.WT cells were xenografted into the skin of BALB/c mice. Tumour-bearing mice were randomly divided into four groups, and given different treatment options (PBS control; C. butyricum; apatinib; C. butyricum + apatinib). Real-time PCR was used to detect C. butyricum content in the intestine of mice given C. butyricum. The effects of various regimens on tumour growth were monitored, and CD31, proliferating cell nuclear antigen (PCNA), Bcl-2 and cleaved caspase-3 expressions in tumour were analysed by immunohistochemistry. C. butyricum combined with apatinib significantly inhibits tumour growth with decreased CD31, PCNA and Bcl-2 expressions, and increased cleaved caspase-3 expressions. Our study confirms that C. butyricum combined with apatinib in the treatment of xenografted colon tumour in mice can significantly inhibit tumour growth and promote cell apoptosis than apatinib alone treatments, providing the reference for clinical treatments.

RGC32 promotes the progression of ccRCC by activating the NF-κB/SHP2/EGFR signaling pathway.

BACKGROUND: The role and clinical significance of the response gene to complement 32 (RGC32) in various cancers have been documented, yet its implications in clear cell Renal Cell Carcinoma (ccRCC) remain underexplored. METHODS: This study investigated RGC32's diagnostic and prognostic relevance in ccRCC using bioinformatics methods with data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). The impact of RGC32 on ccRCC progression was assessed through nude mouse tumor assays. Immunohistochemistry evaluated RGC32 levels in ccRCC and adjacent normal tissues, while cell proliferation, migration, and invasion capabilities were analyzed using CCK-8, monoclonal proliferation assays, Transwell, and wound healing assays, respectively. Western blotting measured relevant protein expressions. RESULTS: Bioinformatics analysis highlighted RGC32's significant role in ccRCC pathogenesis. Elevated RGC32 expression in ccRCC tissues was linked to disease progression. Functionally, RGC32 was found to enhance the expression of proteins such as p-PI3K, CyclinA1, CyclinD1, p-STAT3, MMP2, MMP3, MMP9, p-SMAD2/3, Snail, Slug, and N-Cadherin via the NF-κB/SHP2/EGFR pathway, while decreasing E-cadherin levels. Moreover, RGC32 facilitated ccRCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). CONCLUSION: RGC32 is a pivotal factor in ccRCC development, primarily through the activation of the NF-κB/SHP2/EGFR signaling pathway.

Relationship between gene polymorphisms of two cytokine genes (TNF-α and IL-6) and occurring of lung cancers in the ethnic group Han of China.

Tumor necrosis factor (TNF) is a cytokine involved in inflammation and TNF-α might be synthesized ectopically in malignant tumors. Interleukin-6 (IL-6) is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. The present study is to investigate the relationship between genetic polymorphisms of the TNF-α and IL-6 genes and susceptibility to lung cancers in the ethnic group Han of North China. The genotypes in the -238G locus of TNF-α gene and the -572C locus of the IL-6 gene were determined by PCR-RFLP method in 138 patients with lung cancers and 138 healthy individuals. Software PHASE 1.0 was used to analyze the experimental data. The non-conditional logistic regression model was used to analyze the statistical association of genotypes and susceptibility in two groups adjusted by multiple factors. We found that the TNF-α and IL-6 polymorphisms may be a critical risk for the genetic susceptibility to lung cancers in the ethnic group Han of North China. SNP polymorphisms at the -238G locus of TNF-α gene and the -572C locus of the IL-6 gene were detected by the RFLP-PCR method. We found that high rates of single-base G-to-A alteration at the -238G locus of both alleles and high rates of single-base C-to-G alteration at the -572C locus of both alleles correlated with occurring of lung cancers. It is possible that the SNP markers at the -238G locus of TNF-α gene and the -572C locus of the IL-6 gene serve as biological markers of lung cancers upon further study in the future.

