ALK-rearrangement in non-small-cell lung cancer (NSCLC).

The ALK gene encodes a transmembrane tyrosine kinase receptor. ALK is physiologically expressed in the nervous system during embryogenesis, but its expression decreases postnatally. ALK first emerged in the field of oncology in 1994 when it was identified to fuse to NPM1 in anaplastic large-cell lymphoma. Since then, ALK has been associated with other types of cancers, including non-small-cell lung cancer (NSCLC). More than 19 different ALK fusion partners have been discovered in NSCLC, including EML4, KIF5B, KLC1, and TPR. Most of these ALK fusions in NSCLC patients respond well to the ALK inhibitor, crizotinib. In this paper, we reviewed fusion partner genes with ALK, detection methods for ALK-rearrangement (ALK-R), and the ALK-tyrosine kinase inhibitor, crizotinib, used in NSCLC patients.

Signaling protein signature predicts clinical outcome of non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application. METHODS: A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort. RESULTS: A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P <  0.001) and SCC patients (27 months vs. not reached, HR 9.97; P <  0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018). CONCLUSIONS: Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.

Lipomatous hemangiopericytoma of the stomach: a case report and a review of literature.

Lipomatous hemangiopericytomas (LHPCs) are rare soft-tissue tumors that are histologically characterized by hemangiopericytomatous vasculature and the presence of mature adipocytes. We present the clinicopathological features of a case of gastric LHPC in a 56-year-old female, along with a literature review. Endoscopy and endoscopic ultrasound showed a submucosal tumor 0.8 cm across in the greatest dimension in the lesser curvature side of the gastric antrum. Grossly, the well-defined mass had a solid and tan-white cut surface admixed with myxoid regions and yellowish areas. Histological examination revealed a submucosal well-circumscribed lesion composed of cellular nodules with the classic appearance of an hemangiopericytoma admixed with clusters and lobules of mature adipocytes. The ill-defined tumor cells had weakly eosinophilic cytoplasm and contained spindled nuclei with occasional small nucleoli. Nuclei atypia and mitoses were absent, and no cellular atypia, necrosis or vascular invasion was observed. Immunohistochemistry showed that the tumor cells were diffusely positive for CD34, CD99, and vimentin and were focally reactive for bcl-2. This is the first known report of an LHPC in the stomach. The patient was followed for 12 mo without any evidence of metastasis or recurrence.

Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer.

Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-containing protein-2 (CUEDC2), a ubiquitin-binding motif-containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.

[Expression of granulocyte colony stimulating factor in patients with non-small cell lung cancer and its clinicopathological significance].

OBJECTIVE: To examine granulocyte colony stimulating factor (G-CSF) expression in human non-small cell lung cancer (NSCLC) as well as discuss its clinicopathological significance. METHODS: Specimens were obtained from 114 cases (53 cases with granulocyte infiltration) diagnosed pathologically as NSCLC in General Hospital of PLA. Paraffin-embedded tissues from these 114 cases of NSCLC were examined for expression of G-CSF by immunohistochemical staining. Correlation between G-CSF expression and pathological features, clinical manifestation, prognosis of patients with NSCLC was analyzed statistically. All the patients were retrospectively followed-up. RESULTS: Fifty-five of the 114 NSCLC specimens expressed G-CSF, and among these 41 (41/54, 75.9%) were large cell carcinoma, nine (9/30, 30.0%) were adenocarcinoma and five (5/30, 16.7%) were squamous cell carcinoma. The expression was significantly correlated with infiltration of tumor mass by neutrophilic granulocytes, histological type, necrosis, differentiation, lymph node metastases, distant metastases, recurrence and survival period (P < 0.01). There was no significant correlation with primary tumor size (P > 0.05). Logistic multi-factor analysis revealed that necrosis, lymph nodes metastases and distant metastases RR (risk ratio) in G-CSF positive group was 5.57, 6.28 and 5.24 times higher than those of G-CSF negative group (P < 0.05). There were remarkable difference of 5-year survival rates (0 and 12.1% respectively) and survival period (42 and 62 months respectively) between positive and negative groups (P < 0.01). CONCLUSIONS: NSCLC with G-CSF excretion are mainly large cell lung cancer. The pathologic characteristics of these cases with G-CSF expression included poor differentiation, remarkable atypia, prominent necrosis and infiltration of tumor mass by neutrophils or emperipolesis. These tumors are usually more aggressive in biological behavior and have worse prognosis than those without G-CSF expression.

[Anti-tumor effect of chemotherapeutic drugs on human gastric cancer cells in vitro and the relationship with Bcl-2 expression].

OBJECTIVE: To evaluate in vitro anti-tumor effect of chemotherapeutic drugs on human gastric cancer cells, and investigate the relationship with Bcl-2 expression. METHODS: Single cell suspension was prepared from fresh gastric cancer tissue and exposed to taxol (Tax), 5-fluorouracil (5-FU), cisplatin (CDDP), adriamycin (ADM), mitomycin (MMC) respectively for 48 hours. Metabolic activity and inhibitory rate of cells were detected by MTT assay. Expression of Bcl-2 was examined with immunohistochemistry. RESULTS: The inhibitory rates of cancer cells exposed to chemotherapeutic drugs were different and Tax, 5-FU, CDDP had remarkably higher rates than ADM and MMC. The lower differentiated gastric cancer cells were more sensitive than the higher ones. Positive expression rate of Bcl-2 was 80% and the positive cells showed resistance to 5-FU, ADM and MMC. CONCLUSIONS: Chemosensitive testing by MTT assay can constitute the prediction for the application of chemotherapeutic drugs individually. Overexpression of Bcl-2 may contribute to multiple drug-resistance of tumors.

[Anti-tumor effects of chemotherapeutic drugs on human gastric cancer cells in vitro and the relationship with expression of hTERT mRNA].

OBJECTIVE: To evaluate in vitro antitumor effects of chemotherapeutic drugs, and investgate the relationship with expression of hTERT mRNA in human gastric cancer tissues. METHODS: Fresh samples of gastric cancer obtained from operation room were prepared to single-cell suspension (3 x 10(5) to 5 x 10(5) cells ml(-1)) and were separately exposed to taxol (TAX), cisplatin (CDDP), 5-fluorouracil (5-Fu), adriamycin (ADM), mitomycin (MMC) for 48 hours. Metabolic activity and inhibitory rate of the cells were determined by trypan blue exclusion and MTT assay. Expression of hTERT mRNA was detected by in situ hybridization (ISH). RESULTS: The inhibition rate of cancer cells exposed to chemotherapeutic drugs was different, and that of TAX, CDDP, 5-Fu was significantly higher than that of ADM and MMC. The positive rate of hTERT mRNA expression was 90.0% (54/60) and positive cells showed resistance to 5-Fu and ADM. CONCLUSION: Overexpression of hTERT mRNA may contribute to primary drug-resistance of tumors. Chemosensitivity tests by MTT assay may contribute to prediction of effectness in applying chemotherapeutic drugs and identify drug-resistant cases.