Metastasis Dynamics for Non–Small-Cell Lung Cancer: Effect of Patient and Tumor-Related Factors

BackgroundWe studied event dynamics (probability of an event occurring over a specific time interval) in patients undergoing surgery for early-stage non–small-cell lung cancer (NSCLC) according to patient and tumor characteristics.MethodsBy using a database of 1506 patients who underwent initial surgery for NSCLC, event dynamics, based on a time-specific hazard rate, were evaluated. The event of interest was the development of distant metastases, with or without a local recurrence. The effect of sex, tumor size, nodal involvement, histology, lymphovascular space invasion, pleural invasion, age, and race were studied.ResultsThe hazard rate for developing distant metastases was not constant over time but was characterized by specific peaks, the first being approximately 9 months after surgery and the second at 18 to 20 months for men and 24 to 26 months for women. For women, the hazard rate peaked considerably in the first year. For men, the hazard rate peaks were smaller but lasted for a longer duration. Pathologic factors associated with a higher risk of recurrence (eg, size, lymph node involvement, pleural invasion) all increased the sex-specific hazard rates.ConclusionsThe probability of developing distant metastases after surgery for NSCLC peaks at specific and consistent time intervals after surgery, with specific differences between men and women. A factor-specific modulation of peak heights that ranged from no impact (eg, race) to relevant effects for primary tumor size, nodal involvement, and pleural invasion, possibly related to sex, was also observed. The bimodal distant metastases dynamics may be an intrinsic feature of metastatic progression in NSCLC.     

Establishment of a Conditional Transgenic Mouse Model Recapitulating EML4-ALK–Positive Human Non–Small Cell Lung Cancer

BackgroundAnaplastic lymphoma receptor tyrosine kinase gene (ALK) fusion is a distinct molecular subclassification of NSCLC that is targeted by anaplastic lymphoma kinase (ALK) inhibitors. We established a transgenic mouse model that expresses tumors highly resembling human NSCLC harboring echinoderm microtubule associated protein like 4 gene (EML)-ALK fusion. We aimed to test an EML4-ALK transgenic mouse model as a platform for assessing the efficacy of ALK inhibitors and examining mechanisms of acquired resistance to ALK inhibitors.MethodsTransgenic mouse lines harboring LoxP-STOP-LoxP-FLAGS–tagged human EML4-ALK (variant 1) transgene was established by using C57BL/6N mice. The transgenic mouse model with highly lung-specific, inducible expression of echinoderm microtubule associated protein like 4–ALK fusion protein was established by crossing the EML4-ALK transgenic mice with mice expressing Cre–estrogen receptor fusion protein under the control of surfactant protein C gene (SPC). Expression of EML4-ALK transgene was induced by intraperitoneally injecting mice with tamoxifen. When the lung tumor of the mice treated with the ALK inhibitor crizotinib for 2 weeks was measured, tumor shrinkage was observed.ResultsEML4-ALK tumor developed after 1 week of tamoxifen treatment. Echinoderm microtubule associated protein like 4–ALK was strongly expressed in the lung but not in other organs. ALK and FLAGS expressions were observed by immunohistochemistry. Treatment of EML4-ALK tumor–bearing mice with crizotinib for 2 weeks induced dramatic shrinkage of tumors with no signs of toxicity. Furthermore, prolonged treatment with crizotinib led to acquired resistance in tumors, resulting in regrowth and disease progression. The resistant tumor nodules revealed acquired ALK G1202R mutations.ConclusionsAn EML4-ALK transgenic mouse model for study of drug resistance was successfully established with short duration of tumorigenesis. This model should be a strong preclinical model for testing efficacy of ALK TKIs, providing a useful tool for investigating the mechanisms of acquired resistance and pursuing novel treatment strategies in ALK-positive lung cancer.     