Clinical characteristics and management of immune checkpoint inhibitor-related cardiotoxicity: A single-center experience.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy in the past decade and amplify T-cell-mediated immune responses by disrupting immunoinhibitory signals. The augmented T-cell immune response has led to a range of immune-related adverse effects (irAEs). Immune-related cardiotoxicity has been reported in case series but has been underappreciated due to difficulties in diagnosis. This article describes epidemiological, clinical presentation, subtype, and treatment data and a new systematic framework for the clinical management of cardiotoxicity. Methods: Data were extracted for cancer patients who received ICIs in a single center between January 1, 2020, and February 28, 2022. ICI-associated cardiotoxicity was clinically diagnosed based on clinical presentations, biochemical biomarkers, and imaging features. Results: We identified a total of 12 (2.46%) cases of ICI-related cardiotoxicity from 487 patients who received PD-1 or PD-L1 inhibitors. All patients were diagnosed with advanced or metastatic solid tumors. The severity of ICI-related cardiotoxicity ranged from subclinical cardiac abnormalities (subclinical type) with only asymptomatic troponin-I (TnI) elevations (25.0%) to symptomatic cardiac abnormalities (clinical type) (75.0%). Patients with symptomatic cardiac abnormalities had several manifestations, including tachyarrhythmia (16.7%), bradyarrhythmia (41.7%), or cardiac failure (8.3%). The median immunotherapy exposure time was 1.5 doses (range: 1 to 5), and the median time from the initial immunotherapy to the onset of ICI-related cardiotoxicity was 33.5 days (IQR: 20.3 to 46.8). Most patients, including those with subclinical cardiac abnormalities, were administered systemic corticosteroids (58.3%). One (8.3%) patient was put on mechanical ventilation, one (8.3%) received plasma exchange therapy, one (8.3%) was implanted with a pacemaker, and one (8.3%) was admitted to the ICU. Three patients with symptomatic cardiac abnormalities (25.0%) died, and other patients presented with significant clinical improvement with good outcomes. Conclusion: ICI-related cardiotoxicity is uncommon but critical with a high mortality rate and poor prognosis, especially for a small group of patients with symptomatic cardiac abnormalities. More attention should be given to cardiotoxicity associated with ICIs, and these patients should be given baseline examinations and biochemical analyses before and after the initiation of immunotherapy, intensive cardiac assessments, an accurate and rapid diagnosis, and timely multidisciplinary management with immunosuppressive agents and other necessary clinical interventions.

Impact of endogenous glucocorticoid on response to immune checkpoint blockade in patients with advanced cancer.

Background: Previous studies indicate that exogenous use of glucocorticoid (GC) affects immune checkpoint inhibitor (ICI) efficacy. However, there is a paucity of clinical data evaluating the direct impact of endogenous GC on the efficacy for cancer patients with immune checkpoint blockade. Methods: We first compared the endogenous circulating GC levels in healthy individuals and patients with cancer. We next retrospectively reviewed patients with advanced cancer with PD-1/PD-L1 inhibitor alone or combination therapy in a single center. The effects of baseline circulating GC levels on objective response rate (ORR), durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS) were analyzed. The association of the endogenous GC levels with circulating lymphocytes, cytokines levels, and neutrophil to lymphocyte ratio, and tumor infiltrating immune cells, were systematically analyzed. Results: The endogenous GC levels in advanced cancer patients were higher than those in early-stage cancer patients as well as healthy people. In the advanced cancer cohort with immune checkpoint blockade (n=130), patients with high baseline endogenous GC levels (n=80) had a significantly reduced ORR (10.0% vs 40.0%; p<0.0001) and DCB (35.0% vs 73.5%, p=0.001) compared to those with low endogenous GC levels (n=50). The increased GC levels was significantly associated with reduced PFS (HR 2.023; p=0.0008) and OS (HR 2.809; p=0.0005). Moreover, statistically significant differences regarding PFS, and OS were also detected after propensity score matching. In a multivariable model, the endogenous GC was identified as an independent indicator for predicting PFS (HR 1.779; p=0.012) and OS (HR 2.468; p=0.013). High endogenous GC levels were significantly associated with reduced lymphocytes (p=0.019), increased neutrophil to lymphocyte ratio (p=0.0009), and increased interleukin-6 levels (p=0.025). Patients with high levels of endogenous GC had low numbers of tumor infiltrating CD3+ (p=0.001), CD8+ T (p=0.059), and CD4+ T (p=0.002) cells, and the numbers of circulating PD-1+ NK cells (p=0.012), and the ratio of CD8+PD-1+ to CD4+PD-1+ (p=0.031) were higher in patients with high levels of endogenous GC compared to low levels of endogenous GC. Conclusion: Baseline endogenous GC increase executes a comprehensive negative effect on immunosurveillance and response to immunotherapy in real-world cancer patients accompanied with cancer progression.

