Investigating the genomic alteration improved the clinical outcome of aged patients with lung carcinoma.

BACKGROUND: Lung carcinoma is a common geriatric disease. The development of genotype-targeted therapies greatly improved the management of lung carcinoma. However, the treatment for old patients can be more complex than that for young individuals. RESULTS: To investigate the benefits of genetic detection for older patients with lung carcinoma, we explored the genomic profiling of 258 patients with more than 55 years using a targeted next generation sequencing, and some of these patients were treated with targeted therapies based on the results of genomic detection. KRAS codon 61 mutations were found in 15.2% KRAS-mutated patients, which tend to be co-existing with other classical activating mutations other than codons 12/13. Acquired EGFR C797S mutations were identified in 2 cases and ERBB2 amplification was identified in 1 case. All these 3 cases developed resistance to EGFR tyrosine kinase inhibitors and showed expected results of their followed therapies. The median progression-free survival and median overall survival of patients treated with molecular targeted therapies were better than those of patients treated with chemoradiotherapy alone. CONCLUSIONS: Our findings revealed the specific genomic profiles of patients older than 55 years with lung carcinoma and suggested that these old patients have been benefit from the genetic detection, which helped identify druggable mutations and distinguish resistance mechanisms.

Different gene alterations in patients with non-small-cell lung cancer between the eastern and southern China.

Geographical differences are conspicuous in lung cancer, and the distinct molecular features of lung tumor between Western patients and Asian patients have been demonstrated. However, the etiology of non-small-cell lung cancer (NSCLC) and the distribution of associated molecular aberrations in China have not been fully elucidated. The mutational profiles of 12 lung cancer-related genes were investigated in 85 patients from eastern China and 88 patients from southern China who had been histologically confirmed NSCLC. Overall, 93.6% (162/173) of tumor samples harbored at least one somatic alteration. The most frequently mutated genes were TP53 (56.1%), EGFR (50.3%), and KRAS (14.5%). We found that EGFR mutated much more frequently (60.0% vs 40.9%, P = 0.012) and TP53 mutations had significantly lower incidence (47.1% vs 64.8%, P = 0.019) in eastern cohort than that in southern cohort. Mutational signature analysis revealed a region-related mutagenesis mechanism characterized by a high prevalence of C to T transitions mainly occurring at CpG dinucleotides in southern patients. This study reveals the difference in the mutational features between NSCLC patients in eastern and southern China. The distinct patterns of gene mutation could provide clues for the mechanism of carcinogenesis of lung cancer, offering opportunities to stratify patients into optimal treatment plans based on genomic profiles.

Combination therapy with afatinib and bevacizumab in an EGFR-mutated non-small cell lung cancer patient with acquired ERBB2 amplification: A case report.

INTRODUCTION: Acquired resistance to reversible EGFR tyrosine kinase inhibitors remains a significant obstacle, and acquired ERBB2 amplification is the most common "bypass" mechanism. For patients with sensitizing EGFR mutation who experience resistance via ERBB2 amplification, no targeted drug has been demonstrated to be effective. PATIENT CONCERNS: A 56-year-old female nonsmoker suffered from left leg paralysis and low back pain. Imaging examination revealed a mass in the anterior segment of the right upper lobe lung and possible multiple metastases in the right hilar, mediastinal lymph nodes, bone metastases, and soft tissue invasion. DIAGNOSIS: Transbronchial lung biopsy revealed a moderately differentiated adenocarcinoma (cT4N2M1c, stage IV). An EGFR exon 19 deletion was identified using amplification refractory mutation system. INTERVENTIONS: After the patient was treated with gefitinib initiation (250 mg/d) for 15 months, the tumor progressed with ERBB2 amplification revealed by next-generation sequencing test. Then, the patient was started on afatinib (40 mg/d) plus bevacizumab (7.5 mg/kg every 3 weeks). OUTCOMES: The combination therapy of afatinib and bevacizumab in this patient was effective with some slight side effects. Computed tomography scans showed the tumor shrinkage and the pleural effusion disappeared in the right lung. The overall survival was 23.5 months. CONCLUSION: To date, there is no targeted therapy approved and demonstrated to be effective for non-small cell lung cancer patients with EGFR sensitizing mutations, and ERBB2 amplification. The effectiveness of combination therapy with afatinib and bevacizumab may provide a new therapeutic option for these patients.

Novel TLR7 agonist stimulates activity of CIK/NK immunological effector cells to enhance antitumor cytotoxicity.

Toll-like receptor (TLR) 7/8 agonists have been applied in combination with chemo-, radio- or immunotherapy for lymphoma, and used as topical drugs for the treatment of viral skin lesions and skin tumors. In the present study, the role of an adenine analog, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine [termed Gao Dong (GD)], a novel TLR7 agonist, in the activation of cytokine-induced killer/natural killer (CIK/NK) cells was determined. The results of the present study indicated that GD was able to activate CIK/NK cells. The proportion of GD-induced CD3+CD56+ CIK and CD3-CD56+ NK cells was ~4% higher respectively compared with the control. Notably, combination therapy with CIK/NK cells stimulated by GD, markedly suppressed the proliferation of the chronic myelogenous leukemia K562 cell line. Following GD treatment, the cytotoxicity improved by ~25 and 21% when the effector/target ratio was 20:1 and 10:1, respectively. The results of the present study suggested a novel protocol for CIK/NK cell proliferation and revealed that GD may serve as a potent innate and adaptive immunomodulator in immunocyte culture.

Synergy of purine-scaffold TLR7 agonist with doxorubicin on systemic inhibition of lymphoma in mouse model.

Chemo- and radio-therapy suffer from certain well-recognized drawbacks for lymphoma therapy. Passive immunotherapy with monoclonal antibody has improved outcome for patients with CD20+ B cell lymphoma, but not for T cell lymphoma. Therefore, novel treatment approaches are clearly required for T cell lymphoma. To date, the combined application targeting TLR7, 8 and 9 has established long-term antitumor immunity. We previously synthesized a purine-scaffold TLR7 agonist named GD5. Here, we report that the intratumoral administration of GD5 combined with doxorubicin (DOX), a conventional chemotherapeutic agent in T cell lymphoma. This combined treatment made mice to produce more cytokines in blood, and generate more potent cytotoxic T lymphocyte response, then result in effective eradication of both local and distant tumors in tumor-bearing mice. Our findings demonstrate the potential for enhancing the efficacy of the current standard DOX therapy through combination with TLR7 agonist GD5 to improve antitumor immune responses and provide durable remissions for T cell lymphoma.

[Combined high dose leucovorin and 5-fluorouracil continuous infusion for head-neck and digestive tract cancers].

OBJECTIVE: To evaluate the feasibility of combined high dose leucovorin plus 5-fluorouracil infusion for head-neck and digestive tract cancers. METHODS: Fifty-six patients with head-neck and digestive tract cancer were treated by combined high dose leucovorin (HD-CF) plus 5-fluorouracil (5-Fu) 48 hour continuous infusion with each patient receiving an average of 3.8 cycles (2-6 cycles). Twenty-five of these 56 patients were untreated and 31 recurrent. Their clinical stages were II 4, III 13 and IV 39. RESULTS: The over all response rate (CR + PR) was 35.7% and the clinical beneficial response rate was 80.4%. The main side effects were peripheral phlebitis, suppression of bone marrow, oral ulcer, nausea and vomiting of grade I to II. CONCLUSION: High dose leucovorin plus 5-fluorouracil 48 hour continuous infusion is useful with favorable cost/utility ratio for head-neck and digestive tract cancer patients. Further studies are warranted.