Association of CT findings with invasive subtypes and the new grading system of lung adenocarcinoma.

AIM: To predict the differentiation between invasive growth patterns and new grades of lung adenocarcinoma (LAC) using computed tomography (CT). MATERIALS AND METHODS: The CT features of 180 surgically treated LAC patients were compared retrospectively to pathological invasive subtypes and tumour grades as defined by the new grading system published in 2021 by the World Health Organization. Two radiologists reviewed the images semi-quantitatively and independently. Univariable and multivariable regression models were built from the statistical means of their assessments to predict invasive subtypes and grades. The area under the curve (AUC) calculation was used to select the best models. The Youden index was applied to determine the cut-off values for radiological parameters. RESULTS: The acinar/papillary patterns were associated with ill-defined margins, lower consolidation/tumour ratio and air bronchogram. The solid growth pattern was associated with a well-defined margin and hypodensity, and the micropapillary (MP) subtype with spiculation. From Grades 1 to 3, the amount of air bronchogram decreased and the consolidation/tumour ratio increased. In the sub-analyses, the best model for differentiating Grade 2 from Grade 1 had the following CT features: solid/subsolid type, consolidation/tumour ratio, well-defined margin, and air bronchogram (AUC = 0.783) and Grade 3 from Grade 2: size of the consolidation part/whole tumour ratio, size of the consolidation part, and well-defined margin (AUC = 0.759). The interobserver agreements between the two radiologists varied between 0.67 and 0.98. CONCLUSIONS: Air bronchogram, consolidation/tumour ratio, and well-defined margin are among the best imaging findings to discriminate between both invasive subtypes and the new grades in LAC.

Anti-tumour activity of oncolytic Western Reserve vaccinia viruses in canine tumour cell lines, xenografts, and fresh tumour biopsies.

Cancer is one of the most common reasons for death in dogs. One promising approach is oncolytic virotherapy. We assessed the oncolytic effect of genetically modified vaccinia viruses in canine cancer cells, in freshly excised tumour biopsies, and in mice harbouring canine tumour xenografts. Tumour transduction efficacy was assessed using virus expressing luciferase or fluorescent marker genes and oncolysis was quantified by a colorimetric cell viability assay. Oncolytic efficacy in vivo was evaluated in a nude mouse xenograft model. Vaccinia virus was shown to infect most tested canine cancer cell lines and primary surgical tumour tissues. Virus infection significantly reduced tumour growth in the xenograft model. Oncolytic vaccinia virus has antitumour effects against canine cancer cells and experimental tumours and is able to replicate in freshly excised patient tumour tissue. Our results suggest that oncolytic vaccinia virus may offer an effective treatment option for otherwise incurable canine tumours.

Aleutian mink disease virus in free-ranging mustelids in Finland - a cross-sectional epidemiological and phylogenetic study.

Aleutian mink disease virus (AMDV) can cause severe immune-complex-mediated disease in American mink. AMDV has also been detected in several other mustelid species with potential negative impact on their health and population. A molecular and cross-sectional epidemiological study was conducted to obtain data on the prevalence, distribution, transmission and diversity of AMDV strains in Finnish free-ranging mustelids and risk factors associated with infection. The presence of anti-AMDV antibodies and/or AMDV DNA was tested from 308 samples representing eight mustelid species and 17 administrative regions. Positive samples were detected across Finland, and in 54 % (31/57) of feral American mink, 27 % (7/26) of European badgers and 7 % (1/14) of European polecats. Samples from Eurasian otters, European pine martens, least weasels, stoat and wolverine were negative. Major risk factors for infection were the species American mink with 335 and badger with 74 times higher odds than other species, and the years 2006-2009 with five times higher odds than the years 2010-2014. No clustering according to species, geographical origin or year was evident in phylogeny, except for four divergent sequences from Estonian badgers that formed a separate phylogroup distinct from other AMDV strains. This study showed that AMDV was prevalent in certain species of Finnish free-ranging mustelids and widely distributed across Finland. Furthermore, the free-ranging mustelids carried both strains similar to those found in farmed mink, but also distinct strains that may represent novel amdoparvoviruses.

Long-term indwelling pleural catheter (PleurX) for malignant pleural effusion unsuitable for talc pleurodesis.

AIMS: Talc pleurodesis using talc slurry via chest tube is a primary option in malignant pleural effusion, since life expectancy is short and surgical decortication is hazardous. Incomplete lung expansion after fluid evacuation, and/or excessive fluid secretion predicts failure of pleurodesis. A mini-invasive alternative was investigated. METHODS: Between March 2004 and September 2005, 51 consecutive patients with malignant pleural effusion, and clinically considered unsuitable for talc pleurodesis, received an indwelling pleural catheter (Denver PleurX). In 47, implantation was done bedside using local anaesthesia. There were 24 men and 27 women, median age 63 (range 36-85) years, receiving 39 right side, 10 left side, and 2 bilateral catheters. There were 19 non-small cell lung cancer cases, 7 mesothelioma, and 25 with other malignancy. Chemotherapy was being given to 18 patients and was not interrupted. RESULTS: Discharge to home was possible in 71% (36 of 71 patients) on the following day. At 2 years follow-up in September 2007, one patient was alive. Mean survival was 3 months (range 5 days to 37+months) for all patients, with best median survivals of 5.5-6 months in breast and ovarian cancer. Catheter was removed or replaced in 15% (8 of 51 patients) due to infection, air leak, or blockage. One patient requested decortication for excessive fluid secretion. None required surgery or died due to catheter-related complications. Pleural fusion with subsequent catheter removal was achieved in 21% (11 of 51 patients). CONCLUSIONS: An indwelling pleural catheter is a safe alternative for patients with malignant pleural effusion unsuitable for talc pleurodesis. In some, pleural fusion may be achieved.

Evaluation of pleural disease using MR and CT. With special reference to malignant pleural mesothelioma.

PURPOSE: To evaluate MR imaging and CT in differentiating malignant pleural mesothelioma from other malignancies or benign pleural disease. MATERIAL AND METHODS: Thirty-four patients (18 pleural mesotheliomas, 9 other malignancies, 7 benign pleural diseases) were examined using enhanced CT and MR. Two radiologists reviewed the CT and two others the MR images. Comparisons were made between the diagnostic groups and the imaging methods. RESULTS: The abnormalities commonly found in malignant disease, but significantly less frequently in benign pleural disease, were focal thickening and enhancement of interlobar fissures. In mesothelioma, enhancement of interlobar fissures, tumour invasion of the diaphragm, mediastinal soft tissue or chest wall, were significantly more often observed than in other malignancies and MR was the most sensitive method. In other malignancies, invasion of bony structures was a more common finding and was also better shown by MR. The contrast-enhanced T1 fat-suppressed (CET1fs) sequence detected these features better than other MR sequences. CONCLUSION: MR, especially the CET1fs sequence in three planes, gave more information than enhanced CT. Focal thickening and enhancement of interlobar fissures were early abnormalities indicating malignant pleural disease. MR could be clinically useful for differentiating mesothelioma from other pleural diseases.

Docetaxel and irinotecan (CPT-11) in the treatment of malignant pleural mesothelioma--a feasibility study.

We chose to treat malignant pleural mesothelioma with a combination of docetaxel and irinotecan (CPT-11), because there have been preliminary reports that CPT-11 is active against mesothelioma, and docetaxel and CPT-11 were the most active agents in our in vitro experiments in human mesothelioma cell lines. Fifteen previously untreated patients with pleural mesothelioma (IMIG Stage III-IV) were given docetaxel 60 mg/m2 followed by CPT-11 190 mg/m2 on day 1, repeated every 3 weeks. All the patients were evaluable for toxicity and 13 patients were evaluated for response. No objective responses (complete or partial) were achieved, but there were two minor responses (overall response rate 15%) each of a duration of 4 months. Three patients had stable disease (23%); median time to progression was 7 months. Median survival in all the patients was 8.5 months from the first chemotherapy cycle and 11 months from diagnosis. Toxicity was severe with seven of 15 patients suffering neutropenic fever and six of 15 patients grade 3-4 diarrhea. The trial was discontinued because of toxicity and lack of activity. We do not recommend the combination of docetaxel and CPT-11 using the schedule presented here for further investigation in malignant mesothelioma. However, CPT-11 and docetaxel, individually, still warrant further study in this disease, especially in combination with cisplatin.

In vitro sensitivity of normal human mesothelial and malignant mesothelioma cell lines to four new chemotherapeutic agents.

In this study, we used four human mesothelioma cell lines (M14K, M24K, M25K and M38K), one transformed human mesothelial cell line (MeT-5A) and one primary mesothelial culture (UPL) to test for in vitro sensitivity to docetaxel, paclitaxel, SN-38 [an active metabolite of irinotecan (CPT-11)] and gemcitabine, as single agents. Subconfluent cell cultures were treated with 2x10(-9), 5x10(-9), 10(-8), 2x10(-8) and 5x10(-8) M concentrations of each drug for 48 h. The sensitivity was measured in terms of cell viability using the Trypan blue exclusion method. All four drugs were potent inhibitors of mesothelioma cell growth, but cell lines from different patients diverged in their sensitivity to the individual agents. In most cases docetaxel, paclitaxel and SN-38 were more potent killers of mesothelioma cells than gemcitabine. The induction of DNA damage was investigated using the Comet assay; cells from two cell lines (M14K and M25K) were treated with subtoxic 10(-8) M concentrations of each drug for 4, 24 and 48 h. Each of the agents caused a slight increase in DNA single-strand breaks at a concentration of 10(-8) M.

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis.

Previous molecular cytogenetic studies by comparative genomic hybridization (CGH) on primary tumours of human malignant mesothelioma have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations. Here we further verify the frequency and pattern of deletions at 14q in mesothelioma. A high-resolution deletion mapping analysis of 23 microsatellite markers was performed on 18 primary mesothelioma tumours. Eight of these had previously been analysed by CGH. Loss of heterozygosity or allelic imbalance with at least one marker was detected in ten of 18 tumours (56%). Partial deletions of varying lengths were more common than loss of all informative markers, which occurred in only one tumour. The highest number of tumours with deletions at a specific marker was detected at 14q11.1-q12 with markers D14S283 (five tumours), D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23-q24 with markers D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours). We conclude from these data that genomic deletions at 14q are more common than previously reported in mesothelioma. Furthermore, confirmation of previous CGH results was obtained in all tumours but one. This tumour showed deletions by allelotyping, but did not show any DNA copy number change at 14q by CGH. Although the number of tumours allelotyped was small and the deletion pattern was complex, 14q11.1-q12 and 14q23-q24 were found to be the most involved regions in deletions. These regions provide a good basis for further molecular analyses and may highlight chromosomal locations of tumour suppressor genes that could be important in the tumorigenesis of malignant mesothelioma.

Phase II study of vinorelbine and gemcitabine for inoperable stage IIIB-IV non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy of the combination of vinorelbine and gemcitabine as a non-platinum chemotherapy regimen in patients with inoperable locally-advanced or metastatic non-small-cell lung cancer (NSCLC). Efficacy was assessed primarily in terms of response rate, and secondarily in terms of toxicity, time to progression and survival. PATIENTS AND METHODS: Patients with cytologically- or histologically-proven stage IIIB-IV NSCLC, bi-dimensionally measurable lesions, adequate haematological, hepatic and renal function, WHO performance status < or = 2 and no previous chemotherapy or radiotherapy were eligible. The first 12 patients were entered in a pilot study and received vinorelbine (VNR) 30 mg/m2 on days 1, 8, 15 and 22, and gemcitabine (GEM) 1000 mg/m2 on days 1, 8 and 15, of a 28-day cycle. Subsequently, patients were entered in a phase II trial of VNR 35 mg/m2 and GEM 1200 mg/m2 on days 1 and 15 of each 28-day cycle. Treatment consisted of three cycles of the chemotherapy, with a further three cycles for those patients who achieved stable disease or a complete or partial response (CR/PR) to the first three cycles. Patients who had achieved CR or PR after six cycles continued with the treatment until relapse. RESULTS: The dosage and scheduling of VNR and GEM in the pilot study resulted in neutropenia necessitating reductions or delays in treatment, and consequently low dose intensity. The schedule was thus modified to VNR 35 mg/m2 and GEM 1200 mg/m2 on days 1 and 15 of each 28-day cycle for the phase II trial. Thirty-three patients were enrolled in the phase II trial, and 28 were evaluable for response. The overall intent-to-treat response rate of all 45 patients was 40% (18 of 45), comprising 4 CR (9%) and 14 PR (31%). For the 28 evaluable patients who received the fortnightly chemotherapy the response rate was 46% (13 of 28), CR 11% (3 of 28) and PR 36% (10 of 28). Seven patients (25%) had stable disease. The one-year cumulative survival rate for the 33 patients receiving the fortnightly chemotherapy was 24% and median time-to-progression 4 months (range 1-16 months). Median survival for these patients was eight months. Nine out of twelve patients in the pilot study (75%) suffered grade 3-4 neutropenia. There was one toxic death, attributed to neutropenic fever and sepsis, and two cases of pulmonary embolism. One patient suffered Grade 4 thrombocytopenia. Only eight patients (24%) on the fortnightly schedule suffered grade 3-4 neutropenia, resulting in dose reductions or delays for three of them (9%). None of the patients on the fortnightly schedule suffered thrombocytopenia or anaemia. CONCLUSIONS: The fortnightly schedule of gemcitabine and vinorelbine was a well-tolerated out-patient regimen, producing response and survival rates comparable to those of cisplatin combination regimens, but with a more favourable toxicity profile. Gemcitabine and vinorelbine should now be tested in a triplet combination with a taxane as the third drug, or against a platinum-containing regimen in a phase III study.

High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma.

Twenty six patients with pleural mesothelioma of UICC stage I-IV excluding M1 disease (46% of whom had stage I disease and 38% stage III disease) were treated intravenously with high dose MTX (3 g) and calcium folinate rescue three times at intervals of 2 weeks and three times at intervals of 3 weeks. Natural interferon (IFN)-alpha (3 MIU days 2-10) and recombinant IFN-gamma1b (50 microg m(-2) on days 2, 6 and 10) were injected subcutaneously after each MTX dose. At the end of MTX treatment the IFNs were continued as maintenance therapy until disease progression. Seven partial responses were observed among 24 patients evaluable for response (response rate 29%, 95% confidence interval 13-51%). Median duration of response was 10 months (range 3-24 months). Median survival was 17 months and 1-year and 2-year survival rates 62% and 31% respectively. The toxicity of the chemo-immunotherapy was acceptable. Treatment was stopped in one patient who developed grade IV neurological toxicity. MTX dose reductions were rare (two patients with grade 1-2 renal toxicity). The combination of high dose MTX and IFN-alpha and IFN-gamma is active against malignant pleural mesothelioma and well-tolerated. The survival rates are encouraging.

The clinical importance of magnetic resonance imaging versus computed tomography in malignant pleural mesothelioma.

There is no standard therapy for malignant pleural mesothelioma (MPM), but recent reports have shown that extensive surgery combined with chemo- and radiotherapy prolongs the survival of selected patients with early stage disease. This emphasises the need for accurate staging procedures at diagnosis and reliable imaging methods to assess response to treatment. Computed tomography (CT) of the chest has been the standard imaging method for these purposes for the last decade, but it is limited in its ability to demonstrate accurately the platelike growth pattern of MPM within the thorax due to the partial volume effect on curved surfaces. In order to define the value of magnetic resonance imaging (MRI) in the imaging of MPM, we have compared the findings from 26 parallel paired CT and MRI scans of mesothelioma patients at various stages of the disease. MRI showed tumour spread into the interlobar fissures, tumour invasion of the diaphragm and through the diaphragm, and invasion of bony structures better than CT. Invasion of the chest wall and mediastinal soft tissue and tumour growth into the lung parenchyma were equally well seen on both imaging methods. CT was better for detecting the inactive pleural calcifications. MRI is a sensitive detector of the characteristic growth pattern and extension of MPM and we recommend its use more widely for the clinical management of MPM especially when evaluating tumour resectability and in research protocols when an accurate evaluation of disease extent is essential.

Comparison of a Multidose Powder Inhaler Containing Beclomethasone Dipropionate (BDP) with a BDP Metered Dose Inhaler with Spacer in the Treatment of Asthmatic Patients.

OBJECTIVE: The clinical efficacy, tolerability and acceptability of a new multidose powder inhaler (MDPI) [Easyhaler((R)), Orion Pharma, Finland] containing a high dose (500 microg/dose) of beclomethasone dipropionate (BDP) were compared with those of BDP metered dose inhaler administered with a large volume spacer (MDI-spacer). PATIENTS AND STUDY DESIGN: Recruited patients were adult asthmatics currently receiving 800 to 1000 microg/day of inhaled corticosteroid. The dose of BDP during the study was 1000 mg/day. The study was an open, randomised, parallel-group multicentre study and included a 2-week run-in period followed by a 12-week treatment period. RESULTS: 74 patients were randomised to both groups. During the run-in period the mean morning peak expiratory flow (PEF) was 489 and 478 L/min in the MDPI and MDI-spacer groups, respectively. During the last 2 weeks of the study the morning PEF was 485 L/min in the MDPI group and 477 L/min in the MDI-spacer group. Asthma symptom scores and use of rescue medication were low in both groups. The median dose of histamine required to decrease forced expiratory volume in 1 second (FEV(1)) by 15% was 1.05mg in the MDPI group and 0.64mg in the MDI-spacer group. The most frequent adverse events were hoarseness and sore throat. Mean serum cortisol levels were not affected in either treatment group. Patients' personal opinion regarding acceptability of the devices clearly favoured the MDPI. CONCLUSION: In conclusion, the novel powder inhaler was well tolerated and at least equally effective compared with the conventional MDI-spacer combination in the treatment of asthma with BDP. However, in everyday use the patients clearly favoured the powder inhaler.