SDK1-ALK Fusion in a Lung Adenocarcinoma Patient With Excellent Response to ALK Inhibitor Treatment: A Case Report.

Background: Rearrangements of Anaplastic lymphoma kinase (ALK) have been discovered as a novel driver mutation in patients with non-small-cell lung cancer (NSCLC). Patients' responses to ALK tyrosine kinase inhibitors (TKIs) may vary depending on the variations of ALK rearrangements they have. It is imperative for clinicians to identify druggable ALK fusions in routine practice. Case Presentation: In this study, we discovered a rare ALK rearrangement type (SDK1-ALK) in a Chinese lung adenocarcinoma patient who responded well to ALK inhibitor SAF-189s. The positive expression of ALK in lung biopsy tissue was verified by IHC analysis. A new SDK1-ALK fusion was discovered using NGS. The patient was treated with SAF-189s (160 mg per day) as a first-line therapy and went into continuous remission, with a 12 months progression-free survival at the last follow-up. Conclusion: This is the first case of SDK1-ALK fusion with an excellent response to an ALK inhibitor, which will provide better understanding of ALK-TKI applications for NSCLC patients with ALK fusion in the future.

Myocarditis and myositis/myasthenia gravis overlap syndrome induced by immune checkpoint inhibitor followed by esophageal hiatal hernia: A case report and review of the literature.

Immunotherapy with programmed death 1 (PD-1) inhibitor has shown activity as first- or second-line treatment for various metastatic human malignancies. Immune-related adverse events (irAEs) are now well-described, and most organ sites are potentially influenced, but the prevalence of myocarditis and myositis/myasthenia gravis (MG) overlap syndrome following esophageal hiatal hernia induced by immunotherapy is rarely reported. Here, we describe a 71-year-old woman with a progressed unresectable extrahepatic cholangiocarcinoma and biliary obstruction. She had no prior history of muscle weakness and neuromuscular disease with a normal body mass index. She was treated with sintilimab as a rescue regimen of immunotherapy. After the first cycle of treatment, she experienced a grade 4 myopathy including simultaneous myositis, myalgia, and myocarditis due to multiple injuries in her cardiac, skeletal, and ocular muscles. She had elevated levels of creatine kinase (CK), cardiac troponin I, and myoglobin (MYO), but MG and myositis-specific and myositis-related antibodies were negative. Immunotherapy was discontinued and pulse high-dose methylprednisolone with a slow tapering and intravenous immunoglobulin (IVIG) was initiated. Two weeks later, the patient's clinical presentation improved significantly. A subsequent cardiac magnetic resonance (MR) examination revealed an old myocardial injury that may be a result of immune-related cardiac toxicity. In the third month following the PD-1 inhibitor therapy, she restarted systemic chemotherapy in combination with an anti-angiogenic agent but without immunotherapy. Half a year later, she complained of repeated abdominal distension and radiographic examinations and endoscopy showed a clinically confirmed diagnosis of sliding hiatal hernia of the esophagus and gastroesophageal reflux disease. Due to mild symptoms associated with gastroesophageal reflux, she was suggested close monitoring with acid secretion blockade rather than immediate surgical intervention. The severity for patients with myositis and myocarditis accompanied without MG is similar to those with MG. Considering the use of PD-1 inhibitors is increasing in cancer patients, physicians should therefore pay more attention to immunotherapy-induced myocarditis with myositis/MG overlap syndrome. Since we hypothesize diaphragmatic hiatal hernia as a potential consequence of immunotherapy-induced myositis, reports on hiatal hernias subsequent to immunotherapy-induced myositis are needed.

Primary Squamous Cell Carcinoma of the Liver is Rare but Hostile: Case Series and Comprehensive Review of the Literature.

Primary squamous cell carcinoma (SCC) of the liver is an uncommon cancer type. Only dozens of such cases have been reported in the literature. We reviewed three cases with primary SCC of the liver in a single center from January 2013 to October 2019. One case was positive for hepatitis B infection and simultaneously diagnosed with sigmoid adenocarcinoma and liver cyst. The second patient presented with hepatolithiasis. The remaining one had no history of prior liver insult, hepatic infection or any pre-existing hepatic cysts. Two cases had a long survival of more than one year through chemotherapy, or radical surgery plus transarterial chemoembolization. We also found 25 patients with primary hepatic SCC in the Surveillance, Epidemiology and End Results (SEER) database from 1997 to 2016. The median age was 67 years (range 33-87 years). The median overall survival and disease-specific survival were 7.7 months (range 0.0-76.0 months) and 2.0 months (range 0.0-20.0 months), respectively. Furthermore, patients receiving surgery had a longer median OS (20.0 versus 6.0 months, P = 0.016) and DSS (48.0 versus 8.0 months, P = 0.03) than those receiving palliative treatment. Only 20% of all cases survived for more than a year. Although primary SCC of the liver has an unfavorable prognosis, radical surgery and systematic treatment might be helpful for clinical management.

Adjuvant therapy fails to show survival benefit for patients with spindle cell carcinoma: Evidence from the surveillance, epidemiology, and end results database.

BACKGROUND: Spindle cell carcinoma (SpCC) is a rare tumor type with poor prognosis, and standard treatment modalities are not available yet. However, large-scale studies on this topic are sparse. In this study, data from the surveillance, epidemiology, and end results (SEER) database were used to determine cancer-specific survival (CSS) rates of SpCC and to investigate the impact of different therapeutic strategies including surgery with or without chemotherapy, radiotherapy, or chemoradiotherapy on patient outcome. METHODS: A total of 665 cases of SpCC, diagnosed from 1996 to 2015, were extracted from the SEER database. Kaplan-Meier survival curves and log-rank tests were used to assess CSS rates and differences on survival curves. Multiple COX-proportional hazards models were used to analyze the association between various treatments and prognosis of SpCC patients classified by organs or systems. RESULTS: Different treatments for SpCC in different organ or system were associated with prognosis of SpCC patients. Surgery alone exhibits survival benefit, whereas adjuvant therapy fails to show survival benefit for patients with SpCC. CONCLUSIONS: The prognosis of SpCC patients varied significantly with different clinical treatments. Adjuvant radiotherapy or chemotherapy did not show survival benefit, even increasing the risk of mortality for SpCC patients.

Clinical observation of apatinib-related hypothyroidism in patients with advanced malignancies.

Thyroid dysfunction has been previously reported during treatment with certain small-molecule multi-tyrosine kinase inhibitors, including sunitinib and sorafenib. Apatinib, which has a similar mechanism of action to these inhibitors, has reportedly induced hypothyroidism during treatment. Fully elucidating drug-associated adverse events could aid in patient monitoring and recommendations of suitable management strategies. The current 2-year observational study monitored patients with solid tumors who were prescribed apatinib. A total of 149 patients treated with apatinib from February 2015 to January 2016 were included. Their thyroid function and thyroid ultrastructure was evaluated for at least 24 months or until death. The primary objective of the current study was evaluating accepted thyroid replacement treatment. Secondary objective was ultrastructural changes in the thyroid gland. The current study was approved by the Medical Ethics Committee of Qianfoshan Hospital, affiliated with Shandong University and written informed consent was obtained from all patients prior to commencing the clinical trial. A total of 53 (35.57%) patients developed hypothyroidism, which varied from subclinical (12 cases; 8.05%) to clinical (41 cases; 27.52%). Thyroid nodules were noted in 15 cases (10.07%). Furthermore, 3 cases (2.01%) had thyroid imaging reporting and data system scores of 4a/4b/4c and 12 cases (8.05%) had scores of 1, 2 and 3. A total of 25 patients (16.78%) experienced 1-2 grade fatigue and 2 patients (1.34%) reported 3-4 grade fatigue. There was no reported association between disease control rate and hypothyroidism. Apatinib significantly increased the risk of clinically relevant hypothyroidism and altered thyroid gland structure.

Immune-related organizing pneumonitis in non-small cell lung cancer receiving PD-1 inhibitor treatment: A case report and literature review.

Immune checkpoint blockade with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors has been standard care for metastatic nonsmall cell lung cancer (NSCLC) and after progression using first-line platinum-containing chemotherapy. Although several management guidelines exist for immune checkpoint inhibitor-induced toxicities, uncommon, complicated, and life-threatening immune-related adverse events remain challenging for oncologists. In this report, we presented a male patient with NSCLC who received pembrolizumab during disease progression. He developed interstitial pembrolizumab-induced organizing pneumonia (OP). The patient received 9 months of anti-PD-1 pembrolizumab when he presented with dry cough and fatigue. The patient developed a solitary nodular lung lesion mimicking a newly occurred metastatic lesion in the lung without a significant circulating tumor marker increase. Sputum analysis was negative for acid-fast bacilli and fungi. A computed tomography-guided percutaneous lung biopsy was conducted and showed alveolar fibrous thickness and various lymphocyte infiltration. Immunotherapy-related OP was identified, and he subsequently responded well to corticosteroids. This case describes a clinical situation, where PD-1-induced OP is radiologically similar to NSCLC disease progression in the lungs. Oncologists should be aware of uncommon pulmonary PD-1/PD-L1 inhibitor toxicity. Lung biopsy may help to distinguish immune-related pneumonitis, lung infections, and progressive nodular lesions.

Stathmin is a potential molecular marker and target for the treatment of gastric cancer.

OBJECTIVE: This study is to investigate the expression levels of stathmin in tissues of gastric cancer, and evaluate the therapeutic effects of stathmin antisense oligodeoxynucleotide (ASODN) and/or docetaxel in human gastric cancer cells. METHODS: Immunohistochemistry was performed to detect the expression levels of stathmin in gastric cancer and adjacent tissues. Stathmin ASODN was transfected into gastric cancer SGC 7901 cell lines. The cell proliferation was assessed with the MTT assay, and the inhibitory rates were calculated. RT-PCR and Western blot analysis were performed to detect the mRNA and protein expression levels of stathmin, respectively. The synergistic effects of stathmin ASODN and docetaxel were evaluated. The efficacy and clinical benefit rates of the treatment of docetaxel combined with stathmin evaluation were investigated and compared. RESULTS: Our results showed that the expression of stathmin was elevated in gastric cancer tissues, indicating a possible association between the stathmin expression and the disease occurrence. The MTT assay and tumor growth experiment revealed that stathmin ASODN significantly inhibited the proliferation of gastric cancer cells, both in vitro and in vivo. Furthermore, stathmin ASDON enhanced the inhibitory effects of docetaxel on the proliferation of gastric cancer cells, indicating a synergistic effect for the combination treatment. Importantly, docetaxel treatment was more effective for stathmin-negative gastric cancer patients, compared with stathmin-positive patients. CONCLUSION: Stathmin expression provides evidence for the treatment planning for gastric cancers. Stathmin might be a potential molecular marker and target for the treatment of gastric cancer.

Efficacy assessment of pemetrexed treatment of an NSCLC case with brain metastasis.

Non-small cell lung cancers (NSCLCs) are among the most common malignancies. Although pemetrexed is often used clinically to cure cancers, its efficacy in NSCLC patients with progressive brain metastases remains unclear. Here, we report a successful NSCLC (adenocarcinoma) case treated with pemetrexed. The detected tumors were treated with 900 mg of pemetrexed disodium (500 mg/m(2)) was administered to the patient on day 1, and 40 mg of cisplatin (25mg/m(2)) was administered on days 1-3, at the interval of 3 weeks. After two cycles of chemotherapy, the brain metastases were reduced. The lesion in the lung was reduced as determined by chest CT-scan. Our results suggest that pemetrexed is an effective therapy for patients with NSCLC and progressive brain metastases.

Correlation of polymorphisms of the vascular endothelial growth factor gene and the risk of lung cancer in an ethnic Han group of North China.

Vascular endothelial growth factor (VEGF) is a potent angiogenic mediator. The present study investigated the relationship between genetic polymorphisms of VEGF and susceptibility to lung cancer in a Han ethnic group of North China. The genotypes in the -2578C and 936C loci of VEGF gene were determined using PCR-RFLP method in 150 patients with lung cancers and 150 healthy individuals. Software PHASE 1.0 was used to analyze the experimental data. The non-conditional logistic regression model was used to analyze the statistical association of genotypes and susceptibility in the two groups adjusted by multiple factors. VEGF polymorphisms were found to be a critical risk for the genetic susceptibility to lung cancers in the ethnic Han group of North China. SNP polymorphisms at the -2578C and 936C loci of the VEGF gene were detected by the RFLP-PCR method. High rates of a single-base C-to-A alteration at the -2578 locus and high rates of a single-base C-to-T alteration at the 936 locus of both alleles were correlated with the occurrence of lung cancer. The SNP markers at the -2578C and 936C loci of the VEGF gene may serve as biological markers of lung cancer.