ORCID Profile
0000-0002-8405-9688
Current Organisations
University of Sydney
,
University of Amsterdam Medical Faculty
,
Sydney Local Health District
,
Royal Australasian College of Physicians
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Publisher: American Thoracic Society
Date: 15-06-2015
Publisher: Elsevier BV
Date: 06-2011
Publisher: Springer Science and Business Media LLC
Date: 07-07-2005
DOI: 10.1007/S00405-005-0969-3
Abstract: Total laryngectomy results in a permanent disconnection of the upper and lower airways and inevitably leads to chronic pulmonary complaints like frequent involuntary coughing, increased sputum production and repeated daily forced expectoration to clean the airway. Heat and moisture exchangers (HMEs), applied in an attempt to compensate for the lost functions of the upper respiratory tract, have been found to diminish these symptoms and improve the quality of life significantly. An HME has three physical properties that might be responsible for these improvements. First, its heat and moisture exchanging capacity improves intra-airway preservation of heat and water. Since the condensation and evaporation of moisture are accompanied by the release and uptake of thermal energy, these parameters are inseparable. Secondly, the HME's resistance may reduce dynamic airway compression, thereby improving ventilation. Thirdly, to some extent, an HME might filter out particles, thereby cleaning inspiratory breathing air. This article summarizes our present knowledge of changes in respiratory physiology after total laryngectomy and the influence of the HME by reviewing the physiological impact of these three physical properties separately for in vitro and in vivo data.
Publisher: AMPCo
Date: 02-2016
DOI: 10.5694/MJA15.01209
Publisher: Elsevier BV
Date: 07-1995
DOI: 10.1016/0167-8140(95)01580-A
Abstract: To predict the pulmonary function 3-4 months after irradiation for malignant lymphoma from the three-dimensional (3-D) dose distribution. Dose-effect relations for the relative reduction of local perfusion (Q) and local ventilation (V), were calculated in 25 patients, using correlated SPECT (Single Photon Emission Computed Tomography) and CT data. By combining the 3-D dose distribution of an in idual patient with the dose-effect relations averaged over all patients, the average reduction of local Q and V (i.e., the overall response parameters) in the whole lung was estimated for each patient. Correlation coefficients were calculated between these overall response parameters and the change in standard lung function tests. In addition, the relation between the overall response parameters and the incidence of radiation pneumonitis was determined. The overall response parameter for perfusion was correlated with the change in standard lung function tests, with correlation coefficients varying between 0.53 (p = 0.007) and 0.71 (p < 0.001) for the change of Vital Capacity and Forced Expiratory Volume at 1 s, respectively. For the overall response parameter for ventilation similar correlations were observed. Four out of the 25 patients developed radiation pneumonitis in these four patients the overall response parameter for perfusion was on average somewhat higher (13.2 +/- 1.4% (1 standard error of the mean)) than in patients without radiation pneumonitis (10.5 +/- 1.0%), but this difference was not significant. A higher incidence of radiation pneumonitis was observed for larger values of the overall response parameter for perfusion in patient groups with an overall response parameter for perfusion of 0-5%, 5-10%, 10-15%, and 15-20%, the incidence of radiation pneumonitis was 0 (0/1), 10 (1/10), 13 (1/8) and 33% (2/6), respectively. By combining the 3-D dose distribution with the average dose-effect relations for local perfusion or ventilation, an overall response parameter can be calculated prior to irradiation, which is predictive for the radiation-induced change in the overall pulmonary function, and possibly for the incidence of radiation pneumonitis, in this group of patients.
Publisher: Elsevier BV
Date: 05-1991
DOI: 10.1016/0277-5379(91)90242-6
Abstract: A quality control study was performed during the EORTC phase III study 08844: radiotherapy combined with low dose cisplatin (cDDP) in inoperable non-metastatic non-small cell lung cancer. Radiation alone (55 Gy, split course) was compared to radiotherapy with 30 mg/m2 cisplatin once a week and to radiotherapy with 6 mg/m2 cisplatin daily. The purpose of the control study was to check to which degree protocol guidelines were followed and to measure the extent of differences in assessment of tumour response, recurrence and toxicities between the in idual institutes. A review team, consisting of a data manager, a diagnostic radiologist, a chest physician and two radiotherapists reviewed entry criteria, treatment data, tumour responses, recurrences and late toxicity of 177 patients (a total of 300 patients was required for the trial). Only departments which had entered more than 5% of this number of patients were visited. There was a 15% difference in T staging of the patients and a 17% discrepancy in N stage scoring between the review team and the local investigators. Radiotherapy field sizes were insufficient in 15% of the eligible patients during a period of the radiotherapy in another 17% patients the tumour free margin was less than 1 cm. Radiation doses were incorrectly given to 7% of the patients. The given doses of cisplatin deviated in 10% of the patients treated with combined modalities. The interpretation of chest X-rays and computed tomography (CT) showed important differences in tumour response, tumour recurrence and late toxicity. From these data it is concluded that immediate checks can detect errors in treatments as planned at the local level and will make corrections possible at an early stage in multicentre studies. The quality of trial results will thus be improved. Uniform assessment of treatment outcome, tumour progression and forms of toxicity will lead to more sound trial conclusions.
Publisher: American Association for Cancer Research (AACR)
Date: 31-12-2008
DOI: 10.1158/1078-0432.CCR-08-1258
Abstract: Purpose: Current staging methods are imprecise for predicting prognosis of early-stage non–small-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis. Experimental Design: We used whole-genome gene expression microarrays to analyze frozen tumor s les from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the s les were assigned as the training cohort with the remaining s les set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of in idual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence. Results: We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (P & 0.001 n = 103) and in the independent validation set (P & 0.01 n = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response. Conclusions: Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.
Publisher: Wiley
Date: 10-1990
DOI: 10.1111/J.1365-2273.1990.TB00494.X
Abstract: The incidence and severity of respiratory symptoms after total laryngectomy and their influence on daily living were studied in 59 laryngectomized patients. Daily sputum production was the principal complaint of these patients (98%), followed by coughing (64%) and the need for frequent forced expectoration (more than 5 times a day) in order to clear the airway (57%). Frequent stoma cleaning (more than 5 times a day) was required by 37% of the patients. Significant correlation was found between respiratory symptoms, voice rehabilitation and several aspects of daily living, including fatigue, sleep problems, social contacts and psychological distress. These findings indicate that respiratory symptoms after total laryngectomy are both frequent and troublesome. The development of effective methods for minimizing and/or preventing such respiratory problems would contribute significantly to improving the quality of life of laryngectomized patients.
Publisher: Wiley
Date: 12-1995
DOI: 10.1111/J.1365-2273.1995.TB01589.X
Abstract: A multi-institutional, prospective clinical study was undertaken to investigate whether the use of a heat and moisture exchanger (HME) in the period following total laryngectomy could prevent the development or reduce the severity of respiratory symptoms. Fifty-nine patients from three hospitals were provided with HMEs, either immediately post-surgery or, in the case of post-surgical radiotherapy, upon completion of the radiotherapy. For the total s le (n = 59) statistically significant improvements over time (between 3 and 6 months) could be found in forced expectoration (P < 0.05), in the perceived voice quality (P < 0.001), social anxiety (P < 0.001), social interactions (P < 0.001) and in feelings of anxiety and depression (P < 0.05). Repeated measures analysis of variance indicated statistically significant group differences over time in forced expectoration and stoma cleaning (P < 0.05). No statistically significant differences over time were noted between the regular and non(regular) HME user groups in voice quality or in various aspects of daily living.
Publisher: Wiley
Date: 1995
Abstract: One of the major side effects of photodynamic therapy (PDT) employing Photofrin as the sensitizer is enhanced photosensitivity of the skin. The basic mechanism in PDT damage is believed to be the formation of singlet oxygen and radical species. N-acetylcysteïne (NAC) increases glutathione levels and is known to prevent pathology elicited by radicals and reactive species. NAC was tested in a randomized, open label study for its protective effect on skin photosensitivity. Twenty-seven patients treated with PDT for central obstructive lung cancer or esophageal cancer received either "early" or "delayed" NAC, starting 5 or 10 days after Photofrin, in a dose of 3 x 600 mg per day for 5 days. Light, obtained from a halogen l (fluence rate 200 mW.cm-2) was used to illuminate skin patches of 2.5 cm2 on the back (10, 25, and 50 J.cm-2). Skin response was measured by using a visual scoring system and by measuring the redness using a reflectance meter. Skin responses varied from no changes at 10 J.cm-2 to redness with edema at energies of 50 J.cm-2. In the absence of edema, measurements with the reflectance meter appeared to be more sensitive than visual scoring. In a limited number of patients, there was a trend for decreased sensitivity after NAC, but statistical analysis failed to show any significant protective effect of this short course of NAC.
Publisher: Springer Science and Business Media LLC
Date: 04-09-2014
DOI: 10.1038/BJC.2014.478
Publisher: Wiley
Date: 02-12-2014
Publisher: Elsevier BV
Date: 1992
DOI: 10.1016/0360-3016(92)91072-U
Abstract: Thirty-one patients with recurrences of locally advanced Stage III lung cancer were treated with high dose rate brachytherapy. All patients had previously received a full course external beam irradiation. All treatments were performed under topical anaesthesia and took 6-14 min depending on the strength of the Iridium-192 source. The high dose rate brachytherapy was calculated as 10 Gy at one cm from the source axis for each session and this was repeated every 2 weeks to a maximum of three sessions. All treatments were well tolerated and no immediate treatment related complications were observed. Response evaluation 6 weeks after high dose rate brachytherapy showed that there was a partial response in 22 patients and nine patients were non-responders. Median survival was 7 and 3 months, respectively. All non-responders had initially presented with a T4N3 tumor. Ten patients died because of fatal pulmonary hemorrhages 2-24 weeks after brachytherapy and three others died because of a bronchial fistula. Endobronchial brachytherapy appears to be a valuable treatment alternative for local palliation. However, the relatively high number of complications at follow-up warrants further investigation to establish the optimal benefit to be derived from high dose rate brachytherapy treatment of locally advanced Stage III tumors.
Publisher: Public Library of Science (PLoS)
Date: 09-2011
Publisher: BMJ
Date: 10-1986
Abstract: N-isopropyl-p[123I]iodo hetamine, originally designed for brain scintigraphy, has been found to be retained by the normal lung and to produce excellent camera images. Ten patients with gross abnormalities on their chest radiographs due to lung cancer have been studied with this drug. The diseased parts of the lung consistently showed less uptake and these defects matched those obtained with microspheres labelled with technetium-99m, indicating that 123I-iodo hetamine has the characteristics of a perfusion tracer. In five out of the 10 patients studied sequential studies showed that improved iodo hetamine uptake was encountered shortly after a favourable response to radiotherapy and reduced uptake was seen in congruence with the radiation field at a later stage. This first clinical demonstration indicates that the retention of 123I-iodo hetamine could be a sensitive marker for pulmonary vascular integrity and a useful new tool to identify the extent of disease where the pulmonary circulation is the initial site of the disorder.
Publisher: Elsevier BV
Date: 02-2003
DOI: 10.1016/S0169-5002(02)00446-4
Abstract: Combined modality treatment (CMT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is at present studied extensively. To select patients with truly stage IIIA-N2 disease, however, proves to be difficult with current diagnostic tests. Distant metastases may become clinically overt during induction chemotherapy (IC) or shortly after, revealing the inaccuracies of current staging algorithms. A prospective study with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in IIIA-N2 NSCLC patients was performed to assess its value in the selection of this patient group. Fifty-seven patients received a whole body FDG PET scan as part of an ongoing response monitoring trial. Results were compared with conventional staging. In 32/57 (56%) PET suggested upstaging, which was confirmed in 17/57 (30%) with a median follow-up of 16 (range 2-49) months. These results show that using the conventional staging algorithm a substantial group of patients was understaged. FDG PET improves the selection of patients suitable for CMT.
Publisher: Elsevier BV
Date: 2012
Abstract: This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung cancer (NSCLC). Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS). A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months P=0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade≥3 AEs (experimental arm). Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Elsevier BV
Date: 04-2001
Publisher: Springer Science and Business Media LLC
Date: 03-2003
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2006
Abstract: To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non–small-cell lung carcinoma patients. Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation scheme. Patients were randomly assigned to receive treatment once a week for 6 weeks or once every 2 weeks for 4 weeks. The following cohorts of patients were treated with a reversed schedule once every 2 weeks, in which cisplatin was followed by gemcitabine. The dose-intensity of cisplatin was equal in both schedules. Audiometric evaluations were obtained for each ear at several frequencies. Mean hearing loss after cisplatin treatment was computed for each dose level at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Pure tone averages (PTAs) were also calculated. The pharmacokinetics of cisplatin was determined to study the correlation among the maximum drug concentration, the area under the curve of unbound platinum, and the development of ototoxicity. A total of 328 audiograms were analyzed. At the higher frequencies, a more severe hearing impairment was recorded. Most patients showed a decrease in hearing thresholds at dosages above 60 mg/m 2 cisplatin at the higher frequencies. PTAs at 1, 2, and 4 kHz show a mean hearing loss of 19 dB after cisplatin administration at dosages above 90 mg/m 2 . Threshold shifts at 8 and 12.5 kHz after cisplatin administration were experienced at dosages above 60 mg/m 2 . Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m 2 . It is more pronounced when cisplatin is given once every 2 weeks.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2008
Publisher: Massachusetts Medical Society
Date: 20-02-1992
Publisher: Elsevier BV
Date: 08-1997
DOI: 10.1016/S0027-5107(97)00098-5
Abstract: DNA adducts may serve as a molecular dosimeter of exposure to cigarette smoke-associated carcinogens such as polycyclic aromatic hydrocarbons (PAH). Target tissues for cigarette smoke-induced carcinogenesis are rarely accessible therefore, peripheral blood cells or cells obtained by bronchoalveolar lavage (BAL) may be used as surrogate sources of exposed DNA. However, the relationship between cigarette smoke exposure and aromatic-DNA adducts in white blood cells and BAL cells is still unclear. In this study, we examined DNA adduct formation in lymphocytes and BAL cells in several populations of smoking in iduals by means of 32P-postlabelling. Significant correlations between the amount of cigarettes smoked per day and the level of aromatic-DNA adducts were found in lymphocytes. In BAL cells, DNA adduct levels were associated with age (p = 0.05) and gender (p = 0.10) after adjustment for smoking behaviour. Adduct formation levelled off at higher exposure levels, suggesting less efficient adduct formation decreases in the formation of adducts per unit of exposure were found in lymphocytes (r(s) = -0.80, p < 0.001) and BAL cells (r(s) = -0.72, p < 0.001). To assess intra-in idual variation in adduct levels at constant smoking behaviour, s ling was repeated after a period of 2 and 6 months. In lymphocytes, repeated measurements with an interval of 2 months were highly correlated (r = 0.84, p = 0.009, n = 8), whereas repeated measurements with an interval of 6 months showed no correlation (r = 0.30, p = 0.27, n = 16). Repeated measurements in BAL cells showed a significant correlation after 6 months (r = 0.68, p = 0.03, n = 10). Furthermore, in a group of occupationally exposed aluminium workers, adduct levels in total white blood cells were correlated with the average concentrations of PAH in the ambient air of workers who smoked cigarettes, whereas in non-smokers, no such relationship was found. We conclude that cigarette smoking may directly or indirectly influence DNA adduct levels and saturation of DNA adduct formation may occur, leading to non-linear dose-response relationships.
Publisher: Elsevier BV
Date: 12-2003
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0277-5379(90)90131-C
Abstract: 10 patients with locally advanced bronchioloalveolar carcinoma were treated with interferon-alpha as an inhaled aerosol. Initial doses ranged between 1 and 10 MU daily or thrice weekly and were then increased to 20 MU daily. Treatment was continued until disease progression or excessive toxicity occurred, 9 patients were evaluable for toxicity. In 1 case treatment had to be stopped after 2 weeks due to fever, fatigue and progressive dyspnoea. 2 patients developed fever, 1 had malaise, fatigue and loss of appetite and 2 had dose-dependent transient dyspnoea. According to standard criteria no tumour responses could be detected. In 6 out of 8 evaluated for response to interferon, radiological stabilisation of disease for 7-43 weeks (median 15) was observed. These results point to the feasibility of aerosol inhalation of interferon-alpha, but also to its limited antitumour activity in locally advanced bronchioloalveolar carcinoma.
Publisher: Elsevier BV
Date: 06-1987
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-01-2010
Publisher: Wiley
Date: 21-11-2013
DOI: 10.1111/AJCO.12043
Abstract: The accurate diagnosis of malignant pleural mesothelioma (MPM) is essential for therapeutic and legal reasons. In 2006 the International Mesothelioma Panel advocated the use of a panel, including two mesothelial and two non-mesothelial immunohistochemical (IHC) markers. We assessed the changing use of IHC for the diagnosis of MPM in Australia over two decades in the context of current best practice. Patients with a confirmed clinico-pathological diagnosis of MPM who underwent extrapleural pneumonectomy or pleurectomy and/or decortication between 1988 and 2006 were identified from the cardiothoracic database at Royal Prince Alfred Hospital and combined with consecutive patients reviewed by the Dust Diseases Board between March 2007 and March 2009. Initial diagnostic pathology reports were reviewed. A total of 289 patients were identified. A median of six IHC stains per s le was performed (range 0-18): two (range 0-5) mesothelial markers, two (0-6) carcinoma markers and two epithelial markers. A trend to the higher usage of antibodies in epithelioid tumors versus biphasic and sarcomatoid tumors was noted (P = 0.148 and 0.389, respectively). Testing increased from a median of three stains per s le (1988-1997) to seven (2006-2009). Labeling specimens with > 2 mesothelial markers and > 2 carcinoma markers increased to 72 and 67 percent, respectively, after 2006. Reflecting the acceptance of diagnostic panels and increased availability of antibodies, an increase in the use of IHC stains for MPM diagnosis has occurred over the past two decades although uncertainty persists as to the optimal panel composition.
Publisher: Wiley
Date: 27-09-2021
DOI: 10.1111/ANS.17203
Abstract: Low muscularity is associated with adverse surgical outcomes. We aimed to determine whether low muscularity is associated with an increased risk of post‐operative complications and reduced long‐term survival after oesophago‐gastric cancer surgery. Patients who underwent radical oesophago‐gastric cancer surgery with preoperative abdominal computed tomography (CT) imaging were included. Low skeletal muscle index (SMI), measured by CT, was determined using pre‐defined cut‐points. Oncological, surgical, complications and outcome data were obtained from a prospective database. Of 108 patients, 61% ( n = 66) had low SMI preoperatively. Patients with low SMI had a higher rate of post‐operative pneumonia (30 vs. 7% normal muscularity, P = 0.004). Median length of stay (LOS) was higher in patients with low SMI if they had any complication (19.5 vs. 14 days, P = 0.026) or pneumonia (21 vs. 13 days, P = 0.018). On multivariate analysis, low SMI (OR 3.85, CI 1.10–13.4, P = 0.025), preoperative weight loss (OR 1.13, CI 1.01–1.25, P = 0.027), and smoking (OR 5.08, CI 1.24–20.9, P = 0.024) were independent predictors of having a severe complication. There was no difference in 5‐year overall (62% vs. 69%, P = 0.241) and disease‐free (11% vs. 21.4%, P = 0.110) survival between low SMI and normal muscle mass groups. Low SMI is associated with a significantly increased risk of pneumonia and increased LOS for patients with complications. Assessment of muscle mass may require additional muscle quality, strength, and physical performance measures to enhance preoperative risk assessment.
Publisher: Elsevier BV
Date: 1992
DOI: 10.1016/0959-8049(92)90394-H
Abstract: The EORTC Lung Cancer Cooperative group performed a randomised phase II study in patients with small cell lung cancer comparing the standard cyclophosphamide/doxorubicin/etoposide (CDE) regimen with two regimens containing the new and active cisplatin derivative, carboplatin, 400 mg/m2 in combination with ifosfamide, a drug without important myelotoxicity, at a dose of 5 g/m2 (IMP) or the non-myelotoxic drug vincristine twice 2 mg (VP). Of 178 evaluable patients, 63 received CDE [30 limited disease (LD), 33 extensive disease (ED)], 55 received IMP (22 LD, 33 ED) and 60 (26 LD, 34 ED) were treated with VP. The response duration was not statistically different: CDE 31 weeks, IMP 29 weeks and VP 21 weeks. The time to progression after CEE was 28 weeks, IMP 24 weeks and VP 17 weeks. This was significantly shorter after VP than after CDE (P = 0.017). The 60% response rate of the VP combination was low compared with CDE (83%) and IMP (77%). Toxicity of all three regimens was acceptable, and dose reduction for myelosuppression was necessary in only a minority of the patients. We conclude from this study that the combination of carboplatin, at the maximally tolerated dose of 400 mg/m2, in combination with ifosfamide 5 g/m2, is an active regimen with efficacy comparable with the standard CDE regimen.
Publisher: European Respiratory Society (ERS)
Date: 08-2005
DOI: 10.1183/09031936.05.00127204
Abstract: Controversial results of surgical treatment after induction chemotherapy, especially in relation to the extent of resection, have previously been reported. Mortality and morbidity were studied in the surgical arm of the European Organisation for Research and Treatment of Cancer (EORTC) 08941 trial. EORTC 08941 is a multicentre, prospective, randomised, phase-III trial of surgical resection versus radiotherapy in patients with proven stage IIIA-N2 nonsmall cell lung cancer after an objective response to platinum-based induction chemotherapy. Operative results in the 167 patients randomised in the surgical arm are presented within this study. Among these patients, one switched to the radiotherapy arm and 17 patients did not get any protocol treatment or information is not yet available. Radical resection with negative surgical margins was obtained in 74 patients (49.7%). In 61 patients (40.9%), a pathological down-staging to N0 or N1 was present. Operative 30-day mortality was 4.0%. Post-operative complications were mainly pneumonia, respiratory insufficiency, arrhythmias, air leak, cardiac decompensation, empyema and bronchopleural fistula. In total, 12 (8.1%) patients underwent re-operation due to positive margins, haemothorax, empyema and bronchopleural fistula. In conclusion, surgical resection after induction chemotherapy in the multicentre European Organisation for Research and Treatment of Cancer trial has yielded acceptable rates of morbidity and mortality.
Publisher: Springer Science and Business Media LLC
Date: 22-12-2022
DOI: 10.1038/S41467-022-35358-3
Abstract: Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S. Food and Drug Administration-approved glucosylceramide synthase inhibitor, reduced osteoclast-driven bone loss in preclinical in vivo models of myeloma. In combination with zoledronic acid, a bisphosphonate that treats myeloma bone disease, eliglustat provided further protection from bone loss. Autophagic degradation of TRAF3, a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. Eliglustat blocked autophagy by altering glycosphingolipid composition whilst restoration of missing glycosphingolipids rescued autophagy markers and TRAF3 degradation thus restoring osteoclastogenesis in bone marrow cells from myeloma patients. This work delineates both the mechanism by which glucosylceramide synthase inhibition prevents autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the clinical translational potential of eliglustat for the treatment of myeloma bone disease.
Publisher: Springer Science and Business Media LLC
Date: 09-1997
DOI: 10.1038/BJC.1997.468
Abstract: Five patients with a pleural malignancy (four malignant mesotheliomas and one localized low grade carcinoid) were treated with maximal surgical resection of the tumour followed by intraoperative adjuvant photodynamic therapy (PDT). The additional photodynamic treatment was performed with light of 652 nm from a high power diode laser, and meta-tetrahydroxy phenylchlorin as the photosensitizer. The light delivery to the thoracic cavity was monitored by in situ isotropic light detectors. The position of the light delivery fibre was adjusted to achieve optimal light distribution, taking account of reflected and scattered light in this hollow cavity. There was no 30-day post-operative mortality and only one patient suffered from a major complication (diaphragmatic rupture and haematopericardium). The operation time was increased by a maximum of 1 h to illuminate the total hemithoracic surface with 10 J cm(-2) (incident and scattered light). The effect of the adjuvant PDT was monitored by examination of biopsies taken 24 h after surgery under thoracoscopic guidance. Significant damage, including necrosis, was observed in the marker lesions with remaining malignancy compared with normal tissue s les, which showed only an infiltration with PMN cells and oedema of the striated muscles cells. Of the five patients treated, four are alive with no signs of recurrent tumour with a follow-up of 9-11 months. One patient was diagnosed as having a tumour dissemination in the skin around the thoracoscopy scar and died of abdominal tumour spread. Light delivery to large surfaces for adjuvant PDT is feasible in a relatively short period of time (< 1 h). In situ dosimetry ensures optimal light distribution and allows total doses (incident plus scattered light) to be monitored at different positions within the cavity. This combination of light delivery and dosimetry is well suited for adjuvant treatment with PDT in malignant pleural tumours.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0169-5002(00)00208-7
Abstract: There is little data in literature on survival of patients with lung cancer as a second primary (SP) malignancy. This retrospective study was undertaken to investigate whether a previous malignancy has prognostic significance in operable non-small cell lung cancer (NSCLC). Sixty-six patients with SP NSCLC were compared with 75 'first primary' (FP) NSCLC patients without a previous malignancy. All the 141 patients had been surgically treated with curative intent at The Netherlands Cancer Institute (NKI) between 1977 and 1996. Patients who had undergone resections for lung metastases were excluded. Clinical and pathological characteristics were collected and a multivariate analysis on all the 141 patients was carried out. All the previous malignancies were invasive cancers associated with metastatic potential and predominantly located in the aerodigestive tract. Female-male ratio was higher in the SP group (29 vs. 15%, P = 0.06). Tumour diameter was smaller in the SP group (3.0 vs. 4.7 cm, P < 0.0001). Pneumonectomy was performed less frequently in the SP group. Five-year survival rate was higher in the SP group (61 vs. 34%, P = 0.04). Univariate favourable prognostic factors were small tumour diameter, female gender, favourable pTNM-stage, favourable pT-stage, favourable cTNM-stage, no post-operative radiotherapy and a history of previous malignancy. Multivariate analysis showed tumour diameter, female gender and pTNM-stage to be the major potential confounders. When adjustments were made for these three variables, the prognostic advantage of the SP group disappeared. It was concluded that SP NSCLC has a similar prognosis when compared with FP NSCLC. NSCLC diagnosed during the follow-up of a previous malignancy, and deemed operable, therefore, warrants the same diagnostic and therapeutic approach as NSCLC as first malignancy.
Publisher: Elsevier BV
Date: 1992
Publisher: Elsevier BV
Date: 05-1995
Abstract: Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well recognized causes. Apart from oxidants, cigarette smoke contains several precarcinogens, and it is surprising that not every heavy smoker becomes a victim of malignant disease. This points to the interin idual variability in susceptibility to carcinogens and there are several lines of evidence that metabolic factors are involved in such variability. Metabolism of carcinogens and also the subsequent multisteps of carcinogenesis are affected by host factors and governed by the balance between opposite forces, such as metabolic activation and detoxification, formation, and scavenging of radicals and DNA damage and repair. This implies that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione plays a crucial role in the detoxification of xenobiotics. N-acetylcysteine (NAC), an aminothiol and precursor of intracellular cysteine and glutathione, has been shown not only to be an efficient antidote in acetaminophen poisoning but also to possess important chemopreventive properties. In this article, sites and mechanisms of the therapeutic action of NAC are reviewed with special reference to its chemopreventive characteristics.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2006
DOI: 10.1007/S00259-006-0070-1
Abstract: The purpose of this study was to map treatment-induced (99m)Tc-Hynic-rh-annexin V uptake in normal tissues using co-registration of SPECT and CT. Nineteen patients (11 male, 8 female, mean age 57 years) with various malignant tumours (12 lymphomas, four non-small cell lung cancers and three head and neck squamous cell carcinomas) underwent (99m)Tc-Hynic-rh-annexin V scintigraphy and CT before and within 48 h after the start of anticancer therapy. SPECT and CT were performed separately, with the patient in a reproducible position. Volume-based automated and manual methods were used to match functional and anatomical data. SPECT/CT co-registration was used to evaluate treatment-induced changes in the normal structures. A significant radiation field-related increase in early post-treatment (99m)Tc-Hynic-rh-annexin V uptake in salivary glands and bone marrow was detected in eight of nine patients. Radiation field-related increase in bone marrow activity above the baseline value was detected in all 13 irradiated patients. A minimal, symmetrical increase in activity in the salivary glands was detected after the initial course of platinum-based chemotherapy, and a diffuse prominent increase in (99m)Tc-Hynic-rh-annexin V in the bone marrow was detected in all cases. Precise delineation between the tumour and normal tissue tracer accumulation was accomplished in all cases using SPECT/CT co-registered volumes, enhanced by the "colourwash" technique. Mapping of early treatment-related changes in annexin V uptake by SPECT/CT co-registration permits accurate evaluation of tracer distribution in normal structures and precise delineation from tumour uptake. The associations between tracer distribution in the normal tissues and treatment regimen found in this study may contribute to the evaluation of dose-effect relations in various treatment schedules.
Publisher: Elsevier BV
Date: 09-1999
Publisher: Elsevier BV
Date: 10-2013
Publisher: Elsevier BV
Date: 06-2016
Abstract: Malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPeM) are often grouped together in descriptive epidemiological analyses, resulting in limited understanding of epidemiological patterns for these tumour types. We studied patterns in the incidence, mortality and survival of people diagnosed with MPM (n=4,076) and MPeM (n=293) in New South Wales (NSW), Australia, 1972-2009. We also calculated 5-year relative survival for people diagnosed 1972-2006 followed up to 2007. We assessed patterns for each tumour type and histological subtype and, where possible, by combination of these categories. Annual MPM cases steadily increased over time (n=208 in 2009). There was an increasing trend in the MPM age-standardised incidence rate from 1972 up to 1994. This rate increase has levelled off in the past 10 years. Since 1999, 11 cases of MPeM were diagnosed each year, on average. Five-year relative survival remained stable for MPM and MPeM. However, 5-year relative survival in 2002-2006 was substantially higher for people with MPM epithelioid histological subtype (11.7% [95%CI 6.8-18.2%]) compared to all other non-epithelioid histological subtypes (6.9% [95%CI 5.0-9.1%]), a 70% difference. Survival was also greater for women with MPM (13.4% [95%CI 8.5-19.4%]) compared to men (7.0% [95%CI 5.1-9.2%]). MPM incidence rates have stabilised since the mid-1990s, suggesting that maximum incidence levels have been reached. When more up-to-date data are available, survival estimates should be reanalysed to include people likely to benefit from the wide introduction of combination chemotherapy in 2007, including pemetrexed.
Publisher: Wiley
Date: 07-1996
DOI: 10.1002/(SICI)1097-0347(199607/08)18:4<311::AID-HED1>3.0.CO;2-0
Abstract: Preecl sia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality. The precise pathogenesis of this complex disorder is still unrevealed. We examined the pathophysiological pathways involved in early-onset preecl sia, a specific subgroup representing its most severe presentation, using LC-MS/MS metabolomic analysis based on multi-level extraction of lipids and small metabolites from maternal blood s les, collected at the time of diagnosis from 14 preecl tic and six matched healthy pregnancies. Statistical analysis comprised multivariate and univariate approaches with the application of over representation analysis to identify differential pathways. A clear difference between preecl tic and control pregnancies was observed in principal component analysis. Supervised multivariate analysis using orthogonal partial least square discriminant analysis provided a robust model with goodness of fit (R Metabolomic analysis focusing specifically on the early-onset severe form of preecl sia reveals the interplay between pathophysiological pathways involved in this form. Future studies are required to explore new therapeutic approaches targeting these altered metabolic pathways in early-onset preecl sia.
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/1011-1344(96)07342-3
Abstract: The first reports on photodynamic therapy (PDT) date back to the 1970s. Since then, several thousands of patients, both with early stage and advanced stage solid tumours, have been treated with PDT and many claims have been made regarding its efficacy. Nevertheless, the therapy has not yet found general acceptance by oncologists. Therefore it seems legitimate to ask whether PDT can still be described as "a promising new therapy in the treatment of cancer". Clinically, PDT has been mainly used for bladder cancer, lung cancer and in malignant diseases of the skin and upper aerodigestive tract. The sensitizer used in the photodynamic treatment of most patients is Photofrin, (Photofrin, the commercial name of dihematoporphyrin ether/ester, containing > 80% of the active porphyrin dimers/oligomers (A.M.R. Fisher, A.L. Murphee and C.J. Gomer, Clinical and preclinical photodynamictherapy, Review Series Article, Lasers Surg. Med., 17 (1995) 2-31). It is a complex mixture of porphyrins derived from hematoporphyrin. Although this sensitizer is effective, it is not the most suitable photosensitizer for PDT. Prolonged skin photosensitivity and the relatively low absorbance at 630 nm, a wavelength where tissue penetration of light is not optimal, have been frequently cited as negative aspects hindering general acceptance. A multitude of new sensitizers is currently under evaluation. Most of these "second generation photosensitizers" are chemically pure, absorb light at around 650 nm or greater and induce no or less general skin photosensitivity. Another novel approach is the photosensitization of neoplasms by the induction of endogenous photosensitizers through the application of 5-aminolevulinic acid (ALA). This article addresses the use of PDT in the disciplines mentioned above and attempts to indicate developments of PDT which could be necessary for this therapy to gain a wider acceptance in the various fields.
Publisher: Wiley
Date: 16-01-2015
DOI: 10.1111/RESP.12457
Publisher: Wiley
Date: 27-04-2023
DOI: 10.1111/RESP.14512
Abstract: See related article
Publisher: American Association for Cancer Research (AACR)
Date: 02-2009
DOI: 10.1158/1078-0432.CCR-08-1968
Abstract: Purpose: Patients with head and neck cancer often develop a lung tumor that can be diagnosed as distant metastasis (DM) or second primary tumor (SPT). In this study, we use TP53 mutation analysis for validation of an allelic loss marker panel and a decision algorithm for distinguishing between DM and SPT. Experimental Design: Tumor pairs of 39 patients were analyzed for TP53 mutations, for patterns of allelic loss and immunohistochemical analysis of p53 expression. Results of these three analyses were compared, using mutation analysis as gold standard. Results: Loss of heterozygosity (LOH) analysis indicated DM in 15 and SPT in 23 cases (one inconclusive). TP53 mutation analysis was informative in 15 cases. Based on the p53 mutation status alone, nine tumors were diagnosed as SPT and six as DM. In all 15 cases the LOH analysis was in concordance with the TP53 mutation analysis. Immunostaining for p53 showed promise as a first scan to diagnose lung tumors as SPT but cannot be used to diagnose DM. Conclusion: The TP53 mutation data validate the suitability of the LOH marker panel and decision algorithm for differential diagnosis of DM and SPT in the lung. LOH analysis can theoretically be exploited in almost all cases and is less laborious than TP53 mutation analysis.
Publisher: Elsevier BV
Date: 05-1991
DOI: 10.1016/0277-5379(91)90231-2
Abstract: The aim of this study was to assess the feasibility of using objective data obtained at diagnosis of Hodgkin's disease to predict those patients who were likely to die of progressive disease within 4 years of diagnosis. 92 consecutive patients from one centre (Newcastle upon Tyne) were used to construct a numerical index based on disease stage (Ann Arbor), age, haemoglobin and absolute lymphocyte count. Weight was assigned according to a predictive value in univariate and multivariate analyses based on survival. The index produced was then validated on a separate patient set (455) from other centres within the Scotland and Newcastle Lymphoma Group (SNLG) on whom the same prospective information was available. The index produced provided a useful separation of those patients destined to die of disease. Of 101 patients with index higher than 0.5, 62 (61.4%) were dead at 4 years, whereas with index lower than 0.5, 61 (18%) of 336 patients were dead at 4 years. The index includes Ann Arbor stage but possesses additional practical prognostic value which allows identification of patients with early stage destined to die of disease. Of 149 patients with stage IA and IIA disease 15 patients had index higher than 0.5, and 10 (60%) have died, whereas the remaining patients had survival of 90% and 85% respectively. This numerical index is applicable to all patients at diagnosis and in the SNLG population gives better predictive survival at 4 years than stage alone, and provides a basis for selecting patients for more aggressive therapy.
Publisher: Public Library of Science (PLoS)
Date: 19-08-2013
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.CLLC.2012.09.003
Abstract: We hypothesized that in patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP), high expression of excision repair cross complementation group 1 (ERCC1) and low expression of thymidylate synthase (TS) are associated with prolonged survival. Consecutive patients undergoing EPP at our institutions were reviewed. Tissue microarrays were constructed using five 1-mm cores per patient. TS and ERCC1 protein expression was evaluated by immunohistochemical techniques. The average percentage scores from evaluable cores were assessed and the median score was used to ide the group. Overall survival (OS) from the time of surgery was determined by the Kaplan-Meier method and results were compared by the log-rank test. Eighty patients were included: median age, 58 years 79% men 76% epithelial and 24% biphasic subtypes 25% and pathologic stage I/II and 73% stage III/IV. The median OS was 18.2 months (80% deceased at the censor date). Nineteen patients received neoadjuvant chemotherapy 2 patients received chemotherapy with adjuvant intent and 28 patients received palliative chemotherapy. The median score was 10.2% for TS and 35% for ERCC1. There was no correlation between TS expression and OS (13.7 vs. 21.6 months for low and high levels, respectively P = .32). There was a trend between high ERCC1 expression and longer OS (27.6 vs. 10.3 months P = .06). In this series of patients with MPM undergoing EPP, TS expression was not associated with prolonged survival, but there was a trend for longer survival in patients with high ERCC1 expression.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.EJCA.2006.01.052
Abstract: The aim of this study was to investigate the improvement of quality of radiotherapy and compliance to the protocol amendment of EORTC study 08941. The radiotherapy-specific data were analysed from 154 patients with stage IIIA-N2 Non-Small-Cell Lung Cancer who were actually irradiated after response to 3 cycles of platinum-based induction chemotherapy. The parameters of quality, assessed in 93 patients before and in 61 after protocol amendment, included: time interval between last chemotherapy course and start of thoracic radiotherapy, the use of a 3-D planning CT, dose and fractionation scheme to the primary tumour, the involved and uninvolved mediastinum, duration of radiotherapy and toxicity. A significant improvement of all quality parameters was noted, except for the overall treatment time, which decreased slightly. Protocol amendment resulted in an improvement of the quality and the compliance of most observed parameters, at the cost of some increase in overall treatment time. The latter reflects logistical problems rather than poor compliance.
Publisher: Public Library of Science (PLoS)
Date: 03-03-2014
Publisher: Wiley
Date: 1994
Abstract: The presence of the neural cell adhesion molecule, NCAM, is indicative for a poor prognosis in lung-cancer patients. Using MAb 735, we have investigated the expression of polysialic acid, PSA, on NCAM in a spectrum of neuro-endocrine lung tumors, ranging from the slowly growing typical carcinoids via the atypical carcinoids with clinically unpredictable behavior to the highly aggressive small-cell lung carcinomas. Our immunohistochemical findings indicate a significant association between the presence of PSA on the tumor cells and an aggressive and immature sub-type of the tumor. This might be related to impairment of cell-cell and cell-matrix interactions by the presence of PSA, as we demonstrated in vitro, since detachment is one of the first steps in the metastatic process. The NCAM-MAb 123C3 used in these studies appeared extremely useful in immunoscintigraphy and immunotherapy of SCLC xenografts in nude mice, and for immunoscintigraphy of a SCLC patient. This may be explained by internalization of the 123C3 antibody, which we demonstrated in vitro. 123C3 is the only Cluster-I SCLC MAb studied thus far that becomes internalized.
Publisher: Elsevier BV
Date: 03-1995
DOI: 10.1016/0169-5002(95)00409-T
Abstract: Metal wire expandable stents are increasingly being used to alleviate tracheal obstruction due to malignancies. Patients usually tolerate these stents well and experience good to excellent palliation of their symptoms [1]. We report a case in which severe tracheal obstruction occurred 5 days after placement of a Wallstent, caused by formation of fibrinoid plaques at the proximal end of the stent.
Publisher: Informa UK Limited
Date: 2005
Abstract: Inflammation represents a complex biologic and biochemical process involving cells of the immune system and a plethora of biologic mediators in response to mechanical, chemical or infectious injuries. When mobilization of effector cells and molecules becomes excessive, the beneficial aspect of this response--to limit damage and promote healing, can be overriden, resulting in host-cell and tissue dysfunction. Based on the hypothesis that chronic infections underly some inflammatory diseases, antibacterial therapy has long been assessed in various inflammatory settings. Recently, the anti-inflammatory activity of some antibacterial agents has also been suspected. Of these duel-action drugs, ansamycins represent an interesting family. Although their therapeutic use is restricted to potentially infectious inflammatory diseases, many experimental data suggest that these drugs also possess direct inhibitory activity on some crucial proinflammatory effectors. To date, the potent antimycobacterial activity of the therapeutically useful ansamycins precludes their widespread use in inflammatory diseases. However, biosynthetic manipulation remains an attractive route for the generation of pharmacologically useful analogs.
Publisher: Elsevier BV
Date: 08-2007
Publisher: Elsevier BV
Date: 1992
DOI: 10.1016/0959-8049(92)90065-A
Abstract: Epirubicin 110 mg/m2 was administered intravenously every 3 weeks to 41 elderly and/or unfit, previously untreated patients with small cell lung cancer (SCLC). There were three complete responses, 16 partial responses and 14 treatment failures, with a response rate of 57% in 33 evaluable patients. The main toxicity was haematological, characterised by leukopenia and, less frequently, thrombocytopenia and anaemia. There were three toxic deaths due to infection occurring during leukopenia. Non-haematological side effects were alopecia, nausea, stomatitis and diarrhoea. WHO grade 2 cardiac toxicity was seen in 3 patients after a cumulative dose of more than 740 mg/m2. In conclusion epirubicin is an active agent in untreated SCLC.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.LUNGCAN.2009.07.001
Abstract: The role of surgery in the treatment of patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) is a hot topic. Since variable results of surgery versus radiotherapy after induction chemotherapy are being reported, this study aimed to analyze results of surgery after induction chemotherapy and to identify relevant factors influencing outcome in patients with stage IIIA NSCLC. Patients with stage IIIA (N2) NSCLC, treated with platinum-based induction chemotherapy between 1994 and 2006, were identified. By a retrospective review of hospital records, response to induction treatment, short-term outcome, recurrence of disease and survival were evaluated. Ninety-nine patients, 66 men and 33 women, were identified. Median follow-up was 54 months (range 13-129). Median age at treatment was 62 (range 36-77). Mediastinal downstaging was seen in 32 patients. Forty-three patients received radical radiotherapy and 39 patients underwent surgery: 19 pneumonectomies, 19 lobectomies and one exploratory thoracotomy. Microscopic complete resection (R0) was reached in 30 patients. Pathological response to induction therapy was CR in 5%, PR in 59% and SD in 36%. Postoperative mortality was 3%. The 1-year mortality was 26% after pneumonectomy and 11% after lobectomy. Five-year survival after surgery was 28%, and was better after lobectomy than after pneumonectomy (43% versus 16% p=0.03). Other factors as age, weight loss, clinical mediastinal downstaging, radicality, and histology did not substantially contribute to this difference. Type of surgical resection was the major factor influencing outcome in patients with stage IIIA (N2) NSCLC after induction chemotherapy. These results suggest that patients with stage IIIA (N2) NSCLC may benefit from surgical resection, as long as a lobectomy can be performed.
Publisher: Public Library of Science (PLoS)
Date: 07-10-2014
Publisher: Elsevier BV
Date: 11-1993
DOI: 10.1016/0167-8140(93)90235-Z
Abstract: To determine dose-effect relations for regional lung-function changes after radiotherapy. Single Photon Emission Computed Tomography (SPECT) was performed to quantify regional ventilation and perfusion. CT scans were used to calculate the three-dimensional (3-D) dose distribution. Both SPECT and CT scans were performed prior to radiotherapy and 5 months after the start of the treatment. To obtain combined 3-D information on ventilation, perfusion and dose, the SPECT data were correlated with the corresponding CT data. The relative changes in ventilation and perfusion were calculated in each SPECT voxel (voxel size about 6 x 6 x 6 mm) and related to the dose in that voxel. The average relative changes were determined per dose interval of 4 Gy. This procedure was evaluated using the data from five patients treated for Hodgkin's disease with mantle field irradiation with a prescribed total dose of 40-42 Gy. Dose-effect relations for perfusion were observed in all patients, while in four of the five patients, a dose-effect relation was found for ventilation. The maximal uncertainty of the calculated radiation dose was 11%: a difference between the position of the patient during treatment and during CT scanning caused a maximal dose uncertainty of 6%, while the accuracy of the dose calculation algorithm itself was estimated to be within 5%. The results indicate that the combined use of SPECT and CT information is an effective method for determining dose-effect relations for regional lung function parameters in each in idual patient.
Publisher: Springer Science and Business Media LLC
Date: 06-1993
DOI: 10.1007/BF02547804
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0169-5002(02)00245-3
Abstract: The recent promising results with low-dose CT have stimulated the revival of the scientific discussion on screening for early lung cancer and mark the end of a significant period with lack of progress. At the same time positron emission tomography has quickly shown its value as a staging tool. Also new endobronchial techniques such as autofluorescence bronchoscopy and endobronchial ultrasonography have shown remarkably increased sensitivity when used by experienced hands. Cytopathological risk markers in sputum are being developed and it is expected that combinations of these new diagnostic methods will help to increase the identification of asymptomatic lung cancer patients and turn into better survival figures.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-06-2007
Abstract: The purpose of this study was to evaluate if sequential 99m Tc Hynic-rh- annexin V scintigraphy (TAS) can predict outcome in patients with advanced lung cancer, shortly after the start of platinum-based chemotherapy. In 16 consecutive chemotherapy-naive patients with advanced stage non–small-cell lung cancer scheduled for platinum-based chemotherapy, TAS was performed before and within 48 hours after the start of therapy. Chemotherapy-induced changes in tumor annexin V uptake, calculated as maximum count per pixel and expressed as percentage to baseline value, were compared with treatment response determined according to Response Evaluation Criteria in Solid Tumors. A significant correlation (r 2 = 0.86 P = .0001) was found between annexin V metabolic changes and treatment outcome. All patients with notably increased annexin V tumor uptake showed complete or partial response. Less prominently increased or decreased uptake correlated with stable or progressive disease. TAS is a promising test to predict tumor response in patients with advanced lung cancer early in the course of platinum-based chemotherapy.
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.LUNGCAN.2004.10.005
Abstract: The purpose of this study was to describe the experience with the anti-angiogenic agent thalidomide in the treatment of patients with a malignant pleural mesothelioma (MPM). Patients with a histological confirmed diagnosis of malignant mesothelioma received thalidomide orally at night. Increasing doses of 100, 200 or maximally 400 mg were given till progression or unacceptable toxicity. Patients that did not show signs of progression for > or =6 months were considered responders. Neurological examination included the use a sensory nerve action potential (SNAP) test. Forty patients were evaluable for toxicity and efficacy. Twenty of them (50%) had received prior treatment. Thirty patients (75%) received a dose of 400 mg, 11 (37%) required dose reduction and 10 patients were confined to a dose of 200 mg or less. The major toxicity elicited by thalidomide concerned constipation (18/40 grade I and II) and two patients developed grade II neurotoxicity. A decline in SNAP test (>50%) did not seem to be related to the extent of neurological complaints. Eleven patients (27.5%) showed disease stabilization for >6 months and the median survival was 230 days (CI 130-330). The advised dose for future studies in these patients is 200 mg/day. At this dose level, the toxicity is mild and routine monitoring of neurological toxicity (SNAP test) can be omitted. The percentage of patients seen with prolonged disease stabilization upon thalidomide treatment warrants phase III studies in MPM.
Publisher: Elsevier BV
Date: 12-1989
Publisher: Elsevier BV
Date: 08-0088
DOI: 10.1016/J.JTHO.2017.05.024
Abstract: The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression. PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from s les from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay. In a series of 72 patients with MPM, 18 (25%) had positive PD-L1 staining, and this was more common in patients with the nonepithelioid subtype (p = 0.01). PD-L1 expression was associated with poor survival (median overall survival 4.0 versus 9.2 months with positive versus negative PD-L1 expression [p < 0.001]), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (hazard ratio = 2.2, 95% confidence interval: 1.2-4.1, p < 0.01). In the same patient series, PD-L1 expression was also associated with downregulation of microRNAs previously shown to have tumor suppressor activity in MPM. The median microRNA expression levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the PD-L1-positive s les. Transfecting MPM cell lines with mimics corresponding to miR-15a and miR-16, both of which are predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative G-U-containing target site, also caused PD-L1 downregulation. Together, these data suggest that tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM.
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.EJCA.2005.05.011
Abstract: Lung cancer ranks among the most commonly occurring malignancies and is currently the leading cause of cancer-related death worldwide. This is due to its late diagnosis and relative resistance to standard oncological treatment approaches. The heavy burden of lung cancer and its treatment resistance have elicited an intense interest in the promising approach of chemoprevention. Chemoprevention is defined as a pharmacologic intervention to suppress or reverse the carcinogenic process and the lung is one of the most studied sites for cancer chemoprevention. This review, with a short update on pulmonary carcinogenesis, will summarize the available knowledge of chemoprevention trials and agents with a preventive potential in the 'lung field'.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2002
DOI: 10.1097/00001622-200203000-00008
Abstract: Among all cancers, lung cancer has the highest rate of mortality in the western world, both in men and women. The poor lung cancer survival rates argue powerfully for new approaches to control this disease, such as chemoprevention, which has been defined as the use of agents that reverse, suppress, or prevent lung carcinogenesis. Over 80% of lung cancers are attributed to tobacco and carcinogens from cigarette smoke, which unquestionably links nicotine addiction and lung cancer. Epidemiologic studies show that not more than 15% of heavy smokers will ultimately develop lung cancer. That 85% of heavy smokers will not develop lung cancer points to differences in susceptibility. Diet and genetically determined factors seem to play an important role in modulating in idual susceptibility and are closely linked to the chemoprevention approach. Despite encouraging data from experimental and epidemiologic studies, the evidence for a positive effect in the human situation is still controversial. However, recent developments in molecular biology and increased insight in lung carcinogenesis have led to the potential of more specifically targeted intervention and optimism for new, successful chemopreventive approaches.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.EJSO.2021.02.008
Abstract: Low muscle attenuation, as governed by increased intramuscular fat infiltration (myosteatosis), may associate with adverse surgical outcomes. We aimed to determine whether myosteatosis is associated with an increased risk of postoperative complications and reduced long-term survival after oesophago-gastric (OG) cancer surgery. Patients who underwent radical OG cancer surgery with preoperative abdominal computed tomography (CT) imaging were included. Myosteatosis was evaluated using previously defined cut-points for low skeletal muscle attenuation measured by CT. Oncological, surgical, complications, and outcome data were obtained from a prospective database. Of 108 patients, 56% (n = 61) had myosteatosis. Patients with myosteatosis were older (69.1 ± 9.1 vs. 62.8 ± 9.8 years, p = 0.001) and had a similar body mass index (BMI) (23.4 ± 5.3 vs. 25.9 ± 6.7 kg/m Myosteatosis is associated with a significantly increased risk of overall and severe complications as well as substantially reduced long-term survival. Assessment of muscle attenuation provides analysis beyond standard anthropometrics and may form part of preoperative physiological staging tools used to improve surgical outcomes.
Publisher: Elsevier BV
Date: 1992
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.LUNGCAN.2007.09.007
Abstract: In animal models of lung carcinogenesis, inhaled corticosteroids appear to reduce the number of new lung tumors. In a trial of budesonide in smokers with bronchial dysplasia, the proportion of indeterminate CT detected pulmonary nodules that resolved was larger in the treatment group. We performed a secondary analysis of CT data of subjects at risk of lung cancer enrolled in a chemoprevention trial of fluticasone. Subjects with bronchial squamous metaplasia or dysplasia had a baseline chest CT scan. They were randomized to fluticasone or a placebo. After 6 months a repeat CT was performed and the change in number and size of nodules was evaluated. Two hundred and one subjects were screened. Of the 108 volunteers included in the study, 74 were male, mean age was 53 years and mean number of pack years 48. Baseline: 35 subjects had 91 nodules in total, 62% <4mm. In the fluticasone arm more subjects had a decrease and fewer had an increase in number of nodules, however this trend did not reach statistical significance. In this preliminary study there was a tendency of nodules to resolve, however, studies with CT detected nodules as inclusion criterion are needed.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JGO.2019.02.013
Abstract: Malignant pleural mesothelioma (MPM) is a cancer that primarily affects older adults. However this patient population is frequently under-represented in clinical studies. Therefore, we studied the impact of advancing age on treatment utilisation and clinical outcomes in an extensive series of minimally selected MPM patients. Patients with MPM receiving compensation from the New South Wales (NSW) Dust Diseases Authority (2002-2009) were assessed. They were categorised by age ( 80 years) and chi-square testing was used to assess the relationship between clinical and demographic variables, age, treatment and overall survival (OS). We identified 910 patients 41% were aged 80 years old. Median OS decreased with increasing age: 13.5 months in 80 years as did chemotherapy use (66%, 35% and 8% respectively). Radical surgical intervention, adjuvant, and palliative radiotherapy were less frequently used with advanced age. A Kaplan Meier analysis revealed that there was a significant survival advantage (p < .001) for patients 80 years. Advancing age group of NSW patients with MPM was associated with reduced treatment utilisation and a decline in OS. Prospective studies are warranted to verify if current treatment guidelines are relevant for the older adults with MPM.
Publisher: Elsevier BV
Date: 10-1997
DOI: 10.1016/S0959-8049(97)00174-3
Abstract: This study was undertaken to determine if recombinant interferon-gamma (rIFN-gamma) given every other day as maintenance therapy could prolong the survival of patients with small cell lung cancer (SCLC) who achieved a complete or nearly-complete response to induction therapy. A secondary endpoint was to assess the toxicity of alternate day doses of this treatment. One hundred and seventy seven patients in complete or nearly-complete response following chemotherapy with or without thoracic radiotherapy were studied. Patients were randomised to receive either rIFN-gamma 4 million units (0.2 mg) subcutaneously every other day for 4 months or observation. One hundred and twenty of the 127 registered patients were eligible 59 patients received IFN and 61 patients without maintenance therapy were followed. Alternate day IFN was reasonably well tolerated by the majority of patients, but in 12% substantial non-haematological toxicity (including flu-like syndrome) occurred. One of 3 patients with pneumonitis died after having received 3.6 mg IFN. The median survival time from the date of randomisation was 8.9 months for the IFN arm and 9.9 months for the observation arm. rIFN-gamma at the dose and schedule used in this study failed to prolong response duration and survival in SCLC patients in complete or nearly-complete response. The toxicity seen with every other day doses of IFN was less than that reported with daily dosing. The hypothesis that this agent may increase the deleterious effects of radiation on normal lung tissue was supported by the development of pneumonitis in 3 cases of whom 1 had a fatal outcome. The results do not warrant further studies with rIFN-gamma on maintaining response in SCLC.
Publisher: Informa UK Limited
Date: 17-08-2016
DOI: 10.1080/10937404.2016.1194254
Abstract: Australia is known to have had the highest per-capita asbestos consumption level of any nation, reaching a peak in the 1970s. Although crocidolite was effectively banned in the late 1960s, and amosite use ceased in the mid 1980s, a complete asbestos ban was not implemented until 2003. This resulted in an epidemic of asbestos-related disease, which has only now reached its peak. Between 1982 and 2011, 13,036 in iduals were newly diagnosed with malignant mesothelioma, with 690 diagnosed in 2011. A further 778 cases were identified between 1945 and 1981 from retrospective searches and the first 2 years of the Australian Mesothelioma Program. The age-standardized malignant mesothelioma incidence rate has leveled off in the last 10 years (2.8 per 100,000 in 2011). There has been a marked increase over time in the age-specific incidence rates for in iduals aged 75 years or older. Data from the current Australian Mesothelioma Registry on asbestos exposure history in Australia is available for 449 subjects diagnosed between July 1, 2010, and April 1, 2015. This asbestos exposure history data show that 60% (n = 268) of cases had probable or possible occupational asbestos exposure, with trade-based jobs being the most frequent sources of occupational asbestos exposure. In addition, out of the 449 cases, 377 were recorded as having probable or possible nonoccupational asbestos exposure. Continuous vigilance toward changes over time in the settings in which people are exposed to asbestos and in the descriptive epidemiology of malignant mesothelioma is recommended to enable a comprehensive understanding of the current and future impact of asbestos-related diseases in Australia.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.LUNGCAN.2004.10.014
Abstract: Gemcitabine-platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally. Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes. A significant reduction in overall mortality in favor of gemcitabine-platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84-0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine-platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine-platinum regimens, HR 0.84 (CI: 0.71-0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93 (CI: 0.86-1.01). There was a significant decrease in the risk of disease progression in favor of gemcitabine-platinum regimens, HR 0.88 (CI: 0.82-0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine-platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine-platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77-0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82-0.96).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
Publisher: Wiley
Date: 11-2010
DOI: 10.1111/J.1445-5994.2010.02223.X
Abstract: Malignant mesothelioma (MM) is an aggressive tumour that commonly affects the mesothelial surfaces of the pleural and peritoneal cavities, and occasionally, the tunica vaginalis and the pericardium. Formerly a rare tumour, MM is increasing in incidence in Australia due to the heavy nationwide use of asbestos from 1940 until the 1980s. The incidence is expected to peak in Australia in the next decade, mirroring the long latency period between asbestos exposure and development of MM. Diagnosis of MM can be difficult. Definitive pathological diagnosis is required and it often requires an experienced pathologist to differentiate MM from other benign or malignant processes. Treatment of MM requires a multidisciplinary approach, regardless of palliative or curative intent. Treatment options, such as surgery, chemotherapy, radiotherapy and active symptom control or a combination of these, may be used. Further research is needed to advance the therapeutic options for MM, and strategies to realize personalisation of therapy through discovery of predictive markers. In the Australian society where asbestos contamination of the built environment is very high, education and stringent public health measures are required to prevent a second wave of increased MM incidence.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-11-2005
Abstract: The objective of this study was to determine the accuracy of (early) response measurements using [ 18 F]-2-fluoro-2-deoxy-D-glucose positron emission tomography ( 18 FDG PET) with respect to survival of patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC) undergoing induction chemotherapy (IC), with a comparative analysis of PET methods. In a prospective multicenter study, PET was performed in patients before IC and after one and three cycles. Computed tomography (CT) was performed before and after IC. Glucose consumption (metabolic rate of glucose [MR glu ]) was measured using Patlak graphical analysis and correlated with simplified methods. Mediastinal lymph node (MLN) status was assessed visually. Cox proportional hazards analysis was used to determine the prognostic relevance of CT and PET measures of response with respect to survival. Complete PET data sets were available in 47 patients. Median survival was 21 months. MLN status after IC by PET predicted survival (hazard ratio [HR], 2.33 95% CI, 1.04 to 5.22 P = .04) in contrast with CT (HR, 1.87 95% CI, 0.81 to 4.30 P = .14). Residual MR glu after IC proved to be the best prognostic factor (HR, 1.95 95% CI, 1.28 to 2.97 P = .002). Multivariate stepwise analysis showed that PET identified prognostically different strata in patients considered responsive according to CT. Residual MR glu after one cycle selected patients with different outcomes (HR, 2.04 95% CI, 1.18 to 3.52 P = .01). Simplified quantitative 18 FDG PET methods were correlated with Patlak graphical analysis during and after therapy (r ≥ 0.90). 18 FDG PET has additional value over CT in monitoring response to IC in patients with stage IIIA-N2 NSCLC, and it seems feasible to predict survival early during IC. Simple semiquantitative and complex PET methods perform equally well.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1996
DOI: 10.1097/00001622-199603000-00008
Abstract: Although the overall survival rates for patients with metastatic non-small cell lung cancer have not changed in the past two decades, meta-analytic studies have confirmed that a modest increase in mean survival time can be gained with platinum-based combination chemotherapy. With appropriate selection of patients, chemotherapy will have symptomatic benefits in more than 60% of patients, and concerns regarding the costs of chemotherapy will be lessened by the observation that in some instances chemotherapy is less costly than best supportive care. Until the end of the 1980s, apart from the few active agents and their analogues no new drugs became available, but in the past 5 years several new agents have shown promising results and are now being included in combination programs. Large-scale comparative studies, looking for the combination with the best therapeutic index, are awaited with great interest. The number of patients with non-small cell lung cancer is so great that even modest improvements in therapy will have a great impact on survival rates.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.CLLC.2012.03.011
Abstract: We aimed to examine the prognostic values of established risk factors and to validate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in an independent series of patients with malignant pleural mesothelioma (MPM). A total of 148 patients who applied for compensation at the Dust Diseases Board from 2007 to 2009 were included in this study. Overall survival was determined by the Kaplan-Meier method, and NLR was defined as the absolute neutrophil ided by the lymphocyte count. The prognostic value of the variables was examined by using Cox regression analysis, and all factors were entered into a multivariate model to determine their independent effect. The patient characteristics were median age of 73 years 93% men 59% epithelial subtype median NLR of 3.5 at diagnosis (n = 79) median overall survival of 10.6 months. The following variables were predictive of longer overall survival in univariate analysis: younger age, epithelial subtype, lower tumor stage, low white cell count, low platelet count, low hemoglobin level, and low NLR. Multivariate analysis confirmed that nonepithelial vs. epithelial subtype (hazard ratio [HR], 3.0 P < .001), tumor stage (HR, 1.6 P < .001), hemoglobin level difference ≥10 vs. <10 (HR, 2.0 P = .03), no chemotherapy vs. use of chemotherapy (HR, 2.4 P < .001), and NLR ≥3 vs. <3 (HR, 2.2 P < .01) were independently associated with prognosis. Apart from previously recognized factors, such as histosubtype, tumor stage, and hemoglobin level difference, NLR, an index of systemic inflammation bears prognostic significance that shows that a snapshot of immune status is able to convey important prognostic information.
Publisher: Springer Science and Business Media LLC
Date: 05-1995
DOI: 10.1007/BF01521343
Publisher: Wiley
Date: 04-1991
DOI: 10.1111/J.1365-2273.1991.TB01966.X
Abstract: The influence of a heat and moisture exchanger (HME) on the respiratory symptoms after total laryngectomy was studied in 42 patients. A significant reduction was found in the mean daily frequency of sputum production, forced expectoration in order to clean the airway and stoma cleaning after use of the HME for 6 weeks. Symptoms of fatigue and malaise decreased significantly, while social contact improved. Patients using oesophageal speech or an electrolarynx benefited more than patients using a voice prosthesis. The findings indicate that respiratory problems after total laryngectomy can be reduced significantly with the use of a device with heat and moisture exchanging properties. In turn, reduction of respiratory symptoms results in an improved quality of life.
Publisher: Impact Journals, LLC
Date: 22-06-2015
Publisher: Wiley
Date: 1995
Abstract: Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well-recognized causes. Apart from oxidants (free radicals), cigarette smoke contains such a multitude of (pre)carcinogens that it is astonishing that not every heavy smoker becomes a victim of malignancy. This points to the interin idual variability in susceptibility to carcinogens several lines of evidence suggest that metabolic factors are involved in such variability. Metabolism of carcinogens as well as the subsequent (multi)steps of carcinogenesis are affected by host factors and governed by the balance between opposing forces, such as metabolic activation and detoxification, formation and scavenging of radicals, and DNA damage and repair, which seem to imply that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione (GSH) plays a crucial role in the detoxification of xenobiotics. N-Acetylcysteine (NAC), an aminothiol and synthetic precursor of intracellular cysteine and GSH, has been used for many years in Europe as a mucolytic drug. Clinically, it is a safe agent without major side effects and has been considered to have a place in cancer prevention, too. The antimutagenic and anticarcinogenic properties of NAC could be ascribed to multiple protective mechanisms, such as NAC nucleophilicity, antioxidant activity, its ability to act as a precursor of intracellular reduced GSH, modulation of detoxification, and DNA repair processes. On these grounds, NAC has emerged as a most promising cancer chemopreventive agent.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Oxford University Press (OUP)
Date: 05-1998
Abstract: The 32P-post-labelling assay for DNA adduct quantification gives the opportunity to examine endogenous exposure to DNA reactive compounds. Most human biomonitoring studies applied white blood cells (WBC) or cells obtained by broncho-alveolar lavages (BAL) as source of DNA, but still it is not clear what cell type represents the most reliable indicator for exposure to cigarette smoke-associated genotoxins. At first, we examined DNA adduct levels by means of nuclease P1 (NP1) enriched 32P-post-labelling in separated WBC subpopulations after in vitro incubations for 18 h with 10 microM benzo[a]pyrene (B[a]P). DNA adduct levels were highest in monocytes (10.7 +/- 2.9 adducts/10(8) nucleotides, n = 8), followed by lymphocytes (5.9 +/- 1.7, n = 8), and granulocytes (0.5 +/- 0.2, n = 8). Secondly, aromatic-DNA adduct levels were determined in BAL cells and WBC-subsets from (non-)smoking volunteers. In smoking in iduals, adduct levels were in the ranking order: BAL cells (3.7 +/- 1.0, n = 5) > monocytes (2.0 +/- 0.5, n = 8) > or = lymphocytes (1.6 +/- 0.4, n = 8) > granulocytes (0.8 +/- 0.2, n = 8) by NP1-enrichment and monocytes (9.0 +/- 3.2, n = 5) > or = lymphocytes (8.0 +/- 2.1, n = 6) > granulocytes (2.1 +/- 0.3, n = 7) by butanol-enriched 32P-post-labelling. Aromatic-DNA adduct levels were significantly higher in WBC-subsets of smokers as compared with non-smokers, except for DNA adducts in granulocytes using butanol enrichment. Thirdly, dose-response relationships were investigated in mononuclear white blood cells (MNC, i.e. monocytes plus lymphocytes) and BAL-cells of a larger group of smoking in iduals (n = 78). Adduct levels in MNC were related to daily exposure to cigarette-tar (r = 0.31, P < 0.01). Adduct levels in BAL cells seemed to be correlated with pack-years, but after correction for age this relationship was lost. Butanol extraction resulted in 5-6-fold higher DNA adduct levels in MNC, whereas butanol extraction of BAL-DNA of the same in iduals yielded only 2-fold higher adduct levels. The two enrichment procedures of 32P-post-labelling were correlated in BAL cells (r = 0.86, P < 0.001, n = 12). We conclude that particularly MNC are good surrogates for the detection of smoking-related DNA adducts.
Publisher: Informa UK Limited
Date: 02-04-2016
Publisher: American Association for Cancer Research (AACR)
Date: 04-2004
DOI: 10.1158/1078-0432.CCR-03-0060
Abstract: Purpose: Paclitaxel is a taxane derivative with a profound antitumor activity against a variety of solid tumors. In a previous clinical study in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel, it was shown that paclitaxel plasma concentrations of 0.1 μmol/liter for ≥15 h were associated with prolonged survival. The purpose of this study was to evaluate the feasibility of Bayesian dose in idualization to attain paclitaxel plasma concentrations & .1 μmol/liter for ≥15 h. Experimental Design: Patients with stage IIIb-IV NSCLC were treated with paclitaxel and carboplatin once every 3 weeks for a maximum of six courses. During the first course, a standard paclitaxel dose of 175 mg/m2 was administered i.v. in 3 h. In subsequent courses, the paclitaxel dose was in idualized based on observed paclitaxel concentrations in plasma during the previous course(s) using a Bayesian algorithm. The paclitaxel dose of a subsequent course was increased to the lowest dose for which the predicted time period during which the paclitaxel plasma concentration exceeds 0.1 μmol/liter was & h. Results: A total of 25 patients have been included in the study (92 evaluable courses). During the first course, the median time period above the threshold concentration was 16.3 h (range, 7.6–31.6 h), and was & h for 9 patients (36%). During subsequent in idualized courses, the time period above the threshold concentration was & h in 23% (5 of 22), 14% (2 of 14), 23% (3 of 13), 11% (1 of 9), and 11% (1 of 9) of the patients in the second, third, fourth, fifth, and sixth course, respectively. Dose increments, ranging from 5 to 65 mg/m2, were performed in 29 of the 67 in idualized courses. Patients with increased in idualized doses had similar regimen related toxicities compared with those remaining at a dose of 175 mg/m2. Toxicity was reversible and manageable, and was mainly hematological (granulocytopenia CTC grade 3/4 in 80% of the patients). The objective response rate was 20%. Conclusions: The results indicate that the applied pharmacokinetically guided dosing strategy for paclitaxel is safe and technically feasible. A randomized study is necessary to demonstrate whether dose in idualization may result in improved activity and efficacy in patients with NSCLC.
Publisher: Springer Science and Business Media LLC
Date: 14-02-2013
DOI: 10.1007/S00520-013-1753-3
Abstract: Malignant pleural mesothelioma (MPM) is considered a treatment-resistant disease. We determined the proportion of patients who received treatment in the last month of life and potential factors associated with use of chemotherapy at the end of life. Consenting MPM patients compensated by the Dust Diseases Board (DDB) were included. Patient, treatment and outcome details were obtained through the DDB, treating physicians and Medicare Australia. The association between potential factors (age, gender, geographical location, disease stage, histological subtype, palliative care referral, length of first line chemotherapy and lines of treatment) and chemotherapy use in the last month of life was determined. A total of 147 MPM patients were included in the analysis: 78 received chemotherapy, 50 had radiotherapy and 116 had surgery (77 received more than one treatment modality whilst 56 received one treatment modality). Twenty-one patients received treatment in their last month of life: nine received chemotherapy six, radiotherapy and six had surgery. Those who were treated with second or subsequent lines of chemotherapy were more at risk of receiving chemotherapy until the end of life (six of 19 patients, i.e., 32 %) compared to those who were only treated with first-line therapy (three of 59 patients, i.e., 5 % p < 0.01). Patients who received chemotherapy at the end of life had shorter survival compared to those who did not receive chemotherapy at the end of life (5.3 vs. 12.5 months, respectively p = 0.01). Chemotherapy utilisation in the last month of life is not uncommon in this series of MPM patients. Patients who failed previous chemotherapy were more likely to receive chemotherapy near the end of life. More careful consideration of when to cease chemotherapy needs to be made as patients who received chemotherapy at the end of life had poorer survival outcome.
Publisher: Georg Thieme Verlag KG
Date: 09-02-2021
Abstract: Introduction Long-term percutaneous enteral nutrition forms an important part of treatment for patients with an inability to meet nutrient requirements orally. Radiologically inserted gastrostomy (RIG) is an alternative to the traditionally performed percutaneous endoscopic gastrostomy technique. However, there is marked heterogeneity in the way that RIG is performed. In addition, the role for antibiotic prophylaxis during RIG insertion is not clearly established. This study aimed to assess the safety of RIG insertion using our technique including the role of antibiotics in RIG insertion. Method Retrospective study over 5 years at a tertiary teaching hospital. Periprocedural or early complications within the first 2 weeks of the procedure were collected and correlated with the use of prophylactic antibiotics. Results A total of 116 patients met the inclusion criteria. 18-French tube was used in 96.6%. Note that 58.6% of procedures were done with intravenous sedation. Prophylactic 1 g cefazolin was used in 70 patients with 1 case of infection. Procedures were performed without antibiotics in 46 patients with 3 infections, p = 0.20. There were two major complications (1.7%) consisting of right gastric artery injury requiring embolization and gastric wall injury requiring laparotomy. There were 12 minor complications (10.3%) including 4 cases of infection, 3 of severe pain, 1 of minor bleeding, 2 of early dislodgement, and 2 of leak/bypass of gastric contents around the tube. Conclusion The technique used for RIG insertion at our institution results in a low complication rate. In addition, this study shows no significant difference in early peristomal infection rate with the use of antibiotic prophylaxis.
Publisher: Elsevier BV
Date: 10-2010
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/00016480600868414
Abstract: Annual post-treatment screening of head and neck squamous cell carcinoma (HNSCC) patients for second primary lung cancer and metastatic recurrence appeared to form no major burden for head and neck cancer patients. A majority of patients regard the annual chest X-ray as a reassurance. Given these results a more intensive screening program seems psychologically justifiable for this group. To assess the psychological impact of annual post-treatment screening for second primary lung cancer and metastases in HNSCC patients. In a cohort of 106 patients, 68 men and 38 women, with a mean age of 56, the impact of the yearly chest radiograph was evaluated by means of a nine-item questionnaire. In all, 90% of the patients were in favor of annual post-treatment screening, 2% would not like to receive this screening, and 8% had no preference. A majority (98%) considered the screening as an extra medical check and 76% felt reassured. Although 21% of the patients were very nervous about the outcome of the screening, only 3% wanted to avoid the yearly chest X-ray for this reason.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.LUNGCAN.2011.02.017
Abstract: Erlotinib is a highly potent inhibitor of epidermal growth factor receptor tyrosine-kinase activity that significantly prolongs overall survival in patients with non-small-cell lung cancer (NSCLC), and improves symptom control and quality of life compared with placebo. The safety and efficacy of erlotinib has been investigated in a large, international, phase IV, open-label study (TRUST) in patients (n=6665) with advanced stage IIIB/IV NSCLC. An analysis of efficacy and safety outcomes is reported for patients receiving erlotinib as second-line therapy in TRUST (n=3224). Best response data were available for all 3224 patients. Complete response, partial response and stable disease were achieved in 25 (<1%), 368 (14%) and 1444 (54%) patients, respectively, for a disease control rate of 68%. Median progression-free and overall survivals were 13.6 weeks and 8.6 months, respectively 1-year survival was 39.4%. Safety data were available for all patients. Of these, 389 patients (12%) had an erlotinib-related adverse event (AE) other than pre-specified AEs defined in the protocol only 96 patients (3%) had an erlotinib-related AE ≥ grade 3. Of 1376 patients (43%) with serious AEs (SAEs), only 122 (4%) had treatment-related SAEs and most were gastrointestinal disorders (mainly diarrhoea and nausea). No treatment-related SAE occurred in ≥ 1% of patients. Data on the incidence of erlotinib-related rash were collected for all patients, 2302 (71%) of whom experienced rash. Of these rash events, 83% were of grade 1/2. These data confirm the good efficacy and tolerability of second-line erlotinib in a broad range of patients with NSCLC.
Publisher: Springer Science and Business Media LLC
Date: 06-2016
Publisher: Elsevier BV
Date: 04-1995
DOI: 10.1016/0169-5002(95)00418-Z
Abstract: In recent years, a group of new prognostic factors have been added to the list of well-known clinical prognostic factors of non-small cell lung cancer. Among these are mutations in the K-ras oncogene, abnormalities in p53, the presence of N-CAM expression as measured by Mab immunostaining and elevated serum levels of NSE. These factors have provided important clinical insights into the biology of lung cancer and prospective studies using these biomarkers are now warranted to provide further important clues about their potential significance in treatment selection of patients.
Publisher: Springer Science and Business Media LLC
Date: 09-1996
DOI: 10.1038/BJC.1996.465
Abstract: The EORTC Lung Cancer Cooperative Group undertook a phase II study of paclitaxel in 25 chemotherapy-naive patients with malignant pleural mesothelioma. Paclitaxel was given intravenously at a dose of 200 mg m-2 as a 3 h infusion every 3 weeks, after standard premedication with corticosteroids and antihistamines. This regimen was well tolerated, with < 4% of cycles resulting in severe toxicity. No major objective responses were observed and ten patients had stable disease. Median survival time was 39 weeks and the 1 year survival rate was 30%. In conclusion, paclitaxel at the dose and schedule investigated in this trial had no major activity in the treatment of malignant pleural mesothelioma.
Publisher: Wiley
Date: 15-04-1991
DOI: 10.1002/1097-0142(19910415)67:8<2033::AID-CNCR2820670804>3.0.CO;2-8
Abstract: Twenty-two consecutive patients with malignant diffuse pleural mesothelioma were treated with recombinant gamma-interferon by the intrapleural route. Diagnosis was made by thoracoscopic examination and all cases were confirmed by the French Mesothelioma Panel of Pathologist. Patients were staged based on thoracoscopic examination and computed tomography (CT) scan: 12 patients were classified as Stage I and 10 were Stage II. A solution of gamma-interferon (40 X 106 U) was infused twice a week over 2 months. Every patient experienced fever. One patient had a Grade 2 leukopenia and one patient suffered from pleural empyema. Response evaluation was based on the following: (1) CT scan performed 2 weeks after treatment ended, and (2) repeat thoracoscopic examination with histopathologic verification in nine patients who had demonstrated a stabilization or a regression of the disease on CT scan. From the original group, 19 patients could be evaluated. Four complete thoracoscopic histopathologic responses and one partial response were observed in Stage I patients (56%). One partial response was observed in Stage II patients.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2002
DOI: 10.1038/NG903
Publisher: Elsevier BV
Date: 09-1987
DOI: 10.1016/0277-5379(87)90128-3
Abstract: In 37 patients with small cell lung cancer treatment with five cycles of cyclophosphamide, doxorubicin and etoposide (CDE), resulted in 23 complete (CR) and 14 partial responses (PR). Median response duration was 34 weeks. At relapse all patients were retreated with CDE. In 23 (62%) patients this gave a second response (6 CR, 17 PR). Factors influencing the occurrence of a second response were: 1. a CR after the first five cycles of CDE 18 out of 23 CR patients responded again whereas only five of the 14 PR patients responded (P less than 0.01). 2. 15 out of 19 patients with a first response duration greater than 34 weeks reached a second response and in eight of the other 18 patients retreatment was successful (P less than 0.05). Reinduction at relapse, after short term chemotherapy and a treatment-free interval, with the induction regimen is an effective second line treatment in patients with an initial CR and a first response duration of greater than 34 weeks.
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0169-5002(01)00359-2
Abstract: During the last 15-20 years, several phase II trials have investigated the use of chemotherapy and chemoradiation prior to surgery in the management of stage IIIA non-small cell lung cancer (NSCLC). The results of these studies, in contrast to insignificant outcomes of comparative studies with chemotherapy in the postoperative setting, have been encouraging. Moreover, phase III trials comparing surgery alone with chemotherapy plus surgery have confirmed the efficacy of this multimodality approach. In recent years, newer and more effective chemotherapy combinations have become available and are now being used prior to surgery. One focus of ongoing research is to confirm that preoperative chemotherapy followed by complete resection is a better treatment approach than surgery alone, even for patients with early-stage NSCLC. Recent data suggest that induction chemotherapy in this category of patients yields high response rates and does not compromise the outcome of surgery. Given the systemic nature of lung cancer it is estimated that systemic therapy before local treatment will play an increasingly important role for patients with early-stage NSCLC.
Publisher: Elsevier BV
Date: 1993
DOI: 10.1016/0959-8049(93)90382-P
Abstract: Pulmonary function tests were performed in 78 patients who had been curatively treated for Hodgkin's disease with mantle field irradiation 10-18 years ago. Mean values of the total lung capacity (95.2%), vital capacity (VC) (95.9%), forced expiratory volume in 1 s (FEV1) (90.6%), and carbon monoxide diffusing capacity per unit alveolar volume (82.7%) showed significant deviations from the predicted normal values, standardised for age, sex, race and height. In a multiple regression analysis the normalised total dose of irradiation, the field of irradiation, and the interval since irradiation had independent negative effects on the test results. Patients reported more coughing, wheezing and dyspnoea on exertion in comparison with hospital-visitors. Their smoking habits and reported pulmonary disease were not different. It is concluded that small, but significant impairment of pulmonary function exists after a follow-up of 14 (2) years [mean (S.D.)]. The clinical impact of these findings seems, however, minimal. Further avoidance of pulmonary toxicity requires a careful quantitative study of the effects of the radiation dose and irradiated volume.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JTHO.2016.10.003
Abstract: Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types.
Publisher: Elsevier BV
Date: 03-1986
DOI: 10.1016/0360-3016(86)90354-8
Abstract: A dose finding study was carried out to establish the dose of cis-diammine dichloroplatinum (II), cDDP, that can be combined with high dose radiotherapy routinely in patients with inoperable non-small cell lung cancer. The patients were irradiated over a period of 2 weeks, 5 fractions a week, followed by a rest period of 14 days. Thereafter a second course of 2 weeks was given a total dose of 55 Gy was achieved. The weekly cDDP administration in a 3 hour infusion with pre- and posthydration preceded the first day irradiation. Twenty patients were evaluable for acute toxicity. The dose limiting factor appeared to be severe nausea and vomiting, which was not responsive to anti-emetic therapy at a cDDP level of 35 mg/m2. No renal or significant hematological side effects were observed. Complete response was seen in 10 patients, using X rays and CT scans this was confirmed by bronchoscopy with biopsies in 9 patients. Partial remission was scored in 7 patients and no change in 4 patients. cDDP as a radiosensitizer will be further studied at a dose level of 30 mg/m2 a week or 6 mg/m2 a day in a prospective, randomized EORTC Phase II study.
Publisher: IOP Publishing
Date: 05-1988
DOI: 10.1088/0143-0815/9/2/007
Abstract: Lung volumes, calculated from 81Krm single-photon emission computed tomography (SPECT) of the lungs, were compared with functional residual capacity (FRC), measured with the helium dilution technique in controls and in patients with various pulmonary diseases. SPECT volume was greater than FRC, which was attributed to non-gas-containing structures in the lung such as the alveolar walls, the interstitium, the blood vessels and the blood, included in the SPECT volume. A good correlation (r = 0.91) was found between the two volumes and there was no difference in this relationship between patients and controls. It was concluded that the relative volume distribution, calculated from SPECT, can be used for the quantification of ventilation from 81Krm SPECT steady-state count distributions.
Publisher: Elsevier BV
Date: 09-1994
DOI: 10.1016/0167-8140(94)90019-1
Abstract: To estimate the dose-effect relations for local functional (ventilation and perfusion) and structural (density) changes of the lung, 3-4 months after irradiation. Twenty-five patients with malignant lymphoma were irradiated with a (modified) mantle field to an average dose of 38 Gy, given in 21 fractions. Single photon emission computed tomography (SPECT) ventilation (V) and perfusion (Q) scans, and CT scans were performed before and 3-4 months after radiation treatment. The three-dimensional dose distribution was calculated using the CT data. After correlation of SPECT and CT data sets, the average post-treatment value of V, Q and lung density per voxel was calculated relative to the pre-treatment value, per dose interval of 4 Gy. Subsequently, the dose-effect relations in each patient were normalized to the average value per voxel in the dose interval of 0-12 Gy. In addition, in each dose interval of 4 Gy the fraction of patients with changes larger than 20% was calculated for all three parameters. The dose-effect relations for perfusion and ventilation normalized to the low-dose regions, and the dose-incidence curves for the fraction of patients with changes larger than 20% were fitted for all three parameters, using a logistic model. Marked changes in the distribution of V and Q were found after irradiation. Prior to normalization to the low-dose regions, a change in V and Q was found in most patients in the dose interval of 0-12 Gy, varying from an increase of 37% to a decrease of 10%, which was followed by a decreasing trend at higher doses. The increase in the low-dose regions indicated a redistribution phenomenon, the magnitude of which was dependent of the irradiated volume. The logistic fit of the dose-effect relations for Q and V, normalized to the low-dose regions, resulted in values for D50 of 51 Gy and 54 Gy (given in 21 fractions on average), respectively, and for the steepness parameter k of 4.2 and 4.0, respectively. The logistic fit for the dose-incidence curves for Q, V and lung density resulted in values for D50 and k of 38 Gy, 37 Gy, 44 Gy and 10.3, 7.8 and 9.4, respectively. With the combined use of SPECT and CT scans, we have obtained dose-effect relations for local functional and structural damage in the lung, 3-4 months after irradiation.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Wiley
Date: 10-11-2015
DOI: 10.1111/AJCO.12306
Abstract: Chemotherapy with cisplatin and pemetrexed has been shown to provide a survival benefit and improvement in quality of life in patients with malignant pleural mesothelioma (MPM). The reported chemotherapy utilization rates range from 18% to 61%. This study aimed to estimate the proportion of MPM patients that should receive chemotherapy based on best available evidence. An optimal chemotherapy utilization model for MPM was constructed using indications for chemotherapy identified from evidence-based MPM treatment guidelines. Epidemiological data on the proportion of patients and their tumor-related attributes were combined with the chemotherapy indications to estimate the optimal chemotherapy utilization rate using decision analysis software (TreeAge Pro 2007). Sensitivity analyses were performed to assess the impact of major variations in the epidemiological data on the optimal chemotherapy utilization rate. The optimal rate was compared with the actual rate reported in the literature. Chemotherapy is recommended at least once during the disease trajectory in 65% of MPM patients. Sensitivity analyses indicate an optimal utilization rate ranging from 50% to 65%. This optimal rate is relatively comparable to the rates mentioned in contemporary reports from Canada (61% between 2003 and 2005) and Australia (54% between 2007 and 2009) and high when compared with data from the Netherlands (36% during 2005-2006). An evidence-based model provided an optimal chemotherapy utilization rate of 65% for patients with MPM. Chemotherapy for MPM may be underutilized and barriers are likely multifactorial.
Publisher: Research Square Platform LLC
Date: 04-08-2021
DOI: 10.21203/RS.3.RS-728824/V1
Abstract: Patients with multiple myeloma (MM), an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions. In this study, glycosphingolipids were essential in promoting autophagic degradation of the signaling molecule TRAF3, a key step in bone-resorbing osteoclast differentiation. Specifically altering the glycosphingolipid composition with eliglustat, an FDA approved glucosylceramide synthase inhibitor, arrested osteoclast differentiation this could be rescued by exogenous addition of the missing glycosphingolipids. Eliglustat significantly reduced bone disease in several preclinical models of MM by inhibiting osteoclastogenesis and, due to its unique mode of action, it was able to act in combination with existing bone protective drugs. Furthermore, eliglustat arrested osteoclast differentiation from the bone marrow of MM patients in a glycosphingolipid-dependent way. This work identifies both the mechanism by which glucosylceramide synthase inhibition blocks autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the translational potential of eliglustat to be combined with current treatments.
Publisher: Springer Science and Business Media LLC
Date: 12-1991
DOI: 10.1038/BJC.1991.451
Publisher: Elsevier BV
Date: 04-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2005
DOI: 10.1097/01.CAD.0000176507.78928.4D
Abstract: Our objective was to study the feasibility of schedule- and dose-intensive cisplatin plus gemcitabine in patients with non-small cell lung cancer (NSCLC) when given on 1 day in four 2-weekly cycles. Cisplatin was administered as a 3 h i.v. infusion followed by gemcitabine as a 30-min i.v. infusion on the same day, every 2 weeks. An interval of 1 h between the two infusions was applied. Patients received four courses without any break. An interpatient dose-escalation scheme was used. The starting dose was 87.5 mg/m of cisplatin and 1350 mg/m of gemcitabine. The pharmacokinetics of cisplatin and gemcitabine were determined in plasma and white blood cells. In total, 23 patients were included in the study. Median age of the patients was 56 years (range 27-76) and most patients were in good clinical condition. Thirteen patients received all planned courses. Dose-limiting toxicity was Common Toxicity Criteria grade 2 ototoxicity. The maximum tolerated dose was established at cisplatin 90 mg/m in combination with gemcitabine 1500 mg/m. This short induction schedule is practical and convenient for the patient. We conclude that the combination of cisplatin at a dose intensity of 51 mg/m/week followed by gemcitabine (1500 mg/m) on the same day is clinically feasible in NSCLC patients when given as a 2-weekly cycle.
Publisher: Springer Science and Business Media LLC
Date: 12-2003
Publisher: Elsevier BV
Date: 1991
DOI: 10.1016/0277-5379(91)90379-R
Abstract: We investigated the expression of the neural cell adhesion molecule (NCAM) in a series of surgically resected lung carcinomas of various histological subtypes by means of a panel of monoclonal antibodies recognising different N-CAM epitopes. In a subgroup of 56 tumours, the results of immunostaining with MAb 123C3--the antibody studied most extensively in our material--were compared to the ultrastructure, and in 231 radically resected non-small cell carcinomas, with histological tumour type and with clinical follow-up data. N-CAM expression was not limited to neuroendocrine tumours, as assessed ultrastructurally. Non-small cell lung carcinomas positive for MAb 123C3 showed post-operative overall and disease-free survival times significantly shorter than 123C3-negative non-small cell carcinomas.
Publisher: Elsevier BV
Date: 10-2001
Abstract: To determine the optimal administered dose of meta-tetrahydroxyphenylchlorin (mTHPC) for intraoperative photodynamic therapy (IPDT) in resected malignant pleural mesothelioma (MPM). The primary objective of this combination treatment was to improve local tumor control. Phase I/II dose escalation study. Two Dutch cancer centers. The study included 28 patients (2 women, 26 men), with pathologically confirmed MPM. The mean age was 57 years (age range, 37 to 68 years), and the World Health Organization performance score was 0 to 1. Epithelial mesotheliomas were found in 17 patients, a sarcomatous mesothelioma was found in 1 patient, and mixed epithelial sarcomatous mesotheliomas were found in 10 patients. Patients were injected with 0.075 mg/kg (4 patients), 0.10 mg/kg (19 patients), or 0.15 mg/kg (5 patients) mTHPC 4 or 6 days before undergoing surgery and IPDT. Complete surgical resection (i.e., pleuropneumonectomy) was followed by integral illumination with monochromatic light of 652 nm (10 J/cm(2)). The real-time fluence rate measurements were performed using four isotropic detectors in the chest cavity to calculate the total light dose. Dose-limiting toxicity was reached at the level of 0.15 mg/kg mTHPC. Three patients died in the perioperative period, and one death was directly related to photodynamic therapy. Real-time dosimetry identified 12 patients in whom additional illumination had to be given to the diaphragmatic sinuses, which were unavoidably shielded during integral illumination. In two patients, illumination was cancelled due to the insufficient resectability of the tumor. The median survival time for all 28 patients was 10 months. Local tumor control, 9 months after treatment, was achieved in 13 of the 26 patients treated with IPDT. IPDT using mTHPC, combined with a pleuropneumonectomy, resulted in local control of disease in 50% of the treated cases. The considerable toxicity associated with the procedure, however, precludes its recommendation for widespread use. Stricter patient selection and improvements of the IPDT technique may reduce the toxicity.
Publisher: American Thoracic Society
Date: 15-05-2007
Publisher: Wiley
Date: 05-1986
Abstract: Fifty-four lung carcinomas submitted for routine electron microscopy under the light microscopical diagnosis of small cell carcinoma were investigated. In 42 or of 45 evaluable cases, neuroendocrine granules were considered definitely or probably present, the modification 'probably' being necessary in suboptimal material. In three cases, squamous cell differentiation was seen, but no neuroendocrine granules were found. On revision of these three cases, the light microscopical diagnosis was changed to squamous cell carcinoma in one instance, and neither of the other two cases was considered classical for small cell carcinoma. Patient follow-up of these three cases showed tumour behaviour indicative of non-small cell carcinoma in two evaluable cases, the third case yielding no significant data. These results indicate that neuroendocrine granules can generally be found in small cell lung carcinomas, provided the material is sufficient for evaluation. When these granules are absent, and other differentiation is found on electron microscopy, the final classification of the tumour should incorporate this finding, to warn the clinician that the tumour will not necessarily behave as a small cell carcinoma.
Publisher: Elsevier BV
Date: 11-2011
Publisher: Cold Spring Harbor Laboratory
Date: 18-10-2021
DOI: 10.1101/2021.10.15.21264972
Abstract: Two-s le Mendelian randomization (2SMR) is an increasingly popular epidemiological method that uses genetic variants as instruments for making causal inferences. Clear reporting of methods employed in such studies is important for evaluating their underlying quality. However, the quality of methodological reporting of 2SMR studies is currently unclear. We aimed to assess the reporting quality of studies that used MR-Base, one of the most popular platforms for implementing 2SMR analysis. We created a bespoke reporting checklist to evaluate reporting quality of 2SMR studies. We then searched Web of Science Core Collection, PsycInfo, MEDLINE, EMBASE and Google Scholar citations of the MR-Base descriptor paper to identify published MR studies that used MR-Base for any component of the MR analysis. Study screening and data extraction were performed by at least two independent reviewers. 87 studies were included in the primary analysis. Reporting quality was generally poor across studies with a mean of 53% (SD = 14%) of items reported in each study. Many items required for evaluating the validity of key assumptions made in MR were poorly reported: only 44% of studies provided sufficient details for assessing if the genetic variant associates with the exposure (‘relevance’ assumption), 31% for assessing if there are any variant-outcome confounders (‘independence’ assumption), 89% for the assessing if the variant causes the outcome independently of the exposure (‘exclusion restriction’ assumption), and 32% for assumptions of falsification tests. We did not find evidence of a change in reporting quality over time or a difference in reporting quality between studies that used MR-Base and a random s le of MR studies that did not use this platform. The quality of reporting of two-s le Mendelian randomization studies in our s le was generally poor. Journals and researchers should implement the STROBE-MR guidelines to improve reporting quality. ESRC, CRUK, MRC, John Climax Benevolent Fund, University of Bristol, and the Wellcome Trust. Registration: This study pre-registered on the OSF, and the protocol can be found at DOI 10.17605/OSF.IO/NFM27
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2005
DOI: 10.1158/1078-0432.CCR-05-0257
Abstract: Purpose: To distinguish a metastasis from a second primary tumor in patients with a history of head and neck squamous cell carcinoma and subsequent pulmonary squamous cell carcinoma. Experimental Design: For 44 patients with a primary squamous cell carcinoma of the head and neck followed by a squamous cell carcinoma of the lung, clinical data, histology, and analysis of loss of heterozygosity (LOH) were used to differentiate metastases from second primary tumors. Results: Clinical evaluation suggested 38 patients with metastases and 6 with second primaries. We developed a novel interpretation strategy based on biological insight and on our observation that multiple LOH on different chromosome arms are not independent. LOH analysis indicated metastatic disease in 19 cases and second primary squamous cell carcinoma in 24 cases. In one case, LOH analysis was inconclusive. For 25 patients, LOH supported the clinical scoring, and in 18 cases, it did not. These 18 discordant cases were all considered to be second primary tumors by LOH analysis. Conclusions: A considerable number of squamous cell lung lesions (50% in this study), clinically interpreted as metastases, are suggested to be second primaries by LOH analysis. For these patients, a surgical approach with curative intent may be justified.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2008
Publisher: Elsevier BV
Date: 2007
Abstract: Results of in idualized therapy guided by mutational tumor profile of patients with non-small-cell lung cancer are presented. After confirming the importance of epidermal growth factor receptor (EGFR) and KRAS mutations for (non)response on gefitinib in a retrospective series of patients, EGFR mutations were looked for before--and were a condition for--treatment with gefitinib or erlotinib. To increase the chance to find such a mutation, we selected patients on the basis of smoking status, gender and histopathology. Out of 41 patients selected, 13 (32%) were found to harbor an EGFR mutation. In nine of them it concerned deletions in exon 19 and in none of them KRAS mutations were detected. All nine patients with an exon 19 deletion had a favorable and continuing response to tyrosine kinase inhibitors (TKIs), while four other patients with point mutations responded less favorably: stable disease or a response of short duration. These observations confirm the potential role of EGFR and KRAS mutations in predicting (non)response to TKIs. Exon 19 deletions that are associated with the best responses might be used for first-line treatment selection, while KRAS mutations could play a role in excluding patients from treatment with TKIs.
Publisher: Springer Science and Business Media LLC
Date: 1999
Abstract: In a prospective study we have treated 13 patients with brain metastases from non-small cell lung cancer with intravenous teniposide, at a dose of 150 mg/m2 on days 1, 3 and 5 given every 3 weeks on an out-patient basis. Six of the 13 patients had previously been treated for brain metastases by surgery and/or radiotherapy. Seven patients experienced neurological improvement. Objective response was obtained in 3 patients (23%) (2 PR, 1 CR), and stabilization in 5 patients. Duration of response in the 3 patients with objective response was 16 weeks, 40 weeks and 80 weeks, respectively. In 2 of these patients extracranial disease responded also to teniposide therapy. Although toxicity of teniposide therapy was relatively mild, there was one patient who died as a consequence of leukopenic sepsis. The results demonstrate that teniposide has some activity in de novo as well as recurrent brain metastases from non-small cell lung cancer.
Publisher: Elsevier BV
Date: 03-2004
Publisher: Springer Science and Business Media LLC
Date: 08-04-2014
DOI: 10.1038/BJC.2014.185
Publisher: Elsevier BV
Date: 1993
DOI: 10.1016/0959-8049(93)90112-S
Abstract: 26 previously treated patients with progressive recurrent small cell lung cancer (SCLC) were given vinorelbine (Navelbine), 30 mg/m2 weekly. All patients had responded to first-line chemotherapy and were off therapy for at least 3 months. Partial response was observed in 4 out of 25 eligible patients (16% 95% confidence interval 4-36%), stable disease in 7 patients and progression in 12 patients. The limiting toxicity was a non-cumulative leucopenia (80%, 32% WHO grade 3-4). Reaction at the site of injection was observed in 5 patients, causing treatment discontinuation in 2 cases. Other non-haematological toxicities were moderate. These results suggest acceptable toxicity and some antitumour activity of vinorelbine in pretreated SCLC patients.
Publisher: Informa UK Limited
Date: 1984
DOI: 10.3109/10641968409039584
Abstract: 17 subjects with essential hypertension (14 male, 3 female - ages: 40-69 years), 13 of whom continued their previous anti-hypertensive therapy, completed a double-blind cross-over trial of ketanserin 40 mg twice daily versus placebo tablets twice daily - each treatment phase was six weeks in duration. For the group as a whole, blood pressure (BP) was reduced in the ketanserin phase compared with the placebo phase supine mean BP decrease: 4 +/- 1 mm Hg (p less than 0.05) standing mean BP decrease: 7 +/- 1 mm Hg (p less than 0.001). Heart rate (HR) was also significantly decreased in the ketanserin phase by 5 +/- 1 beats/minute (p less than 0.001). When in idual subgroups were analysed the reductions in BP and HR were greater in subjects already receiving anti-hypertensives, diuretic and/or beta blockers. Changes were observed in 24 hour urine sodium and potassium excretion - sodium (mmol/day): placebo 137 +/- 17, ketanserin 174 +/- 19 (p less than 0.05) potassium (mmol/day): placebo 74 +/- 8, ketanserin 57 +/- 5. For the group as a whole there were no significant adverse effects during the ketanserin phase, although two subjects had a dose reduction of ketanserin because of drowsiness and dizziness. Two additional subjects withdrew from the study due to adverse effects, one in the placebo phase. In conclusion ketanserin in the dose administered has a modest hypotensive effect which is best seen in subjects already receiving other anti-hypertensive agents.
Publisher: Elsevier BV
Date: 09-1987
DOI: 10.1016/S0167-8140(87)80071-3
Abstract: Roughly 3 million years ago, an inactivating deletion occurred in CMAH, the human gene encoding CMP-Neu5Ac (cytidine-5'-monophospho-N-acetylneuraminic acid) hydroxylase (Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A. 1998. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan ergence. Proc Natl Acad Sci USA. 95:11751-11756). This inactivating deletion is now homozygous in all humans, causing the loss of N-glycolylneuraminic acid (Neu5Gc) biosynthesis in all human cells and tissues. The CMAH enzyme is active in other mammals, including mice, where Neu5Gc is an abundant form of sialic acid on cellular membranes, including those in cardiac and skeletal muscle. We recently demonstrated that the deletion of mouse Cmah worsened the severity of pathophysiology measures related to muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy (Chandrasekharan K, Yoon JH, Xu Y, deVries S, Camboni M, Janssen PM, Varki A, Martin PT. 2010. A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med. 2:42-54). Here, we demonstrate similar changes in cardiac and skeletal muscle pathology and physiology resulting from Cmah deletion in α-sarcoglycan-deficient (Sgca(-/-)) mice, a model for limb girdle muscular dystrophy 2D. These experiments demonstrate that loss of mouse Cmah can worsen disease severity in more than one form of muscular dystrophy and suggest that Cmah may be a general genetic modifier of muscle disease.
Publisher: Future Medicine Ltd
Date: 08-2016
Abstract: miRNAs are responsible for post-transcriptional control of gene expression, and are frequently downregulated in cancer. It has become well established that restoring miRNA levels can inhibit tumor growth, and many studies have demonstrated this in preclinical models. This in turn has led to the first clinical trials of miRNA replacement therapy. This special report focuses on the development of TargomiRs – miRNA mimics delivered by targeted bacterial minicells – and the very first clinical experience of a miRNA replacement therapy in thoracic cancer patients in the Phase I MesomiR-1 trial.
Publisher: Wiley
Date: 04-05-2021
DOI: 10.1002/RRQ.399
Abstract: Research syntheses have demonstrated that morphological instruction can improve the literacy skills of poor readers and spellers. However, studies have used a wide variety of training methods. Questions remain about what type of morphological instruction is most effective and under which circumstances. In this study, we conducted a randomized controlled trial evaluating the effectiveness of Structured Word Inquiry for poor readers and spellers. Structured Word Inquiry teaches students the logic of the English spelling system via instruction in morphology and etymology. Students in grades 3 and 5 with poor reading and spelling skills were randomly assigned to receive either Structured Word Inquiry instruction or a comparison instruction method involving robust vocabulary instruction and reciprocal teaching. Instruction was delivered by teaching assistants over the course of a full school year. After training, there were few differences between the groups in terms of literacy or vocabulary skills. However, teaching assistants found Structured Word Inquiry instruction challenging to deliver, which is likely to have impacted the results. Our findings have implications for the nature and content of morphological instruction for poor readers and spellers, and for future attempts to scale up the delivery of morphological interventions.
Publisher: Elsevier BV
Date: 11-1997
DOI: 10.1016/S0959-8049(97)00183-4
Abstract: Intravenous and oral etoposide (VP 16-213) were tested in two sequential phase II trials in chemotherapy-naive patients with malignant pleural mesothelioma. In the first trial, etoposide was given intravenously (i.v.) at a dose of 150 mg/m2 on days 1, 3 and 5 every 3 weeks. The second trial investigated a daily oral dose of 100 mg for 21 days followed by a 2-week treatment-free period, and then recycling. In both trials, the treatment was given until disease progression, intolerable toxicity or patient refusal. In the i.v. trial, 49 patients were included, 2 patients were ineligible. The oral trial recruited 45 patients, 4 patients were not eligible. In both trials, the main side-effects were moderate leucopenia, alopecia, nausea and vomiting. Two partial responses (4%) and three partial responses (7%) were reported in the i.v. and oral trials, respectively. The median survival was 29 weeks and 38 weeks in the i.v. and oral trials, respectively. In conclusion, further investigation of etoposide in malignant mesothelioma is not recommended.
Publisher: Wiley
Date: 31-01-2017
DOI: 10.1111/RESP.12981
Abstract: Whilst the impact of clinicopathological factors on the prognosis of malignant pleural mesothelioma (MPM) is well understood, socioeconomic and geographic factors have received less attention. We analysed the relationship between geographic and socioeconomic factors upon survival and treatment provision in a large series of patients with MPM. We assessed MPM patients awarded compensation between 2002 and 2009 with additional MPM incidence data from the New South Wales (NSW) Cancer Registry. The impact of geographic remoteness, distance from oncological multidisciplinary team (MDT) and Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) upon survival, clinical features and treatment received was analysed. We identified 910 patients (67% residing in major cities 92% 70 (hazard ratio (HR) = 1.39), male gender (HR =1.36), non-epithelioid histological subtype (HR = 2.18) and IRSAD status by decreasing quintile (HR = 1.06) were independent prognostic factors. There was no significant advantage for patients residing in major cities (10.6 months vs 8.8 months P = 0.162) or within 50 km of MDT (10.3 months vs 7.8 months P = 0.539). Patient's geographic location and distance to MDT did not impact chemotherapy, adjuvant radiotherapy or extrapleural pneumonectomy provision. Socioeconomically disadvantaged patients were significantly less likely to receive chemotherapy (37.4% vs 54.8% P = 0.001). This study provides evidence for differences in the treatment and survival according to socioeconomic status for compensated MPM patients in NSW. Further research is warranted to seek additional explanations for the differences noted by comparing the treatments and outcomes of compensated and non-compensated MPM patients in NSW.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Wiley
Date: 05-1986
Abstract: We studied 14 lung tumours which on light microscopy had posed difficulties on classification as either small cell or non-small cell carcinomas. The light and electron microscopical features were compared with patient follow-up data. Electron microscopy showed neuroendocrine granules in 12 cases, and adeno- and squamous cell differentiation but no neuroendocrine granules in the remaining two cases. The latter two cases showed prolonged patient survival (both patients alive after 2 1/2 and 2 years, respectively). Ten of the cases with neuroendocrine granules showed a rapid course of disease (death between 2 1/2 weeks and 15 months after diagnosis) and marked initial response to multiagent chemotherapy. Thus, the clinical impression of these cases was that of small cell carcinoma. The remaining two cases with neuroendocrine granules showed a more protracted course, with death after 1 1/2 and 2 1/2 years. These two tumours did not show the light microscopical features of atypical carcinoid. The results illustrate the value of electron microscopy in predicting clinical behaviour of carcinomas difficult to place into small cell or non-small cell carcinoma groups. They also point to the existence of neuroendocrine carcinomas other than carcinoids with a more protracted course than small cell carcinomas.
Publisher: Wiley
Date: 15-03-1994
Abstract: The tumoricidal effect of interstitial photodynamic therapy (IPDT) using Photofrin was found to increase when combined with the bioreductive alkylating agent mitomycin C (MMC) and, to a lesser extent, with the indoloquinone EO9. When MMC was given prior to IPDT or RIF1 tumours, the light dose required for a given regrowth time or for 50% cure was reduced by a factor of 2 compared with IPDT alone. MMC given immediately after illumination did not increase the effects of IPDT, although MMC plus illumination without photosensitizer produced a significant increase in regrowth time compared with MMC or light alone. Combination of IPDT with EO9, given directly before illumination, only marginally increased the tumour regrowth times at non-toxic doses. These results demonstrate that combining IPDT with MMC greatly improves the tumour response. Factors such as PDT-induced hypoxia, pH changes, temperature increases and production of toxic reactive oxygen species by both drugs may play a role in the enhanced MMC cytotoxicity.
Publisher: Elsevier BV
Date: 04-2000
Publisher: Elsevier BV
Date: 07-1992
Abstract: A 44-year old man with squamous cell carcinoma of the left lower lobe extending to the mucosa of the main carina, was treated with high dose rate brachytherapy prior to surgery. A significant reduction of tumor infiltration was achieved allowing a radical pneumonectomy instead of a sleeve pneumonectomy with resection of the main carina. He remains disease-free after a follow-up period of 43 months.
Publisher: Oxford University Press (OUP)
Date: 21-06-2000
Abstract: Preclinical evidence suggests that retinoids and antioxidants may prevent or delay the occurrence of cancer in the upper or lower airways, but such effects have not been reliably established in clinical studies. To assess the chemopreventive effects of vitamin A (retinyl palmitate) and N-acetylcysteine, we conducted a large randomized intervention study in patients with head and neck cancer or with lung cancer, most of whom had a history of smoking. From June 1988 through July 1994, a total of 2592 patients (60% with head and neck cancer and 40% with lung cancer) were randomly assigned to receive 1) retinyl palmitate (300000 IU daily for 1 year followed by 150000 IU for a 2(nd) year), 2) N-acetylcysteine (600 mg daily for 2 years), 3) both compounds, or 4) no intervention. All statistical tests were two-sided. Of the patients, 93.5% had smoked tobacco at sometime in their lives (and 25% continued to smoke after cancer diagnosis). After a median follow-up of 49 months, 916 patients were reported with an event (recurrence, second primary tumor, or death). No statistically significant difference was observed in overall survival or event-free survival between patients who received retinyl palmitate and patients who did not. Similarly, no difference was seen in overall survival or event-free survival between patients who received N-acetylcysteine and patients who did not. There was a lower incidence of second primary tumors in the no intervention arm, but the difference was not statistically significant. A 2-year supplementation of retinyl palmitate and/or N-acetylcysteine resulted in no benefit-in terms of survival, event-free survival, or second primary tumors-for patients with head and neck cancer or with lung cancer, most of whom were previous or current smokers.
Publisher: Elsevier BV
Date: 12-2013
Abstract: Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches to therapy are needed. Reduced expression of miR-15/16 in a range of cancer types has suggested a tumour suppressor function for these microRNAs, and re-expression has been shown to inhibit tumour cell proliferation. The miR-15/16 status in MPM is largely unknown. MicroRNA expression was analysed by TaqMan-based RT-qPCR in MPM tumour specimens and cell lines. MicroRNA expression was restored in vitro using microRNA mimics, and effects on proliferation, drug sensitivity and target gene expression were assessed. Xenograft-bearing mice were treated with miR-16 mimic packaged in minicells targeted with epidermal growth factor receptor (EGFR)-specific antibodies. Expression of the miR-15 family was consistently downregulated in MPM tumour specimens and cell lines. A decrease of 4- to 22-fold was found when tumour specimens were compared with normal pleura. When MPM cell lines were compared with the normal mesothelial cell line MeT-5A, the downregulation of miR-15/16 was 2- to 10-fold. Using synthetic mimics to restore miR-15/16 expression led to growth inhibition in MPM cell lines but not in MeT-5A cells. Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine. In xenograft-bearing nude mice, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose-dependent inhibition of MPM tumour growth. The miR-15/16 family is downregulated and has tumour suppressor function in MPM. Restoring miR-16 expression represents a novel therapeutic approach for MPM.
Publisher: Wiley
Date: 28-10-2008
DOI: 10.1002/HED.20952
Abstract: Patients with head and neck squamous cell carcinoma (HNSCC) are at risk for developing both pulmonary metastasis and second primary lung cancer (SPLC). The objective of this study was to determine survival characteristics of patients with pulmonary lesions after curative treatment for HNSCC. Lung resection or biopsy specimens of 36 patients, curatively treated for HNSCC between 1978 and 2002, were defined as second primary squamous cell lung cancer or metastasis by loss of heterozygosity (LOH analysis). Twenty-two of them underwent surgical resection. Survival characteristics were estimated using Kaplan-Meier analysis according to the LOH characterization. The number of resected lung lesions ranged from 1 to 3. Median overall survival after lung surgery was 23.1 months for SPLC (n = 14) and 25.1 months for lung metastases (n = 8). Fourteen patients, SPLC (n = 6) and metastases (n = 8), did not undergo surgical resection, and their median overall survival was 3.7 and 4.4 months, respectively. Survival after resection of metachronic lung lesions following curative treatment of HNSSC is similar for lesions characterized as second primary squamous cell lung cancer and those characterized as metastases.
Publisher: Elsevier BV
Date: 03-1993
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.EJCA.2006.09.005
Abstract: A randomised phase III study was performed comparing sequential (S) and concurrent (C) chemo-radiotherapy (CRT) in non-small cell lung cancer (NSCLC) patients. One hundred and fifty-eight patients were randomised to receive two courses of Gemcitabine (1250mg/m(2) days 1, 8) and Cisplatin (75mg/m(2) day 2) prior to, or daily low-dose Cisplatin (6mg/m(2)) concurrent with radiotherapy, consisting of 24 fractions of 2.75Gy in 32 days, with a total dose of 66Gy. Acute haematological toxicity grade 3/4 was more pronounced in the sequential (S) (30% versus 6%), oesophagitis grade 3/4 more frequent in the concurrent (C) arm (5% versus 14%). Late oesophagitis grade 3 was 4% (S and C), pneumonitis grade 3/4 14% (S) and 18% (C). Because of the poor power of the study no significant differences in median survival (MS), overall survival (OS) and progression-free survival (PFS) could be detected. MS was 16.2 (S) and 16.5 (C) months, 2-year OS was 34% (S) and 39% (C), 3-year OS was 22% (S) and 34% (C). Radiotherapy 66Gy given concurrently with daily low-dose Cisplatin or after two courses of Gemcitabine/Cisplatin was well tolerated. Due to early closure no conclusions can be reached on the relative merits both arms showed good OS.
Publisher: Wiley
Date: 09-06-2023
DOI: 10.1002/JSO.27366
Abstract: Low muscle mass, measured using computed tomography (CT), is associated with poor surgical outcomes. We aimed to include CT‐muscle mass in malnutrition diagnosis using the Global Leadership Initiative on Malnutrition (GLIM) criteria, compare it to the International Classification of Diseases 10th Revision (ICD‐10) criteria, and assess the impact on postoperative outcomes after oesophagogastric (OG) cancer surgery. One hundred and eight patients who underwent radical OG cancer surgery and had preoperative abdominal CT imaging were included. GLIM and ICD‐10 malnutrition data were assessed against complication and survival outcomes. Low CT‐muscle mass was determined using predefined cut‐points. GLIM‐defined malnutrition prevalence was significantly higher than ICD‐10‐malnutrition (72.2% vs. 40.7%, p 0.001). Of the 78 patients with GLIM‐defined malnutrition, low muscle mass (84.6%) was the predominant phenotypic criterion. GLIM‐defined malnutrition was associated with pneumonia (26.9% vs. 6.7%, p = 0.010) and pleural effusions (12.8% vs. 0%, p = 0.029). Postoperative complications did not correlate with ICD‐10 malnutrition. Severe GLIM (HR: 2.51, p = 0.014) and ICD‐10 (HR: 2.15, p = 0.039) malnutrition were independently associated with poorer 5‐year survival. GLIM criteria appear to identify more malnourished patients and more closely relate to surgical risk than ICD‐10 malnutrition, likely due to incorporating objective muscle mass assessment.
Publisher: Springer Science and Business Media LLC
Date: 02-1996
DOI: 10.1038/BJC.1996.79
Abstract: The efficacy of three murine monoclonal antibodies (MAbs) for immunoscintigraphy of small-cell lung cancer (SCLS) xenografts was studied in a Balb/c nu/nu mouse model. These Mabs, 123C3, 123A8 and MOC191, belong to cluster 1 of anti-SCLC MAbs and bind to the neural cell adhesion molecule (NCAM) with similar affinity. After intraperitoneal injection of these MAbs, labelled with 125I, the highest uptake in tumour tissue was obtained with MAb 123C3. Seven days after the administration of this MAb 13.9% of the injected dose per gram of tumour tissue was retained in the tumour. The corresponding tumour tissue ratios ranged from 3.97 for blood to 31.03 for colon. The imaging results and the tumour uptake were less favourable for the two other MAbs, 123A8 and MOC191 (fractions of injected dose respectively 6.7% and 9.2%), although affinity, biological activity after labelling and uptake in non-tumour tissues were very similar for all three MAbs. These results may be explained by the differences in the interaction between the MAbs and the tumour cells. Mab 123C3 is internalised into tumour cells, whereas both other anti-NCAM Mabs are not. Internalisation into NCI H69 cells was demonstrated in vitro by radioimmunoassay, confocal laser scanning microscopy and electron microscopy. The internalised fraction of MAb 123C3 was 22.3% after 24h, whereas this fraction was only 7.5% for MAb 123A8. Although the internalised radiolabeled Mabs are usually degraded and dehalogenated intracellularly, the retained radioactivity is high. Apparently, intracellular degradation of radiolabelled MAb 123C3 and subsequent secretion of radioactive iodine did not prevent the accumulation of intracellular radioactivity. In conclusion, accumulation and retention of radioactivity in the tumour tissue, due to internalisation of radiolabelled MAbs, may improve the results immunoscintigraphy.
Publisher: Oxford University Press (OUP)
Date: 1992
Abstract: Smokers of cigarettes are exposed to a number of carcinogens, including polycyclic aromatic hydrocarbons (PAHs), and are at a high risk for lung cancer. PAHs exert their carcinogenic activity after metabolic activation to reactive intermediates that can damage DNA through adduct formation. Measuring DNA adducts in peripheral white blood cells (WBC) could serve as a means of monitoring human exposure to genotoxic agents and subsequently risk assessment. In this study, DNA from WBC obtained from 39 lung cancer patients was examined for PAH-DNA adducts both in an ELISA using a polyclonal antibody against benzo[a]pyrene 7,8-diol-9,10-epoxide (BPDE)-DNA and the 32P-post-labeling technique. The ELISA results showed BPDE-DNA antigenicity in WBC DNA from 12/38 (32%) patients and adduct levels ranged from 1.5 to greater than 150 adducts in 10(8) nucleotides. The autoradiographs of chromatograms of 32P-post-labeled digests of WBC DNA from the 38 patients showed a variety of adduct spots relative adduct labeling (RAL) values ranged from 0.3 to 407 adducts in 10(8) nucleotides. In 18 of the 38 (47%) persons an adduct spot was detected that co-chromatographed with the major BPDE-DNA adduct (BPDE-dG) RAL values ranged from 0.03 to 382 adducts in 10(8) nucleotides. Correlations were not significant between the adduct levels in WBC and smoking habits, age or sex. From 20 patients of the same group lung tissue was collected at surgery and examined for PAH-DNA adducts by ELISA and 32P-post-labeling assay. No significant correlation was found between DNA adduct levels in blood and lung. This finding stresses the limitations of the use of WBC as a surrogate for adduct levels in the target organ.
Publisher: Elsevier BV
Date: 09-2007
Publisher: S. Karger AG
Date: 1979
DOI: 10.1159/000128079
Publisher: Elsevier BV
Date: 10-2005
Publisher: Massachusetts Medical Society
Date: 08-10-1987
DOI: 10.1056/NEJM198710083171504
Abstract: Whereas it is known that the metabolic syndrome (MetS) has a paradoxically lower prevalence in non-Hispanic black adolescents than in non-Hispanic whites or Hispanics, the relative severity of MetS by race/ethnicity is unknown. Inflammation, indicated by high-sensitivity C-reactive protein (hsCRP), is a key factor linking MetS to cardiovascular disease and type 2 diabetes. Our goal was to determine whether elevations of hsCRP vary by race/ethnicity among adolescents with MetS. We used the National Health and Nutrition Examination Survey (1999-2008) and evaluated adolescents (age 12-19 years) using a pediatric/adolescent adaptation of the ATP III definition of MetS. We used linear regression to evaluate the interaction between MetS status and ethnicity with respect to hsCRP concentration. For male and female adolescents, MetS was associated with elevated hsCRP levels compared with adolescents without MetS. However, the elevation in hsCRP between adolescents with and without MetS was greater in non-Hispanic blacks compared with that in non-Hispanic whites (P = 0.04) but not that in Hispanics (P = 0.18). hsCRP concentrations correlated with in idual MetS components similarly among all ethnicities. In an evaluation of adolescents diagnosed with MetS, non-Hispanic blacks had higher BMI and more hypertension than other ethnicities but there were no other racial/ethnic differences in the features of MetS. Non-Hispanic black adolescents have a greater differential in hsCRP between those with and those without MetS than the differential in non-Hispanic whites but not that in Hispanics. Therefore, even though MetS has a low prevalence in non-Hispanic blacks, MetS is a particularly good indicator of inflammation in non-Hispanic black adolescents.
Publisher: Elsevier BV
Date: 03-2009
Publisher: Elsevier BV
Date: 09-2004
Publisher: Elsevier BV
Date: 08-2007
Publisher: Elsevier BV
Date: 1992
DOI: 10.1016/0959-8049(92)90522-4
Abstract: 26 patients with inoperable non-small cell lung cancer (NSCLC) were treated with photodynamic therapy (PDT) with intravenous Photofrin II 2 mg/kg. 10 out of 11 stage I patients achieved a complete response. The remaining patient, and 11 out of 15 stage III patients had a partial response. No response was seen in 4 patients, 2 of whom had inadequate illumination. Thus, the objective response rate was 85% (22/26). Although lung function did not improve, dyspnoea was ameliorated in 7 (58%) of the partial responders. 4 stage III patients had tumour progression and died of pulmonary haemorrhages 1.5-6 months after PDT. All had received external irradiation, Nd-YAG laser and/or brachytherapy before PDT. 4 patients had grade I-II skin photosensitivity. Although of value in stage I NSCLC, the clinical benefit of PDT in stage III disease was small.
Publisher: BMJ
Date: 06-07-2022
DOI: 10.1136/JCLINPATH-2013-201609
Abstract: Pleural malignant mesothelioma (MM) includes several unusual and even rare but distinctive histological subtypes, in addition to the usual sub ision into epithelioid, biphasic and sarcomatoid MM. Criteria for discrimination between fibrous pleuritis versus desmoplastic mesothelioma include evidence of neoplastic invasion for diagnosis of desmoplastic MM, but this histological assessment is complicated by the recently-described 'fake fat phenomenon' in cases of fibrous pleuritis. The distinction between biphasic and monophasic synovial sarcoma of the pleura versus biphasic and sarcomatoid MM can be problematical and is most cogently based upon molecular detection of the t(X ) translocation, whereas a clear diagnosis of MM for a pleural tumour histologically resembling synovial sarcoma is favoured by a negative result for this translocation and, probably, microRNA evidence supportive of a diagnosis of MM. Aquaporin-1 (AQP1) is a molecule involved in the growth of MM cells, and yet is a factor reported to correlate with improved survival rates for MM with an epithelioid component, in comparison to AQP1-poor MM, as assessed from AQP1 expression by epithelioid MM cells only (apart from co-expression by stromal endothelial cells in addition to the tumour cells). Recent reports have also focused upon germline mutations in the BRCA1-associated protein 1 (BAP1), not only in cases of familial mesothelioma, but also BAP1 deletion in sporadic MM. Prognostic factors for MM include not only the histological subtypes, but other independent variables that include (among others), AQP1 expression by mesothelioma cells, the clinical status of the patient, the serum neutrophil:lymphocyte ratio and blood thrombocytosis.
Publisher: Elsevier BV
Date: 06-1993
Abstract: We describe a patient who suffered from a bacterial pneumonia and had a left-sided infiltrate on his chest radiograph. He was found to be cytopenic and acute myeloid leukemia was diagnosed. A complete remission was achieved after chemotherapy, and the patient was scheduled to have autologous bone marrow transplantation. Bronchoscopy was performed because of persistent hemoptysis and a squamous cell carcinoma in the right upper lobe bronchus was found. This small tumor was successfully treated with photodynamic therapy preventing any delay in the treatment of his leukemia, which would have occurred if surgery had been the treatment of choice. The patient is still in complete remission after a follow-up period of 12 months.
Publisher: Springer Science and Business Media LLC
Date: 18-02-2016
DOI: 10.1038/BJC.2015.470
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.LUNGCAN.2005.04.010
Abstract: Twenty-five patients with histologically proven malignant mesothelioma participated in a trial of imatinib mesylate (Glivec) with a starting dose of 400 mg per day taken orally, up to a maximal dose of 800 mg. No responses were observed in the patient group, while three patients showed prolonged (>6 months) stabilization of disease. The median survival time was 398 days (range 88-840) the median time to progression was 63 days (range 29-275). Side effects of the medication were mild and included edema, nausea, constipation and diarrhea. We conclude that further investigation with monotherapy imatinib in mesothelioma is not warranted.
Publisher: Elsevier BV
Date: 11-1994
Publisher: Wiley
Date: 11-2002
Publisher: Elsevier BV
Date: 09-1988
DOI: 10.1016/0277-5379(88)90347-1
Abstract: Previously, we demonstrated that reproductive senescence was associated with mitochondrial deficits comparable to those of female triple-transgenic Alzheimer's mice (3xTgAD). Herein, we investigated the impact of chronic ovarian hormone deprivation and 17β-estradiol (E2) replacement on mitochondrial function in nontransgenic (nonTg) and 3xTgAD female mouse brain. Depletion of ovarian hormones by ovariectomy (OVX) in nontransgenic mice significantly decreased brain bioenergetics, and induced mitochondrial dysfunction and oxidative stress. In 3xTgAD mice, OVX significantly exacerbated mitochondrial dysfunction and induced mitochondrial β-amyloid and β-amyloid (Aβ)-binding-alcohol-dehydrogenase (ABAD) expression. Treatment with E2 at OVX prevented OVX-induced mitochondrial deficits, sustained mitochondrial bioenergetic function, decreased oxidative stress, and prevented mitochondrial β-amyloid and ABAD accumulation. In vitro, E2 increased maximal mitochondrial respiration in neurons and basal and maximal respiration in glia. Collectively, these data demonstrate that ovarian hormone loss induced a mitochondrial phenotype comparable to a transgenic female model of Alzheimer's disease (AD), which was prevented by E2. These findings provide a plausible mechanism for increased risk of Alzheimer's disease in premenopausally oophorectomized women while also suggesting a therapeutic strategy for prevention.
Publisher: Elsevier BV
Date: 10-1993
DOI: 10.1016/0360-3016(93)90394-B
Abstract: Combining the bioreductive drug SR 4233 with interstitial photodynamic therapy to improve efficacy. RIF1 tumors were implanted subcutaneously in mice and treated with interstitial photodynamic therapy. The bioreductive drug SR 4233 (a benzotriazine which exhibits preferential cell killing under hypoxic conditions) was combined with photodynamic therapy to exploit the induced hypoxia. SR 4233 was given to mice prior to or just after illumination. The effect of multiple SR 4233 injections given over the first 3 days after treatment was also evaluated. The results from experiments with a 24 hr interval between Photofrin and illumination showed that SR 4233 produced only a small additional growth delay compared with photodynamic therapy alone (light doses of 300 or 400 J/cm, combined with 6 x 15 mg/kg SR 4233). Some cures (6/60), however, were found in groups treated with 200 to 400 J/cm with SR 4233, whereas only two cures (2/77) occurred at light doses up to 400 J/cm after photodynamic therapy alone. Reducing the interval between Photofrin injection and illumination increased the number of cures in the combination group, although this was associated with a marked increase in toxicity. A small increase in cure rate was observed for the combination of photodynamic therapy (6 hr interval) and SR 4233, although this was not significant due to the limited number of mice that survived treatment. Only a limited effect of combining SR 4233 and interstitial photodynamic therapy was observed in this tumor model. A possible explanation could be the rapid conversion of SR 4233 into inactive metabolites.
Publisher: Elsevier BV
Date: 06-2003
DOI: 10.1016/S0003-4975(03)00010-9
Abstract: Patients with localized malignant pleural mesothelioma (MPM) can be considered for surgical resection with or without additional treatment. For this approach it is imperative to select patients without mediastinal lymph node involvement. In this study cervical mediastinoscopy (CM) is compared with computer tomography (CT) scanning for its diagnostic accuracy in assessing mediastinal lymph nodes during preoperative workup. Computer tomography scans of the chest and CM were performed in 43 patients with proven unilateral MPM. The CT scans were reviewed by one radiologist and two chest physicians. At CM the lymph node s les were taken from stations Naruke 2, 3, 4, and 7. Computer tomography and CM results were compared with final histopathologic findings obtained at thoracotomy or, if this was not performed, at CM. Computer tomography scanning revealed pathologic enlarged lymph nodes with a shortest diameter of at least 10 mm in 17 of 43 patients (39%). There was histopathologic evidence of lymph node metastases at CM in 11 of these patients (26%). This resulted in a sensitivity of 60% and 80%, a specificity of 71% and 100%, and a diagnostic accuracy of 67% and 93% for CT and CM, respectively. Cervical mediastinoscopy is a valuable diagnostic procedure for patients with MPM who are considered candidates for surgical-based therapy. Results of CM are more reliable than those obtained by CT scanning. Our data confirm results of previous studies reporting that mediastinal lymph node involvement is a frequent event in MPM.
Publisher: Elsevier BV
Date: 03-1994
DOI: 10.1016/0169-5002(94)91690-X
Abstract: A three-arm randomized trial was performed to assess the acute and late toxicity and the impact on survival of the combination high-dose, split-course radiotherapy with 30 mg/m2 cisplatin (cDDP) weekly, with 6 mg/m2 cisplatin daily compared to radiotherapy alone in patients with non-small cell lung cancer (NSCLC). The study started in May 1984 and was closed in May 1989 after 331 patients were randomised. The analysis was performed after a minimum follow-up period of 22 months. Radiotherapy (RT) consisted of 30 Gy, 10 fractions, five fractions a week then a 3-week split followed by 25 Gy in 10 fractions. Nausea and vomiting were increased for a majority of the patients in the combined treatment arms during treatment. There was no addition of bone marrow suppression, renal dysfunction or esophagitis. Increase of late radiation damage was not observed. Local control (= absence of local progression) was improved for patients treated according to the daily cisplatin arm. This has lead to an improvement in overall survival. There was no effect in time to distant metastasis due to the combined modality. The treatment influence was confirmed in the multivariate analysis. local control and survival can be improved by combining radiotherapy with daily low-dose cisplatin in patients with inoperable NSCLC.
Publisher: Elsevier BV
Date: 05-2004
Publisher: Frontiers Media SA
Date: 2013
Publisher: BMJ
Date: 1984
DOI: 10.1136/THX.39.1.57
Abstract: Three further patients are presented who developed evidence of a parenchymal pulmonary disturbance in the course of treatment with amiodarone. In one case the progress of the condition was rapid and ended fatally. Histological examination of the lungs showed evidence of diffuse alveolar damage. The concentration of amiodarone was from four to seven times higher in the lungs than in other organs studied. The concentration of the metabolite desethylamiodarone in the lungs was even higher in relation to other organs studied. The remaining two patients showed a more insidious onset and improvement after withdrawal of amiodarone and treatment with corticosteroids. Gallium 67 scintigraphy appeared to be a sensitive indicator of this adverse effect. Review of published reports revealed 35 cases of amiodarone pneumonitis, including the cases reported in this study. In 11 instances the dose of amiodarone was 400 mg or less. The onset was either insidious or rapidly progressive. Exertional dyspnoea was always present and a nonproductive cough, hypoxaemia, a raised erythrocyte sedimentation rate and diminished carbon monoxide diffusing capacity (transfer factor) were usually noted. Chest radiographs showed either a reticular pattern or diffuse patchy alveolar infiltrates. Discontinuation of amiodarone and an institution of corticosteroid treatment was usually followed by improvement or resolution.
Publisher: Ecancer Global Foundation
Date: 2010
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.LUNGCAN.2007.08.028
Abstract: The combination of radiotherapy and concurrent chemotherapy followed by surgery (trimodality treatment) is currently regarded as optimal treatment for non-small cell lung cancer of the superior sulcus (SST) or Pancoast tumour. The possibility to administer intensive combined modality treatment is influenced by tumour stage, comorbidity and performance status of these patients, and therefore a strict patient selection is necessary. This study focuses on patient selection and its results. We retrospectively evaluated choices of treatment and outcome of all patients with SST treated in the Netherlands Cancer Institute from 1994 to 2004. After identification of patients with SST in registration databases, the following characteristics were analyzed: symptoms, comorbidity, tumour stage, treatment characteristics, toxicity, local control, disease-free and overall survival. Fifty-two patients, 37 men and 15 women, were identified. They were diagnosed with stage IIB (27%), stage IIIA (8%), stage IIIB (42%) and stage IV (23%). Twelve patients after induction (chemo)radiotherapy underwent surgical resection. In eight patients a pathologic complete response was found. The 2- and 5-year survival after induction treatment and surgery was 75 and 39%, respectively. Other patients did not receive surgical treatment because of stage IV disease (n=12), comorbidity (n=8), irresectability (extensive tumour growth and/or persisting N2-3 status n=14) or insufficient response to induction treatment (n=6). Eleven patients were treated with concurrent chemoradiotherapy (5-year survival 20%) and 17 patients with (sequential) radiotherapy and/or chemotherapy (5-year survival 6%). Local recurrence rates were 0% after induction treatment and surgical resection, 32% after concurrent chemoradiotherapy and 72% after (sequential) radiotherapy and/or chemotherapy. In conclusion, only 30% of M0 patients with SST were eligible for combined modality treatment followed by surgery. In this subgroup, concurrent chemoradiotherapy followed by surgery was associated with excellent local control and acceptable survival.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.CRITREVONC.2010.11.004
Abstract: The control of gene expression by microRNAs influences many cellular processes and has been implicated in the control of many (patho)physiological states. Recently, microRNAs have been detected in serum and plasma, and circulating microRNA profiles have now been associated with a range of different tumour types, diseases such as stroke and heart disease, as well as altered physiological states such as pregnancy. Here we review the disease-specific profiles of circulating microRNAs, and the methodologies used for their detection and quantification. We also discuss possible functions of circulating microRNAs and their potential as non-invasive biomarkers.
Publisher: Wiley
Date: 04-2013
DOI: 10.1111/J.1445-5994.2012.02925.X
Abstract: The silent epidemic of mesothelioma in Australia is steadily increasing, and 30% of cases occur in New South Wales (NSW). To describe the patterns of care and outcomes of patients with malignant pleural mesothelioma (MPM) in NSW. MPM patients in NSW applying for compensation at the NSW Dust Diseases Board from 2007 to 2009 were included. Survival from time of diagnosis was determined by the Kaplan-Meier method. The Chi-squared test was used to determine if there was an association between utilisation of treatment and geographical location. A total of 138 patients was included: median age was 72.5 91.3% male 60.1% epithelial subtype and 65.2% lived in major cities. All patients had at least one chest X-ray and computed tomography scan, and 21% had a positron emission tomography scan 93.5% and 4.3% had histological or cytological confirmation respectively. Thoracoscopy (59.4%) was the most commonly used diagnostic procedure. Treatment utilisation: 53.6% chemotherapy 35.5% radiotherapy 9.4% extrapleural pneumonectomy (EPP) and 72.5% had palliative care involvement. There were no major differences in treatment utilisation between patients living in major cities and those in regional NSW (chemotherapy P = 0.42 radiotherapy P = 0.13 and palliative care P = 0.60), except for a higher rate of EPP in regional patients (16.7% vs 5.6% P = 0.03). Median survival was 9.7 versus 12.3 months for city and regional patients respectively (P = 0.22). Survival and treatment utilisation was not significantly different between MPM patients living in major cities and regional NSW, except for a higher rate of EPP in patients in regional NSW.
Publisher: MDPI AG
Date: 04-08-2021
Abstract: Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody–drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2009
Abstract: We performed a randomized phase II trial comparing pemetrexed with pemetrexed plus carboplatin (PC) in patients experiencing relapse after platinum-based chemotherapy. Main eligibility criteria were histologic or cytologic proof of advanced non–small-cell lung cancer (NSCLC), relapse more than 3 months after platinum-based chemotherapy, normal organ function, and Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned to pemetrexed 500 mg/m 2 (arm A) or carboplatin area under the curve 5 and pemetrexed 500 mg/m 2 (arm B), both administered intravenously every 3 weeks. Response assessment was performed every 6 weeks toxicity assessment was performed every 3 weeks. Primary end point was time to progression (TTP) secondary end points were objective response rate (ORR), overall survival (OS), and toxicity. The study was designed to detect a 33% decrease in the hazard of disease progression in the combination arm (α = 0.05, two-sided log-rank test). Polymorphisms of thymidylate synthase, the reduced folate carrier, γ-glutamyl hydrolase, and methylenetetrahydrofolate reductase (MTHF) were investigated in peripheral WBCs of consenting patients. Two hundred forty patients were enrolled. Median TTP was 2.8 months for arm A versus 4.2 months for arm B (hazard ratio, 0.67 95% CI, 0.51 to 0.89 P = .005). Median OS was 7.6 months and 8.0 months and ORR was 4% and 9% for arms A and B, respectively. Subgroup analyses found adenocarcinoma to be associated with favorable outcome. Toxicities in both arms was negligible, with one potential toxic death in arm A. Patients with MTHFR C677T homozygous mutation had increased progression-free survival compared with patients with wild-type or heterozygous mutations (P = .03). PC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone.
Publisher: Oxford University Press (OUP)
Date: 1990
Abstract: In an attempt to probe for polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human subjects resulting from smoking (or other chronic environmental exposure), lung tissue and lung tumours were obtained from patients hospitalized for lung cancer. DNA was isolated from the tissue s les and examined both in an ELISA using a polyclonal antibody against (+/-)trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE)-DNA as well as by the nuclease P1-mediated modification of the 32P-post-labelling technique. The ELISA results showed BPDE-DNA antigenicity in lung DNA from 6 out of 21 patients, and adduct levels ranged from 2 to 134 adducts per 10(8) nucleotides. For all 21 patients, the autoradiographs of chromatograms of 32P-postlabelled digests of DNA from non-tumorous lung tissue showed a strong diagonal radioactive zone (DRZ). This DRZ was generally absent in tumorous tissue. DNA s les that were positive in the ELISA contained a dominant spot within the DRZ that co-chromatographed with the major BPDE-DNA adduct (BPDE-dG). The quantities of the BPDE-dG spots ranged from 2.1 to 42 adducts in 10(9) nucleotides. These values were lower than the levels found in the ELISA but correlated well with the ELISA results (Kendall W = 0.97 P = 0.00). The levels of the DRZ adducts ranged from 1.9 to 34 adducts in 10(8) nucleotides. Correlations between smoking and DNA adduct levels were poor because of the small number of current smokers (n = 13). However, smokers of filter cigarettes had significantly lower DNA adduct levels compared with smokers of cigarettes without a filter (P = 0.02 by Fischer's exact test).
Publisher: Elsevier BV
Date: 08-1993
Publisher: Elsevier BV
Date: 12-2013
Publisher: Elsevier BV
Date: 04-2023
Publisher: Springer Science and Business Media LLC
Date: 31-08-2013
DOI: 10.1007/S00520-012-1569-6
Abstract: Malignant pleural mesothelioma (MPM) is a highly aggressive and symptomatic disease. We examined the relationship between health-related quality of life (HRQoL) and inflammatory markers, and the prognostic role of HRQoL in MPM patients. MPM patients from two parallel phase II studies (thalidomide alone or thalidomide with chemotherapy) were included. HRQoL was assessed at baseline using the modified Lung Cancer Symptom Scale (LCSS). Baseline inflammatory markers and cytokines were measured. Spearman correlation was used to examine the relationship between inflammatory markers and HRQoL measures. The prognostic value of the HRQoL domains was examined using Cox proportional hazard model. Sixty-three patients were included: median age 61 years (range 44-79) 82% male 77% Eastern Cooperative Oncology Group (ECOG) performance status 0-1 44% epithelial histology subtype. Baseline systemic symptoms of anorexia and fatigue, the summation symptoms of overall symptomatic distress, interference with normal activity and global QoL and the aggregate score of total LCSS score were all associated with elevated neutrophil-to-lymphocyte ratio, C-reactive protein and vascular endothelial growth factor levels at baseline (rho ≥ 0.25 p < 0.05). Baseline anorexia, fatigue, cough, dyspnoea, pain, overall symptomatic distress, interference with normal activity, global QoL and total LCSS score were all significantly related to survival (p < 0.05) after adjusting for established prognostic factors (age, gender, histological subtype and performance status) and treatment effect. In conclusion, HRQoL seems to relate to a patient's systemic inflammatory status and is associated with survival in MPM patients.
Publisher: Wiley
Date: 12-2007
DOI: 10.1002/HED.20643
Abstract: High-resistance heat and moisture exchangers (HMEs) have been reported to increase transcutaneous oxygenation (tcpO(2)) values in laryngectomized in iduals and to negatively influence patient compliance. The goal of the present study was to validate earlier published results on short-term transcutaneous oxygenation changes by high-resistance HMEs. We conducted a randomized crossover study, monitoring the influence of an HME on tcpO(2) over a 2-hour time interval in 20 subjects. No evidence of an immediate HME effect (95% CI: -14.9-13.3 mm Hg, p = .91), or a time-dependent HME effect (95% CI: -.121 - .172 mm Hg/minute, p = .74), on tcpO(2) was found. After fitting the statistical model without time dependency, again no evidence of HME presence was seen (95% CI: -.5 mm Hg - 3.6 mm Hg, p = .15). In contrast to earlier suggestions, there is no evidence of increased tcpO(2) levels by high-resistance HMEs in laryngectomized in iduals. Thus, using such HMEs has no added clinical value in this respect.
Publisher: Elsevier BV
Date: 08-1996
DOI: 10.1016/0959-8049(96)00129-3
Abstract: High-dose chemotherapy with autologous bone marrow and/or peripheral blood stem cell (PBSC) support is increasingly employed in the adjuvant treatment of high-risk breast cancer. Subsequent radiotherapy has been reported to be associated with morbidity and mortality resulting from pulmonary toxicity. In addition, the course of radiation therapy may be h ered by excess myelosuppression. The aim of this study was to investigate the contribution to radiation-induced toxicity of a high-dose chemotherapy regimen (CTC) that incorporates cyclophosphamide, thiotepa and carboplatin, in patients with high-risk breast cancer. In two randomised single institution studies, 70 consecutive patients received anthracycline-containing adjuvant chemotherapy (FEC: 5-fluorouracil, epirubicin and cyclophosphamide) followed by radiotherapy to achieve maximal local control. Of these patients, 34 received high-dose CTC with autologous PBSC support. All patients tolerated the full radiation dose in the planned time schedule. Radiation pneumonitis was observed in 5 patients (7%), 4 of whom had undergone high-dose chemotherapy (P = 0.38). All 5 responded favourably to prednisone. Fatal toxicities were not observed. Myelosuppression did not require interruption or untimely discontinuation of the radiotherapy, although significant reductions in median nadir platelet counts and haemoglobin levels were observed in patients who had received high-dose chemotherapy (P = 0.0001). The median nadir of WBC counts was mildly but significantly decreased during radiotherapy (P = 0.01). Red blood cell or platelet transfusions were rarely indicated. Adequate radiotherapy for breast cancer can be safely administered after high-dose CTC with autologous PBSC support. Radiation-induced myelotoxicity is clearly enhanced following CTC, but this is of little clinical significance. Radiation pneumonitis after high-dose therapy may occur more often in patients with a history of lung disease or after a relatively high radiation dose to the chest wall. Other high-dose regimens, particularly those incorporating drugs with known pulmonary toxicity (such as BCNU), may predispose patients to radiation pneumonitis.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2010
DOI: 10.1158/1078-0432.CCR-10-2245
Abstract: Purpose: Asbestos-induced chronic inflammation is implicated in the pathogenesis of malignant mesothelioma (MM). We have investigated blood neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation, as a prognostic factor in MM patients. Experimental Design: Patients with MM who had systemic therapy at participating institutes were studied. Potential prognostic factors such as age, gender, performance status, histologic subtype, and baseline laboratory parameters, including NLR, were analyzed. Overall survival from commencement of therapy was determined by the Kaplan–Meier method. Multivariate analyses using Cox Regression model were performed with significant factors (P ≤ 0.05) to determine their independent effect. Results: A total of 173 MM patients undergoing systemic therapy including 119 patients receiving first-line therapy and 54 patients receiving second- or third-line therapy were included in this retrospective evaluation. Forty-two percent of patients had an elevated NLR at baseline. The following variables were predictive of survival: female gender (P = 0.044), epithelioid histologic subtype (P & 0.001), baseline white blood cell count less than 8.3 × 109/L (P = 0.008), baseline platelet count 400 × 109/L or less (P = 0.05), and NLR of 5 or less (P & 0.001). After multivariate analysis, histologic epithelioid subtype [hazard ratio (HR) = 2.0 95% confidence interval (CI) = 1.3–2.9 P = 0.001], and NLR less than 5 (HR = 2.7 95% CI = 1.8–3.9 P & 0.001) remained independent predictors. The 1-year survival rate was 60% versus 26%, whereas the 2-year survival rate was 34% versus 10% for NLR less than 5 and 5 or greater, respectively. In the separate analyses of chemotherapy-naive and previously treated patient groups, NLR was an independent predictor of survival in both groups. Conclusion: Our results indicate that NLR is an independent predictor of survival for patients with MM undergoing systemic therapy. Clin Cancer Res 16(23) 5805–13. ©2010 AACR.
Publisher: Oxford University Press (OUP)
Date: 20-03-2007
DOI: 10.1093/JNCI/DJK093
Abstract: Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy. Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan-Meier analyses from time of randomization. Induction chemotherapy resulted in a response rate of 61% (95% confidence interval [CI] = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups. In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiotherapy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/S0169-5002(03)00307-6
Abstract: The statistics on lung cancer form a powerful argument to develop new methods to control this most deadly form of cancer. Chemoprevention is one of these new approaches. Carcinogens from cigarette smoke form the link between nicotine addiction and lung cancer. At the same time it has become increasingly clear that dietary and genetically determined factors play an important role in modulating the in idual susceptibility and are linked to the chemoprevention approach. In spite of many positive pre-clinical observations, most of the experiences with potential chemopreventive agents such as retinoids and antioxidants in in iduals at risk for lung cancer have been negative so far. Moreover, beta-carotene was associated with an increased lung cancer incidence in two large randomized studies, most likely due to negative interaction with cigarette smoke. The recent progress in diagnostic techniques and molecular biology has led to a new paradigm for chemoprevention and there is considerable optimism regarding the potential of new molecules and antibodies that target specific cellular receptors or mutations. This article reviews the lung cancer chemoprevention efforts of the last two decades and also gives prospects for the next coming years.
Publisher: BMJ
Date: 27-06-2013
DOI: 10.1136/JCLINPATH-2012-201303
Abstract: The detection of neoplastic invasion remains the linchpin for a clear diagnosis of malignant mesothelioma. Cytology-only diagnosis of epithelioid mesothelioma on aspirated effusion fluid remains controversial. A major problem is poor sensitivity, although cytodiagnosis is achievable in many cases at a high order of specificity, especially when a large volume of effusion fluid is submitted for cytological evaluation, enabling the preparation of cell-block sections for immunohistochemical investigation and when the cytological findings can be correlated with imaging studies to assess the anatomical distribution of the lesion and evidence of nodularity of the pleural disorder and, in some cases, to demonstrate evidence of invasion. Although 'positive' and 'negative' immunohistochemical markers have proved remarkably effective in distinguishing between epithelioid mesothelioma and secondary carcinoma and other malignant tumours metastatic to serosal membranes, no mesothelial marker has 100% sensitivity and specificity for mesothelioma diagnosis, so that panels of 'positive' antibodies and markers with negative predictive value are required. At present, no tissue or serum marker (including the molecular detection of p16/CDKN2A) has been proved to have sufficient specificity, consistency and reproducibility that it can replace evidence of invasion as the decisive marker for diagnosis when there is any uncertainty concerning a diagnosis of epithelioid mesothelioma and in the case of atypical fibrous lesions of the pleura (especially collagen-rich lesions, namely fibrous pleuritis vs desmoplastic mesothelioma), in which even the assessment of invasion can be problematical as illustrated in part 2 of this review.
Publisher: Elsevier BV
Date: 2006
Publisher: Springer Science and Business Media LLC
Date: 25-04-2006
Publisher: Elsevier BV
Date: 2004
Publisher: Elsevier BV
Date: 07-2012
Publisher: Oxford University Press (OUP)
Date: 10-2009
DOI: 10.1016/J.EJCTS.2009.04.069
Abstract: Superior sulcus tumours (SSTs) or Pancoast tumours are preferably treated with chemoradiotherapy (CRT) followed by surgical resection. However, when followed by surgery, it is associated with an increased complication rate. This study aims to evaluate the efficacy and safety of a concurrent induction protocol of 66Gy radiotherapy with cisplatinum and evaluate the rationale for subsequent surgery. Patients with SST treated in our institute from 1994 to 2006 were identified. The preferred induction treatment consisted of accelerated radiation (66 Gy in fractions of 2.75 Gy) with concurrent daily cisplatinum 6 mgm(-2). Surgical resection was planned 4-6 weeks thereafter. Performance status, co-morbidity, clinical and pathological tumour stage, (response to) treatment and survival were reviewed. Survival analysis was performed using the Kaplan-Meier method. Over these 12 years, 85 patients with Pancoast tumours, 57 men and 28 women, were referred. Mean follow-up was 42 months (range: 2-120 months). Twenty-five patients had stage IIB (29%), seven had stage IIIA (8%), 32 had stage IIIB (38%) and 21 had stage IV (25%). Of the 64 patients presenting with stage II or III disease, 38 medically operable patients with potentially resectable tumours received induction therapy. After restaging, 22 patients underwent resection. All resections were complete and local recurrences were not observed. In 13 patients (62%) a pathologic complete response was found. In most cases, pathologic response was not evident from radiological imaging. The morbidity of surgery after induction treatment was acceptable. There was no fatal toxicity or treatment-related mortality. The 2- and 5-year overall survival of this selected group was 70% and 37%, respectively. This schedule of induction therapy with high-dose radiation and concurrent cisplatinum was safe and highly effective in fit patients. At this time, pathologic complete response cannot be reliably recognised preoperatively, and better tools for response assessment are critical for more tailored treatment of patients with SST.
Publisher: Elsevier BV
Date: 12-1991
DOI: 10.1016/0277-5379(91)90430-L
Abstract: 46 patients with malignant pleural mesothelioma were entered in a phase II study of mitoxantrone 14 mg/m2 every 3 weeks. Histology was confirmed by a pathology panel. None of the patients had received previous chemotherapy. Toxicity was mainly mild gastrointestinal and haematological side-effects. Out of 34 patients evaluated for response, only 1 partial response was recorded. Mitoxantrone at this dose and schedule has marginal activity in malignant mesothelioma.
Publisher: Elsevier BV
Date: 03-1993
Publisher: Elsevier BV
Date: 02-2002
Abstract: No established curative treatment is available for pleural thymoma metastases and malignant pleural mesothelioma (MPM). Recently, peritoneal malignancies have been treated by cytoreductive surgery and intraoperative hyperthermic intracavitary perfusion chemotherapy (HIPEC). We investigated the feasibility and safety of this multimodality treatment in the thoracic cavity. Patients with pleural thymoma metastases or early-stage MPM were enrolled in a feasibility study. Morbidity, recurrence, and survival rates were recorded. The Netherlands Cancer Institute. Three patients with pleural thymoma metastases and 11 patients with pleural mesothelioma were treated. Cytoreductive surgery and intraoperative hyperthermic intrathoracic perfusion chemotherapy (HITHOC) with cisplatin and adriamycin were performed. The mesothelioma patients received adjuvant radiotherapy on the thoracotomy wound and drainage tracts. Morbidity and mortality rates were 47% and 0%, respectively. Reoperation was necessary in four cases. Severe chemotherapy-related complications were not observed. A solitary mediastinal and a contralateral pleural thymoma recurrence were successfully treated by radiotherapy and a contralateral HITHOC procedure. All thymoma patients were alive and free of disease after a mean follow-up period of 18 months. After a mean follow-up period of 7.4 months, nine mesothelioma patients are alive. Two mesothelioma patients died of contralateral pleural and peritoneal recurrent disease, while one patient is alive with locoregional recurrence. Cytoreductive surgery and HITHOC with cisplatin and adriamycin is feasible in patients with pleural thymoma metastases and early-stage MPM, and is associated with acceptable morbidity rates. Early data on locoregional disease control are encouraging, and a phase II study will be conducted.
Publisher: Massachusetts Medical Society
Date: 30-08-1990
Publisher: Elsevier BV
Date: 1993
Publisher: Springer Science and Business Media LLC
Date: 10-12-2013
DOI: 10.1038/BJC.2013.731
Publisher: Wiley
Date: 07-06-2013
DOI: 10.1002/PATH.4209
Abstract: Oncogenic fusion genes that involve kinases have proven to be effective targets for therapy in a wide range of cancers. Unfortunately, the diagnostic approaches required to identify these events are struggling to keep pace with the erse array of genetic alterations that occur in cancer. Diagnostic screening in solid tumours is particularly challenging, as many fusion genes occur with a low frequency. To overcome these limitations, we developed a capture enrichment strategy to enable high-throughput transcript sequencing of the human kinome. This approach provides a global overview of kinase fusion events, irrespective of the identity of the fusion partner. To demonstrate the utility of this system, we profiled 100 non-small cell lung cancers and identified numerous genetic alterations impacting fibroblast growth factor receptor 3 (FGFR3) in lung squamous cell carcinoma and a novel ALK fusion partner in lung adenocarcinoma.
Publisher: Elsevier BV
Date: 1993
DOI: 10.1016/S0959-8049(05)80347-8
Abstract: 15 patients with small-cell lung cancer were treated with an "accelerated" chemotherapy consisting of standard-dose cyclophosphamide-doxorubicin-etoposide administered every 15 days (as opposed to the usual 21-day intervals) along with granulocyte-macrophage colony stimulating factor (10 micrograms/kg/day) administered prophylactically subcutaneously from day 4 to 13. The primary objective of this study was to examine the possibility of achieving a 50% dose-intensity increase by a shortening of chemotherapy intervals. 9 patients were not able to complete the planned six courses of chemotherapy owing to cumulative haematological toxicity. In fact, while leukopenia was acceptable and constant during treatment, both thrombocytopenia and anaemia progressively worsened with subsequent courses, becoming particularly severe after the 4th cycle when interruption of the treatment was often required. 13 patients who completed four courses of chemotherapy received a median of 96% of the planned dose-intensity. This corresponded with an average relative dose-intensity actually delivered of 1.44 compared with the planned dose-intensity of a standard cyclophosphamide-doxorubicin-etoposide every 21 days. In conclusion, acceleration of cyclophosphamide-doxorubicin-etoposide chemotherapy combined with granulocyte-macrophage colony stimulating factor can lead to a significant increase of dose-intensity but it is feasible only for a limited number of courses.
Publisher: Elsevier BV
Date: 03-2011
Publisher: BMJ
Date: 22-01-2016
DOI: 10.1136/OEMED-2015-103309
Abstract: Australia is known to have had one of the highest per-capita asbestos consumption rates, yet there are few contemporary reports on malignant mesothelioma trends. Data on 10 930 people with malignant pleural mesothelioma (MPM) and 640 people with malignant peritoneal mesothelioma diagnosed in Australia during 1982-2009 were analysed. Observed incidence rate trends were quantified. Incidence rates were projected up to 2030 using observed incident cases during 1982-2012. The relative per-decade change in excess mortality during 1999-2009 was estimated. During 1982-2009, acceleration in MPM age-standardised incidence rates were highest for women and those aged 75 years and above, with average annual percentage changes of +4.9 (95% CI 3.6 to 6.2) and +7.2 (95% CI 5.4 to 9.0), respectively. Age-standardised incidence rates for men with MPM aged 0-64 years decelerated rapidly during 2003-2009, an average annual percentage change of -5.1% (95% CI -7.6% to -2.5%). Overall, male age-specific MPM incidence rates in the age group of 65-74 year during 2010-2030 are projected to decline with rates projected to increase for older men and women with MPM. There was a statistically significant 16% relative reduction in the excess mortality rate (EMR) up to 5 years postdiagnosis for people diagnosed with malignant pleural and peritoneal mesothelioma combined in 2009 compared with those diagnosed in 1999, an EMR ratio of 0.84 (95% CI 0.77 to 0.92). Australia's malignant mesothelioma incidence rates appear to have reached maximum levels but with differences over time by age, gender and tumour location. Improvements over time in survival provide a glimpse of hope for this almost invariably fatal disease.
Publisher: Elsevier BV
Date: 03-2007
Publisher: Wiley
Date: 30-05-2016
DOI: 10.1111/RESP.12809
Publisher: Elsevier BV
Date: 11-2011
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.CRITREVONC.2012.03.001
Abstract: The relationship between asbestos exposure and malignant mesothelioma (MM) has been well established. Despite bans on asbestos use in an increasing number of nations, the prolonged latency from exposure to diagnosis, and the ongoing presence and use of these dangerous fibres, have led to the increasing prevalence of this deadly disease worldwide. Whilst occupational contact has been implicated in the bulk of diagnosed cases over the past 50 years, a significant proportion of disease has been linked to para-occupational, domestic and environmental exposure. In this review, we will provide an update on the impact of historical and ongoing asbestos contact in both occupational and non-occupational settings. Furthermore, we will address the unresolved controversies surrounding the use of chrysotile asbestos, the effect of gender and genetics on development of this disease, childhood mesothelioma and co-aetiological factors including SV40 exposure.
Publisher: Elsevier BV
Date: 03-1990
DOI: 10.1016/0277-5379(90)90236-M
Abstract: Serum levels of NSE were monitored in 20 SCLC patients who completely responded to combination chemotherapy. An elevation of NSE was observed in five of nine patients with recurrent disease, but predated a relapse in only one. No elevation in NSE level was noted in nine patients who remained in complete remission. The addition of serial assays of LDH to NSE monitoring did not result in any gain in early warning of relapse. This study suggests that the value of serial NSE measurements for predicting a relapse of disease is limited.
Publisher: Springer Science and Business Media LLC
Date: 09-1995
No related grants have been discovered for Nico van Zandwijk.