Preoperative induction chemotherapy with cisplatin and irinotecan for pathological N2 non-small cell lung cancer

We conducted a phase I/II study to investigate whether the surgical resection after induction chemotherapy with cisplatin and irinotecan was feasible and could improve the treatment outcome for patients with pathological N2 non-small cell lung cancer. Fifteen patients with stage IIIA non-small cell lung cancer having mediastinal lymph node metastases proved by mediastinoscopy were eligible. Both cisplatin (60 mg m−2) and irinotecan (50 mg m−2) were given on days 1 and 8. Patients received two cycles of chemotherapy after 3–4 weeks interval. Induction was followed by surgical resection in 4–6 weeks. Patients who had documented tumour regression after preoperative chemotherapy received two additional cycles of chemotherapy and other patients received radiotherapy postoperatively. After the induction chemotherapy, the objective response rate was 73%. All the 15 patients received surgical resection and complete resection was achieved in 11 (73%) patients. There was no operation-related death and one death due to radiation pneumonitis during postoperative radiotherapy. The median time from entry to final analysis was 46.5 months, ranging from 22 to 68 months. The 5-year survival rate was 40% for all the 15 patients and it was 55% for the 11 patients who underwent complete resection. We conclude that the surgical resection after induction chemotherapy with cisplatin and irinotecan is feasible, and associated with low morbidity and high respectability

Differentially expressed alternatively spliced genes in Malignant Pleural Mesothelioma identified using massively parallel transcriptome sequencing

<p>Abstract</p> <p>Background</p> <p>Analyses of Expressed Sequence Tags (ESTs) databases suggest that most human genes have multiple alternative splice variants. The alternative splicing of pre-mRNA is tightly regulated during development and in different tissue types. Changes in splicing patterns have been described in disease states. Recently, we used whole-transcriptome shotgun pryrosequencing to characterize 4 malignant pleural mesothelioma (MPM) tumors, 1 lung adenocarcinoma and 1 normal lung. We hypothesized that alternative splicing profiles might be detected in the sequencing data for the expressed genes in these samples.</p> <p>Methods</p> <p>We developed a software pipeline to map the transcriptome read sequences of the 4 MPM samples and 1 normal lung sample onto known exon junction sequences in the comprehensive AceView database of expressed sequences and to count how many reads map to each junction. 13,274,187 transcriptome reads generated by the Roche/454 sequencing platform for 5 samples were compared with 151,486 exon junctions from the AceView database. The exon junction expression index (EJEI) was calculated for each exon junction in each sample to measure the differential expression of alternative splicing events. Top ten exon junctions with the largest EJEI difference between the 4 mesothelioma and the normal lung sample were then examined for differential expression using Quantitative Real Time PCR (qRT-PCR) in the 5 sequenced samples. Two of the differentially expressed exon junctions (ACTG2.aAug05 and CDK4.aAug05) were further examined with qRT-PCR in additional 18 MPM and 18 normal lung specimens.</p> <p>Results</p> <p>We found 70,953 exon junctions covered by at least one sequence read in at least one of the 5 samples. All 10 identified most differentially expressed exon junctions were validated as present by RT-PCR, and 8 were differentially expressed exactly as predicted by the sequence analysis. The differential expression of the AceView exon junctions for the ACTG2 and CDK4 genes were also observed to be statistically significant in an additional 18 MPM and 18 normal lung samples examined using qRT-PCR. The differential expression of these two junctions was shown to successfully classify these mesothelioma and normal lung specimens with high sensitivity (89% and 78%, respectively).</p> <p>Conclusion</p> <p>Whole-transcriptome shotgun sequencing, combined with a downstream bioinformatics pipeline, provides powerful tools for the identification of differentially expressed exon junctions resulting from alternative splice variants. The alternatively spliced genes discovered in the study could serve as useful diagnostic markers as well as potential therapeutic targets for MPM.</p

Comparison of CT and integrated PET-CT based radiation therapy planning in patients with malignant pleural mesothelioma

