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Personalized peptide vaccination in patients with refractory non-small cell lung cancer.

Since the prognosis of non-small cell lung cancer (NSCLC) remains poor, the development of novel therapeutic approaches, including cancer vaccines, is highly desirable. In the current study, we conducted a phase II study of personalized peptide vaccination (PPV), in which a maximum of 4 peptides were selected based on pre-existing humoral immune responses and administered subcutaneously (weekly for 6 consecutive weeks and bi-weekly thereafter) in refractory NSCLC patients.

Forty-one refractory NSCLC patients (4 stage IIIb, 22 stage IV and 15 recurrent), who had failed to respond to chemotherapy and/or targeted therapy (median number of regimens, 3; median duration, 10 months), were enrolled. Median overall survival (OS) was 304 days with a one-year survival rate of 42% in the enrolled patients. The main toxicity of PPV was skin reactions at the injection sites, but no serious adverse events were observed. In order to identify potential biomarkers for predicting OS, pre-vaccination and post-vaccination clinical findings and laboratory data were retrospectively assessed and evaluated by multivariate Cox regression analysis.

Among the pre-vaccination factors examined, high C-reactive protein (CRP) level was a significant predictor of unfavorable OS [hazard ratio (HR)=10.115, 95% confidence interval (CI)=2.447-41.806, P=0.001]. Among the post-vaccination factors, high CRP level and low frequency of CD3+CD26+ cells were significant predictors of unfavorable OS (HR=23.127, 95% CI=2.919-183.233, P=0.003; HR=0.952, 95% CI=0.917-0.989, P=0.012). Taken together, our results suggest the feasibility of PPV for the treatment of refractory NSCLC.

Evaluation of the identified factors before or at an early stage of vaccination could be potentially useful for selecting NSCLC patients who would likely have better prognosis following PPV

microRNAs as tumor inhibitors, oncogenes, biomarkers for drug efficacy and outcome predictors in lung cancer (Review).

Lung cancer remains the leading cause of cancer-related death worldwide for both men and women, and non-small cell lung cancer (NSCLC) accounts for approximately 80% of all cases. Despite improvements in early diagnosis and newly developed therapies, the 5-year survival rate for NSCLC patients remains low (15%).

Therapy in NSCLC has reached a plateau. Understanding genomic medicine may provide insight into the oncogenesis of lung cancer and open the door to molecular diagnosis, new biomarkers and a more accurate prognosis of lung cancer. It is well known that almost half of the genes regulated by microRNAs (miRNAs) are located in cancer-associated genomic regions.

In the present study, we discuss the potential of miRNAs to function as suppressors and biomarkers for chemoresistance and prognosis of lung cancer.

Factors affecting survival time after recurrence of non-small-cell lung cancer treated with concurrent chemoradiotherapy.

Dose-fractionation schedules of palliative or salvage radiotherapy (RT) for recurrence of non-small-cell lung cancer (NSCLC) are various because they highly depend on patient prognosis. For optimal selection of dose-fractionation schedules, factors affecting survival time after recurrence were examined.

MATERIALS AND METHODS: From 1992 to 2005, 115 patients with stage III NSCLC received curative-intent concurrent chemoradiotherapy (CCRT). Among these patients, 74 underwent recurrence and were reviewed. Evaluated factors were age at recurrence, gender, initial stage, histological subtype, initial radiation-field size, recurrent patterns (locoregional alone vs. distant ± locoregional), time to recurrence (≤6 vs. >6 months), and treatment for recurrence (chemotherapy, RT).

RESULTS: Median follow-up time after recurrence was 7 (range 0-59) months. One- and 2-year overall survival rates after recurrence were 28 and 11%, respectively. Based on multivariate analysis, time to recurrence (p = 0.0001) and administration of chemotherapy for recurrence (p = 0.0190) were the independently significant factors.

CONCLUSIONS: Early recurrence was the most significant factor for survival after post-CCRT recurrence of NSCLC. Administration of chemotherapy for recurrence was also a significant factor, whereas RT for recurrence was not significant. When RT was given to patients with post-CCRT recurrence of NSCLC, dose-fractionated schedules should be determined considering these factors.

Cytoplasmic estrogen receptor β as a potential marker in human non-small cell lung carcinoma.

Estrogen has been reported to promote an increased susceptibility to lung cancer development.

This study focusses on the role of cytoplasmic estrogen receptor β (c-ERβ) in NSCLC. Methods: NSCLC (n = 162) cases were analyzed using immunohistochemistry (IHC) for c-ERβ expression and its association with clinicopathological variables. Significance of c-ERβ expression was further examined using in vitro studies in NSCLC cell lines.

Results: Among ERβ and aromatase positive NSCLC females, c-ERβ was significantly associated with greater tumor diameter and tended to be associated with worse overall survival. A549 and LCAM1 cells expressed aromatase, as well as c-ERβ and nuclear ERβ (n-ERβ). U0126 (MAPK/extracellular-signal-regulated kinase (ERK) inhibitor) abrogated MAPK phosphorylation, caused by estradiol via c-ERβ, more effectively than ICI 182780 (ER blocker) in either cell line. However, ICI 182780 completely abrogated the estrogen responsive elements (ERE)-luciferase activity caused by estradiol. Combination therapy with ICI 182780 and U0126 turned out to be far more effective than either treatment alone in either A549 or LCAM1 cells.

Conclusion: The results indicated that ERβ may contribute to NSCLC via non-genomic action of estrogen through its cytoplasmic form, in addition to the genomic actions via n-ERβ. These actions of estrogen in NSCLCs may be abrogated by combination therapy with ICI 182780 and U0126.

Crizotinib: a drug that crystallizes a unique molecular subset of non-small-cell lung cancer.

CrizotinibCrizotinib (Pfizer, CA, USA) is an oral small-molecule RTK inhibitor that targets ALK and MET, and potentially other RTKs. Crizotinib was approved by the US FDA on 26 August 2011 for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), as detected by ALK break-apart FISH assay. This conditional approval was based on response rates of 50-61% from 255 ALK-rearranged NSCLC patients enrolled in two ongoing single-arm crizotinib trials.

Side effects of crizotinib mostly consist of grade 1-2 gastrointestinal events (nausea, vomiting, diarrhea and constipation), grade 1-2 edema and fatigue, grade 1 visual disorders, rare cases of elevated liver enzymes and pneumonitis (1.6%). Confirmatory trials comparing crizotinib to standard chemotherapy in upfront (ClinicalTrials.gov identifier: NCT01154140) and salvage (ClinicalTrials.gov identifier: NCT00932451) treatment settings of ALK-rearranged NSCLC are ongoing.

It took an unprecedented rapid 4 years from the publication of the discovery of ALK-rearranged NSCLC in August 2007 to the conditional approval of crizotinib in August 2011.

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