Soluble and cell-associated transferrin receptor in lung cancer.

The expression of transferrin receptor (TfR) has been identified in many malignant tumours. In lung cancer, lymphoma and breast cancer, it has been shown that the expression of TfR correlates with tumour differentiation, probably implying some prognostic value. A soluble form of TfR (sTfR) in human serum has been shown to be proportional to the number of cellular TfRs. Based on these data we examined the utility of measuring sTfR in the serum and bronchoalveolar lavage (BAL) fluid of patients with lung cancer (n = 32) and patients with chronic obstructive pulmonary disease (n = 22). BAL fluid was centrifuged to separate the supernatant from the cellular component. Cells were lysed in a detergent and cell-associated TfR was measured by enzyme-linked immunosorbent assay (ELISA) and expressed as ng 10(-6) cells in this cellular component. There was no difference in serum sTfR between the cancer and chronic obstructive pulmonary disease (COPD) groups. A higher level of cell-associated TfR was found in BAL of non-small-cell lung cancer patients than in COPD patients (P = 0.01). The calculated number of TfR molecules per cell in BAL correlated positively with the percentage of macrophages in BAL (P < 0.0001), suggesting that cell-associated TfR in BAL originates primarily from macrophages in this fluid. No correlation existed between BAL cell-associated TfR and tumour size, nodal status, the presence of metastases and serum sTfR. BAL cell-associated TfR was negatively correlated with BAL supernatant neuron-specific enolase (NSE) (P = 0.01). A combination of BAL supernatant NSE and cell-associated TfR detected lung cancer with a sensitivity of 91%, a specificity of 59% and positive and negative predictive values of 81% and 71% respectively. In conclusion, BAL cell-associated TfR may help in the differential diagnosis of lung cancer vs pneumonia

Tyrosine kinase inhibitors for the therapy of anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is often incurable so new therapeutic approaches are needed. Tyrosine kinases inhibitors (such as imanitib, sunitinib or sorafenib) are under evaluation for the treatment of ATC. Other vascular disrupting agents, such as combretastatin A4 phosphate, and antiangiogenic agents, such as aplidin, PTK787/ZK222584 and human VEGF monoclonal antibodies (bevacizumab, cetuximab), have been evaluated. Small-molecule adenosine triphosphate competitive inhibitors directed intracellularly at EGFRs tyrosine kinase, such as erlotinib or gefitinib, are also studied. Furthermore, new molecules have been shown to be active against ATC, such as CLM94 and CLM3. However, more research is needed to finally identify therapies able to control and to cure this disease

Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors.

Purpose:To evaluate the safety, recommended phase II dose (RP2D) and efficacy of pexidartinib, a colony stimulating factor receptor 1 (CSF-1R) inhibitor, in combination with weekly paclitaxel in patients with advanced solid tumors. Patients and Methods:In part 1 of this phase Ib study, 24 patients with advanced solid tumors received escalating doses of pexidartinib with weekly paclitaxel (80 mg/m2). Pexidartinib was administered at 600 mg/day in cohort 1. For subsequent cohorts, the dose was increased by ⩽50% using a standard 3+3 design. In part 2, 30 patients with metastatic solid tumors were enrolled to examine safety, tolerability and efficacy of the RP2D. Pharmacokinetics and biomarkers were also assessed. Results:A total of 51 patients reported ≥1 adverse event(s) (AEs) that were at least possibly related to either study drug. Grade 3-4 AEs, including anemia (26%), neutropenia (22%), lymphopenia (19%), fatigue (15%), and hypertension (11%), were recorded in 38 patients (70%). In part 1, no maximum tolerated dose was achieved and 1600 mg/day was determined to be the RP2D. Of 38 patients evaluable for efficacy, 1 (3%) had complete response, 5 (13%) partial response, 13 (34%) stable disease, and 17 (45%) progressive disease. No drug-drug interactions were found. Plasma CSF-1 levels increased 1.6- to 53-fold, and CD14dim/CD16+ monocyte levels decreased by 57-100%. Conclusions:The combination of pexidartinib and paclitaxel was generally well tolerated. RP2D for pexidartinib was 1600 mg/day. Pexidartinib blocked CSF-1R signaling, indicating potential for mitigating macrophage tumor infiltration

Comparison of serum and bronchoalveolar lavage fluid sialic acid levels between malignant and benign lung diseases

BACKGROUND: It is known that tissue and serum sialic acid levels may be altered by malignant transformation. In this study, sialic acid levels were determined in bronchoalveolar lavage fluid (BAL) and serum in two groups of patients with lung cancer and non-malignant diseases of the lung. METHODS: Colorimetric methods were used for determination sialic acid in serum and in BAL samples. Flexible bronchoscopy was used to obtain the latter. RESULTS: Sialic acid levels in bronchoalveolar lavage fluid and serum did not show any statistically significant difference between subjects with malignant and the non-malignant lung diseases (p > 0.05). Sialic acid levels were also unrelated to the stage and localization of the tumor (p > 0.05). CONCLUSIONS: Sialic acid levels do not appear to be a good marker for discriminating malignant from non-malignant diseases of the lung

The Role of Monoclonal Antibody in Combination with First-Line Chemotherapy in Asian Patients with Advanced Non-Small Cell Lung Cancer

The strategies of incorporating monoclonal antibodies (MoABs) have now proved efficacy in the first-line treatment of advanced non-small cell lung cancer (NSCLC). These include targeting the vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR). Bevacizumab is a MoAB targeting the vascular endothelial growth factor (VEGF), an important mediator of new blood vessel formation. Cetuximab is a MoAB directed at EGFR. Binding cetuximab to EGFR blocks signal transduction and promotes receptor internalization and degradation. In this review, we present current data of bevacizumab and cetuximab for the first line treatment of advanced NSCLC. We also refer to their potential for Asian patients with advanced NSCLC in the first-line setting

Pimecrolimus cream in repigmentation of vitiligo

Background: Vitiligo is a chronic disease that mostly affects children and young adults. Nowadays many treatment options are available; however, most of them have limited efficacy and in most cases would result in undesirable complications. Objective: To determine the extent of repigmentation according to the location of the lesions after applying topical cream pimecrolimus 1 in vitiligo patients. Materials and Methods: Thirty consecutive patients with vitiligo lesions affecting less than 20 of body surface area without any previous history of spontaneous repigmentation were treated with pimecrolimus cream 1 twice daily for 12 weeks. The extent of repigmentation in vitiligo lesions was determined in each patient after 6 and 12 weeks. Results: Moderate to excellent response (repigmentation >26) was observed in 6.6 and 25.9 of vitiligo lesions 6 and 12 weeks after treatment, respectively. More responsive lesions were located on the trunk, face and elbow (85.7, 75 and 70). Conclusion: Pimecrolimus cream 1 results in repigmentation in vitiligo in different extents according to the location of the lesion; however, to clearly prove its efficacy as monotherapy or in combination with other available treatment options, double-blind placebo-controlled studies are essential. Copyright © 2007 S. Karger AG

A Predictive 7-Gene Assay and Prognostic Protein Biomarkers for Non-small Cell Lung Cancer

This study aims to develop a multi-gene assay predictive of the clinical benefits of chemotherapy in non- small cell lung cancer (NSCLC) patients, and substantiate their protein expression as potential therapeutic tar- gets. Patients and methods: The mRNA expression of 160 genes identified from microarray was analyzed in qRT-PCR assays of independent 337 snap-frozen NSCLC tumors to develop a predictive signature. A clinical trial JBR.10 was included in the validation. Hazard ratio was used to select genes, and decision-trees were used to construct the predictive model. Protein expression was quantified with AQUA in 500 FFPE NSCLC samples. Results: A 7-gene signature was identified from training cohort (n = 83) with accurate patient stratification (P = 0.0043) and was validated in independent patient cohorts (n = 248, P b 0.0001) in Kaplan-Meier analyses. In the predicted benefit group, there was a significantly better disease-specific survival in patients receiving adjuvant chemotherapy in both training (P = 0.035) and validation (P = 0.0049) sets. In the predicted non-benefit group, there was no survival benefit in patients receiving chemotherapy in either set. The protein expression of ZNF71 quantified with AQUA scores produced robust patient stratification in separate training (P = 0.021) and validation (P = 0.047) NSCLC cohorts. The protein expression of CD27 quantified with ELISA had a strong correlation with its mRNA expression in NSCLC tumors (Spearman coefficient = 0.494, P b 0.0088). Multiple sig- nature genes had concordant DNA copy number variation, mRNA and protein expression in NSCLC progression. Conclusions: This study presents a predictive multi-gene assay and prognostic protein biomarkers clinically appli- cable for improving NSCLC treatment, with important implications in lung cancer chemotherapy and immunotherapy

Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate

BACKGROUND: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD). METHODS: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA). RESULTS: The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods. CONCLUSIONS: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy