•Chemotherapy may be proposed for advanced stages or recurrent thymic tumours.•Cisplatin-based regimens showed the most effectiveness.•Adding anthracycline or etoposide to platinum demonstrated ...similar activity.•Immunomodulatory agents, acting on the PD1 axis showed promising results.
Thymic tumours are rare diseases that for most of the cases are cured with surgery and eventually adjuvant radiotherapy. However, about 30% of patients present with advanced stage or relapsing tumours, which require administration of chemotherapy. While cisplatin-adriamycin-cyclophosphamide combination is regularly prescribed, other drugs have been assessed in the literature. Our aim is to evaluate the effectiveness (response rate) of systemic treatments, whatever the therapeutic line, including chemotherapy, targeted therapies and immunotherapies, in thymoma and thymic carcinoma, using the principles of evidence-based medicine. A systematic review was designed using the PICO system, by an experienced librarian and clinicians’ experts in thoracic oncology, through the Ovid Medline system. Only phase II-IV trials and retrospective studies including at least 14 patients treated with the same regimen were considered. Articles were independently selected by at least two investigators. Fifty-five eligible articles were retrieved. Sixty% were dealing with platinum-based regimens, mainly cisplatin, and showed overall similar activity (mostly response rate above 50%) independently of the line of treatment or histological type (thymoma versus thymic carcinoma). Non-platinum based regimens included octreotide-prednisone and capecitabine-gemcitabine. Promising data of immunotherapy with antiPDL1 antibody (pembrolizumab) requires confirmation. Based on available data, the most popular and active regimens are cisplatin-anthracycline (CAP or ADOC) or cisplatin-etoposide combinations that should be recommended when considering first-line chemotherapy in thymoma or thymic carcinoma.
Summary Background Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural ...mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival. Methods This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov , number NCT00128102. Findings From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7–36·1) versus 27·1 weeks (23·1–31·9) for placebo (hazard ratio 0·98, 95% CI 0·83–1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 16% patients in the vorinostat group vs 25 8% in the placebo group) and dyspnoea (35 11% vs 45 14%). Interpretation In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma. Funding Merck & Co, Inc.
Few validated prognostic factors are available for survival in patients with lung cancer. 18F-fluoro-2-deoxy-d-glucose positron emission tomography has been shown to be of additional value to ...conventional imaging for staging lung cancer. The prognostic value of this lung tumor metabolic activity was studied in a first systematic review of studies published until 2006.
As further studies have appeared since 2006, this report has as objective to confirm and to estimate with less variability the prognostic value of primary tumor standardized uptake value (SUV) measured with 18F-fluoro-2-deoxy-d-glucose positron emission tomography on the basis of an updated search of eligible studies.
Ten additional studies were eligible for the updated review and eight of them provided, in the publication, data allowing survival results aggregation. All together, 21 studies were analyzed. Comparing patients with low and high SUV, using preferentially the median SUV value of each study as threshold, we obtained a poor prognostic value for high SUV compared with low SUV with an overall combined hazard ratio of 2.08, significantly different from one with a 95% confidence interval ranging from 1.69 to 2.56. No interaction between older and newer studies was detectable (P = 0.60) as well as between studies having selected non metastatic patients or studies without selection criterion related to stage (P = 0.46).
We confirmed the results of our previous review showing that SUV is potentially a very interesting factor for predicting patient outcome. We believe that a meta-analysis based on individual patient data would be of great value as allowing to assess the independent prognostic value, to take into account some factors responsible for heterogeneity between studies (SUV assessment method, disease stage, and histology), and to update survival data. We are planning to conduct such a meta-analysis on behalf of the International Association for the Study of Lung Cancer Staging Project.
To respond to the legitimate questions raised by the application of invasive methods of monitoring and life-support techniques in cancer patients admitted in the ICU, the European Lung Cancer Working ...Party and the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique, set up a consensus conference. The methodology involved a systematic literature review, experts’ opinion and a final consensus conference about nine predefined questions
1. Which triage criteria, in terms of complications and considering the underlying neoplastic disease and possible therapeutic limitations, should be used to guide admission of cancer patient to intensive care units?
2. Which ventilatory support High Flow Oxygenation, Non-invasive Ventilation (NIV), Invasive Mechanical Ventilation (IMV), Extra-Corporeal Membrane Oxygenation (ECMO) should be used, for which complications and in which environment?
3. Which support should be used for extra-renal purification, in which conditions and environment?
4. Which haemodynamic support should be used, for which complications, and in which environment?
5. Which benefit of cardiopulmonary resuscitation in cancer patients and for which complications?
6. Which intensive monitoring in the context of oncologic treatment (surgery, anti-cancer treatment …)?
7. What specific considerations should be taken into account in the intensive care unit?
8. Based on which criteria, in terms of benefit and complications and taking into account the neoplastic disease, patients hospitalized in an intensive care unit (or equivalent) should receive cellular elements derived from the blood (red blood cells, white blood cells and platelets)?
9. Which training is required for critical care doctors in charge of cancer patients?
The 2-18F-fluoro-2-deoxy-d-glucose positron emission tomography is an imaging tool for assessing clinical tumor, node, metastasis in non-small cell lung cancer (NSCLC). Primary tumor standardized ...uptake value (SUV) has been studied as a potential prognostic factor for survival. However, the sample sizes are limited leading to conduct a meta-analysis to improve the precision in estimating its effect.
We performed a systematic literature search. For each publication, we extracted an estimate of the hazard ratio (HR) for comparing patients with a low and a high SUV and we aggregated the individual HRs into a combined HR, using a random-effects model.
We found 13 eligible studies dedicated to NSCLC. Most of them included patients with stages I to III/IV and used a SUV assessment corrected for body weight. Number of patients ranged from 38 to 315 (total: 1474); 11 studies identified a high SUV as a poor prognostic factor for survival although two studies found no significant correlation between SUV and survival. SUV measurement and SUV threshold for defining high SUV were study dependent, eight studies looked for a so-called best cutoff (maximizing the logrank test statistic) without adjusting the p value for multiplicity. Overall, the combined HR for the 13 reports was 2.27 (95% confidence interval CI: 1.70–3.02); excluding the studies proposing a “best” cutoff, it was 2.08 (95% CI: 1.431–3.04).
Our meta-analysis suggests that the primary tumor SUV measurement has a prognostic value in NSCLC; these results should be confirmed in a meta-analysis on individual patients’ data.
Primary ciliary dyskinesia (PCD) is an inherited chronic respiratory obstructive disease with randomized body laterality and infertility, resulting from cilia and sperm dysmotility. PCD is ...characterized by clinical variability and extensive genetic heterogeneity, associated with different cilia ultrastructural defects and mutations identified in >20 genes. Next generation sequencing (NGS) technologies therefore present a promising approach for genetic diagnosis which is not yet in routine use. We developed a targeted panel-based NGS pipeline to identify mutations by sequencing of selected candidate genes in 70 genetically undefined PCD patients. This detected loss-of-function RSPH1 mutations in four individuals with isolated central pair (CP) agenesis and normal body laterality, from two unrelated families. Ultrastructural analysis in RSPH1-mutated cilia revealed transposition of peripheral outer microtubules into the 'empty' CP space, accompanied by a distinctive intermittent loss of the central pair microtubules. We find that mutations in RSPH1, RSPH4A and RSPH9, which all encode homologs of components of the 'head' structure of ciliary radial spoke complexes identified in Chlamydomonas, cause clinical phenotypes that appear to be indistinguishable except at the gene level. By high-resolution immunofluorescence we identified a loss of RSPH4A and RSPH9 along with RSPH1 from RSPH1-mutated cilia, suggesting RSPH1 mutations may result in loss of the entire spoke head structure. CP loss is seen in up to 28% of PCD cases, in whom laterality determination specified by CP-less embryonic node cilia remains undisturbed. We propose this defect could arise from instability or agenesis of the ciliary central microtubules due to loss of their normal radial spoke head tethering.
Objectives
To determine whether CT can depict early perfusion changes in lung cancer treated by anti-angiogenic drugs, allowing prediction of response.
Methods
Patients with non-small cell lung ...cancer, treated by conventional chemotherapy with (Group 1;
n
= 17) or without (Group 2;
n
= 23) anti-vascular endothelial growth factor (anti-VEGF) drug (bevacizumab) underwent CT perfusion before (TIME 0) and after 1 (TIME 1), 3 (TIME 2) and 6 (TIME 3) cycles of chemotherapy. The CT parameters evaluated included: (1) total tumour vascular volume (TVV) and total tumour extravascular flow (TEF); (2) RECIST (Response Evaluation Criteria in Solid Tumours) measurements. Tumour response was also assessed on the basis of the clinicians’ overall evaluation.
Results
In Group 1, significant reduction in perfusion was identified between baseline and: (1) TIME 1 (TVV,
P
= 0.0395; TEF,
P
= 0.015); (2) TIME 2 (TVV,
P
= 0.0043; TEF,
P <
0.0001); (3) TIME 3 (TVV,
P
= 0.0034; TEF,
P
= 0.0005) without any significant change in Group 2. In Group 1: (1) the reduction in TVV at TIME 1 was significantly higher in responders versus non-responders at TIME 2 according to RECIST (
P
= 0.0128) and overall clinicians’ evaluation (
P
= 0.0079); (2) all responders at TIME 2 had a concurrent decrease in TVV and TEF at TIME 1.
Conclusion
Perfusion CT demonstrates early changes in lung cancer vascularity under anti-angiogenic chemotherapy that may help predict therapeutic response.
Key Points
• Perfusion CT has the potential of providing in vivo information about tumour vasculature.
• CT depicts early and specific perfusion changes in NSCLC under anti-angiogenic drugs.
• Specific therapeutic effects of anti-angiogenic drugs can be detected before tumour shrinkage.
• Early perfusion changes can help predict therapeutic response to anti-angiogenic treatment.
• Perfusion CT could be a non-invasive tool to monitor anti-angiogenic treatment.
Numerous lung cell lines are currently used as in vitro models for pharmacological and toxicological studies. However, no exhaustive report about the metabolic capacities of these models in ...comparison with those of lung tissues is available. In the present study, we used a high-throughput quantitative real-time reverse transcription-polymerase chain reaction strategy to characterize the expression profiles of 380 genes encoding proteins involved in the metabolism and disposition of xenobiotics in 10 commonly used lung cell lines (A549, H292, H358, H460, H727, Calu-1, 16HBE, 1 HAEO, BEAS-2B, and L-132) and four primary cultures of human bronchial epithelial cells. Expression results were then compared with those previously obtained in human nontumoral and tumoral lung tissues. Our results revealed disparities in gene expression between lung cell lines or when comparing lung cell lines with primary cells or lung tissues. Primary cell cultures displayed the highest similarities with bronchial mucosa in terms of transcript profiling and therefore seem to be the most relevant in vitro model for investigating the metabolism and bioactivation of toxicants and drugs in bronchial epithelium. H292 and BEAS-2B cell lines, which exhibited the highest homology in gene expression pattern with primary cells and the lowest number of dysregulated genes compared with nontumoral lung tissues, could be used as surrogates for toxicological and pharmacological studies. Overall, our study should provide references for researchers to choose the most appropriate in vitro model for analyzing the cellular effects of drugs or airborne toxicants on the airway.
Purpose: We evaluated the expression of endocan, a soluble lung- and kidney-selective endothelial cell-specific dermatan sulfate proteoglycan,
in non–small cell lung tumors compared with normal lung ...and studied the significance of high levels of circulating endocan
in patients with non–small cell lung cancer.
Material and Methods: Endocan and vascular endothelial growth factor mRNA expression were evaluated by semiquantitative PCR in tumoral and nontumoral
lung tissue samples from a first series of 24 patients submitted to curative surgery. Relationships between survival, time
to tumor progression, and serum levels of endocan were evaluated in a second series of 30 previously untreated patients addressed
for staging.
Results: In non–small cell lung cancers, endocan mRNA was overexpressed compared with control lung. Immunohistochemistry shows that
endocan was expressed only by tumor endothelium in all cases, especially in the periphery of the tumors, with no differences
between adenocarcinoma and squamous cell carcinoma. Endocan and vascular endothelial growth factor mRNA expression was positively
correlated in lung tumors. Serum endocan levels, as well as tumor, node, and metastasis status, were correlated with both
survival and time to tumor progression. However, endocan serum level was not an independent prognostic factor due to its correlation
with the presence of metastasis.
Conclusion: Endocan is overexpressed in non–small cell lung tumors compared with healthy lung and probably represents a response of tumoral
endothelium to proangiogenic growth factor stimulation. Circulating levels of endocan might reflect tumor angiogenic stimulation
and present prognostic significance.
There are no international guidelines for an appropriate and cost-effective follow-up for resected nonsmall cell lung cancer (NSCLC). We retrospectively reviewed the outcome of NSCLC patients after ...curative surgery. Follow-up included physical examination and chest radiography every 3 months, and chest computed tomography (CT) scan, bronchoscopy, abdominal ultrasound, brain CT scan and bone scan every 6 months for 3 years, then every year over the following 2 years. Prognostic factors and costs were analysed. Median overall survival following surgery for NSCLC in 162 patients was 38.5 months. Recurrence occurred in 85 (52.5%) patients including 41 (48%) symptomatic subjects. Disease-free survival was similar between patients with asymptomatic recurrence versus symptomatic patients (11.4 versus 12 months; p=0.41). Recurrence was detected by physical examination or chest radiography in 47 (55.3%) patients. Curative-intent therapy was provided in 18 (41%) out of 44 patients with asymptomatic recurrence and in four (10%) out of 41 symptomatic cases (p=0.001). Median overall survival from time of recurrence was higher in asymptomatic patients than in symptomatic patients (15.5 versus 7.2 months; p=0.001). The cost per year of life gained was USD32 700 (€22 397). An extensive follow-up, with acceptable cost, may improve the outcome of patients with resected NSCLC through detection of asymptomatic recurrences; however, validation by prospective studies is required.
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