<p>Abstract</p> <p>Background</p> <p>When combined with adequate tumoricidal doses, accurate target volume delineation remains to be the one of the most important predictive factors for radiotherapy (RT) success in locally advanced or medically inoperable malignant pleural mesothelioma (MPM) patients. Recently, 18-fluorodeoxyglucose positron emission tomography (PET) has demonstrated significant improvements in diagnosis and accurate staging of MPM. However, role of additional PET data has not been studied in RT planning (RTP) of patients with inoperable MPM or in those who refuse surgery. Therefore, we planned to compare CT with co-registered PET-CT as the basis for delineating target volumes in these patients group.</p> <p>Methods</p> <p>Retrospectively, the CT and co-registered PET-CT data of 13 patients with histologically proven MPM were utilized to delineate target volumes separately. For each patient, target volumes (gross tumor volume [GTV], clinical target volume [CTV], and planning target volume [PTV]) were defined using the CT and PET-CT fusion data sets. The PTV was measured in two ways: PTV1 was CTV plus a 1-cm margin, and PTV2 was GTV plus a 1-cm margin. We analyzed differences in target volumes.</p> <p>Results</p> <p>In 12 of 13 patients, compared to CT-based delineation, PET-CT-based delineation resulted in a statistically significant decrease in the mean GTV, CTV, PTV1, and PTV2. In these 12 patients, mean GTV decreased by 47.1% ± 28.4%, mean CTV decreased by 38.7% ± 24.7%, mean PTV1 decreased by 31.1% ± 23.1%, and mean PTV2 decreased by 40.0% ± 24.0%. In 4 of 13 patients, hilar lymph nodes were identified by PET-CT that was not identified by CT alone, changing the nodal status of tumor staging in those patients.</p> <p>Conclusion</p> <p>This study demonstrated the usefulness of PET-CT-based target volume delineation in patients with MPM. Co-registration of PET and CT information reduces the likelihood of geographic misses, and additionally, significant reductions observed in target volumes may potentially allow escalation of RT dose beyond conventional limits potential clinical benefits in tumor control rates, which needs to be tested in future studies.</p

Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura

Matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and -9), play a significant role in tumour invasion and angiogenesis. The expression and activities of MMPs have not been characterised in malignant mesothelioma (MM) tumour samples. In a prospective study, gelatinase activity was evaluated in homogenised supernatants of snap frozen MM (n = 35), inflamed pleura (IP, n = 12) and uninflammed pleura (UP, n = 14) tissue specimens by semiquantitative gelatin zymography. Matrix metalloproteinases were correlated with clinicopathological factors and with survival using Kaplan-Meier and Cox proportional hazard models. In MM, pro- and active MMP-2 levels were significantly greater than for MMP-9 (P = 0.006, P<0.001). Active MMP-2 was significantly greater in MM than in UP (P=0.04). MMP-2 activity was equivalent between IP and MM, but both pro- and active MMP-9 activities were greater in IP (P=0.02, P=0.009). While there were trends towards poor survival with increasing total and pro-MMP-2 activity (P=0.08) in univariate analysis, they were both independent poor prognostic factors in multivariate analysis in conjunction with weight loss (pro-MMP-2 P = 0.03, total MMP-2 P = 0.04). Total and pro-MMP-2 also contributed to the Cancer and Leukemia Group B prognostic groups. MMP-9 activities were not prognostic. Matrix metalloproteinases, and in particular MMP-2, the most abundant gelatinase, may play an important role in MM tumour growth and metastasis. Agents that reduce MMP synthesis and/or activity may have a role to play in the management of MM. © 2003 Cancer Research UK

The strengths and limitations of routine staging before treatment with abdominal CT in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Advanced colorectal cancer (CRC), either locally advanced, metastasized (mCRC) or both, is present in a relevant proportion of patients. The chances on curation of advanced CRC are continuously improving with modern multi-modality treatment options. For incurable CRC the focus lies on palliation of symptoms, which is not necessarily a resection of the primary tumor. Both situations motivate adequate staging before treatment in CRC. This prospective observational study evaluates the outcomes after the introduction of routine staging with abdominal CT before treatment.</p> <p>Methods</p> <p>In a prospective observational study of 612 consecutive patients (2007-2009), the ability of abdominal CT to find liver metastases (LM), peritoneal carcinomatosis (PC) and T4 stage in colon cancer (CC) was analysed.</p> <p>Results</p> <p>Advanced CRC was present in 58% of patients, mCRC in 31%. The ability to find LM was excellent (99%), cT4 stage CC good (86%) and PC poor (33%). In the group of surgical patients with emergency presentations, the incidences of both mCRC (51%) and locally advanced colon cancer (LACC) (69%) were higher than in the elective group (20% and 26% respectively). Staging tended to be omitted more often in the emergency group (35% versus 12% in elective surgery).</p> <p>Conclusions</p> <p>The strengths of staging with abdominal CT are to find LM and LACC, however it fails in diagnosing PC. On grounds of the incidence of advanced CRC, staging is warranted in patients with emergency presentations as well.</p

Malignant mesothelioma

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis