Virtual Library

Abstract
In patients receiving radiation for a diversity of diagnoses (e.g. Hodgkin’s Disease, breast cancer, seminoma), multiple studies demonstrate that incidental irradiation of the heart can increase the cardiac morbidity and mortality. While there is limited data in patients irradiated for lung cancer, RT-induced heart disease is likely clinically important and care should be taken to minimize incidental cardiac irradiation. Breast Cancer: Dose-response and evolution of techniques: In patients irradiated for breast cancer, there is a fairly well-defined dose/volume response for radiation-induced cardiac injury. The radiation techniques used to treat patients with breast cancer have evolved over the last several decades with a corresponding marked reduction in incidental cardiac doses (and corresponding decreased cardiac risks). For example, it has been estimated that mean heart doses were in the range of 10-15 Gy with anterior photon fields (directed to the internal mammary nodes), ≈5 Gy with tangents and medial IMN electrons, 1-2 Gy with partly-wide tangents, and <1 Gy with conformal cardiac blocking and breath hold. The cardiac implications for patients with breast cancer can be large. In some older studies the detrimental cardiac effects of radiation totally off-set the improvements in cancer-specific survival provided by RT. More modern radiation techniques clearly reduce the cardiac exposure and appear to reduce the frequency or RT-induced heart disease. However, the follow-up duration in the studies utilizing these modern techniques is not as long as are the follow-up durations in the studies using the older techniques. Thus, the long-term safety of “modern” RT can still be questioned. Timing of RT-associated heart injury in patients irradiated for breast cancer: In a classic meta-analysis (Cuzick; Recent Results Cancer Research 111:108-129, 1988; and JCO 12:452, 1994), post-mastectomy RT was associated with a reduction in overall survival at follow-up times >15 years post-RT. This observation helped fuel the traditional belief (recently being challenged) is that RT-induced cardiac injury is manifest at only extended follow-up intervals. This led our group and others to look for more short-term subclinical surrogates for RT-induced cardiac injury. Summary of our prospective study: We prospectively assessed RT-induced changes in regional myocardial perfusion in patients being treated for left-sided breast cancer using modern CT-based techniques. We noted a volume-dependent new perfusion abnormalities 6-24 months post-RT. These perfusion defects largely persist up to 6 years post-RT. The distribution of the perfusion defects follows the path of the tangential radiation field, and not the territory of a coronary artery, and thus represent microvasculature (rather than named coronary artery) injury. In patients with greater than 5% of the left ventricle within the tangential field, the incidence of new perfusion abnormalities si >50%. The functional consequences of these perfusion defects are uncertain. At short follow-up times, they are associated with a slightly increased rate of regional wall motion abnormalities. These wall motion abnormalities, however, do not always persist long-term. There are minimal, if any changes in ejection fraction noted in patients with perfusion defects. However, in patients with "severe" perfusion defects (scored by the summed rest score, SRS), there is suggestion that there might be a more meaningful reduction in ejection fraction (Marks 63:214, 2005, Lind IJROBP 55:914, 2003, Prosnitz Cancer, 110:1840, 2007). The clinical relevance of these perfusion defects remains uncertain. Perfusion defects may represent a reduction in collateral circulation making the patient more prone to develop ischemia when they (at a much later date) develop coronary artery disease. Therefore, care should be taken to minimize cardiac exposure for patients receiving left-sided RT. The use of conformal blocking (heart block), respiratory gating, and electron beam techniques are often useful to reduce cardiac exposure. Reconsideration of the timing of RT-induced cardiac injury in light of the recent analysis by Darby et al (NEJM 368:11, 2013): Darby’s report suggests that RT-induced cardiac injury in patients with breast cancer is clinically manifest relatively soon post-RT (i.e. within a few years), and that the cumulative risk increases continually up to 20 years post-RT. This suggests that the microvascular changes seen in our study (noted above) might have a clinical relevance in the short post-RT interval. Therefore, an alternative interpretation Cuzick et al (cited above) is that there is a clinically-meaningful increase in cardiac mortality in the 1-15 year post-RT interval, but that this is offset by the reduction in breast-cancer specific mortality during that time (resulting in a no net change in overall survival vs. the control group). At >15 years, the excess cardiac events exceed the cumulative anti-cancer effects, leading to the reduced overall survival noted. Lung Cancer: In patients early-stage lung cancer (N0-1), post-operative RT (PORT) is associated with an excess mortality within 0-5 years (Lancet 352:257; ’98). While the causes of the excess deaths are not noted in most studies, at least one study has noted increased cardiac deaths in this setting (Dautzenberg Cancer 86:265, ‘99). Two more-recent studies of “smaller field-PORT” (Mayer: Chest 112:954, ’97; Tradella Radio Oncol 62:11, 2002) demonstrate an improvement in overall survival with PORT, again suggesting that there is a delicate balance between RT-induced reductions in cancer-specific death and normal tissue-induced injury (Miles, IJROBP 68:1047, ‘07), totally analogous to the situation with breast cancer (Marks & Prosnitz, IJROBP 48:625, 2000). With definitive RT for lung cancer, RT-induced cardiac injury is not often reported. However, this might be under-reported as the symptoms of cardiac dysfunction (e.g. dyspnea) might be ascribed to lung disease. Better sparing of the heart during definitive RT for lung cancer is likely to improve the overall outcome. There are no clear dose/volume limits for the heart in patients with lung cancer (Gagliardi IJROBP 2010). Non-axial beams are often useful in reducing cardiac exposure, especially in patients with lower lobe tumors (Quaranta Journal Applied Clinical Medical Physics, 11:3010, 2010). Some portions of the heart might be particularly important in the genesis of RT-induced cardiac injury (e.g. pericardium, coronary arteries, left ventricle) and thus sophisticated techniques to redistribute incidental cardiac dose might be helpful. Dr Marks’s department receives grants from, or has relations with, from Elekta, Siemens, Accuray, Morphormics. Supported by NIH CA069579.

Abstract
Introduction The improved survival in locally advanced non-small cell lung cancer (NSCLC) patients treated with concurrent chemo-radiation (CCRT) comes at a price of increased esophagus toxicity. Acute esophagus toxicity (AET) occurs within 3 months after CCRT and late esophagus toxicity (LET) consists of symptoms persisting or occurring >3 months after treatment. AET is treated with dietary changes, proton pump inhibitors, analgesics, promotility agents, intravenous fluids, and/or nasogastric- or gastrostomy tube insertion. Patients who develop stenosis, perforation or fistula are categorized as severe LET (grade 3-5). Patients with stenosis are treated by dilatation. Some patients will develop a fistula, which can be treated with intraluminal stenting. However the prognosis for patients with a fistula is grim. Estimation of the probability and severity of radiation esophagitis after CCRT treatment is crucial. This allows the individual prescription of tumor doses. Several prediction models have been reported to estimate the risk of AET based on the planned dose distributions. Currently used models to predict acute esophageal toxicity (AET) in lung cancer patients after Intensity Modulated Radiotherapy (IMRT) and concurrent chemotherapy were derived from patients treated with 3D-conformal-radiotherapy (3DCRT). These models first reduce the dose-volume histograms to a single parameter like the volume of esophagus receiving more than a certain threshold dose (V~x~). In a large multi-institutional study on 1082 patients treated with 3DCRT, or IMRT concurrent with chemotherapy, the high-dose volumes were the most important predictors for radiation esophagitis [ref 1]. The V60 emerged as the best predictor for both moderate and severe esophagus toxicity. A low-risk subgroup was identified with a very low V60 of <0.07%, an intermediate-risk subgroup with a V60 of 0.07%-16.99%, and a high-risk subgroup with a V60 of ≥17%. Severe LET seriously affects the patients’ quality of life or even leads to death. For LET predicting models are lacking. With improved survival in patients treated with CCRT, it is important and feasible to analyze LET. This abstract is a summary from a series of studies conducted at NKI on esophagus toxicity in a large NSCLC patient cohort. The patients were all treated with hypofractionated radiotherapy, 66 Gy in 24 fractions, and concurrent daily low dose cisplatin. The following items were investigated: 1) Comparison of AET incidence in patients treated with 3DCRT and CCRT to sequential chemoradiation and RT only.¨ 2) Compare incidence of AET with 3DCRT to IMRT. 3) Analysis of prognostic factors for AET using IMRT. 4) Correlation of radiotherapy dose to the oesophagus wall and AET by means of post-RT 18FDG-PET scans acquired after CCRT. 5) Relations between severe LET and the clinical and dosimetric variables. Material and methods The dose-effect relation of AET (185 patients) [ref 3] and LET ≥grade 3 (171 patients) [ref 6] and dose-volume parameters of the esophagus after hypofractionated IMRT (66 Gy/24 fractions) and concurrent low dose cisplatin were investigated. The dose distributions were first converted to Normalized Total Doses to account for fractionation effects with an α/β-ratio of 10 Gy (AET) or 3 Gy (LET). Equivalent Uniform Dose (EUD) to the esophagus and the volume percentage receiving more than x Gy (Vx) were evaluated by Lyman-Kutcher-Burman model. The association between AET and severe LET (grade ≥3 RTOG/EORTC) was tested through Cox-proportional-hazards model Clinical parameters, onset and recovery times were analyzed as well. Results Acute Esophagus Toxicity -For NSCLC patients treated with 3DCRT and concurrent chemotherapy, the incidence of AET grade ≥ 2 was 27% and significantly higher compared to patients treated with sequential chemoradiation or radiotherapy only regimens [ref 2]. -The AET incidences were not significantly different between 3DCRT based and IMRT based CCRT patients. In order to illustrate the differences between 3DCRT and IMRT we show the Vx (α/β-ratio=10) in steps of 5 Gy derived from the AET study by Kwint et al, and also for 36 CCRT patients treated in the EORTC 08972 trial. From Figure 1 it can be appreciated that with IMRT the volume of esophagus receiving a dose from 5-40 Gy was significantly smaller, while at 70 Gy it was increased. Moreover, the LKB model based on the V50 was not significantly different between IMRT and 3DCRT [ref 3]. -A total of 22% NSCLC patients developed AET toxicity ≥ grade 3 after IMRT to 66 Gy in 24 fractions and concurrent daily low dose cisplatin. The V50 was identified as most accurate predictor of grade ≥ 3 AET [ref 3]. -The median time to AET grade 3 was 30 days, with a median duration of >80 days. Higher grade of AET was also associated with a lower recovery rate [ref 4]. -Post-CCRT esophageal FDG uptake on 18FDG-PET is associated with AET grade. SUV predictability of grade 2-3 AET was significantly improved by using the derived relation between RT dose and PETpost [ref 5]. Results Late Esophagus Toxicity A total of 6% patients developed LET ≥ grade 3 at a median follow-up of 33 months (95% CI 29~37) with a median overall survival of 24 months (95% CI 16~32) [ref 6]. The median onset time was 5 months (range 3~12). Patients with un-recovered AET had a significantly (p<0.001) higher risk of developing severe LET, compared to patients without AET or with a recovered AET. In the EUD; n=0.03 model, all severe LET patients had an NTD >70 Gy on the esophagus. In the EUD~n~-LKB model, the fitted values and 95% confidence intervals were TD~50=~76.1 Gy (73.2~78.6), m=0.03 (0.02~0.06) and n=0.03 (0~0.08). In the V~x~-LKB model, the fitted values and 95% CIs were Tx~50~=23.5% (16.4~46.6), m=0.44 (0.32~0.60) and x=76.7 Gy (74.7~77.5). Conclusions In routine clinical practice it is possible to provide insight in the probability and severity of esophagus toxicity for each individual lung cancer patient treated with CCRT. Both the maximum grade and the recovery rate of AET were significantly associated with severe LET. In clinical practice, NTD corrected esophagus EUD<70 Gy could be a dose constraint to minimize severe LET. AET was not changed with the use of IMRT.

Abstract
Treatment toxicity not only reduces quality of life, but also may be life threatening (and can be unidentified) when it is severe. Radiation induced lung toxicity (RILT) is among the most important dose limiting toxicity in the treatment of lung cancer, particularly locally advanced non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The current standard of RT techniques considers the whole lung as a uniform organ and uses the same dose limit for all patients with the assumption that all have a SAME sensitivity to radiation damage. However, patients with NSCLC frequently have a respiratory comorbidity such as chronic obstructive pulmonary disease (COPD) that results in heterogeneous function within different lung regions. Patients often respond remarkably differently to the same amount of radiation dose. Furthermore, the presence of the tumor itself often affects local vascular supply and ventilation, and changes function level. In this presentation, I will review the current functional imaging for lung and predictive biomarkers for RILT with an emphasis on recent advances regarding 1) ventilation/perfusion single photon emission tomography (V/Q SPECT) for treatment planning and RILT prediction, and 2) blood markers and its integration with physical and functional dosimetric factors for RILT prediction. Ultimately, we would like to generate Functional Imaging and Biophysical Model (FunBipM) to guide individualized treatment planning to minimize treatment toxicity V/Q SPECT is a commonly available technique in most hospitals to image the perfusion (Q) and ventilation (V) of the lung. It has been proposed that Q-SPECT images can be used to guide RT planning so that radiation is directed to the non-functional lung regions [1-4]. It was known to us that the Q-SPECT-guided plans produced more favorable functional dose volume histograms (DfVHs) compared to non-SPECT guided plans, with the fV20 and fV30 values reduced by an average of 13.6% ± 5.2% and 10.5% ± 5.8%, respectively [2]. We have further demonstrated that 1) NSCLC often presents with defect regions on V/Q SPECT, some of which are from tumor compression that improves with tumor shrinkage during- RT; 2) SPECT defect regions are more resistant to post-RT function reduction; 3) V/Q SPECT guided radiation therapy can reduce dose to functional lung without increasing doses to the total physical lung; 4) V/Q SPECT based DfVHs from during-RT may predict clinical significant RILT more accurately than anatomic CT lung based DVH. From treatment planning point of view, I will use example cases to demonstrate that we can avoid V/Q SPECT functional regions in pre- and during- RT to minimize damage to functional lung, particularly by the combined use of pre- and during-. V/Q SPECT adds lung ventilation mapping on top of the Q-SPECT, providing more information (including the mechanism for lung function defects and their potential for recovery). During-RT V/Q SPECT allows adaptive-RT because lung function changes globally and locally during RT, largely due to RT-induced tumor volume reduction improving the vascular supply and ventilation[5]. The combination of pre- and during- V/Q SPECT can classify the lung into different functional regions and strategize to differentially prioritize certain regions, a technique our group developed to minimize lung damage. Additionally, we can compute DfVHs from both pre- during- SPECT scans to predict post-treatment functional loss and clinically significant RILT. Patients with the same dosimetric parameters have shown very different levels of toxicity largely due to their biologically different intrinsic sensitivity to radiation damage [6]. Many studies have been conducted to understand the correlation between pro-inflammatory and pro-fibrogenic cytokines, including TGF-ß1, IL-1ß, IL-6, IL-8, and TNF-α and radiation-induced normal tissue injury [7]. TGFß1, a fibrogenic and radiation-inducible cytokine, has been known to play a key role in this process. Animal studies demonstrated significantly elevated TGFß1 mRNA and protein expression within type II pneumocytes and fibroblasts in radiation-sensitive mice after thorax radiation [8-11], which subsequently contributed to increased TGFß1 levels in circulation. The Duke University group reported that plasma TGFß1 levels at the end of radiation are correlated with the later onset of symptomatic RILT in patients treated with definitive radiation therapy [9][,][12][,][13]. Though the result was not consistently reproduced by others [14], possibly due to technique issues [15], end-of-treatment TGFβ1 correlation nevertheless has limited value. We have demonstrated that TGFß1 elevation in the middle of treatment (2-4 weeks during-treatment) relative to pre-treatment is highly correlated with late-onset grade >2 RILT in NSCLC patients [16][,][17] . Most recently, we have demonstrated that combining baseline IL-8, during-treatment TGF-ß1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) for RILT compared to either variable alone [16]. The findings on baseline and during-treatment markers are more important than end-treatment markers, as they provide us an opportunity to adjust treatment accordingly. More importantly, an individual’s susceptibility to radiation normal tissue toxicity may be genetically determined, which can be measured pre-RT. Germ-line genetic variations, most often single nucleotide polymorphisms (SNPs), may play an important role in radiation damage pathogenesis. SNPs associated with molecules involved in radiation damage pathways, such as DNA double-strand break repair (ATM, XRCC1) and inflammation (TGF β1 and cytokines) have been studied for their association with clinical toxicity [18][,][19]. It was reported that SNPs in TGFβ1 and NOS3 were associated with a lower risk for radiation pneumonitis [20][,][21] whereas SNPs in ATM, IL1A, IL8, TNFa, TNFRSF1B and MIF were associated with an increased risk of radiation pneumonitis [20][,][22]. TGFβ1 rs1800470 was positively associated with RILT [21]. We also demonstrated that SNPs of TGFβ1 genes may be associated with overall risk of other organs’ toxicity, including esophagus or heart/pericardium [23]. This finding is also very important because after limiting lung toxicity to less than certain level (such as 15-17%), increased dose to the most resistant tumors may increase toxicity of other organs. This is complicated but should be taken into consideration. In summary, we may generate a FunBipM through the combination of pre- and during-RT V/Q functional dosimetric parameters and blood biomarker data to predict the risk of lung toxicity for each individual patient: i.e. using a FunBipM that integrates biologic markers into the existing dosimetry-based model. By identifying high-risk patients, adjusting lung dose limit according to the threshold of tolerance, and applying the FunBipM to optimize radiation planning for dose and dose arrangement, we may anticipate a significant reduction of the incidence of toxicity without compromised tumor control.1. Seppenwoolde Y, Engelsman M, De Jaeger K, et al. Optimizing radiation treatment plans for lung cancer using lung perfusion information. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. May 2002;63(2):165-177.2. McGuire SM, Zhou S, Marks LB, Dewhirst M, Yin FF, Das SK. A methodology for using SPECT to reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung. International journal of radiation oncology, biology, physics. Dec 1 2006;66(5):1543-1552.3. Lavrenkov K, Christian JA, Partridge M, et al. A potential to reduce pulmonary toxicity: the use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of non-small cell lung cancer. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. May 2007;83(2):156-162.4. Lavrenkov K, Singh S, Christian JA, et al. Effective avoidance of a functional spect-perfused lung using intensity modulated radiotherapy (IMRT) for non-small cell lung cancer (NSCLC): an update of a planning study. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. Jun 2009;91(3):349-352.5. Yuan S, Frey KA, Gross M, Hayman J, Arenberg D, Cai X. Changes in global function and regional ventilation and perfusion on SPECT during the course of radiotherapy in patients with non-small-cell lung cancer. International journal of radiation oncology, biology, physics. 2012;82(4):e631-638.6. Kong FM, Ao X, Wang L, Lawrence TS. The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer control : journal of the Moffitt Cancer Center. Apr 2008;15(2):140-150.7. Kong FM, Ten Haken R, Eisbruch A, Lawrence TS. Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis. Seminars in oncology. Apr 2005;32(2 Suppl 3):S42-54.8. Yi ES, Bedoya A, Lee H, et al. Radiation-induced lung injury in vivo: expression of transforming growth factor-beta precedes fibrosis. Inflammation. Aug 1996;20(4):339-352.9. Anscher MS, Kong FM, Marks LB, Bentel GC, Jirtle RL. Changes in plasma transforming growth factor beta during radiotherapy and the risk of symptomatic radiation-induced pneumonitis. International journal of radiation oncology, biology, physics. Jan 15 1997;37(2):253-258.10. Bai YH, Wang DW, Cui XM, et al. Expression of transforming growth factor beta in radiation interstitial pneumonitis. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 1997;16(1):15-20.11. Rube CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation. International journal of radiation oncology, biology, physics. Jul 1 2000;47(4):1033-1042.12. Vujaskovic Z, Marks LB, Anscher MS. The physical parameters and molecular events associated with radiation-induced lung toxicity. Seminars in radiation oncology. Oct 2000;10(4):296-307.13. Kong FM, Anscher MS, Sporn TA, et al. Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury. International journal of radiation oncology, biology, physics. Jan 1 2001;49(1):35-41.14. De Jaeger K, Seppenwoolde Y, Kampinga HH, Boersma LJ, Belderbos JS, Lebesque JV. Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer. International journal of radiation oncology, biology, physics. Apr 1 2004;58(5):1378-1387.15. Zhao L, Wang L, Ji W, Lei M, Yang W, Kong FM. The influence of the blood handling process on the measurement of circulating TGF-beta1. Eur Cytokine Netw. Mar 1 2012;23(1):1-6.16. Stenmark M, Cai X, Shedden K, et al. Combining Physical and Biologic Parameters to Predict Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Definitive Radiotherapy. International journal of radiation oncology, biology, physics. In press.17. Zhao L, Wang L, Ji W, et al. Elevation of plasma TGF-beta1 during radiation therapy predicts radiation-induced lung toxicity in patients with non-small-cell lung cancer: a combined analysis from Beijing and Michigan. Int J Radiat Oncol Biol Phys. Aug 1 2009;74(5):1385-1390.18. Damaraju S, Murray D, Dufour J, et al. Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. Apr 15 2006;12(8):2545-2554.19. Hart JP, Broadwater G, Rabbani Z, et al. Cytokine profiling for prediction of symptomatic radiation-induced lung injury. International journal of radiation oncology, biology, physics. Dec 1 2005;63(5):1448-1454.20. Hildebrandt MA, Komaki R, Liao Z, et al. Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. PLoS One. 2010;5(8):e12402.21. Yuan X, Liao Z, Liu Z, et al. Single nucleotide polymorphism at rs1982073:T869C of the TGFbeta 1 gene is associated with the risk of radiation pneumonitis in patients with non-small-cell lung cancer treated with definitive radiotherapy. J Clin Oncol. Jul 10 2009;27(20):3370-3378.22. Zhang L, Yang M, Bi N, et al. ATM polymorphisms are associated with risk of radiation-induced pneumonitis. Int J Radiat Oncol Biol Phys. Aug 1 2010;77(5):1360-1368.23. Xie C, Yuan S, Ellingrod V, Hayman J, Arenberg D, Curtis JL. The Value of Single Nucleotide Polymorphisms in TGFβ1, TPA and ACE in Survival Prediction in Patients with Non-small Cell Lung Cancer. International journal of radiation oncology, biology, physics. 2010;78(3 suppl):199S - 200S.

Abstract
Overview of acute and late toxicities of brain irradiation Acute side effects of brain irradiation (BI) include common effects such as scalp erythema, alopecia, and fatigue and less common effects such as otitis externa, impaired sense of taste, nausea, and headache. Early delayed and late side effects from BI may include hyperpigmentation of the scalp, alopecia, hearing loss, behavioral changes, somnolence syndrome, radiation necrosis and neurocognitive decline. Brain Metastases (BM) often have a devastating impact on neurocognitive function (NCF). BI has been shown to treat, prevent or delay the incidence of BM in lung cancer. However, it can also cause toxicity resulting in a decline in NCF. To date there is limited data available regarding the effects of BI on NCF in patients with lung cancer. This is due to the lack of intensive NCF testing in lung cancer trials. Mechanisms of injury The pathophysiology of late radiotherapy injury is a dynamic and complex interaction between the vasculature and the parenchyma. The vascular hypothesis of radiation-induced injury describes a process of accelerated atherosclerosis causing vascular insufficiency, resulting in a picture similar to small vessel disease seen with vascular dementia. For this reason there is interest in studying vascular dementia treatments to prevent or reduce radiation-induced NCF decline. Glutamate is the principle excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is involved in learning and memory. Ischemia can induce excessive NMDA stimulation and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia. Memantine, an NMDA receptor antagonist, has been shown to be neuroprotective in preclinical models. Additionally, two placebo-controlled phase III trials found memantine to be well-tolerated and effective in treatment for vascular dementia. On these basis, RTOG launched a placebo-controlled, double-blind, randomized trial to evaluate the potential protective effect of memantine on NCF in patients receiving whole brain radiation (WBRT). The results of this study (RTOG 0614) were recently reported. Predisposing factors It is the therapeutic ratio of benefits vs. risks that helps determine the advisability of a treatment such as BI. Clinical trials of prophylactic cranial irradiation (PCI) can enable us to develop strategies that can potentially increase the benefits and decrease the risks. Potential strategies that can increase the benefits of BI may require better ways of identifying a subgroup of patients with the highest risk of developing BM such as those with small cell lung cancer (SCLC), adenocarcinoma, young age, high volume of disease and predictive markers. These are the patients most likely to benefit from PCI. In order to develop strategies to decrease the risks, we must identify and understand those risks. Identifying a subgroup of patients with the highest risk of developing NCF toxicities, such as older age or other patient factors such as hypertension and diabetes, may also improve the therapeutic ratio. Dose volume determinants Due to the concerns with NCF with WBRT, stereotactic radiosurgery (SRS) approaches are being actively studied. Combined therapy (SRS+WBRT) for BM are favored based on Phase III findings that brain control with combined therapy is significantly better than with SRS alone or WBRT alone. On the other hand, a phase III study found that the risk of neurocognitive deficit is doubled with the addition of WBRT to SRS. The published data demonstrate continued evolution of clinical trials and different management strategies are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following BI. To reduce cognitive injury of conventional WBRT, several groups are exploring modified WBRT approaches, such as hippocampal-avoidance WBRT (HA-WBRT). In this approach, complex planning techniques are used to reduce dose to bilateral hippocampal structures while treating the rest of the brain. Hippocampal-dependent functions of learning, memory, and spatial information processing seem to be preferentially affected by RT. It is argued that since <5% of BM occur within 5 mm of the hippocampus, reducing dose to the hippocampus is safe and feasible. The feasibility of this approach has been studied prospectively in a multi-institutional setting by the RTOG study 0933. Clinical features and diagnosis Publications on radiation-induced neurotoxicity have used different assessment methods, time to assessment, and definition of impairment, thus making it difficult to accurately assess the rate and magnitude of the NCF decline that can be expected. There is a paucity of data on neurocognitive impairment after BI, which has previously been assessed using various different neuropsychological tests, as well as different definitions of neurocognitive impairment. It must be remembered that NCF is affected by a number of factors (i.e. BM volume, disease progression (intra and/or extra-cranial progression), chemotherapy, hormonotherapy, surgery, radiation, prior neurologic disease, medications, paraneoplastic effects, etc.) which should be considered when evaluating of the actual neurocognitive effect of treatments such as BI. In addition, a challenge that plagues most studies in patients with advanced cancers, is the decline in compliance with NCF testing over time. Nevertheless, many studies have been completed and will be presented. Prevention and treatment. Because treatment of NCF decline after radiation is limited, treatments ideally would be developed to prevent the detrimental cognitive effects of BI as discussed above. Determining the impact of BI on NCF would provide support for therapeutic decision making for an individual patient, for which we need to use sensitive cognitive assessments to elucidate the incidence, time course, intensity, domains of NCF changes following BI and their actual impact on patient quality of life (QOL). Selected References Sun A, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: Neurocognitive and quality-of-life analysis. J Clin Oncol 2011;29:279-286. Chang EL, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol 2009;10:1037-1044. Wolfson AH, et al. Primary analysis of a phase III randomized trial radiation therapy oncology group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with LD-SCLC. IJROBP 2011;81:77-84.

Abstract
Introduction: Excellent cure rates for central lung cancer can be achieved with local endobronchial therapy if lesions can be detected at a pre-invasive stage. Flexible white light bronchoscopy is the most commonly used imaging tool to evaluate the central airways but it has a limited ability to detect small pre-invasive central lung cancers. Screening with low dose thoracic CT (LDCT) has been shown to be useful in the early detection of lung cancer, but it largely detects peripheral lesions. Despite advances in CT technology, LDCT cannot detect early pre-invasive central lung cancers due to limitation of resolution. Method: Optical imaging modalities that are both established and in development will be reviewed and discussed. These include techniques such as autofluorescence bronchoscopy, narrow band imaging, optical coherence tomography, confocal microendoscopy, endocystoscopy and raman spectroscopy. Results: Autofluoresence imaging is the most well proven imaging tool to be used in conjunction with white light bronchoscopy to rapidly detect small preinvasive lesions. Narrow band imaging may also be useful but further comparative studies are needed. Optical coherence tomography and raman spectroscopy are promising techniques that can be easily applied via small probes during flexible bronchoscopy to further evaluate abnormal lesions. Further development of in-vivo microscopic evaluation of abnormal lesions is ongoing using confocal microendoscopy and endocystoscopy although tissue staining and direct contact is currently required. Conclusion: The detection of early central lung cancers requires more sophisticated tools than conventional white light bronchoscopy. The future utilisation of other imaging tools as part of a minimally invasive flexible bronchoscopic procedure appears promising. A multimodality approach will enable the rapid detection and diagnosis of early curable central lung cancers in selected high-risk populations.

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Stereotactic ablative radiotherapy (SABR) is an established treatment modality in the curative treatment of early stage peripheral non-small cell lung cancer (NSCLC). The local control rates of SABR in many publications have exceeded 90% when tumors of up to 5 cm were treated, with corresponding regional nodal failure rates of approximately 10%. SABR has been reported in many series to have only modest early and late toxicity, generally maintaining pulmonary function and preserving health-related quality of life. Following the publication of an phase II study, which showed an 11-fold increase in severe toxicity in the subgroup of patients with centrally located lung tumors that had been treated with a high dose per fraction, these central locations had been considered to be a ‘no fly zone’ for SABR [Timmerman 2006]. Although several subsequent single center studies have shown that SABR performed with an adapted fractionation scheme using daily fractions of 6.0–7.5 Gy to total doses of 48–60 Gy has been both effective and safe, the results of the ongoing Radiation Therapy Oncology Group (RTOG) phase II trial (0813) for SABR in central tumors, have to be awaited to determine the maximum tolerated dose which can be delivered in five fractions. A recently published systematic review of the literature identified a total of 20 studies reporting on the outcome of SABR in 315 patients with centrally located early stage NSCLC, including two phase II studies [Senthi 2013]. The overall survival rates reported for centrally located tumors appeared to be similar to those of peripheral tumors. Similar to what has been described for peripheral lesions, central tumors showed a dose–response relationship for local control, with four studies reporting improved outcomes with a biological effective dose of 100 Gy~10~ or higher compared to lower doses. In those studies where fractionation schedules with a biological effective dose of 100 Gy~10~ or higher were used, the local control rates exceeded 85%. Post-SABR grade 3 or 4 toxicity occurred in 8.6% of central tumors treated with SABR, and the risk of treatment-related mortality was less than 1% if the biological effective dose for late responding tissues (BED Gy~3~) remained below 210 Gy~3~. In conclusion, SABR for central tumors has been shown to be both effective and safe, provided that appropriate risk-adapted fractionation schemes are used and careful contouring of organs at risk with quality assurance of all aspects of treatment planning and delivery are taken into account. The results of the RTOG dose-finding phase II study 0813, in which already 120 patients are entered, will further strengthen the data on the use of SABR for centrally located tumors.

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Cancer is the leading cause of death in the world, accounting for approximately 7.6 million deaths in 2008. Lung cancer accounted for 1.37 million of those deaths.Identification of molecular markers in lung cancer has lead to the development of targeted therapies resulting in improved survival in selected groups of lung cancer patients. Despite the advancements in treatments, the survival for patients with lung cancer, particularly in the metastatic or locally advanced patients (stage IIIb/IV), is generally poor with a 5-year survival of only 6%. The current poor prognosis and latest advances made in the field of lung cancer highlight the importance of clinical trial development, participation and analysis. Participation in clinical trials for the general cancer patient’s is low, between 5-9%. This low percentage is similar to those seen for lung cancer patients. Early stage clinical trials have a smaller number of participants by design and are aimed at establishing a maximum tolerated dose of a drug or treatment, not establishing efficacy.These clinical trials are not designed with curative intent but rather are designed to evaluate drug absorption, distribution, metabolism, excretion and mechanism of action. Only a small number of cancer patients and even a smaller number of advanced stage lung cancer patients enroll into phase I clinical trials. The number of international clinical trials has seen a rapid increase over the past decade. Recently the Office of Inspector General (OIG) reported that as of 2008, 80% of marketing applications for drugs and biologics approved by the US Food and Drug Administration (FDA) contained data from US clinical trials conducted outside of the USA. Despite the importance and availability of clinical trials for lung cancer, participation in early stage clinical trials by advanced stage lung cancer patients remains very low. There are multiple barriers that contribute to these low numbers of participants, some of which include: (1) fear of unknown benefit from the investigational treatment, (2) negative family and family physician influence, (3) logistical and attitudinal constraints – too cumbersome to participate and not willing to be the subject of “experiments”, (4) lack of knowledge, understanding and fear of the complexities of the clinical trial, (5) risk of inability to tolerate related investigational drug / treatment toxicity due to more weaken condition and (7) financial and insurance barriers.Identifying and overcoming the barriers that exist for each patient early in their diagnosis has the potential to improve both the quality and quantity of their lives and potentially help others with the same barriers in the future. Another significant barrier is the real and perceived conflict that exists between the need for palliative and/or Hospice levels of care for advanced stage lung cancer patients. The need for Hospice benefits and palliative care can and does have a significant impact on the decision to participate in early stage clinical trials to the point that participation may not even be an option. Funding and other system related issues act as barriers to participation in early stage clinical trials as well as the philosophical basis of the hospice/palliative care approach to treatment/care. Over the past decade the availability of symptom management and palliative care clinical trials has increased the awareness of this barrier and in many respects further clouded the issue for patients, their families and their healthcare providers. The primary ethical concern is does enrollment into clinical trials interfere with the spirit of hospice care or does it offer hope to a dying patient? Identifying issues that exist globally may help to increase enrollment by advance stage patients while at the same time moving early phase clinical trials forward and onto the phase II/III stage of study. Phase I trials are not designed with curative intent and phase I agents are not likely to prolong life or change the course of a disease. The life expectancy of phase I cancer patients’ averages between 5-6.5 months. Hospice providers and research investigators are in agreement that phase I clinical trials should be open and available to advanced stage lung cancer patients who are concurrently enrolled in hospice care. Overcoming the barriers and obstacles for advanced stage lung cancer patients to participate in early stage clinical trials can only happen in the setting of a committed multidisciplinary research team.Methods to utilize in an effort to move toward that goal include: (1) recognizing the importance of patient and family education, (2) recognizing the importance of healthcare provider education and awareness, (3) careful review and reinforcement of the informed consent process, (4) identifying and recognizing the potential benefit of phase I clinical trial enrollment for advanced stage lung cancer patients – clinical and altruistic, (5) recognizing and assisting patients and families with individual barriers and obstacles to participation and (6) employing effective marketing, recruiting and screening methods that are multidisciplinary in approach. Thoracic Oncology Nurses are well suited to serve as educators, advocates, resources, facilitators, and intermediaries. Nurses traditionally spend a greater amount of time in direct patient care and family interaction. Expanding and clarifying clinical information patients receive from their treating physicians is a vital role nurses play in ensuring patients are well informed and compliant with their plan of care. This is a model that can and has been extended into the realm of clinical trial work.Studies have shown that nurses play an important role in educating and recruiting cancer patients in clinical trials.A randomized clinical trial compared nurses with surgeons recruitment of patients into a clinical trial for prostate cancer and the results indicated that surgeons and nurses were equally as effective in their recruiting and educating abilities and effectiveness. With the proper education about early stage clinical trials, the conduct of clinical research, knowledge of the disease process of advance stage lung cancer and a high degree of self-motivation, thoracic oncology nurses are well suited to improve access and enrollment of advanced stage lung cancer patients into early phase clinical trials.

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Abstract
Thymomas are epithelial neoplasms arising in the thymus with a spectrum of morphology, genetic characteristics and clinical behavior. Thymomas are composed of a mixture of neoplastic epithelial cells and non-neoplastic T lymphocytes, admixed in varying proportions. Much of the controversy about classification of thymic epithelial tumors can be attributed to confusion about differences in histologic classification versus grading. While genetic studies have provided some insights into the biology of these tumors and classification, a major hurdle is how to identify molecular abnormalities specific to the epithelial cells of B1 and B2 tumors because the genetic findings are dominated by the numerous lymphocytes in the tumor stroma. Thymic epithelial tumors are classified into thymomas and thymic carcinomas according to the 2004 World Health Organization (WHO). Thymomas are classified into Type A and Type B tumors with the latter being divided into B1, B2 and B3 with an increasing percentage and degree of atypia of epithelial cells and decreasing numbers of lymphocytes. THYMOMA Type A thymoma, is composed of bland spindle or oval shaped and few lymphocytes. Type AB thymoma, , is composed of two components, one resembling the type A thymoma and one with plump cells and predominant lymphocytic infiltrate. Type B1 thymoma, is composed of a prominent lymphocyte population with a minor component of epithelial tumor cells with vesicular nuclei and small nucleoli. Type B2 thymoma, is a thymoma with relatively even mixtures of lymphocytes and plump epithelial cells with vesicular nuclei. Type B3, is predominantly composed of polygonal or round epithelial cells with mild atypia. This category shows variable degree of cytologic atypia. THYMIC CARCINOMA Thymic carcinoma was previously classified as Type C thymoma, but in the 2004 classification this term was dropped. These tumors show much greater degree of cytologic atypia than thymoma. CLASSIFICATION ISSUES Histologic heterogeneity is common, with more than one histologic subtype frequently present in a given tumor, making histologic subclassification difficult. The clinical relevance of the WHO classification system has been validated by many studies. In general the classification from type A to AB, B1, B2 and B3, then thymic carcinoma represent an increasing histologic grade that corresponds to increasing aggressiveness of clinical behavior. Increasing molecular alterations are also found along this spectrum from A to B3 thymoma and thymic carcinoma. Thymic epithelial cells stain for epithelial markers such as keratin and squamous markers such as p63 or p40 while thymic lymphocytes stain for T-cell markers such as TdT and CD3. Type A thymomas tend to have fewer immature (CD1a+) lymphocytes and more mature (CD1a-) lymphocytes, while the type B thymomas have many CD1a+ lymphocytes. PAX8 has been reported to be positive in tumor cells of thymomas. Confusion between histologic classification and grading has led to proposals to collapse the classification into a smaller number of entities. One meta-analysis suggested that the current WHO classification scheme of thymomas could be simplified into three types with significant prognostic value: A/AB/B1, B2, and B3. However, what these authors propose is more of a grading system based on clinical behavior rather than histologic typing. The proposal suggests combining two tumors that are completely different morphologically and genetically (type A and B1) both of which are low grade tumors with indolent clinical behavior. Genetic studies have shown distinct gene expression profiles that support the WHO subclassification of thymomas, as far as the subdivision in type A and B thymomas is concerned. Type AB thymomas are genetically heterogeneous, being more closely related to type B thymomas. Expression of the autoimmune regulator AIRE is lost in approximately 95% of thymomas. Genetic alterations in thymomas are most frequent on chromosome 6p23.3 (major histocompatibility complex locus) and 6q25.2 to 25.3. Thymic carcinoma has a distinctive morphology and biology. It is composed of highly atypical cells with cytoarchitectural features of carcinoma similar to those seen in other organs. Although many lymphocytes can be seen in its stroma, they are of B cell type and mature T cell type. Thymic carcinoma lacks the immature T cell lymphocytes that are present in thymoma. Thymic carcinomas are cytologically malignant.{Travis, 2004 #21463} While a certain amount of necrosis, atypia, and mitoses can be encountered in occasional epithelial thymomas, these findings are common in thymic carcinomas. An infiltrative growth pattern associated with desmoplastic stroma is often seen, without evidence of immature T lymphocytes. Thymic carcinomas display a variety of histologic subtypes, emphasizing the ability of thymic epithelium to differentiate toward different cells: squamous cell carcinoma, basaloid carcinoma, mucoepidermoid carcinoma, lymphoepithelial-like carcinoma, sarcomatoid carcinoma, clear cell carcinoma, adenocarcinoma, and NUT carcinoma with t(15:19) translocation. Several immunohistochemical studies have been employed in an attempt to confirm the diagnosis of thymic carcinoma. Several studies have found that CD5 will stain the epithelial cells of some thymic carcinomas. C-kit (CD117) also frequently stains thymic carcinomas. However, neither of these markers are found in all thymic carcinomas and uncommonly they can be positive in B3 thymomas or carcinomas from other sites such as the lung. Comprehensive genomic analysis using comparative genomic hybridization has shown thymic carcinomas are molecularly distinct from thymomas and squamous cell carcinomas of the lung. While c-Kit expression is common in thymic carcinomas mutations are rare. Despite multiple trials of molecular targeted therapies for the EGFR pathway, angiogenesis inhibition, c-kit pathway, histone deacetylase inhibition, octreotide, an IGF-1 receptor pathway, there are no validated targeted therapies that can be recommended at this time. With some of these approaches in early therapeutic trials, and active molecular investigation of these rare tumors, hopefully, in the near future, new treatment options for patients with advanced disease will become available. So far, molecular studies have provided useful insights into the histologic subtypes of thymic epithelial tumors and provide genetic validation of the existing classification, but they have not demonstrated superiority over morphology in classifying these tumors. Hopefully molecular markers can be identified that will aid in refining the existing classification or in separating the existing subtypes.

Abstract
There are many impediments to achieving scientific progress in thymic malignancies, starting with the fact that these are relatively rare tumors. Another problem is the fact that there is no official stage classification system. At least 15 different systems have been proposed, all of which have been based on a limited number of patients, and none of which has been universally adopted with clear definitions that are consistently interpreted. This lack of a common basic language is a crucial fundamental building block for scientific advancement. The International Thymic Malignancies Interest Group (ITMIG) is an academic organization devoted to promoting the scientific advancement in thymic and other mediastinal malignancies. ITMIG has partnered with IASLC to develop proposals to the AJCC/UICC for the 8[th] edition of the stage classification system. This process began in 2010 and is now in full swing. ITMIG has pulled together an international database of approximately 9,000 patients. This involves 77 centers and 16 countries, with a notable major contribution from the Japanese Association for Research in the Thymus (JART). This data, together with an additional approximately 1,800 patients provided by the ESTS have been made available to CRAB, the statistical center for IASLC stage classification analyses. The Thymic Domain of the Staging and Prognostic Factors Committee (SPFC) is currently analyzing this data. The committee is considering multiple factors, starting with an analysis of the prognostic value of the Masaoka and Masaoka-Koga stage classification systems. Subcommittees of the thymic domain are also looking specifically at T, N, M factors, the impact of tumor size, invasion into particular structures and clinical stage. Internal validation will be performed, considering treatment factors, clinical stage, histologic subtypes, geographic regions and taking into account both survival and recurrence. Potentially useful factors will be compared to assess the relative impact, and to select the best factors to propose for use in the 8[th] edition stage classification system.

Abstract
Introduction: Thymic tumors are rare malignancies and most of the current literature is composed of single-institutional series collecting small number of patients spanned over short time periods. The European Society of Thoracic Surgeons (ESTS) thymic working group developed a retrospective database among its members collecting patients with thymic tumors submitted to surgical resection between 1990 and 2010. Methods: A total of 2151 patients were collected from 35 Institutions, including 1798 thymomas, 191 thymic carcinomas (TC), and 41 Neuroendocrine Thymic Tumors (NETT)). 1709 patients (89%) received a complete resection. