Overcoming resistance to anti-PD-1 immunotherapy in lymphoepithelioma-like carcinoma: A case report and review of the literature.

OBJECTIVES: Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of non-small-cell lung cancer with no established treatment protocols. Immunotherapy is rarely used as a second-line choice in patients with advanced LELC, and more cases of this condition should be presented. MATERIALS AND METHODS: We present a patient with advanced primary pulmonary LELC overcoming the resistance to second-line anti-programmed death-1 (PD-1) immunotherapy. We also review the literature to summarize the current immunotherapy landscape of this rare disorder. RESULTS AND CONCLUSION: The LELC patient progressed after first-line chemotherapy, was treated by immunotherapy alone and progressed again. To overcome the developed resistance to immunotherapy, chemotherapy with nedaplatin plus paclitaxel in addition to nivolumab was administered and a progression-free survival (PFS) of 5 months was achieved. It was also observed that the blood levels of neuron-specific enolase may act as an efficacy biomarker in LELC. Patients with this rare disorder resistant to anti-PD-1 immunotherapy might benefit from therapy based on PD-1 inhibition; this is a future avenue of research.

Pathologic complete response to preoperative immunotherapy in a lung adenocarcinoma patient with bone metastasis: A case report.

Anti-programmed cell death 1 (PD-1) and its ligand (PD-L1) has emerged as a novel immunotherapy for non-small cell lung cancer (NSCLC). However, the proportion of patients who may benefit from immunotherapy is limited and the factors sensitive or resistant to immunotherapy are not completely clear. Therefore, to identify reliable biomarkers as predictors of clinical response and resistance to anti-PD-1/PD-L1 therapies have become increasingly important. Here, we report a case of a patient with bone metastatic NSCLC, who achieved a pathologic complete response after preoperative pembrolizumab treatment. Postoperative pathological examination found no viable cancer cells in the resected pulmonary nodules and lymph nodes. Several high-frequency DNA damage response and repair (DDR) gene mutations including two germline mutations were identified in the primary lesion. Moreover, high PD-L1 expression, Kirsten rat sarcoma viral oncogene homolog (KRAS) combined with tumor protein 53 (TP53) mutations without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) driver alterations, high infiltration level of CD8-positive cells and M1 macrophages were observed, which were favorable characteristics for immunotherapy. We explored the possible factors related to an excellent response to immune checkpoint inhibitor in this patient and determined that preoperative use of anti-PD-1 therapy might apply to late-stage lung adenocarcinoma patients with multidimensional advantageous biomarkers for treatment with immune checkpoint inhibitors (ICIs). KEY POINTS: We characterized the genomic features and immune microenvironment signature of a lung adenocarcinoma in a patient with bone metastasis who achieved pathologic complete response after pembrolizumab treatment. To evaluate multidimensional advantageous biomarkers for immunotherapy.

A case report of immune checkpoint inhibitor nivolumab combined with anti-angiogenesis agent anlotinib for advanced esophageal squamous cell carcinoma.

INTRODUCTION: The PD-1 inhibitors have shown good response in the treatment for many types of malignant tumors, but as monotherapy for advanced esophageal squamous carcinoma, the objective response rate is low. Here we report a case of the patient with advanced esophageal squamous cell carcinoma (ESCC) showing a completely response to nivolumab combined with a small molecule multi-target tyrosine kinase inhibitor (TKI) anlotinib. PATIENT CONCERNS: A 61-year-old male was put under a surgery as the response to the diagnosis of ESCC in March 2014. The post-operative follow-up in March 2018 suggested a recurrence based on imagological findings, and symptoms such as shortness of breath and cough were also observed in October 2018. DIAGNOSIS: The patient was diagnosed as advanced metastatic ESCC in October 2018. INTERVENTIONS: Radical resection and esophagogastrostomy under aortic arch with left thoracotomy was performed in March 2014. As a treatment against the post-surgical recurrence, 4 courses of paclitaxel combined with nedaplatin was administered in April 2018 with an outcome of PR, followed by a combined administration of Nivolumab and anlotinib in November 2018. OUTCOMES: Chest CT during a 3-month follow-up revealed the disappearance of all the metastases, and no adverse effect was observed during the treatment. CONCLUSION: The combined treatment of nivolumab and anlotinib is likely to be considered as an optional management of advanced ESCC.

Maximum allele frequency observed in plasma: A potential indicator of liquid biopsy sensitivity.

Personalized medicine is revolutionizing the diagnosis and treatment of cancer; however, for personalized medicine to be used accurately, patient information is essential to determine the appropriate diagnosis, prognosis and treatment. The detection of genomic mutations in liquid biopsy samples is a non-invasive method of characterizing the genotype of a tumor. However, next generation sequencing-based plasma genotyping only has a sensitivity of ~70%. Identifying potential indicators that may reflect the sensitivity of a liquid biopsy analysis could offer important information for its clinical application. In the present study, 47 pairs of patient-matched plasma and tumor tissue samples obtained from patients with advanced lung cancer were sequenced using a panel of 56 cancer-associated genes. The plasma maximum allele frequency (Max AF) was identified as a novel biomarker to indicate the sensitivity of plasma genotyping. Using the identified somatic mutations in patient tissue biopsy samples as a reference, the sensitivity of the corresponding patient plasma test was investigated. The by-variant sensitivity of the plasma test was 68.1%, with 79 matched and 37 missed genetic aberrances. The by-patient sensitivity was calculated as 83%. Patients with a high plasma Max AF value (>2.2%) demonstrated a higher concordance with the range of mutations identified in the patient-matched tissue samples. The Max AF observed in patient plasma samples was positively correlated with liquid biopsy sensitivity and could be used as a potential indicator of liquid biopsy sensitivity. Therefore, patients with a low plasma Max AF (≤2.2%) may need to undergo further tissue biopsy to allow personalized oncology treatment. In summary, the present study may offer a non-invasive testing method for a sub-group of patients with advanced lung cancer.

MDM2 promotes epithelial-mesenchymal transition through activation of Smad2/3 signaling pathway in lung adenocarcinoma.

BACKGROUND: Mouse double minute 2 (MDM2) contributes to cancer metastasis and epithelial-mesenchymal transition (EMT). This study aimed to investigate small mothers against decapentaplegic (Smad) signaling in MDM2-mediated EMT in lung adenocarcinoma (LAC). MATERIALS AND METHODS: Expression patterns of MDM2 in LAC tissues, adjacent tissues, and cell lines (BEAS-2B, PC9, H1975, and A549) were detected. We then overexpressed MDM2 in PC9 cells and knocked it down in H1975 cells. To explore whether MDM2 activates EMT through the Smad2/3 signaling pathway, Smad2 and Smad3 were also silenced by siRNA in H1975 cells. Male BALB/c nude mice were used in in vivo model to validate the effects of MDM2 on LAC cells. RESULTS: MDM2 was significantly upregulated in LAC tissues compared with adjacent tissues. The expression of MDM2 was relatively higher in PC9 cells and relatively lower in H1975 cells compared with A549 cells. Overexpression of MDM2 significantly increased cell proliferation, migration, and invasion in LAC cells, while inhibiting apoptosis in PC9 cells. On the contrary, silencing of MDM2 significantly inhibited the expression of EMT-related genes N-cadherin and vimentin, while promoting the expression of E-cadherin and ß-catenin. In vivo, MDM2 knockdown inhibited tumor growth. In addition, the expression of Smad2/3 was correlated with MDM2 in H1975 cells transfected with Smad2 and Smad3 siRNAs, which inhibited EMT progress. CONCLUSION: MDM2 can activate the Smad2/3 signaling pathway, which promotes the proliferation and EMT progress of LAC cells.

Subcostal thoracoscopic extended thymectomy for patients with myasthenia gravis.

BACKGROUND: Extended thymectomy is indicated for patients with myasthenia gravis (MG) when drug-resistance or dependence is seen. We have employed a technique for subcostal thoracoscopic extended thymectomy (STET) on patients with MG. METHODS: Clinical data of 15 eligible patients who underwent STET in our department from February 2015 to November 2015 by the same surgical team were retrospectively analyzed. The operation time, blood loss, duration of postoperative hospital stay, thoracic drainage periods were concerned. RESULTS: All the surgeries were finished successfully without conversion to sternotomy. Mean operation time was 157.53±40.31 min (range, 73-275 min). Mean blood loss was 56.33±7.07 mL (range, 10-200 mL). Mean pleural drainage volume in the first 24 hours was 72.67±17.68 mL (range, 0-250 mL). Mean postoperative thoracic drainage periods were 1.20±0.71 days (range, 0-3 days). Mean duration of postoperative hospital stay was 6.13±0.71 days (range, 3-22 days). CONCLUSIONS: This procedure showed satisfactory results for patients with MG. Moreover, the STET approach is more easily for surgeons to fully reveal the bilateral phrenic nerve and the upper thymic poles. We believe that STET is a satisfactory procedure for performing extended thymectomy in well selected patients.