Resistance to Both Chemotherapy and EGFR-TKI in Small Cell Lung Cancer With EGFR 19-Del Mutation: A Case Report.

Epidermal growth factor receptor (EGFR) mutations are common in non-small cell lung cancers, but rare in small cell lung cancers (SCLCs). In previous reports, some SCLC patients with EGFR mutations could benefit from EGFR tyrosine kinase inhibitors (TKIs). In this study, we reported a case in which an SCLC patient with EGFR exon 19 deletion (19-Del) mutation did not benefit from EGFR-TKIs. Interestingly, the standard treatment strategies for SCLC also failed to control tumor progression. Moreover, we screened 43 SCLC patients in China and found that the frequency of EGFR mutations in Chinese SCLC patients was about 4.65% by next-generation sequencing (NGS). Collectively, this case illustrated a rare subtype of SCLCs which harbored EGFR mutations and was intrinsically resistant to standard treatments and EGFR-TKIs. We also tried to explore the mechanisms underlying drug resistance. The literature concerning SCLCs with EGFR mutations is reviewed.

Complete response to the combination of Lenvatinib and Pembrolizumab in an advanced hepatocellular carcinoma patient: a case report.

BACKGROUND: The majority of patients diagnosed with hepatocellular carcinoma (HCC) have advanced diseases and many are not eligible for curative therapies. CASE PRESENTATION: We report a rare case of HCC from a patient who had a complete response (CR) with the use of combination of Lenvatinib and Pembrolizumab. A 63-year-old man presented at the hospital with serious abdominal pain and was found to have a mass with heterogeneous enhancement and with hemorrhage in segment III of the liver after the examination of abdominal computerized tomography (CT) scan. The patient's history of viral hepatitis B infection, liver cirrhosis and the ɑ-fetoprotein (AFP) level of 14,429.3 ng/ml supported the clinical diagnosis of HCC and laboratory results demonstrated liver function damage status (Child-Pugh class B, Score 8). The patient first received hepatic arterial embolization treatment on 28th November 2017. At this stage supportive care was recommended for poor liver function. In February 2018, combined immunotherapy of Pembrolizumab (2 mg/kg, q3w) and Lenvatinib (8 mg-4 mg, qd) were performed. Nine months following the treatment he had a CR and now, 22 months since the initial treatment, there is no clinical evidence of disease progression. The current overall survival is 22 months. CONCLUSIONS: HCC is a potentially lethal malignant tumor and the combination of immunotherapy plus anti-angiogenic inhibitors shows promising outcome for advanced diseases.

Chemokine CXCL1 may serve as a potential molecular target for hepatocellular carcinoma.

The purpose of this study was to screen for changes in chemokine and chemokine-related genes that are expressed in hepatocellular carcinoma (HCC) as potential markers of HCC progression. Total RNA was extracted from tumor and peritumor tissues from mice with HCC and analyzed using a PCR microarray comprising 98 genes. Changes in gene expression of threefold or more were screened and subsequently confirmed by immunohistochemical analyses and western blotting. Furthermore, whether chemokine knockdown by RNA interference (RNAi) could significantly suppress tumor growth in vivo was also evaluated. Finally, total serum samples were collected from HCC patients with HBV/cirrhosis (n = 16) or liver cirrhosis (n = 16) and from healthy controls (n = 16). The serum mRNA and protein expression levels of CXCL1 in primary liver cancer patients were detected by qRT-PCR and western blot analysis, respectively. Several genes were up-regulated in tumor tissues during the progression period, including CXCL1, CXCL2, CXCL3, and IL-1ß, while CXCR1 expression was down-regulated. CBRH-7919 cells carrying CXCL1 siRNA resulted in decreased tumor growth in nude mice. The differences in serum CXCL1 mRNA and protein levels among the HCC, hepatic sclerosis (HS), and control groups were significant (P < 0.001). The mRNA and protein levels of CXCL1 in the HCC group were up-regulated compared with the HS group or the control group (P < 0.001). Several chemokine genes were identified that might play important roles in the tumor microenvironment of HCC. These results provide new insights into human HCC and may ultimately facilitate early HCC diagnosis and lead to the discovery of innovative therapeutic approaches for HCC.

Targeted silencing of CXCL1 by siRNA inhibits tumor growth and apoptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignancy and a major cause of cancer-related mortality worldwide. Our previous study shows that chemokine (C-X-C motif) ligand 1 (CXCL1) was upregulated and CXCR1 was downregulated in tumor tissues as compared to peritumor tissues by chemotaxis assay. As the status of CXCL subgroups and their receptors affect progression of HCC, we evaluated potential mechanisms of CXCL1 associated with anticancer effects in HCC based on our previous study. The effects of targeting CXCL1 by RNA interference (RNAi) on the proliferation and apoptosis of CBRH-7919 cells were observed in vitro and in vivo. Additionally, whether CXCL1 knockdown significantly reduce the activity of STAT3, NF-κB and HIF-1 or not were also estimated. RNAi of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice by inhibited cells proliferation and induced apoptosis. In conclusion, these findings suggest that CXCL1 plays critical roles in the growth and apoptosis of HCC. RNAi of CXCL1 inhibits the growth and apoptosis of tumor cells, which indicates that CXCL1 may be a potential molecular target for use in HCC therapy.

Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma.

AIM: To study the inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma (HCC) in nude mice. METHODS: CBRH-7919 HCC cells were injected into the subcutaneous region of nude mice. Beginning two weeks after the challenge, tumor growth was measured every week for six weeks. The stromal microenvironment and inflammatory cell infiltration was assessed by immunohistochemistry in paired tumor and adjacent peritumoral samples, and macrophage phenotype was assessed using double-stain immunohistochemistry incorporating expression of an intracellular enzyme. A chemokine PCR array, comprised of 98 genes, was used to screen differential gene expressions, which were validated by Western blotting. Additionally, expression of identified chemokines was knocked-down by RNA interference, and the effect on tumor growth was assessed. RESULTS: Inflammatory cell infiltrates are a key feature of adjacent peritumoral tissues with increased macrophage, neutrophil, and T cell (specifically helper and activated subsets) infiltration. Macrophages within adjacent peritumoral tissues express inducible nitric oxide synthase, suggestive of a proinflammatory phenotype. Fifty-one genes were identified in tumor tissues during the progression period, including 50 that were overexpressed (including CXCL1, CXCL2 and CXCL3) and three that were underexpressed (CXCR1, Ifg and Actb). RNA interference of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice and inhibited expression of CXCL2, CXCL3 and interleukin-1ß protein. CONCLUSION: These findings suggest that CXCL1 plays a critical role in tumor growth and may serve as a potential molecular target for use in HCC therapy.