Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Patients with Lung Adenocarcinoma at Risk for Cancer-Associated Thrombosis: The Observational ROADMAP-CAT Study.

BACKGROUND: The aim of this prospective study was to identify the most clinically relevant hypercoagulability biomarkers in lung adenocarcinoma patients for elaboration of an improved risk assessment model (RAM) for venous thromboembolism (VTE). SUBJECTS, MATERIALS, AND METHODS: One hundred fifty ambulatory patients with lung adenocarcinoma were prospectively enrolled. Thrombin generation, procoagulant phospholipid-dependent clotting time (Procoag-PPL), tissue factor activity (TFa), factor VIIa (FVIIa), factor V (FV), antithrombin, D-Dimers, P-selectin, and heparanase levels were assessed in platelet-poor plasma at inclusion (baseline) and at the end of the third chemotherapy cycle (third chemotherapy). Cox regression analysis was used to identify independent VTE predictors. RESULTS: At baseline, patients had significantly attenuated thrombin generation, shorter Procoag-PPL, higher levels of TFa, D-Dimers, and heparanase, and lower levels of FVIIa and P-selectin, compared with controls. A significant increase in Procoag-PPL, FV, and FVIIa and a decrease of P-selectin levels were observed between baseline and third chemotherapy. Hospitalization within the last 3 months prior to assessment, time since cancer diagnosis less than 6 months, mean rate index (MRI) of thrombin generation, and Procoag-PPL were independently associated with symptomatic VTE. Accordingly, a prediction model including Procoag-PPL and MRI showed significant discriminating capacity (area under the curve: 0.84). CONCLUSION: Ambulatory patients with lung adenocarcinoma may display pronounced blood hypercoagulability due to decreased Procoag-PPL, increased endothelial cell activation, and increased degradation of fibrin. Incorporation of Procoag-PPL and MRI of thrombin generation may improve the accuracy of a VTE-RAM in the above setting. IMPLICATIONS FOR PRACTICE: The prospective ROADMAP-CAT study identified two biomarkers of hypercoagulability, the procoagulant phospholipid-dependent clotting time (Procoag-PPL) and the mean rate index (MRI) of the propagation phase of thrombin generation assessed with the Calibrated Automated Thrombinoscope, as being clinically relevant for the classification of ambulatory patients with lung adenocarcinoma receiving a maximum of one cycle of chemotherapy into high and intermediate/low risk for venous thromboembolism. Measurement of Procoag-PPL and MRI within 1 month after the administration of the first chemotherapy cycle provides significant accuracy of the assessment. Association of the Procoag-PPL and MRI with the clinical risk assessment model for cancer-associated thrombosis in ambulatory patients with solid tumors (COMPASS-CAT RAM) further improved its accuracy.

The diverse roles of adiponectin in non-small-cell lung cancer: current data and future perspectives.

In recent years, there is growing research interest for the biological role of adipose tissue-derived bioactive factors, mainly including adipokines, in various forms of cancer. Adiponectin (APN) is the most abundant circulating adipokine, and a key mediator of several cancer-related processes, such as cell proliferation, apoptosis, regulation of tumor cell invasion and angiogenesis. In this review we summarize and critically discuss the published literature on the diverse roles of APN in non-small-cell lung cancer, including its implication in lung cancer development, its use as a diagnostic and prognostic biomarker, and its correlation with cancer-related cachexia. The main challenges and future perspectives, mainly with regard to the potential development of APN-targeted therapeutic agents in cancer therapeutics, are also briefly presented and discussed.

Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive tumour with poor prognosis whose early diagnosis is difficult. Mesothelin, megakaryocyte potentiating factor (MPF) and osteopontin have attracted attention as biomarkers. The aim of the present review is to provide an overview regarding these candidate biomarkers for MM, and discuss their potential role in today's clinical practice. Mesothelin and MPF have good specificity but sub-optimal sensitivity for detection of MM, being negative both in the sarcomatoid histological sub-type and in almost half of epithelioid mesothelioma, especially in the early stages. Osteopontin is a marker of the duration of asbestos exposure, but lacks specificity for mesothelioma. Several patient characteristics influence the diagnostic accuracy of biomarkers and make the establishment of the "optimal" diagnostic threshold difficult. Mesothelin and MPF have proved useful in assessing response to treatment. Combining different markers together may lead to an improvement in diagnostic accuracy, but there is still need for research in this area. Extensive validation and further research is required to improve the use of serum markers in mesothelioma management. In the near future, their application in clinical practice is probably in monitoring response to therapy, rather than in guiding diagnostic decisions and risk assessment of asbestos-exposed populations.

Hypersensitivity reactions to oxaliplatin: a retrospective study and the development of a desensitization protocol.

BACKGROUND: We recorded the epidemiologic and clinical features of hypersensitivity reactions (HSRs) to oxaliplatin in colorectal cancer (CRC) patients in order to provide information on the management of these patients. We also developed a desensitization protocol and evaluated its clinical application. For these reasons, we analyzed retrospectively the records of 215 CRC patients treated with oxaliplatin-containing regimens either as an adjuvant, first-line, second-line, or more. PATIENTS AND METHODS: Data from 52 patients with HSRs were analyzed according to the Common Toxicity Criteria for Adverse Events (CTCAE), v3.0. Three patients were chosen for the desensitization protocol. After determining the starting point for desensitization, we applied the standard protocol for parenteral desensitization to b-lactam antibiotics. Oxaliplatin treatment was then carried out with serial 10-fold dilutions in sufficient volume to administer the total dose. A total of 52 patients (24.2%) were recorded as having an allergic reaction to oxaliplatin. RESULTS: Hypersensitivity reactions were recorded after a mean of 6.5 (SD +/- 4.5) cycles. Only 4 patients (4 of 215; 1.8%) developed CTCAE grade 3/4 HSRs. Hypersensitivity reactions were seen more likely in patients receiving second-line or more of chemotherapy compared with chemotherapy-naive patients. No other correlations were seen (the presence of atopic disease, positive skin prick test). The 3 patients, having completed the parenteral desensitization protocol, completed their treatment uneventfully as well. CONCLUSION: Hypersensitivity reactions from oxaliplatin respond quickly to the discontinuation of the drug and appropriate support. Premedication and an increased infusion time could allow for readministration. The desensitization protocol we developed can provide a reliable alternative to permanent discontinuation of oxaliplatin.

Khorana Score: Νew Predictor of Early Mortality in Patients With Lung Adenocarcinoma.

Venous thromboembolism (VTE) is a typical complication in patients with lung cancer. Khorana score is an established tool for thromboembolic risk stratification of ambulatory patients with cancer undergoing outpatient chemotherapy. The aim of this study was to evaluate the predictive value of the Khorana score for VTE and death in patients with lung adenocarcinoma during first-line or adjuvant chemotherapy. Medical records of 130 patients with lung adenocarcinoma receiving first-line or adjuvant chemotherapy were retrospectively studied during the time period June 2013 to May 2015. Venous thromboembolism occurred in 13 (10.0%) patients. Thromboembolic events were significantly correlated with reduced survival during treatment period (hazard ratio [HR]: 3.24; 95% confidence interval [CI]: 1.11-9.49; P = .032). The VTE rates did not present statistically significant difference between different Khorana score groups ( P = .96). In univariate analysis, the risk of death during treatment period (median: 16 weeks) was 3.75 times higher in high-risk versus intermediate-risk patients (HR: 3.75, 95% CI: 1.36-10.36; P = .001) and had 2.25 times higher per point increase in the Khorana score (HR: 2.25, 95% CI: 1.36-3.73; P = .002); the above results were also reproduced in multivariate analysis. Khorana score represents a valuable tool for identifying patients with cancer in low thromboembolic risk but does not preserve its predictive value for higher risk individuals. Khorana score is an independent risk factor for death in patients with lung adenocarcinoma receiving first-line or adjuvant chemotherapy.

PET/CT and brain MRI role in staging NSCLC: prospective assessment of the accuracy, reliability and cost-effectiveness.

AIM: To determine whether PET/CT and brain MRI used in staging NSCLC can be accurate, reliable and cost-effective tools. NSCLC represents 80-85% of lung cancer and adequate information on the initial tumor staging is critical for planning an optimal therapeutic strategy. PATIENTS & METHODS: Data from 30 newly diagnosed NSCLC patients in Greece were collected and prospectively recorded. Patients with potential resectable disease were evaluated to ensure that there are no detectable metastases that would rule out the possibility of a curative surgery. RESULTS: Divergence occurred in 50% of cases of staging with CT or PET/CT alone, while metastases undetectable by the CT were revealed using PET/CT. Unnecessary thoracotomies were avoided by 10% of patients and another 10% was operated on after chemotherapy with a better prognosis. CONCLUSION: PET/CT and brain MRI combined are reliable for correct staging, reducing avoidable thoracotomies, morbidity rates and costs.

The prognostic value of serum and bronchoalveolar lavage levels of adiponectin in advanced non-small-cell lung cancer.

AIM: We aimed to explore the prognostic implications of adiponectin (APN) levels in the serum and bronchoalveolar lavage (BAL) of patients with advanced NSCLC. MATERIALS & METHODS: 29 newly diagnosed patients with stage IV NSCLC were prospectively enrolled. Baseline serum and BAL levels of APN were assayed by ELISA and correlated with various clinicopathological parameters, including overall survival. RESULTS: No statistically significant correlations were observed between the serum or BAL levels of APN and the clinicopathological parameters evaluated. The only prognostic factor identified, both by univariate and multivariate survival analyses, was performance status. CONCLUSION: The results of our cohort failed to reveal any prognostic significance of serum and BAL levels of APN in stage IV NSCLC.

Endoscopic and endobronchial ultrasound-guided needle aspiration in the mediastinal staging of non-small cell lung cancer.

Invasive staging of mediastinal lymph nodes is recommended for the majority of patients with potentially resectable non-small cell lung cancer. In the past, 'blind' transbronchial needle aspiration during bronchoscopy and mediastinoscopy, a surgical procedure conducted under general anesthesia, were the only diagnostic methods. The latter is still considered the 'gold standard'; however, two novel, minimally-invasive techniques have emerged for the evaluation of the mediastinum: endoscopic (transesophageal) and endobronchial ultrasound--both performed using a dedicated echoendoscope, facilitating the ultrasound-guided, real-time aspiration of mediastinal lymph nodes. These methods are well-tolerated under local anesthesia and moderate sedation, with very low complication rates. Current guidelines on the invasive mediastinal staging of lung cancer still state that a negative needle aspiration result from these methods should be confirmed by mediastinoscopy. As more experience is gathered and echoendoscopes evolve, a thorough endosonographic evaluation of the mediastinum by both techniques, will obviate the need for surgical staging in the vast majority of patients and reduce the number of futile thoracotomies.

Bevacizumab-induced hypertension: pathogenesis and management.

Bevacizumab, a recombinant humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), has been approved in the US as first- and second-line treatment of colorectal cancer and in the first-line treatment of advanced non-small cell lung cancer. The US FDA has also granted approval for the use of bevacizumab for the treatment of patients with metastatic renal cell carcinoma and glioblastoma, and in Europe, it is also approved in metastatic breast cancer in combination with paclitaxel. Bevacizumab is under investigation in the first-line and adjuvant setting of almost all types of solid tumors. However, anti-VEGF therapy is associated with significant toxicity. The incidence of grade 3-4 hypertension differs among the various malignancies in which bevacizumab is administered, possibly because of drug interactions with co-administered chemotherapy drugs. Hypertension appears to be dose dependent, and it is under investigation as a biomarker for VEGF inhibition efficacy. There are three main theories concerning the underlying pathophysiology: (i) the nitric oxide theory; (ii) the renal impairment theory; and (iii) the pre-eclampsia-like theory. The correct evaluation of the levels of hypertension is of critical importance and home blood pressure monitoring seems to be the most effective technique. A baseline assessment and follow-up monitoring of blood pressure is considered necessary for all patients receiving bevacizumab. There are no evidence-based recommendations regarding which antihypertensives are more appropriate for the management of bevacizumab-related hypertension. It has been suggested that the benefits from antihypertensive treatment are largely independent of the drugs used, as long as they adequately lower blood pressure. Randomized prospective studies are necessary to provide data that will be useful for the development of specific guidelines for the management of bevacizumab-related hypertension. In the meantime, treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general.

Increased serum levels of ghrelin at diagnosis mediate body weight loss in non-small cell lung cancer (NSCLC) patients.

OBJECTIVE: Ghrelin is an orexigenic peptide implicated in body weight regulation, while cachexia is a multifactorial effect of non-small cell lung cancer (NSCLC) presented in patients with advanced disease. The aim of this study was to detect the role of ghrelin in cachexia and systemic inflammation of advanced NSCLC patients as well as its role as a diagnostic and prognostic tool. METHODS: Ghrelin serum levels were measured in 101 inoperable NSCLC patients before receiving any therapy (75 patients with weight loss and 26 without weight loss) and 60 healthy control volunteers. Epidemiological, anthropometrical and laboratory data were assessed for all participants (patients and healthy volunteers). RESULTS: NSCLC patients presented significantly higher ghrelin serum levels than healthy individuals, adjusted for sex, age and BMI (0.5+/-0.4 ng/ml vs. 0.4+/-0.3 ng/ml, P<0.001). NSCLC patients with weight loss presented significantly increased ghrelin serum levels (0.56+/-0.24 ng/ml vs. 0.52+/-0.44 ng/ml, P=0.017), compared to NSCLC patients without weight loss. CONCLUSIONS: Ghrelin serum levels are significantly increased in NSCLC patients, mainly in the subgroup of patients diagnosed with cachexia, indicating a possible implication in the pathogenesis of lung cancer. Further studies are needed to determine its potential role as predictive and prognostic marker.

Hypersensitivity reactions to oxaliplatin: a retrospective study and the development of a desensitization protocol.

Background: We recorded the epidemiologic and clinical features of hypersensitivity reactions (HSRs) to oxaliplatin in colorectal cancer (CRC) patients in order to provide information on the management of these patients. We also developed a desensitization protocol and evaluated its clinical application. For these reasons, we analyzed retrospectively the records of 215 CRC patients treated with oxaliplatin-containing regimens either as an adjuvant, first-line, second-line, or more. Patients and Methods: Data from 52 patients with HSRs were analyzed according to the Common Toxicity Criteria for Adverse Events (CTCAE), v3.0. Three patients were chosen for the desensitization protocol. After determining the starting point for desensitization, we applied the standard protocol for parenteral desensitization to b-lactam antibiotics. Oxaliplatin treatment was then carried out with serial 10-fold dilutions in sufficient volume to administer the total dose. A total of 52 patients (24.2%) were recorded as having an allergic reaction to oxaliplatin. Results: Hypersensitivity reactions were recorded after a mean of 6.5 (SD +/- 4.5) cycles. Only 4 patients (4 of 215; 1.8%) developed CTCAE grade 3/4 HSRs. Hypersensitivity reactions were seen more likely in patients receiving second-line or more of chemotherapy compared with chemotherapy-naive patients. No other correlations were seen (the presence of atopic disease, positive skin prick test). The 3 patients, having completed the parenteral desensitization protocol, completed their treatment uneventfully as well. Conclusion: Hypersensitivity reactions from oxaliplatin respond quickly to the discontinuation of the drug and appropriate support. Premedication and an increased infusion time could allow for readministration. The desensitization protocol we developed can provide a reliable alternative to permanent discontinuation of oxaliplatin.

Carboplatin-pemetrexed adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC): a phase II study.

BACKGROUND: The aim of this study was to determine the progression-free survival (PFS) and toxicity associated with adjuvant administration of carboplatin and pemetrexed for completely resected patients with stage IB, II and IIIA non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-five eligible NSCLC patients received surgical resection for pathological stage IB, II or IIIA followed by postoperative adjuvant chemotherapy with carboplatin AUC5 and pemetrexed administered on days 1 and 14 on a 28-day cycle. Recombinant human granulocyte colony-stimulating factor (rhG-CF) was given prophylactically. RESULTS: The mean time to disease progression of patients was 26 months. Toxicities were generally mild to moderate and entirely manageable. CONCLUSION: The administration of carboplatin and pemetrexed is a safe, well-tolerated and convenient regimen in the adjuvant setting of completely resected NSCLC, with efficacy similar to that reported in other regimens but less toxicity.