Craig R. Lewis

Exhaled breath analysis: Novel approach for early detection of lung cancer

Lung cancer is a leading cause of cancer death, with the prognosis adversely affected by late diagnosis. Early diagnosis of lung cancer is desirable, but current evidence does not support the application of screening with techniques such as chest radiography, sputum cytology or computed tomography. Breath analysis, which includes gaseous phase analysis that measures volatile organic compounds using electronic noses, exhaled nitric oxide, and exhaled breath condensate (EBC), has been proposed as a non-invasive and simple technique to investigate neoplastic processes in the airways. EBC can be easily collected by breathing into a cooling system that condenses the water vapour in the breath. EBC has already been demonstrated to be useful in investigating inflammatory and oxidative stress changes in various respiratory conditions as it contains measurable mediators of airway inflammation and oxidative stress markers. Furthermore, EBC has also been shown to be a useful method to monitor severity of diseases such as asthma and to act as a surrogate measure of compliance to medical therapy. Presently, there still remains a relative paucity of lung cancer research involving EBC. However, since EBC is a simple, non-invasive technique that can be easily performed, even in ill patients, it has the potential to be validated for use in screening for the early diagnosis of lung cancer.

The role of BRCA mutation testing in determining breast cancer therapy

Landmark discoveries in the field of breast cancer research include the identification of germline BRCA mutations as a cause of hereditary disease, and the use of gene-expression profiling to identify distinct subtypes of breast cancer. These findings, coupled with the availability of rapid germline testing, make it possible to identify a BRCA mutation carrier contemporaneous with a diagnosis of breast cancer. For the first time, testing for a germline mutation that predisposes to cancer has the potential to influence the immediate surgical, radiotherapeutic, and drug treatment choices of an individual with a new diagnosis of breast cancer. In this Review, we examine the implications of moving germline BRCA mutation testing from highly specialized family cancer clinics to mainstream settings.

A breath test for malignant mesothelioma using an electronic nose

Malignant mesothelioma (MM) is a rare tumour which is difficult to diagnose in its early stages. Earlier detection of MM could potentially improve survival. Exhaled breath sampling of volatile organic compounds (VOCs) using a carbon polymer array (CPA) electronic nose recognises specific breath profiles characteristic of different diseases, and can distinguish between patients with lung cancer and controls. With MM, the potential confounding effect of other asbestos-related diseases (ARDs) needs to be considered. We hypothesised that as CPA electronic nose would distinguish patients with MM, patients with benign ARDs, and controls with high sensitivity and specificity. 20 MM, 18 ARD and 42 control subjects participated in a cross-sectional, case–control study. Breath samples were analysed using the Cyranose 320 (Smiths Detection, Pasadena, CA, USA), using canonical discriminant analysis and principal component reduction. 10 MM subjects created the training set. Smell prints from 10 new MM patients were distinguished from control subjects with an accuracy of 95%. Patients with MM, ARDs and control subjects were correctly identified in 88% of cases. Exhaled breath VOC profiling can accurately distinguish between patients with MM, ARDs and controls using a CPA electronic nose. This could eventually translate into a screening tool for high-risk populations.

Elevated Levels of Oxidative Stress Markers in Exhaled Breath Condensate

Introduction: Lung cancer is the leading cause of cancer death and oxidative stress secondary to carcinogens such as cigarette smoke has been implicated in its pathogenesis. Therefore, lung cancer patients were hypothesized to have higher levels of oxidative stress markers in their exhaled breath compared with controls. Methods: Exhaled breath condensate (EBC) was collected from newly diagnosed subjects with non-small cell lung cancer (NSCLC) and control subjects in a cross-sectional observational study. The samples were then analyzed for hydrogen peroxide (H2O2), pH, 8-isoprostane, and antioxidant capacity. Results: A total of 71 subjects (21 NSCLC patients, 21 nonsmokers, 13 exsmokers, and 16 smokers) were recruited. NSCLC patients had significantly higher EBC H2O2 concentration (NSCLC subjects versus smokers, 10.28 &mgr;M, 95% confidence interval [CI]: 4.74–22.30 and 2.29 &mgr;M, 95% CI: 1.23–4.25, respectively, p = 0.003) and lower antioxidant capacity (NSCLC versus smokers, 0.051 mM, 95% CI: 0.042–0.063 and 0.110 mM, 95% CI: 0.059–0.206, p = 0.023; NSCLC versus all controls as a group, 0.051 mM, 95% CI: 0.042–0.063 and 0.087 mM, 95% CI: 0.067–0.112, p = 0.001). They also had significantly lower pH (5.9, 3.3–7.3) compared with exsmokers (6.7, 5.8–7, p = 0.009). Conclusion: The significant increase of H2O2 and reduction in antioxidant capacity in the EBC of lung cancer patients further support the concept of the disequilibrium between levels of oxidants and antioxidants in lung cancer, which leads to increased oxidative stress. These findings suggest oxidative stress is implicated in the development of lung cancer and may be an early marker of the disease.

Comparison of Two Standard Chemotherapy Regimens for Good-Prognosis Germ Cell Tumors: Updated Analysis of a Randomized Trial

BACKGROUND The Australian and New Zealand Germ Cell Trials Group conducted a multicenter randomized phase III trial in men with good-prognosis germ cell tumors of two standard chemotherapy regimens that contained bleomycin, etoposide, and cisplatin but differed in the scheduling and total dose of cisplatin, the total dose of bleomycin, and the scheduling and dose intensity of etoposide. The trial was stopped early at a median follow-up of 33 months after a planned interim analysis found a survival benefit for the more dose-intense regimen. The aim of this analysis was to determine if this survival benefit was maintained with long-term follow-up. METHODS Between February 1994 and April 2000, 166 men with good-prognosis metastatic germ cell tumors defined by modified Memorial Sloan-Kettering criteria were randomly assigned to receive 3B(90)E(500)P (three cycles, repeated every 21 days, of 30 kU bleomycin on days 1, 8, and 15; 100 mg/m(2) etoposide on days 1-5; and 20 mg/m(2) cisplatin on days 1-5; n = 83) or 4B(30)E(360)P (four cycles, repeated every 21 days, of 30 kU bleomycin on day 1, 120 mg/m(2) etoposide on days 1-3, and 100 mg/m(2) cisplatin on day 1; n = 83). Endpoints included overall survival, progression-free survival, and quality of life and side effects, which were assessed using the Spitzer Quality of Life Index and the GLQ-8, respectively, before random assignment and during and after treatment. All analyses were by intention to treat. All P values are two-sided. RESULTS The median follow-up was 8.5 years. All but five survivors (3%) were followed up for at least 5 years. Overall survival remained better in those assigned to 3B(90)E(500)P than in those assigned to 4B(30)E(360)P (8-year survival: 92% vs 83%; hazard ratio of death = 0.38, 95% confidence interval = 0.15 to 0.97, P = .037). Progression-free survival favored 3B(90)E(500)P but was not statistically significantly different between the treatment groups (8-year progression-free survival, 3B(90)E(500)P vs 4B(30)E(360)P: 86% vs 79%; hazard ratio of progression = 0.6, 95% confidence interval = 0.3 to 1.1, P = .15). At the end of treatment, average scores for most side effect scales favored 3B(90)E(500)P. After the completion of treatment, average GLQ-8 scores for numbness (P = .003) and hair loss (P = .04) and the Spitzer Quality of Life Index (P = .05) favored 3B(90)E(500)P. CONCLUSION The survival benefit of 3B(90)E(500)P over 4B(30)E(360)P was maintained with long-term follow-up.

Early, progressive, and sustained dysfunction of sensory axons underlies paclitaxel-induced neuropathy

Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long‐lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early‐stage breast cancer. After administration of 529 ± 41 mg/m2 paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 ± 3.3 μV to 42.4 ± 3.4 μV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 ± 3.0 μV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow‐up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies. Muscle Nerve, 2011

Breath Analysis of Lung Cancer Patients Using an Electronic Nose Detection System

Background. The measurement of gaseous compounds in exhaled breath, such as volatile organic compounds (VOCs), may provide a noninvasive technique for assessing lung pathology, some of which are associated with lung cancer (LC). VOC analysis is laborious while electronic noses are emerging as rapid detectors of an array of gaseous markers recognizing a characteristic “smellprint.” Objectives. To conduct a pilot breath analysis using an electronic nose to test the hypothesis that there would be significant differences in the smellprint patterns between newly diagnosed LC patients and control subjects. Methods. Eighty-nine subjects were recruited, consisting of nonsmokers (33), ex-smokers (11), smokers (18), patients with respiratory disorders (11), and LC patients (16). Subjects exhaled into gas-impermeable bags for offline eNose measurements with a six-channel electronic detection module ENS Mk 3 (E-Nose Pty, Sydney). The time-response curve from each channel was evaluated for four parameters: rate to peak height, peak height, rate to recovery, and area under the curve. Results. The results showed significant differences between lung cancer and control groups when measuring peak height in channel 1 (p = 0.025); rate to recovery in channel 3 (p = 0.045); and rate to peak height in channel 3 (p = 0.001). Conclusion. The results show promise in that there were significant differences in the smellprint of subjects with lung cancer compared with control subjects. Further standardization of the technique will assist in improving the sensitivity and specificity of the method, with potential to use the analysis in a number of diseases where characteristic signatures occur in the breath.

Accelerated BEP for metastatic germ cell tumours: a multicenter phase II trial by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)

BACKGROUND This Australian single-arm, multicenter, phase II trial evaluated feasibility, tolerability and activity of accelerated bleomycin, etoposide and cisplatin (BEP) as first-line chemotherapy for metastatic germ cell tumours. PATIENTS AND METHODS Patients were planned to receive cisplatin 20 mg/m(2) and etoposide 100 mg/m(2) days 1-5, and pegfilgrastim 6 mg day 6, all repeated every 2 weeks for four cycles (three cycles for good prognosis). Bleomycin was given at 30 000 IU weekly to a total of 12 doses (9 doses for good prognosis). Primary end point was feasibility, defined as the proportion of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50. RESULTS Twelve poor, 16 intermediate and 15 good prognosis (n = 43) eligible patients were enrolled. Two patients aged >40 years were ineligible and excluded from analyses. The regimen was feasible in 86%, not feasible in 7% and not assessable in 7% of patients. Most common grade 3/4 adverse events were non-neutropenic infection (16%) and febrile neutropenia (12%). Complete response (CR) to chemotherapy and surgery was achieved in 33% poor-prognosis, 81% intermediate-prognosis and 100% good-prognosis patients. At median follow-up of 27 months (range 6-42), the 2-year progression-free survival was 50% for poor-prognosis, 94% for intermediate-prognosis and 92% for good-prognosis patients. CONCLUSION Accelerated BEP is feasible and tolerable. Efficacy data appear to be promising. This trial and a similar UK study provide the rationale for a randomised trial comparing accelerated versus standard BEP. Australian New Zealand Clinical Trials Registry Registration number. ACTRN 12607000294459.

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial

BACKGROUND We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

Oxidative Stress and Exhaled Breath Analysis: A Promising Tool for Detection of Lung Cancer

Lung cancer is one of the few neoplasia in which the principal aetiology is known, with cigarette smoke donating a considerable oxidative burden to the lungs. This may be part of the aetiology of lung cancer, but the neoplastic process is also associated with increased oxidative stress. Nonetheless, it is difficult to study the mechanisms behind the induction of lung cancer in smokers, but newer techniques of breath analysis targeting markers of oxidative stress and anti-oxidant capacity show promise in unravelling some of the pathways. This review highlights recent developments in the assessment of oxidative stress by non-invasive methods of breath analysis which are becoming powerful research techniques with possible clinical applications.