Expression of estrogen receptor beta predicts a clinical response and longer progression-free survival after treatment with EGFR-TKI for adenocarcinoma of the lung

Purpose

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (EGFR-TKI) demonstrates a dramatic clinical response for the lung adenocarcinoma patients harboring a somatic mutation of EGFR. Such EGFR mutations are frequently found in adenocarcinoma with a strong expression of estrogen receptor (ER) beta, which has been shown to correlate with a favorable prognosis for the patients with EGFR mutations. The aim of this study is to elucidate the correlation between expression of ER beta and the therapeutic effect of EGFR-TKI in adenocarcinoma of the lung.

Patients and methods

Forty-three patients who were treated with EGFR-TKI for adenocarcinoma of the lung were evaluated. The expression of ER beta and the EGFR mutation were evaluated by immunohistochemistry and the polymerase chain reaction, respectively. Patients divided into two groups by the nuclear expression of ER beta. The clinical response and survival data were compared between the two groups.

Result

Strong (S) and weak (W) expression of ER beta was observed in 21 and 22 patients, respectively. EGFR mutations were detected in 30 (69.8%) cases. The S group had more frequent EGFR mutations than the W group (85.7%, 54.5%, p = 0.045). The S group had better response rate (p = 0.006) and longer progression-free survival (PFS; p = 0.001) than the W group. Even in a limited analysis in the patients with EGFR mutations, the S group had tended to have a better response rate (77.8%, 41.7%, p = 0.063), and significant longer PFS (p = 0.012) than the W group.

Conclusion

A strong expression of ER beta predicts a good clinical outcome for patients with adenocarcinoma of the lung after treatment with EGFR-TKI. This suggests that the expression status of ER beta can be a candidate surrogate marker for EGFR-TKI treatment of patients with adenocarcinoma of the lung. Further investigation will be necessary to identify biomarkers using a larger cohort of patients in a prospective study.     

Duration of prior gefitinib treatment predicts survival potential in patients with lung adenocarcinoma receiving subsequent erlotinib

Purpose

We investigated survival potential in patients receiving erlotinib after failure of gefitinib, focusing on response and time to progression (TTP) with gefitinib.

Methods

We retrospectively reviewed lung adenocarcinoma patients who received erlotinib after experiencing progression with gefitinib. Our primary objective was to evaluate the prognostic significance of erlotinib therapy.

Results

A total 42 lung adenocarcinoma patients were included in this study. Overall disease control rate was 59.5% (partial response [PR], 2.4%; stable disease [SD], 57.1%). Median overall survival was 7.1 months, and median progression-free survival was 3.4 months. The number of patients who achieved PR and non-PR (SD+ progressive disease [PD]) with gefitinib were 22 (52%) and 20 (48%), respectively. Patients with PR for gefitinib showed significantly longer survival times than those with non-PR (9.2 vs. 4.7 months; p = 0.014). In particular, among PR patients, those with TTP <12 months on gefitinib showed significantly longer survival times than those with TTP ≥12 months (10.3 vs. 6.4 months; p = 0.04).

Conclusions

Erlotinib may exert survival benefit for lung adenocarcinoma patients with less than 12 months of TTP of prior gefitinib who achieved PR for gefitinib.     

Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: A phase II trial

Purpose

We aimed to assess the safety and efficacy of preoperative intensity-modulated radiotherapy (IMRT) with oral capecitabine in patients with locally advanced mid-low rectal cancer using a concomitant boost technique.

Materials and methods

Patients with resectable locally advanced mid-low rectal cancer (node-negative ?T3 or any node-positive tumor) were eligible. The eligible patients received IMRT to 2 dose levels simultaneously (50.6 and 41.8 Gy in 22 fractions) with concurrent capecitabine 825 mg/m² twice daily 5 days/week. The primary end point included toxicity, postoperative complication, and pathological complete response rate (ypCR). The secondary endpoints included local recurrence rate, progression-free survival (PFS), and overall survival (OS).