Molecular Mechanisms of Cancer Invasion and Metastasis

Metastasizing cancer cells can invade the extracellular matrix using surface motor organelles,termed invadopodia that contact and dissolvethe matrix.Various membrane-bound proteases and their associated proteins such as integrins localized on the invadopodial membranes are re-sponsible for the extracellular matrix degradation and cell invasion,A control mechanism of cancer invasion and metastasis may involve the for-mation of such invadopodial protease assembly(IPA),induction of IPA,and the regulation of invasion by a novel immune complex in senum.     

Strategies to Prevent Brain Metastasis in High-Risk Non–Small-Cell Lung Cancer: Lessons Learned From a Randomized Study of Maintenance Temozolomide Versus Observation

BackgroundThis study investigated whether maintenance temozolomide (TMZ) after definitive therapy for locally advanced non–small-cell lung cancer (NSCLC) could decrease the incidence of brain metastasis (BM).Patients and MethodsEligible patients included those with stage IIIA, IIIB, or IV (for stage IV, only with malignant pleural/pericardial effusion) NSCLC with no BM at diagnosis and stable disease, partial response, or complete response after first-line chemotherapy using at least 2 agents. Patients were randomized to observation or TMZ (75 mg/m² for 21 consecutive days followed by a 7-day rest for up to 6 cycles or progression). The primary end point was incidence of radiographically diagnosed BM within 12 months from day 1 of first-line chemotherapy. Secondary end points included overall survival (OS), time to progression, incidence of BM at first progression, and toxicity.ResultsThe study was closed early on the basis of a futility analysis; 45 of 53 enrolled patients were evaluable from an original target of 100. No difference was noted in the incidence of BM at 1 year in the TMZ and observation groups (18% and 13%, respectively), in median time to progression (11.7 and 10.7 months, respectively), or in median OS (27.1 and 22.5 months, respectively). Common Terminology Criteria for Adverse Events grade 3 or 4 adverse events were 46% in the TMZ group and 19% in the observation group.ConclusionsTMZ monotherapy does not appear to decrease the incidence of BM in patients with locally advanced NSCLC. These results considered in the context of the existing literature have implications for future clinical trial design.     

The Analysis of High-Risk Molecular Markers for Cervical Cancer Patients under Thirty-Five

OBJECTIVE To explore molecular markers for cervical cancer in female patients below thirty-five years of age, so that the markers may be used to formulate a prognosis and to provide some useful targets for improving therapy. METHODS Pathological data were collected from 64 cervical cancer patients under the age of 35 from June, 1995 to June, 2000 in our institution. The data were retrospectively analyzed as a study group, and compared to data obtained from 90 cervical cancer cases over the age of 35 as controls who underwent treatment during the same time period. Immuno-histochemical and quantified image analyses were conducted to look for differences between the two groups in expression of survivin, p27, CD44v6, MMP-2 and TIMP-2. RESULTS The overall 5-year survival rate (65.6%) of the study group was significantly lower (P<0.05) compared to the control group (84.4%). The expression of survivin, MMP -2 and CD44v6 was much higher in the younger study group compared to the older control group, but TIMP-2 displayed higher expression in the control group (P<0.05). There was no significant difference in p27 expression between the two groups (P>0.05). CONCLUSION Young women patients with cervical cancer have a poorer prognosis compared to old women. Our study reveals that survivin, MMP-2, TIMP-2 and CD44v6 expression have a correlation with shorter 5-year survival. Improvement in the prognosis for young cervical cancer patients can be expected using biomedical therapy which targets these molecular markers.     

Clinical Experience of Lobectomy With Pulmonary Artery Reconstruction for Central Non–Small-Cell Lung Cancer

