Sequential ALK inhibitor treatment benefits patient with leptomeningeal metastasis harboring non-EML4-ALK rearrangements detected from cerebrospinal fluid: A case report.

A 47-year-old female with ALK-rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first-line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non-EML4-ALK rearrangements, LOC388942-ALK and LINC00211-ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re-escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The LINC00211-ALK fusion, which retains the ALK kinase domain, detected from the CSF was the mechanism of treatment efficacy in this patient. The central nervous system (CNS) has been increasingly recognized as a site of treatment failure in multiple cancers, including non-small cell lung cancer (NSCLC). Our case demonstrated that alectinib dose-escalation and lorlatinib overcame ALK inhibitor resistance in the CNS in an ALK-positive LM patient. Furthermore, we provide the first clinical evidence of the efficacy of sequential ALK inhibitors in targeting LINC00211-ALK in a patient with LM.

Comparison of Clinicopathological Features and Prognosis between ALK Rearrangements and EGFR Mutations in Surgically Resected Early-stage Lung Adenocarcinoma.

BACKGROUND: A number of mutations in key oncogenes have been identified as important for the initiation and maintenance of lung adenocarcinoma (LAC). This study elucidated the prevalence and prognostic significance of mutations in the epidermal growth factor receptor gene (EGFR) and rearrangements in the anaplastic lymphoma kinase gene (ALK) in patients with surgically resected primary LAC. PATIENTS AND METHODS: We retrospectively analyzed 675 consecutive patients who underwent radical resection at a single institution. We concurrently analyzed mutations in EGFR and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) by reverse transcription (RT)-PCR, and investigated ALK rearrangements by immunohistochemistry. LAC with or without various oncogenic mutations was studied for clinicopathological features and their association with disease-free survival (DFS) and overall survival (OS). RESULT: ALK rearrangements and EGFR mutations were detected in 75 and 312 patients, respectively, with coexistence in 5 cases. ALK rearrangements and mutations in EGFR and KRAS were mutually exclusive. Compared with patients with EGFR mutations, ALK rearrangements were more common in younger patients, and those with advanced tumors, lymph node metastases, and higher rates of postoperative adjuvant therapy. Histologically, EGFR mutations were more common than ALK rearrangements in patients with the acinar predominant subtype and the lepidic predominant subtype of LAC, whereas ALK rearrangements were more frequent in the solid predominant subtype with mucin production and invasive mucinous adenocarcinomas. ALK-positive patients had a significantly worse DFS than those with EGFR mutations and wild-type (WT) patients. The mean OS after surgical procedures was significantly longer in EGFR-mutated versus WT patients. No significant differences were found in patients with ALK-positive tumors compared with EGFR-mutated and WT patients. CONCLUSION: Clinicopathological features of LAC with ALK rearrangements differ from those of LAC with EGFR mutations. Patients with ALK rearrangements had a significantly worse DFS than those harboring EGFR mutations. Thus, ALK rearrangements are an adverse prognostic factor in surgically-resected LAC patients, while EGFR mutations are associated with a better prognosis.

Worse disease-free, tumor-specific, and overall survival in surgically-resected lung adenocarcinoma patients with ALK rearrangement.

INTRODUCTION: This study determined the prevalence of anaplastic lymphoma kinase (ALK) rearrangement, and identified the associations of ALK rearrangement with clinicopathologic characteristics and treatment outcomes in patients with surgically-resected stage I-III lung adenocarcinoma. METHODS: A total of 534 surgically-resected lung adenocarcinoma patients were studied. The prevalence of ALK protein over-expression was determined by a fully-automated immunochemistry assay (with mouse monoclonal Ventana D5F3 antibody), and the associations of ALK rearrangement with clinicopathologic characteristics and treatment outcomes were analyzed. RESULTS: Forty-two (7.9%) of the 534 lung adenocarcinoma patients were ALK IHC-positive. ALK rearrangement was significantly associated with younger age (P = 0.011), high T-stage (P = 0.025), high pathologic stage (P = 0.002), solid predominant adenocarcinoma with mucin production (P = 0.006), invasive mucinous adenocarcinoma (P = 0.009), and receipt of adjuvant therapy after surgery (P = 0.036), but no significant associations were found between the ALK rearrangement and sex or smoking status. ALK IHC-positivity was significantly associated with a shorter disease-free survival, tumor-specific survival, and overall survival (P = 0.001, 0.026, and 0.007, respectively). Multivariate analysis showed that ALK IHC-positivity was an adverse prognostic factor for disease-free survival (HR, 1.80; 95% CI 1.18-2.77; P = 0.007), tumor-specific survival (HR, 2.59; 95% CI 1.35-4.97; P = 0.004), and overall survival (HR, 1.92; 95% CI 1.07-3.44; P = 0.030). CONCLUSION: The clinical characteristics of patients with ALK-positive lung adenocarcinoma were similar to those of EGFR-mutated patients. ALK rearrangement was an adverse prognostic factor in surgically-resected lung adenocarcinoma patients.

Histological transformation from gastric mucosa-associated lymphoid tissue lymphoma to gastric diffuse large B-cell lymphoma.

This study evaluated the clinical features, treatment and prognosis in Chinese patients with histological transformation (HT) from gastric mucosa-associated lymphoid tissue lymphoma to gastric diffuse large B-cell lymphoma. We reviewed the medical records of 71 patients diagnosed with HT between 2001 and 2013, retrospectively. Patients had a median age of 56 years. The ratio of sex (male:female) was 1.3:1. The clinical course was often insidious, lacking specific clinical presentation. Macroscopically, the antrum was the most commonly involved site. Thirty-one patients (45%) presented at stage I, and 25 (35%) presented with local (18/71, 25%) or distant (7/71, 10%) nodal involvement. There were also stage IIE (9/71, 12%) and stage IV (6/71, 8%) patients with advanced stages. For all 71 patients, the 5-year progression-free survival (PFS) and overall survival (OS) estimates were 50 and 56%, respectively. There was no statistical difference in 5-year PFS and OS estimates between patients receiving Helicobacter pylori (H. pylori) containing eradication (HPE) (p=0.189) and those receiving non-HPE (p=0.359). Upon the Cox regression model, advanced stages were the only independent prognostic factors associated with shorter PFS, and m-IPI was independently associated with shorter PFS and OS. There was no specific clinical manifestation for patients with HT. HPE is thus a promising therapeutic approach for such patients. Moreover, advanced stages and m-IPI significantly influenced patient outcome.

Vav1 expression is increased in esophageal squamous cell carcinoma and indicates poor prognosis.

Recently, Vav1 has been suggested to play an essential role in the progression of human cancers. However, the correlation between Vav1 expression and prognosis of esophageal squamous cell carcinoma (ESCC) is still unknown. The aim of this study was to investigate Vav1 expression and its prognostic value in ESCC. The expression of Vav1 was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting in ESCC tissues and matched nontumorous tissues. Immunohistochemistry (IHC) was carried out to detect Vav1 expression in paraffin samples from 112 primary ESCC patients. Survival analysis was performed using Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate the correlation of Vav1 expression with prognosis of ESCC patients. The expression levels of Vav1 mRNA and protein in ESCC tissues were both significantly higher than those in adjacent nontumorous tissues. High Vav1 expression was significantly correlated with larger tumor size (P = 0.015), depth of tumor invasion (P = 0.023), lymph node metastasis (P = 0.008) and TNM stage (P < 0.001). The rate of overall survival (OS) was significantly lower in patients with high Vav1 expression than those with low Vav1 expression (P = 0.014). Multivariate Cox analysis indicated that Vav1 expression is an independent prognostic factor for OS (HR = 1.660, 95%CI = 1.058-2.607, P = 0.028). In summary, our findings demonstrate that Vav1 may be a candidate molecular prognostic marker for patients with ESCC.

Does tumor size improve the accuracy of prognostic prediction in patients with esophageal squamous cell carcinoma after surgical resection?

This study aimed to investigate whether the inclusion of tumor size could improve the prognostic accuracy in patients with esophageal squamous cell cancer (ESCC). A total of 387 patients with ESCC who underwent curative resection were enrolled in this analysis. The patients were categorized into small-sized tumors (SSTs) and large-sized tumors (LSTs) using an appropriate cut-off point for tumor size. Kaplan-Meier survival curve and log-rank test were used to evaluate the prognostic value of tumor size. A Cox regression model was adopted for multivariate analysis. Their accuracy was compared based on the presence or absence of tumor size. Using 3.5 cm as the optimal cut-off point, 228 and 159 patients presented with LSTs (≥ 3.5 cm) and SSTs (< 3.5 cm), respectively. The patients with LSTs had significantly worse prognoses than patients with SSTs (23.9% vs. 43.2%, P < 0.001). Multivariate analysis revealed that tumor size, histological type, invasion depth, and lymph node metastasis were independent predictors of overall survival. The addition of tumor size to the AJCC TNM staging improved the predictive accuracy of the 5-year survival rate by 3.9%. Further study showed that tumor size and T stage were independent predictors of the prognosis of node-negative patients, and the combination of tumor size and T stage improved the predictive accuracy by 3.7%. In conclusion, tumor size is indeed a simple and practical prognostic factor in patients with ESCC. It can be used to improve the prognostic accuracy of the current TNM staging, especially for patients with node-negative disease.

Evaluation of the clinical characteristics, management, and prognosis of 103 patients with gastric mucosa-associated lymphoid tissue lymphoma.

The diagnosis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is difficult owing to its non-specific symptoms and various endoscopic findings. Treatments such as radiotherapy (RT) for localized and chemotherapy (CT) for advanced stages of the disease are employed. The aim of the present study was to examine the clinical characteristics and prognostic factors of Helicobacter pylori (H. pylori) eradication (HPE) in patients with gastric MALT lymphoma. The medical records of 103 patients with gastric MALT lymphoma for the period 2001-2013, were analyzed. The 103 median age of the patients was 53 years and the male to female ratio was 1:1. Serum lactate dehydrogenase and ß2-microglobulin were within normal range. Macroscopically, the most commonly involved site was the antrum, followed by the corpus and fundus. A total of 97 patients (94%) tested positive for H. pylori. Forty patients (39%) had stage I, 35 patients (35%) had local or distant nodal involvement, 20 of 103 patients had stage IIIE (19%) and 8 of 103 patients had stage IV (7%) disease. Complete remission, after HPE, was achieved in 54 of the 69 patients (78%) that were H. pylori-positive and in 2 of the 4 patients (50%) that were H. pylori-negative. HPE had a superior trend in the H. pylori-positive patients although no significant difference was identified in the two groups (p=0.194). In patients with advanced disease, the 5-year progression-free survival (PFS) and overall survival (OS) estimates were significantly improoved for patients receiving HPE with CT or RT than those receiving CT or RT (p=0.046 and 0.035, respectively). The multivariate analysis revealed that, the advanced stages were independently associated with shorter PFS, and the modified-International Prognostic Index (m-IPI) (≥2) was associated with shorter OS. In conclusion, gastric MALT lymphoma had a favorable outcome with a high OS rate. HPE was an effective treatment for gastric MALT lymphoma. The patients with advanced stages and m-IPI (≥2) had a much worse prognosis.

Gene mutation characteristics of nonsmall-cell lung carcinoma patients with wild-type epidermal growth factor receptor and sensitivity to Tarceva therapy.

OBJECTIVE: To explore characteristic gene mutations in nonsmall-cell lung carcinoma (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) and sensitivity to Tarceva therapy; to observe the efficacy and safety of Tarceva therapy for NSCLC patients with wild-type EGFR. MATERIALS AND METHODS: NSCLC patients with wild-type EGFR and KRAS were selected. Their tumor specimens were assessed for mutations in seven key genes in pathways downstream of EGFR, including HRAS, NRAS, BRAF, PIK3CA, AKT1, MEK1, and PTEN. Then the patients were subjected to Tarceva therapy to explore the relationship between curative effects and any gene mutations. RESULTS: Among 10 cases, one NRAS mutation was detected in one patient who was resistant to Tarceva, and no mutations were detected in the other patients. Seven cases responded to Tarceva; 1 case obtained partial relief, and 6 cases were in stable condition. CONCLUSION: Patients with wild-type EGFR can also benefit from Tarceva therapy. However, an association between Tarceva therapy sensitivity and mutations in genes downstream of EGFR was not detected.

Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients.

CD4(+)FoxP3(+) regulatory T cells (Tregs) represent a major cellular mediator of cancer immune evasion. The expression of tumor necrosis factor receptor type II (TNFR2) on Tregs is reported to identify the maximally suppressive Treg population in both mice and human. We therefore investigated the phenotype and function of TNFR2(+) Tregs present in the peripheral blood (PB) of 43 lung cancer patients. Further, the association of TNFR2 expression on Tregs with clinicopathological factors was analyzed. The results showed that in the PB of lung cancer patients, Tregs expressed markedly higher levels of TNFR2 than conventional T cells (Tconvs). Expression of TNFR2 appeared to correlate better than CD25(+) and CD127(-) with FoxP3 expression. PB TNFR2(+) Tregs in lung cancer patients were more proliferative and expressed higher levels of the immunosuppressive molecule CTLA-4, and consequently more potently suppressed IFNγ production by cocultured CD8 CTLs. More importantly, higher TNFR2 expression levels on Tregs were associated with lymphatic invasion, distant metastasis and more advanced clinical stage of lung cancer patients. Therefore, our study suggests that TNFR2(+) Tregs play a role in promoting tumor progressive metastasis and expression of TNFR2 by PB Tregs may prove to be a useful prognostic marker in lung cancer patients.

Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes.

Advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) activating mutations usually are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs), but whether EGFR-mutant lung adenocarcinoma is also responsive to pemetrexed-based chemotherapy remains controversial. We conducted a retrospective study to evaluate the efficacy and outcome of pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR mutation statuses. Sixty-nine EGFR-mutant and 89 wild-type patients with advanced lung adenocarcinoma were enrolled. They all had received pemetrexed-based treatments. Chemotherapy objective response rate (ORR), median progression-free survival (mPFS), and thymidylate synthase (TS) expression levels of EGFR-mutant patients were compared with those of EGFR-wild-type patients. For the EGFR-mutant patients treated with first-line platinum/pemetrexed combinations, the ORR was significantly higher than that of the wild-type patients treated with similar regimens (43 vs. 21%, p = 0.039). Nonetheless, for the patients treated with pemetrexed monotherapy, the difference in ORR was not significant between patients with EGFR mutations and those with wild-type EGFR in any line of treatments (in the first-line setting 20 vs. 13%, p = 0.715; in the second-/third-line setting 13 vs. 8%, p = 0.655). On the other hand, the mPFS for the EGFR-mutant patients treated with first-line combinations was also obviously prolonged (8.3 vs. 6.7 months, p = 0.004). However, among the patients receiving second-line platinum/pemetrexed combinations or any line of single-agent pemetrexed, there was no difference in PFS between EGFR-mutant and wild-type patients. Our results indicated that the efficacies and outcomes of pemetrexed treatment in advanced lung adenocarcinoma patients with EGFR activating mutations were similar to those in patients with EGFR-wild-type genotype, except in the setting of first-line platinum/pemetrexed combination chemotherapy.

T1aN0M0 and T1bN0M0 non-small cell lung cancer: a retrospective study of the prognosis.

BACKGROUND: Stage IA of non-small cell lung cancer (NSCLC) is divided into two subgroups, T1aN0M0 (d ≤ 2 cm) and T1bN0M0 (2 < d ≤ 3 cm), in the International Association for the Study of Lung Cancer, seventh edition of TNM Classification of Malignant Tumors. OBJECTIVE: The purpose of this study was the identification of independent clinicopathological predictors of prognosis of these two subgroups of NSCLC. METHODS: Between 1986 and 2005, a cohort of 1,929 cases of stage IA NSCLC in Tian Jin Medical University Cancer Institute and Hospital were retrospectively analyzed. The impact of clinicopathological characteristics on patients' survival was investigated. RESULTS: The overall 5-year survival rate was 71.07%. Patients with T1aN0M0 NSCLC had a better 5-year survival than those with T1bN0M0 (73.98 vs. 68.18%, p = 0.0135). The Cox proportional hazard model revealed that the prognostic factors of T1aN0M0 were intratumoral vessel invasion (p = 0.035) and histologic differentiation (p = 0.004). In patients with T1bN0M0 NSCLC, the prognostic factors were histologic differentiation (p < 0.01), intratumoral vessel invasion (p < 0.01), removal of 6 or more lymph node stations (p < 0.01), and removal of lymph node station 7 (p < 0.01). CONCLUSION: Prognostic factors of T1aN0M0 and T1bN0M0 NSCLC are different. In patients with T1bN0M0 NSCLC, 6 or more lymph node stations and lymph node station 7 should be removed.

Expression of CLDN1 and CLDN10 in lung adenocarcinoma in situ and invasive lepidic predominant adenocarcinoma.

BACKGROUND: Non-mucinous bronchioloalveolar carcinoma (BAC) is considered the early stage of lung adenocarcinoma and is classified as the lung adenocarcioma in situ (AIS) by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. This study was designed to investigate the gene expression differences between AIS (formerly non-mucinous BAC) and invasive lepidic predominant adenocarcinoma (LPA, formerly non-mucinous BAC pattern with >5 mm invasion, mixed type adenocarcinoma with BAC features) and to investigate the mechanism of the progression of lung adenocarcinoma in situ to invasive adenocarcinoma. METHODS: Gene expression analysis was performed by using Agilent 4 × 44 K Whole Human Genome Oligo Microarray on 10 fresh frozen tissue samples of AIS and LPA, respectively. Real time RT-PCR was used to validate the differential expression of 13 genes selected by cDNA microarray on fresh frozen tissue samples from 41 patients with lung adenocarcinoma and 4 genes were confirmed. These 4 genes were then validated by western blotting. Immunohistochemical staining for these validated genes was performed on formalin-fixed, paraffin-embedded tissue samples from 81 cases of lung adenocarcinomna. RESULTS: We identified a 13 gene expression signature by comparative analysis of gene expression. Expression of these genes strongly differed between AIS and LPA. Four genes (MMP-2, c-fos, claudin 1 (CLDN1) and claudin 10(CLDN10)) were correlated with the results of microarray and real time RT-PCR analyses for the gene-expression data in samples from 41 patients with lung adenocarcinoma. As confirmed by western blotting, the expression levels of MMP-2 and c-fos were higher in LPA than those in AIS; the expression levels of CLDN1 and CLDN10 in LPA were lower than those in AIS. Immunohistochemical staining for these genes in samples from 81 cases of lung adenocarcinoma demonstrated the expressions of CLDN1 and CLDN10 were correlated with overall survival of patients with lung adenocarcinoma. CONCLUSIONS: CLDN1 and CLDN10 may play important roles in the development of AIS to LPA. Overexpression of CLDN1 and CLDN10 indicates a favorable prognosis for overall survival in some patients with lung adenocarcinoma. Expression of CLDN10 may be regulated by the c-fos pathway.

A retrospective analysis of primary gastric diffuse large B-cell lymphoma with or without concomitant mucosa-associated lymphoid tissue (MALT) lymphoma components.

Primary gastric diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease entity that includes patients with (DLBCL/MALT) and without detectable mucosa-associated lymphoid tissue (MALT) lymphoma components (de novo DLBCL). We sought to evaluate the clinical characteristics and outcome of this disease in a large number of cases. Patients with primary gastric DLBCL (n=162) seen on 2001-2011 at the Tianjin Medical University Cancer Institute and Hospital and the First affiliated Hospital of Chinese PLA General Hospital were retrospectively reviewed. The distribution of sex, age, Lugano staging, and other main clinical characteristics was similar between the de novo DLBCL and DLBCL/MALT groups (p>0.05). However, the proportion of patients with a stage-modified international prognostic index (m-IPI) ≥ 2 was higher in the de novo DLBCL (34 %) than the DLBCL/MALT group (17 %) (p=0.026). In addition, the Helicobacter pylori infection rates were higher in the DLBCL/MALT (75 %) than the de novo DLBCL group (36 %) (p<0.001). Five-year progression-free survival (PFS) and overall survival (OS) estimates were similar for patients in the de novo DLBCL (p=0.705) and DLBCL/MALT groups (p=0.846). Surgical treatment did not offer survival benefits when compared with chemotherapy for 5-year PFS (p=0.607) and OS estimates (p=0.554). There were no significant differences in 5-year PFS and OS estimates for patients treated with rituximab-chemotherapy (p=0.261) or conventional chemotherapy (p=0.227). Non-GCB subtype and m-IPI ≥ 2 were independently associated with shorter OS, and advanced stages of lymphoma were independently associated with shorter PFS.

Expression of the coxsackie and adenovirus receptor in human lung cancers.

The aim of this study is to elucidate the relation between expression of coxsackie and adenovirus receptor (CAR) and formation of lung cancer. We investigated the expression of CAR by immunohistochemistry, Western blot and real-time RT-PCR in 120 lung cancers. We found that CAR expression in tumor tissues was significantly higher than that in normal lung tissues. CAR expression had a correlation with the histological grade of lung squamous cell carcinoma; however, there was no relationship between the CAR expression and the other clinical pathological features. In vitro, silencing or overexpression of CAR could significantly inhibit or promote colony formation, cell adhesion, and invasion in A549 cells. Our findings demonstrated that CAR may play an essential role in the formation of lung cancer.

[Significance of expression of chemokine receptor and matrix metalloproteinase in small cell lung cancer].

OBJECTIVE: To explore the expressions of CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase-9 (MMP-9) and examine their correlations with metastasis and prognosis in small cell lung cancer (SCLC). METHODS: Immunohistochemistry was employed to detect the expressions of CXCR4 and MMP-9 in the tissue samples from 65 SCLC patients treated in Cancer Institute and Hospital Attached to Tianjin Medical University from January 2003 to October 2009. And their correlations with metastasis and prognosis were analyzed by Chi-square test and Kaplan-Meier method and Cox regression. RESULTS: The positive expression rates of CXCR4 and MMP-9 were 100.0% (65/65) and 87.7% (57/65) in SCLC tissues respectively. Significant difference of the expression rate of CXCR4 was found between patients undergoing bone metastasis or not (P = 0.004). But the differences were not significant between brain metastasis or not (P = 0.068) and lymph node metastasis or not (P = 0.085). A high expression rate of MMP-9 was significantly associated with pathological staging (P = 0.048). But the difference between lymph node metastasis or not was not significant (P = 0.085). Univariate analysis suggested that a high expression rate of CXCR4 was significantly correlated with the disease-free survival (DFS) of SCLC patients (P = 0.005). But a high expression rate of MMP-9 was not associated with DFS (P = 0.341). Multivariate analysis suggested that a high expression rate of CXCR4 was an independent prognostic factor for DFS in SCLC. CONCLUSIONS: The elevated levels of CXCR4 and MMP-9 are found in SCLC tissues. And the expression rate of CXCR4 may be correlated with bone metastasis, but the correlation is not notable for MMP-9. The expression rate of CXCR4 is an independent prognostic factor for DFS in SCLC.

The value of biomarkers in patients with sarcomatoid carcinoma of the lung: molecular analysis of 33 cases.

UNLABELLED: To better understand the prognosis of sarcomatoid carcinoma of the lung, the correlation between several biomarkers (ERCC1 [excision repair cross-complementation group 1] and EGFR [epidermal growth factor receptor] expression, EGFR and KRAS mutations, and EGFR copy number) and clinical outcomes in 33 patients with lung sarcomatoid carcinoma was evaluated. Survival analysis identified several significant factors that predicted overall survival. BACKGROUND: Sarcomatoid carcinoma (SC) of the lung is a rare histologic group of lung cancers with a poor prognosis. To better understand the prognosis of lung SC, in this study, we evaluated the correlation between several biomarkers and clinical outcomes in patients with lung SC. PATIENTS AND METHODS: A cohort of 33 patients with lung SC was studied. Protein expressions of excision repair cross-complementation group 1 (ERCC1) and epidermal growth factor receptor (EGFR) were examined by immunohistochemistry. Somatic EGFR and KRAS mutations were identified by direct sequencing. EGFR gene copy number was evaluated by fluorescence in situ hybridization. ERCC1 messenger RNA expression in paraffin-embedded tumor specimens was detected by branched DNA assay. RESULTS: Our analyses identified 9 patients (9/32) with EGFR mutations and only 1 patient (1/32) with a KRAS mutation. No exon 19 deletion of EGFR gene was detected. Lower messenger RNA levels of ERCC1 were detected in patients with EGFR mutations and/or fluorescence in situ hybridization amplified status. Survival analysis identified several significant factors, including performance status and clinical staging, that predicted for overall survival. CONCLUSION: SC exhibits diverse genotypic variations. Results of our study suggest that chemotherapy could still be an optimal solution for untreated advanced SC, whereas EGFR tyrosine kinase domain inhibitors alone may not be an effective approach.

Surgical outcomes of gastrointestinal stromal tumors of the stomach: a single unit experience in the era of targeted drug therapy.

The stomach is the most common site of gastrointestinal stromal tumors (GISTs), but the surgical outcomes of gastric GISTs in the era of targeted drug therapy are unclear. This study aimed to assess factors associated with adverse outcomes and to analyze the effects of targeted drug therapy on gastric GISTs. The surgical outcomes and follow-up records of consecutive patients with gastric GISTs treated at Tianjin Medical University Cancer Institute & Hospital between June 2002 and December 2008 were reviewed. Eighty-five patients were included. Surgery was undertaken in all patients with curative intent. Imatinib mesylate was administered preoperatively to 6 (7%) patients (neoadjuvant therapy), and the median durations of therapy were 6 months (range 3-17 months). Imatinib mesylate was administered postoperatively to 18 (21%) patients with high-risk lesions (adjuvant therapy) and 19 (22%) patients with recurrent disease, and the median durations of therapy were 22 months (range 6-24 months) and 25 months (range 1-64 months), respectively. Tumor size greater than 10 cm (P = 0.015), high mitotic index (P = 0.021), and no adjuvant imatinib therapy (P = 0.046) were the only significant factors associated with higher recurrence-free survival in multivariate analysis. Large tumors, high mitotic index, and the absence of imatinib treatment are associated with high recurrence-free survival. Adjuvant imatinib therapy of 2 years appears to decrease the recurrence of gastric GISTs.

Absence of gene mutations in KIT-positive carcinoma showing thymus-like elements of the thyroid.

KIT, a tyrosine kinase receptor protein encoded by the proto-oncogene c-kit, is overexpressed in human neoplasms such as gastrointestinal stromal tumors and thymic squamous cell carcinoma. However, the role of KIT expression and mutations in carcinoma showing thymus-like elements is not fully understood. In the current study, 8 cases of carcinoma showing thymus-like elements were reported, and immunohistochemical staining with KIT and CD5 was performed. Mutation analyses in the juxtamembrane domains (exons 9 and 11) and in the tyrosine kinase domains (exons 13 and 17) were performed on KIT-positive samples using polymerase chain reaction and direct DNA sequencing. KIT- and CD5-positive stainings were observed in all 8 cases. However, none of the tested samples showed mutations in any of the 4 exons. The primary carcinoma showing thymus-like elements of the thyroid frequently expresses KIT and CD5 proteins; similar to thymic squamous cell carcinoma, the overexpression of KIT does not necessarily indicate a gene mutation in this tumor. KIT, along with CD5, could be a useful marker for the difficult diagnosis of carcinoma showing thymus-like elements, which should be added to the list of KIT-positive neoplasms.

Comparison of KRAS and EGFR gene status between primary non-small cell lung cancer and local lymph node metastases: implications for clinical practice.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have been widely used for the treatment of non-small cell lung cancer (NSCLC). KRAS and EGFR somatic mutations in NSCLC may predict resistance and responsiveness to TKI, respectively. Nevertheless, most research to date has been conducted on samples from primary tumors. For many patients with advanced disease, their samples can only be obtained from metastases for test. The molecular characteristics of metastasized tumors may be different from those of primary tumors. MATERIALS AND METHODS: Mutation status of KRAS and EGFR between primary tumors and local lymph node metastases of 80 Chinese patients with NSCLC were analyzed by direct sequencing. Five of them were given gefitinib as neoadjunvant treatment after the EGFR-TKI sensitive mutations were detected in their biopsies of mediastinal lymph nodes metastases. McNemar's test was used to compare the EGFR and KRAS mutation status between primary tumors and corresponding local lymph node metastases. Data evaluation was carried out with SPSS_13.0 statistical software. RESULTS: Among the 160 samples, one primary tumor and seven metastases were identified with KRAS mutations and 21 primary tumors and 26 metastases were found to have EGFR mutations. KRAS and EGFR mutation status was different between primary tumors and corresponding metastases in 6 (7.5%) and 7 (8.75%) patients, respectively. One patient with no TKI sensitive mutations detected in the primary tumor showed disease progression. CONCLUSION: Our results suggest that a considerable proportion of NSCLC in Chinese population showed discrepancy in KRAS and EGFR mutation status between primary tumors and corresponding metastases. This observation may have important implication for the use of targeted TKI therapy in the treatment of NSCLC patients.