Results

Sixty-three eligible patients were enrolled; five patients did not undergo surgery. Of the 58 patients evaluable for pathologic response, the ypCR rate was 31.0% (95% CI 19.1-42.9). Grade 3 toxicities included diarrhea (9.5%), radiation dermatitis (3.2%), and neutropenia (1.6%). There was no Grade 4 toxicity reported. Four (6.9%) patients developed postoperative complications. Two-year local recurrence rate, PFS, and OS were 5.7%, 90.5%, and 96.0%, respectively.

Conclusions

The design of preoperative concurrent boost IMRT with oral capecitabine could achieve high rate of ypCR with an acceptable toxicity profile.     

Factors associated with recurrence in patients with curatively resected stage I-II lung cancer

Background

Patients with stage I-II non-small cell lung cancer (NSCLC) show variability in recurrence after curative resection. Several factors have been proposed as prognostic of recurrence in previous studies. However, because of the heterogeneity of the populations studied, these reports did not yield consistent results. The aim of our study was to identify risk factors for recurrence in patients with curatively resected stage I-II NSCLC.

Methods

We reviewed the medical records of pathological stage I-II NSCLC patients after curative surgery performed in a tertiary referral center (Seoul National University Hospital) from January 2002 to December 2004. Demographic factors, radiological, histopathological, and laboratory findings, and surgery-related factors were analyzed. Patients with invasive cancer other than lung cancer that was present 5 years prior to surgery were excluded. The Cox proportional hazard regression model was used for multivariate analyses.

Results

Three hundred and ten patients were included. Among them, local recurrence occurred in 27 patients (8.7%), whereas distant recurrence occurred in 79 patients (25.5%). Adenocarcinoma histology (OR, 2.74; 95% CI, 1.14-6.58; P = 0.024), carcinoembryonic antigen (CEA) level > 2.3 ng/mL (OR, 2.26; 95% CI, 1.02-5.00; P = 0.045), and standard uptake values (SUV) of tumor in positron emission tomography (PET) > 4.5 (OR, 5.45; 95% CI, 1.82-16.31; P = 0.002) were independent predictors of recurrence in addition to TNM stage. We also constructed a recurrence prediction model based on these findings, which yielded better diagnostic performance than the TNM staging system.

Conclusion

Adenocarcinoma histology, CEA level, and SUV of PET could be considered as prognostic factors for recurrence in patients with curatively resected stage I-II NSCLC.     

A phase II trial of accelerated hypofractionated three-dimensional conformal radiation therapy in locally advanced non-small cell lung cancer

Purpose

The aim of this study is to evaluate the safety and efficacy of accelerated hypofractionated radiotherapy (HypoRT) combined with sequential chemotherapy in locally advanced non-small cell lung cancer (NSCLC).

Materials and methods

A total of 34 patients with stage III NSCLC were enrolled. All patients received accelerated HypoRT (initially 50 Gy/20 fractions, then a fraction dose of 3 Gy) using three-dimensional conformal radiation therapy (3D-CRT), omitting elective nodal irradiation (ENI), to a total dose of 65-68 Gy. All patients received two cycles of induction chemotherapy; 1-2 cycles of consolidation chemotherapy were given to 31 patients. The primary outcome measure was a profile of radiation toxicity. The secondary endpoints included overall survival (OS), progression-free survival (PFS), locoregional PFS (LR-PFS) and the pattern of initial failure.

Results

Radiation toxicity was minimal. The median and 3-year OS, PFS were 19.0 months, 32.1%; 10.0 months, 29.8%, respectively. The 1-, 2-, and 3-year LR-PFS were 69.6%, 60.9% and 60.9%, respectively. No patient experienced isolated elective nodal failure as the first site of failure.

Conclusion

This study suggests that accelerated HypoRT using 3D-CRT omitting ENI can be used in combination with sequential chemotherapy in locally advanced NSCLC.     

Stereotactic body radiation therapy for lung metastases

Introduction

Stereotactic body radiation therapy (SBRT) has an emerging role in patients affected with pulmonary metastases. Purpose of this study was to evaluate efficacy and tolerability of SBRT in a cohort of patients treated between 2003 and 2009 at our institution.

Methods

A total of 61 patients with oligometastatic lung tumors (single pulmonary nodules in 73.7%) were included in the study. SBRT was performed with a stereotactic body frame and a 3D-conformal technique. Fifty-one patients received 26 Gy in 1 fraction, 22 a dose of 45 Gy in 3 fractions and 3 a dose of 36 Gy in 4 fractions. Primary tumor was lung cancer in 45.7% of patients, colorectal cancer in 21.3% and a variety of other origins in 33%. The primary endpoint was local control, secondary endpoints were survival and toxicity.

Results

After a median follow-up interval of 20.4 months, local control rates at 2 and 3 years were 89% and 83.5%, overall survival 66.5% and 52.5%, cancer-specific survival 75.4% and 67%, progression-free survival 32.4% and 22.3%. Tumor volume was significantly associated to survival, with highest rates in patients with single small tumors. Median survival time was 42.8 months, while median progression-free survival time was 11.9 months. Toxicity profiles were good, with just one case of grade III toxicity (pneumonitis).

Conclusion

This study shows that SBRT is an effective and safe local treatment option for patients with lung metastases. Definitive results are strictly correlated to clinical selection of patients.     

Early pulmonary toxicity following lung stereotactic body radiation therapy delivered in consecutive daily fractions

Background and purpose

Identify the incidence of early pulmonary toxicity in a cohort of patients treated with lung stereotactic body radiation therapy (SBRT) on consecutive treatment days.

Material and methods

A total of 88 lesions in 84 patients were treated with SBRT in consecutive daily fractions (Fx) for medically inoperable non-small cell lung cancer or metastasis. The incidence of pneumonitis was evaluated and graded according to the NCI CTCAE v3.0.

Results

With a median follow-up of 15.8 months (range 2.5-28.6), the median age at SBRT was 71.8 years (range 23.8-87.8). 47 lesions were centrally located and 41 were peripheral. Most central lesions were treated with 48 Gy in 4 Fx, and most peripheral lesions with 54 Gy in 3 Fx. The incidence of grade ?2 pneumonitis was 12.5% in all patients treated, and 14.3% among the subset of patients treated with 54 Gy in 3 Fx. A total of two grade 3 toxicities were seen as one grade 5 toxicity in a patient treated for recurrence after pneumonectomy.

Conclusions

Treating both central and peripheral lung lesions with SBRT in consecutive daily fractions in this cohort was well tolerated and did not cause excessive early pulmonary toxicity.     

Stereotactic radiotherapy of histologically proven inoperable stage I non-small cell lung cancer: Patterns of failure

Background and purpose

To report patterns of failure of stereotactic body radiation therapy (SBRT) in inoperable patients with histologically confirmed stage I NSCLC.

Materials and methods

Ninety-two inoperable patients (median age: 75 years) with clinically staged, histologically proven T1 (n = 31) or T2 (n = 61), N0, M0 non-small cell lung cancer (NSCLC) were included in this study. Treatment consisted of 3-5 fractions with 7-15 Gy per fraction prescribed to the 60% isodose.

Results

Freedom from local recurrence at 1, 3 and 5 years was 89%, 83% and 83%, respectively. All 10 local failures were observed in patients with T2 tumors. Isolated regional recurrence was observed in 7.6%. The crude rate of distant progression was 20.7%. Overall survival at 1, 3, and 5 years was 79%, 38% and 17% with a median survival of 29 months. Disease specific survival at 1, 3, and 5 years was 93%, 64% and 48%. Karnofsky performance status, T stage, gross tumor volume and tumor location had no significant impact on overall and disease specific survival. SBRT was generally well tolerated and all patients completed therapy as planned.

Conclusion

SBRT for stage I lung cancer is very well tolerated in this patient cohort with significant cardiopulmonal comorbidity and results in excellent local control rates, although a considerable portion develops regional and distant metastases.     

Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations

Introduction

Erlotinib and gefitinib are tyrosine kinase (TK) inhibitors of epidermal growth factor receptor (EGFR) that are effective in treating non-small cell lung cancer (NSCLC). This study aimed to compare their clinical uses and the influence of EGFR mutation.

Methods

The usages of erlotinib and gefitinib in advanced NSCLC were analyzed. Clinical data and EGFR mutational status of tumors were collected.

Results

Seven hundred and sixteen (716) patients received gefitinib (n = 440) or erlotinib (n = 276) for stage IIIb or IV NSCLC. Erlotinib was prescribed more frequently than gefitinib in males (58.2% vs. 41.8%, p < 0.001), smokers (60.5% vs. 39.5%, p < 0.001), and non-adenocarcinoma (70.6% vs. 29.4%, p < 0.001). Of the 716 study patients, 327 underwent testing for EGFR mutations (170 with mutant EGFR and 157 with wild-type EGFR). Adenocarcinoma in patients with mutant EGFR and non-smoker status in patients with wild-type EGFR were associated with better overall survival after TK inhibitor treatment. In both patient groups with mutant EGFR or wild-type EGFR, the effectiveness of gefitinib and erlotinib, including drug response or overall survival, were not different.

Conclusions

Our study revealed the obvious disparity in drug selection between erlotinib and gefitinib in clinical practice. Type of TK inhibitors did not influence treatment outcomes in patients with EGFR mutation or wild-type EGFR.     

Apigenin affects leptin/leptin receptor pathway and induces cell apoptosis in lung adenocarcinoma cell line

Background

Apigenin, a common edible plant flavonoid, is a well characterised antioxidant. The adipokine leptin exerts proliferative and anti-apoptotic activities in a variety of cell types. In cancer cells, apigenin may induce a pro-apoptotic pathway whereas leptin has an anti-apoptotic role. The purpose of the study is to investigate the role of apigenin and of leptin/leptin receptor pathway on proliferation and on apoptosis in lung adenocarcinoma.

Methods

Immunocytochemistry, flow cytometry and RT-q-RT PCR, were used to investigate the expression and modulation of leptin receptors on the lung adenocarcinoma cell line A549 in presence or absence of apigenin and of leptin, alone or combined. Clonogenic test to evaluate cell proliferation was assessed. Exogenous leptin binding to its receptors by flow cytometry, reactive oxygen species (ROS) by dichlorofluorescein diacetate analysis, cell death by ethidium bromide and apoptosis by annexin V analysis were assessed. Apoptosis was assessed also in presence of lung adenocarcinoma pleural fluids (PF) (n = 6).

Results

A549 express leptin/leptin receptor pathway and its expression is upregulated by apigenin. Apigenin alone or combined with leptin significantly decreases cell proliferation and significantly increases the spontaneous release of ROS, with augmented cell death and apoptosis, this latter also in the presence of lung adenocarcinoma PF. Leptin alone significantly increases cell proliferation and significantly decreases cell death.

Conclusions

These results strongly suggest the potential utility of the flavonoid apigenin in the complementary therapeutic approach of patients with lung adenocarcinoma.     

Assessment of lung-cancer mortality reduction from CT Screening

Background

CT screening has been shown to increase lung cancer curability and we now assess the corresponding reduction in lung cancer mortality.

Methods

Lung-cancer mortality in a cohort of 7995 smokers who underwent CT screening for lung cancer in New York State (NYS) was compared with two unscreened cohorts (CPS-II and CARET). The standardized mortality ratio (SMR) of observed to expected lung cancer deaths for NYS was jointly adjusted for age, sex, and smoking history. As more current NYS smokers might have quit as a result of the screening, thus reducing deaths from lung cancer, another analysis was restricted to those participants smoking at entry and still smoking 6 years later.

Results

The SMR was 64/99.8 = 0.64 (P = 0.84 × 10⁻⁴) and 28/77.6 = 0.36 (P = 0.83 × 10⁻¹⁰), showing a significant reduction in deaths from lung cancer of 36% and 64% for CPS-II and CARET, respectively. Considering participants who were smoking at entry and still smoking 6 years later, the SMR using CPS-II rates was 29/49.1 = 0.59 (P = 0.001) and using CARET rates it was 21/57.4 = 0.37 (P = 0.31 × 10⁻⁷).

Conclusions

CT screening significantly reduces lung-cancer mortality.     

Adjuvant chemoradiotherapy with or without intraoperative radiotherapy for the treatment of resectable locally advanced gastric adenocarcinoma

Purpose

To document the long-term efficacy of intraoperative electron radiotherapy (IOERT) followed by concurrent chemotherapy and external-beam radiotherapy (EBRT) in the management of locally advanced gastric cancer.

Materials and methods

A total of 97 consecutive patients with T3/4 or N+ gastric adenocarcinoma were enrolled. Fifty-one patients received adjuvant chemoradiotherapy (EBRT group) and 46 received IOERT (dose range, 12-15 Gy) followed by chemoradiotherapy (EBRT + IOERT group).

Results

The 5-year locoregional control rates were 50% and 35% in the two groups with or without IOERT, respectively (p = 0.04). Two patients had recurrence within the IOERT field in the EBRT + IOERT group and 14 patients recurred in the same area in the EBRT group (p = 0.02). Multivariate analyses revealed that adjuvant IOERT was an independent prognosticator for both local-regional control (p = 0.02) and disease-free survival (p = 0.05). G3/4 late toxicity was observed in 5 patients in the EBRT + IOERT group, but none in the EBRT group (p = 0.02).

Conclusions

Higher radiation dose may contribute to the improvement of local control, especially in the field encompassed by IOERT. The addition of IOERT to surgery and adjuvant chemoradiation deserves further investigation in a randomized trial.     

Promoter methylation of BRMS1 correlates with smoking history and poor survival in non-small cell lung cancer patients

Purpose

To investigate whether methylation of BRMS1 is associated with clinical outcomes in patients with NSCLC.

Methods

Methylation status of BRMS1 was examined in 325 NSCLC patients who were treated with surgery. We analyzed associations between the methylation of BRMS1 genes separately and available epidemiologic and clinical information including smoking status, gender, age, and histological type, or the stage of the tumor.

Results

In the cohort of 325 NSCLC cases, 152 samples were identified as methylated (46.77%). Promoter methylation of BRMS1 was present only in 6 specimens (8.42%) in adjacent non-cancerous tissues (P = 2.257 × 10⁻¹⁴). Patient smoking history had a positive correlation with methylation rate of BRMS1 (OR = 2.508, 95%CI(1.516, 4.151)). Compared with unmethylated group, methylated group showed the lower level of BRMS1 mRNA (P = 0.013). And patients with a high level of BRMS1 mRNA expression had significantly better overall survival than those with low expression (P = 0.002). Multivariate Cox proportional hazard regression analysis also showed that promoter methylation of BRMS1 was significantly unfavorable prognostic factors (hazard ratio, 1.912; 95% CI, and 1.341-2.726).

Conclusions

These results provide clinical evidence to support the notion that BRMS1 is a NSCLC metastasis suppressor gene. Measuring methylation status of BRMS1 promotor is a useful marker for identifying NSCLC patients with worse disease-free survival.     

Impact of smoking on the expression of claudins in lung carcinoma

Rationale

Tight junctions regulate the paracellular permeability and orientation of cells and claudins are key components of tight junctions.

Objectives

To study the influence of cigarette smoke on claudin expression in vitro and in lung cancer patients.

Methods

We studied the effect of smoking on claudin expression by exposing a bronchial cell line (BEAS-2B) and two carcinoma cell lines (SK-LU1 and SK-MES1) to tobacco smoke for 48 h and analysed their claudin mRNA expression. The relation between smoked pack years and protein expression of claudins 1-5 and 7 in 344 lung cancer patients was determined by immunohistochemistry.

Measurements and main results

In BEAS-2B cells and SK-LU1 cells, an initial increase was followed by a decline in the mRNA expression of several claudins. In SK-MES1 cells, no evident elevation in claudin expression was observed.Intense claudin 1 and 4 positivity was found more often in cancer samples of smokers and ex-smokers compared to non-smokers (p < 0.001 and p = 0.003, respectively). Heavy smokers with longer than 40 pack-years consumption had more often intense claudin 1 (p = 0.011), 4 (p = 0.050) or 7 (p = 0.058) expression in squamous cell carcinoma compared to non-smokers or smokers with fewer pack-years. Claudin 1 positivity predicted a better survival in adenocarcinoma (p = 0.044) and in squamous cell carcinoma (p = 0.027) and claudin 4 positivity in adenocarcinoma only (p = 0.048). In squamous cell carcinoma, claudin 7 positivity was associated with a better survival (p = 0.011).

Conclusions

Bronchial BEAS-2B cells and SK-LU1 cells respond to tobacco smoke by changing their claudin mRNA synthesis and resulting tight junction permeability changes may thus contribute to tobacco induced carcinogenesis both during initiation and progression. This concept is strengthened by findings in the clinical tumour material, where tobacco consumption was associated with claudin expression.     

Curative chemoradiotherapy for isolated retroperitoneal lymph node recurrence of colorectal cancer

Purpose

To investigate the efficacy of curative chemoradiotherapy for isolated retroperitoneal lymph node recurrence of colorectal cancer.

Materials and methods

Twenty-two colorectal cancer patients who received three-dimensional conformal radiotherapy (n = 20) or helical tomotherapy (n = 2) for isolated retroperitoneal lymph node recurrence were analyzed retrospectively. Radiation dose was 55.8 Gy in 31 fractions or 63 Gy in 35 fractions, and 60 Gy in 20 fractions by helical tomotherapy. All patients received concurrent chemotherapy and 16 (72.7%) received adjuvant chemotherapy.

Results

The treatment response was complete in 13 (59.1%), partial in 6 (27.3%), and stable in 3 (13.6%) patients. Median follow-up for 11 (50%) surviving patients was 32 months (range, 27-61). The 3- and 5-year overall survival rates were 64.7% and 36.4%, and median overall survival was 41 months. Recurrences developed in 15 (68.2%) patients; outside the retroperitoneum in 13. The 3- and 5-year recurrence-free survival rates were 34.1% and 25.6%, and median recurrence-free survival was 20 months. Response and adjuvant chemotherapy were significant prognostic factors for overall survival. Gastrointestinal toxicity ? Grade 3 was not observed.

Conclusions

Definitive chemoradiotherapy is an effective salvage treatment for isolated retroperitoneal lymph node recurrence of colorectal cancer without severe complications.     

Positive urinary cytology in patients with lung cancer in the absence of obvious urine tract metastases

Purpose

To study the phenomenon of positive urine cytology in patients with lung cancer in the absence of obvious urothelial metastases.

Patients and methods

150 patients with small (SCLC) and non-small cell lung cancer (NSCLC) of all stages and 3 control groups were prospectively studied. Immunocytochemical study (cytokeratins 7-20, TTF1) in all positive urine specimens and chemokine profile (CXCR4, CCL21) study of the primary tumor in selected positive patients was performed. In experimental study, C57Bl/6 BALB/C mice injected with LLC lung and 4T1 mammary cancer cells were used for the detection of positive urine cytology.

Results

11% of patients with NSCLC, 7% of patients with SCLC and none of the control group had positive urine cytology. In NSCLC, metastatic disease and high tumor burden positively correlated (p = 0.01 and 0.03 respectively) with the phenomenon. In SCLC, correlation with extensive disease and multiple metastatic sites (p = 0.02 and 0.04 respectively) was found. No correlation was found in either group with: age, gender, histology, performance status, line of chemotherapy, previous platinum-based chemotherapy, adrenal metastases, renal function, abnormal urinary sediment, response to chemotherapy and overall survival (p = 0.9). Distinctive chemokine expression was identified in positive patients studied and was not observed in negative patients (×2 p = 0.008). In the experimental study, only the LLC lung cancer cells were detected in the urine cytology of mice.

Conclusion

This phenomenon, carrying undefined pathophysiological mechanisms, seems to characterize only patients with metastatic/extensive disease and high tumor burden. Further studies are needed to validate our preliminary chemokine expression results.     

Post-operative radiotherapy in N2 non-small cell lung cancer: A retrospective analysis of 175 patients

Background and purpose

Post-operative radiotherapy (PORT) in radically resected non-small cell lung cancer (NSCLC) has the aim to reduce loco regional recurrence and to improve overall survival. PORT has been evaluated in several trials but indication to post-operative treatment in N2 patients is still debated.

Material and methods

We retrospectively analyzed 175 patients treated at University of Florence between 1988 and 2004 with completely resected NSCLC stages IIIA-IIIB, N2 disease. Surgery consisted in a lobectomy in 58.9% and in a bi-lobectomy or in a pneumonectomy in 41.1% of patients. One hundred and nineteen patients underwent PORT and 56 patients did not receive PORT (no-PORT).

Results

At a median follow-up of 27.6 months (range 4-233 months), we found a significant reduction in local recurrence (LR) in PORT group (log-rank test p = 0.015; HR: 0.45; 95%CI: 0.24-0.87). No statistical difference were found in terms of overall survival (OS) (log-rank test p = 0.92). Concerning other prognostic factors, male sex emerged as statistically significant (HR:4.33;1.04-18.02) on local progression free survival (LPFS) at univariate analysis. Acute and long-term toxicity was mild.

Conclusion

Our retrospective analysis showed that PORT may improve local disease control in N2 NSCLC patients with an acceptable treatment-related toxicity.     

Loss of lamin A/C expression in stage II and III colon cancer is associated with disease recurrence

Aim of the study

Loss of the nuclear lamina protein lamin A/C (LMNA) has been observed in several human malignancies. The present study aimed to investigate associations between LMNA expression and clinical outcome in colon cancer patients.

Patients and methods

Clinicopathological data and formalin-fixed paraffin embedded tissues were collected from 370 stage II and III colon cancer patients. Tissue microarrays were constructed, stained for lamin A/C and evaluated microscopically. Microsatellite instability status was determined for 318 tumours.

Results

Low levels of LMNA expression were observed in 17.8% of colon tumours, with disease recurrence occurring in 45.5% of stage II and III colon cancer patients with LMNA-low expressing tumours compared to 29.6% of patients with LMNA-high expressing tumours (p = 0.01). For stage II patients, disease recurrence was observed for 35.7% of LMNA-low compared to 20.3% of LMNA-high expressing tumours (p = 0.03). Microsatellite stable (MSS) tumours exhibited more frequently low LMNA expression than microsatellite instable (MSI) tumours (21% versus 9.8%; p = 0.05). Interestingly, disease recurrence among LMNA-low and LMNA-high expressing MSS tumours varied significantly for stage III patients who had not received adjuvant chemotherapy (100% versus 37.8%; p < 0.01) while no such difference was observed for patients who received adjuvant chemotherapy (46.7% versus 46.0%; p = 0.96).

Conclusion

These data indicate that low expression of LMNA is associated with an increased disease recurrence in stage II and III colon cancer patients, and suggest that these patients in particular may benefit from adjuvant chemotherapy.     

Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma

Background

Individualized treatment is an attractive challenge that may allow for more effective and safer treatment of human disease. Activating mutations in the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma are associated with a dramatic clinical response to EGFR-tyrosine kinase inhibitors (TKIs). However, patients often experience a relapse after treatment with EGFR-TKIs, even when the tumors are initially highly sensitive. However, the “whole picture” regarding acquired resistance remains unclear.

Methods

Tumor specimens were collected from 11 lung adenocarcinoma patients before and after treatment with gefitinib. The status of the EGFR and K-ras genes were investigated by PCR-based analyses. Immunohistochemistry and real-time PCR assays were used to evaluate the MET gene in terms of its tyrosine phosphorylation and amplification, respectively. The expression of HGF, PTEN, and EGR-1, and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E-cadherin and gamma-catenin as epithelial markers, and vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry.

Results

Seven (64%) of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type K-ras gene expression. No MET amplification was detected in any of the samples, nor was there phosphorylation of MET detected in any of the resistant samples. Neither MET gene amplification, nor the overexpression of HGF was observed in samples without the T790M mutation. A strong expression of HGF was detected in 6 of 8 specimens with the T790M mutation. Three (38%) of 8 cases showed a loss of PTEN in samples with the T790M mutation. A loss of EGR-1 was detected in 2 (29%) of 7 cases, including one tumor without PTEN. Four (57%) of 7 cases showed positive expression of phosphorylated Akt (p-Akt). A change in the EMT status between pre-and post-treatment was observed in 4 (44%) of 9 cases. In all examined samples cases, some alterations of gene or proteins were observed.

Conclusions

The current results showed that these alterations in gene or protein expression can account for all resistant mechanisms. This phenomenon suggests the existence of complicated relationships among acquired resistance-related genes.