BackgroundIn patients with central lung cancer, lobectomy can be achieved without pneumonectomy by surgical reconstruction of the pulmonary artery (PA). Herein, we report our clinical experience of 34 patients who had lobectomy with PA reconstruction, including perioperative administration, morbidity, mortality, and long-term survival.Patients and MethodsThe clinical records of 34 patients who received lobectomy with PA reconstruction in our department between August 2003 and September 2005 were reviewed.ResultsIn our series, PA reconstruction with end-to-end anastomosis was performed in 18 patients (52.9%). Seven patients (20.6%) required partial PA reconstruction with autologous pericardium patch. Five patients (14.7%) with a lower lobe tumor required PA reconstruction with artery flap. The perioperative mortality was 2.9%, and 1 patient died on postoperative day 13 because of severe bronchopleural fistula. Another 2 patients had acute respiratory distress syndrome (ARDS) and required reintubation in our Intensive Care Unit. The overall Kaplan-Meier 3-year and 5-year survival rates were 46% and 37%, respectively. As compared with the stage III patients, stage I patients had significantly greater 5-year survival (80% vs. 11%; P = .005). Patients with pN0 disease also had greater 5-year survival than patients with pN2-3 disease (71% vs. 9%; P = .004).ConclusionIn our department, PA reconstruction has been more frequently and actively performed for patients with central lung cancer, especially for some patients with a lower lobe tumor. Although the morbidity and mortality is acceptable, surgeons should be more attentive to lethal postoperative complications such as ARDS induced by lung ischemia-reperfusion injury.     

Molecular Adequacy of Image-Guided Rebiopsies for Molecular Retesting in Advanced Non–Small Cell Lung Cancer: A Single-Center Experience

Introduction

In the era of biomarker-driven systemic therapy for advanced NSCLC, the role of routine repeated biopsies for decision making outside EGFR-mutant disease remains unproven. We report our center’s experience of safety and adequacy for molecular retesting of tumor material obtained from image-guided lung rebiopsies in NSCLC.

Non–small-cell Lung Cancer With Brain Metastasis at Presentation

Background

Data on the prevalence of brain metastases at presentation in patients with non–small-cell lung cancer (NSCLC) are limited. We queried the National Cancer Data Base to determine prevalence, clinical risk factors, and outcomes of patients with NSCLC presenting with brain metastases.

Incorporation of a Molecular Prognostic Classifier Improves Conventional Non–Small Cell Lung Cancer Staging

IntroductionDespite adoption of molecular biomarkers in the management of NSCLC, the recently adopted eighth edition of the TNM staging system utilized only clinicopathologic characteristics and validated improvement in risk stratification of early-stage disease has remained elusive. We therefore evaluated the integration of a clinically validated molecular prognostic classifier into conventional staging.MethodsA novel staging system, the TNMB (with the B denoting biology) system, which integrates a 14-gene molecular prognostic classifier into the eighth edition of the TNM staging system, was developed by using data from 321 patients with NSCLC at the University of California, San Francisco. The TNMB staging system was subsequently validated in an independent, multicenter cohort of 1373 patients, and its implementation was compared with adoption of the seventh and eighth edition staging systems utilizing metrics of reclassification.ResultsCompared with staging according to the eighth edition of the TNM system, the TNMB staging system enhanced the identification of high-risk patients, with a net reclassification improvement of 0.33 (95% confidence interval [CI]: 0.24–0.41). It better predicted differences in survival, with a relative integrated discrimination improvement of 22.1% (95% CI: 8.8%–35.3%), and it improved agreement between observed and predicted survival, with a decrease in the reclassification calibration statistic of from 39 to 21. The seventh and eighth editions failed to change the net reclassification improvement (0.01 [95% CI: –0.04 to 0.03] and 0.03 [95% CI: 0.00 to 0.06], respectively) or relative integrated discrimination improvement (2.1% [95% CI: –5.8 to 9.9] and –2.5% [95% CI: –17.6 to 12.4], respectively); in addition, the eighth edition worsened calibration, with an increase in the reclassification calibration statistic from 23 to 25.ConclusionsIncorporation of a molecular prognostic classifier significantly improved identification of high-risk patients and survival predictions compared with when conventional staging is used. The TNMB staging system may lead to improved survival of early-stage disease through more effective application of adjuvant therapy.     

Close Margins After Transoral Robotic Surgery for Human Papillomavirus–Positive Oropharyngeal Carcinoma: A Review of the Literature and Practical Recommendations

The purpose of this article is to summarize the literature and practical recommendations from experienced centers for close margins after transoral robotic surgery for human papillomavirus–positive oropharyngeal carcinoma.