Prognostic value of pre-operative glucose-corrected maximum standardized uptake value in patients with non-small cell lung cancer after complete surgical resection and 5-year follow-up.

INTRODUCTION: In this study we evaluated the value of pre-operative glucose corrected maximum standard uptake value (GC-SUVmax) as prognostic factor in patients with early stage non-small cell lung cancer (NSCLC) after complete surgical resection. METHODS: This study was designed as a retrospectively evaluated single center study with prospective data registry. Inclusion criteria were: histologically proven stage I NSCLC, 18F-FDG-PET/CT scan prior to surgery, complete resection (R0) and follow up in our outpatient department. Exclusion criteria were: history of malignancy other than NSCLC, diabetes and (neo) adjuvant therapy. Follow up period was 5 years. RESULTS: Between 2006 and 2008 a total of 33 patients (16 males, 17 females) met the inclusion criteria. SUVmax and GC-SUVmax were strongly correlated (Spearman's ρ = 0.97). Five-year overall survival (OS) rate was 70 % (95 % CI = 56-87 %). Patients who died within 5 years of follow up had significantly higher pre-operative GC-SUVmax (median = 10.6, IQR = 8.3-14.4) than patients who were alive at 5-year follow up (median = 6.4, IQR = 3.0-9.8), p = 0.04. SUVmax showed similar differences: 10.4 (8-12.9) vs. 6.6 (3.0-8.8), p = 0.047. The area under the receiver-operating characteristic (ROC) curve at 5 years was 0.70 (95 % CI = 0.50-0.90) for GC-SUVmax and 0.71 (95 % CI = 0.51-0.91) for SUVmax (p = 0.75). CONCLUSION: Pre-operative FDG tumor uptake in patients with NSCLC is predictive for survival after complete surgical resection. GC-SUVmax, as an additional value to SUVmax, may better approach competitive inhibition of FDG and glucose in tumors, however, in this study this potential advantage, if any, was very small.

Germline polymorphisms in patients with advanced nonsmall cell lung cancer receiving first-line platinum-gemcitabine chemotherapy: a prospective clinical study.

BACKGROUND: The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum-gemcitabine (PG) chemotherapy. METHODS: In total, 137 patients with stage IIIB/IV NSCLC were included who received first-line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty-three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression-free survival (PFS), treatment response, overall survival (OS), and toxicity. RESULTS: The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross-complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild-type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x-ray cross-complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate-dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild-type genotype carriers. Patients who carried the homozygous mutant glutathione S-transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum-associated polyneuropathy (18% vs 3% in wild-type vs heterozygous mutant patients, respectively; P = .01). CONCLUSIONS: To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum-containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively.

Optical spectroscopy for the classification of malignant lesions of the bronchial tree.

Optical spectroscopy may be used for in vivo, noninvasive distinction of malignant from normal tissue. The aim of our study was to analyze the accuracy of various optical spectroscopic techniques for the classification of cancerous lesions of the bronchial tree. We developed a fiberoptic instrument allowing the measurement of autofluorescence spectroscopy (AFS), diffuse reflectance spectroscopy (DRS), and differential path length spectroscopy (DPS) during bronchoscopy. Spectroscopic measurements were obtained from 191 different endobronchial lesions (63 malignant and 128 nonmalignant) in 107 patients. AFS, DRS, and DPS sensitivity/specificity for the distinction between malignant and nonmalignant bronchial lesions were 73%/82%, 86%/81%, and 81%/88%, respectively. All three optical spectroscopic modalities facilitate an increase of the positive predictive value of autofluorescence bronchoscopy for the detection of endobronchial tumors. Even better results were obtained when the three spectroscopic techniques were combined.

Measurement of hypoxia-related parameters in bronchial mucosa by use of optical spectroscopy.

RATIONALE: Tumor hypoxia has both prognostic and therapeutic consequences for solid tumors. We developed a novel noninvasive technique, differential path-length spectroscopy (DPS), which allows the measurement of hypoxia-related parameters in the superficial microvasculature of tissue. OBJECTIVES: The aim of this study was to measure the microvascular oxygenation of histologically normal endobronchial mucosa and of neoplastic lesions during bronchoscopy using DPS. METHODS: Sixty-four patients with known or suspected malignancies of the lung were studied. One hundred and five endobronchial lesions (38 histologically normal, 37 metaplastic/mild dysplastic lesions, and 30 invasive carcinomas) were detected by white and/or autofluorescence bronchoscopy and measured using DPS. RESULTS: We observed that bronchial tumors are characterized by a lower blood oxygen saturation and a higher blood content than normal mucosa. No differences were observed between normal and metaplastic/mild dysplastic mucosa. CONCLUSION: DPS is a new optical technique allowing the noninvasive study of endobronchial tumor hypoxia.

Improving the specificity of fluorescence bronchoscopy for the analysis of neoplastic lesions of the bronchial tree by combination with optical spectroscopy: preliminary communication.

Detection of malignancies of the bronchial tree in an early stage, such as carcinoma in situ (CIS), augments the cure rate considerably. It has been shown that the sensitivity of autofluorescence bronchoscopy is better than white light bronchoscopy for the detection of CIS and dysplastic lesions. Autofluorescence bronchoscopy is, however, characterized by a low specificity with a high rate of false positive findings. In the present paper we propose to combine autofluorescence bronchoscopy with optical spectroscopy to improve the specificity of autofluorescence imaging, while maintaining the high sensitivity. Standard autofluorescence bronchoscopy was used to find suspect lesions in the upper bronchial tree, and these lesions were subsequently characterized spectroscopically using a custom made fiberoptic probe. Autofluorescence spectra of the lesions as well as reflectance spectra were measured. We will show in this preliminary report that the addition of either of these spectroscopic techniques decreases the rate of false positives findings, with the best results obtained when both spectroscopic modalities are combined.

In vivo measurement of the local optical properties of tissue by use of differential path-length spectroscopy.

We demonstrate the capability of differential path-length spectroscopy (DPS) to determine the local optical properties of tissue in vivo. DPS measurements on bronchial mucosa are analyzed and yield information on the local blood oxygenation, blood content, average microvessel diameter, and wavelength dependence of the reduced scattering coefficient. Our data collected to date show that cancerous bronchial mucosa has a lower capillary oxygenation and a larger average capillary diameter than normal bronchial mucosa.

Proteomic analysis of exosomes secreted by human mesothelioma cells.

Exosomes are small membrane vesicles secreted into the extracellular compartment by exocytosis. Tumor exosomes may be involved in the sampling of antigens to antigen presenting cells or as decoys allowing the tumor to escape immune-directed destruction. The proteins present in exosomes secreted by tumor cells have been poorly defined. This study describes the protein composition of mesothelioma cell-derived exosomes in more detail. After electrophoresis of exosome preparations, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) was used to characterize the protein spots. MHC class I was found to be present together with the heat shock proteins HSC70 and HSP90. In addition, we found annexins and PV-1, proteins involved in membrane transport and function. Cytoskeleton proteins and their associated proteins ezrin, moesin, actinin-4, desmoplakin, and fascin were also detected. Besides the molecular motor kinesin-like protein, many enzymes were detected revealing the cytoplasmic orientation of exosomes. Most interesting was the detection of developmental endothelial locus-1 (DEL-1), which can act as a strong angiogenic factor and can increase the vascular development in the neighborhood of the tumor. In conclusion, mesothelioma cells release exosomes that express a discrete set of proteins involved in antigen presentation, signal transduction, migration, and adhesion. Exosomes may play an important role in the interaction between tumor cells and their environment.

Single-scattering spectroscopy for the endoscopic analysis of particle size in superficial layers of turbid media.

We report on the development of an optical-fiber-based diagnostic tool that is sensitive to single-scattering events close to the fiber-optic probe tip. By using a single fiber to deliver and detect white light we optimised the detection probability of singly scattered photons from small depths. The sampling depth of this delivery-and-collection fiber was investigated by use of a tissue phantom. We found that for our phantom 90% of the single-scattering signal in the delivery-and-collection fiber originated from less than 200 microm from the fiber tip. The contribution of multiply scattered light from a greater depth to the signal was measured with an additional collection fiber. Several tissue phantoms demonstrated our fiber-optic probes sensitivity to light scattering from superficial layers of tissue and thereby its potential to detect superficial precancerous epithelial lesions.