HER-2/neu protein expression and gene alteration in stage I-IIIA non-small-cell lung cancer: a study of 140 cases using a combination of high throughput tissue microarray, immunohistochemistry, and fluorescent in situ hybridization.

Regarding HER-2/neu expression (gene or protein level) in lung cancer, several studies with inconsistent results have been recently reported, partially due to variable techniques used and/or heterogeneous populations examined. The objective of this study was to examine HER-2/neu expression in a well-defined cohort of non-small-cell lung cancers (NSCLC) and in nonneoplastic lung tissue utilizing a combination of high-density tissue microarray, immunohistochemistry (IHC), and fluorescent in situ hybridization (FISH) under uniform test conditions. One hundred forty stage I-IIIA primary NSCLCs and 38 non-neoplastic lung samples were examined. IHC, using an FDA-approved Hercept monoclonal antibody kit, was performed and HER-2/neu gene alteration was assessed by FISH. The association of expression of HER-2/neu with clinicopathologic parameters was analyzed. Ninety-four percent of tumor samples (131/140) were fully interpretable after tissue processing. Twenty-five of them (19%) overexpressed (2+, 3+) HER-2/neu, while 106 (81%) had no or weak expression. All thirty-four interpretable non-neoplastic lung samples were negative for HER-2/neu alteration at protein and gene level. HER-2/neu protein overexpression correlated well with HER-2/neu gene amplification (r =.83, P < 0.001). HER-2/neu overexpression was significantly associated with histologic subtype: 19 adenocarcinomas (19/82, 23%) versus 4 squamous cell carcinomas (4/44, 9%) overexpressed Her-2/neu (P = 0.04). Statistical significance was observed between HER-2/neu expression and tumor differentiation, with strong positive (3+) expression observed more frequently in poorly differentiated tumors (P = 0.01). Patients with HER-2/neu abnormalities, particularly HER-2/neu gene amplification, exhibited a shorter survival (P = 0.043). The statistically significant difference (P < 0.005) between HER-2/neu alteration in tumor samples(25/131, 19%) and in the nonneoplastic tissue (0/34, 0%) implies that HER-2/neu may have a role in the carcinogenesis of NSCLC. The findings provide evidence supporting the hypothesis that the HER-2/neu receptor may represent a useful molecular target in the treatment of NSCLC. The significant association of HER-2/neu expression and gene amplification with poorly differentiated carcinoma compared with well differentiated carcinoma suggests that HER-2/neu may be involved in NSCLC tumor evolution. Patients with HER-2/neu gene amplification and strong positive expression of HER-2/neu protein showed a strong tendency toward shorter survival.     

Therapeutic Potential of 5′-Methylschweinfurthin G in Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer predominantly caused by the human Merkel cell polyomavirus (MCPyV). Treatment for MCC includes excision and radiotherapy of local disease, and chemotherapy or immunotherapy for metastatic disease. The schweinfurthin family of natural compounds previously displayed potent and selective growth inhibitory activity against the NCI-60 panel of human-derived cancer cell lines. Here, we investigated the impact of schweinfurthin on human MCC cell lines. Treatment with the schweinfurthin analog, 5′-methylschweinfurth G (MeSG also known as TTI-3114), impaired metabolic activity through induction of an apoptotic pathway. MeSG also selectively inhibited PI3K/AKT and MAPK/ERK pathways in the MCPyV-positive MCC cell line, MS-1. Interestingly, expression of the MCPyV small T (sT) oncogene selectively sensitizes mouse embryonic fibroblasts to MeSG. These results suggest that the schweinfurthin family of compounds display promising potential as a novel therapeutic option for virus-induced MCCs.     

Is the Technically Limited Echocardiographic Study an Endangered Species? Endocardial Border Definition with Native Tissue Harmonic Imaging and Optison Contrast: A Review of 200 Cases

OBJECTIVE: Our goal was to determine whether contrast adds diagnostic value to both fundamental and native tissue harmonic imaging (NTHI) for endocardial border definition. METHODS: Two hundred consecutive patients who underwent stress echocardiography imaging were studied in either fundamental (n = 52) or NTHI mode (n = 148) with an Acuson Sequoia echocardiographic system. Contrast agent (Optison) was administered (0.5 to 1 mL) for enhancement of endocardial borders. Two- and 4-chamber views were analyzed before and after administration of contrast at peak stress for grading of 5 endocardial border segments. Scores from 0 to 5 were assigned to each study for all the images both before and after contrast (0 = 0 segments completely visualized; 5 = 5 segments completely visualized). RESULTS: The use of Optison contrast significantly enhanced border definition when imaging was performed in either fundamental or NTHI mode. Addition of contrast resulted in better endocardial border definition in fundamental mode (4.1 + or - 1.0 versus 2.3 + or - 1.3, P <.001). However, in NTHI mode, the presence of contrast resulted in enhanced definition of endocardial border compared with its absence (4.8 + or - 0.5 versus 3.3 + or - 1.1, P <.001). The combination of NTHI and contrast resulted in more visualization of endocardium when compared with the combination of fundamental imaging and contrast (4.8 + or - 0.5 versus 4.1 + or - 1.0, P <.001). In addition, interobserver agreement for border detection increased from 83% in fundamental mode without contrast to 95% with the use of NTHI with Optison (P <.001). CONCLUSION: As defined in 200 cases, the combination of NTHI with Optison contrast results in nearly complete and consistent endocardial border definition.     

Small Cell Carcinoma of the Esophagus: A SEER Database Analysis

Background

Small cell cancer (SCC) of the esophagus is an uncommon malignancy with perceived poor prognosis, but there are few data to guide therapeutic decisions. We examined the Surveillance, Epidemiology, and End Results (SEER) database to identify prognostic factors for survival.

Methods

All patients with esophageal cancer in the SEER database between 1973 and 2009 were included. Univariate and multivariate analyses were performed in patients with and without SCC, examining the relationship of small cell histology, surgery, and other potential prognostic factors with overall survival (censored at 72 months).

Results

Of 64,799 esophageal cancer patients identified in the SEER database, 387 (0.6 %) had small cell histology. As compared with non-small cell histology, patients with small cell histology were similar in age and race but had a higher proportion of women (p < 0.001), had a higher stage at diagnosis (p < 0.001), and were less likely to undergo surgical resection (p < 0.01). Multivariate predictors associated with poor survival in the overall cohort included age, female gender, black race, and stage. In patients treated with surgery, multivariate predictors associated with poor survival included age, male gender, race, and stage but not small cell histology. In patients with small cell histology, both age and stage were associated with poor survival, but surgery and preoperative radiotherapy were associated with improved survival.

Conclusions

SCC of the esophagus presents at an advanced stage and confers a poor prognosis. The survival benefit of surgery and radiotherapy suggests that all esophageal SCC patients should be considered for preoperative radiotherapy and surgery in a stage-appropriate fashion.     

Outcomes of endoscopic resection for high-grade dysplasia and esophageal cancer

Background

Endoscopic resection (ER) is an important advance in the management of esophageal tumors. It has been used successfully for superficial esophageal cancer and high-grade dysplasia (HGD) arising out of Barrett epithelium.

Methods

From a single institution within the Department of Surgery, patients who underwent ER for esophageal tumors between December 2001 and January 2012 were evaluated. Demographic, clinical, and pathologic variables were collected and reviewed.

Results

We identified 81 patients who underwent ER for esophageal lesions. Median patient age was 69 years, and the median follow-up was 3.25 years. In patients with HGD, at the time of last endoscopy, the complete eradication rate of HGD was 84 % and cancer-specific survival was 100 %. During surveillance, one patient developed an invasive carcinoma that required endoscopic therapy. Patients with T1a and negative deep margins on ER had a recurrence-free and cancer-specific survival of 100 %. There were seven patients with T1b and negative margins on ER. Three patients underwent esophagectomy; final pathology revealed no residual malignancy or lymph node metastasis. Two patients had definitive chemoradiation, and two patients were observed. To date, there has been no cancer recurrence. In all patients who underwent ER, there was one episode of bleeding that required endoscopic treatment and admission for observation.

Conclusions

ER can be performed safely and can adequately stage and often treat patients with HGD and superficial cancers. Patients with HGD and T1a disease with negative margins are cured with ER alone. Observation and surveillance may be an option for select patients with low-risk, early submucosal disease (T1b) and negative margins.     

Minimally invasive pneumonectomy

Technical advances have resulted in the growing popularity and success of video-assisted thoracoscopic lobectomy for the treatment of nonsmall cell lung cancer. Several investigators have used similar techniques to safely perform pneumonectomies. Minimally invasive pneumonectomy may be indicated for patients who have centrally located malignant lesions and who are not candidates for sleeve resections. Adequate exposure of the proximal hilar vessels is mandatory. Short-term results are encouraging, but prospective long-term data are essential.     

Epidermal growth factor receptor-directed therapy in esophageal cancer

Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US. The long-term survival of patients with this cancer remains poor; only 25% of patients undergoing surgical excision are alive after 5 years. Multimodal programs that incorporate radiotherapy, chemotherapy and surgery for localized tumors may result in a modest survival advantage. However, significant strides in this disease can result from the inclusion of targeted therapies. The epidermal growth factor receptor (EGFR) family represents one such target and is receiving increasing attention due to the advent of specific inhibitors. Studies conducted by us and others have shown that the overexpression of EGFR family signaling intermediates is common in Barrett's esophagus and EAC. In the latter case, EGFR expression may have prognostic significance. EGFR inhibitors, including oral tyrosine kinase inhibitors and monoclonal antibodies, result in a synergistic antitumor effect with chemotherapeutic agents or with radiotherapy. Therefore, several ongoing studies include EGFR-directed therapy either alone or in combination with chemoradiotherapy for this disease. Our study of gefitinib, oxaliplatin and radiotherapy suggested that gefitinib can be safely incorporated into an oxaliplatin-based chemoradiation program for esophageal cancer, although the clinical activity of this combination is modest. Herein, we review the current literature on this subject.     

Cruciferous vegetable intake is inversely associated with lung cancer risk among smokers: a case-control study

Background  

Inverse associations between cruciferous vegetable intake and lung cancer risk have been consistently reported. However, associations within smoking status subgroups have not been consistently addressed.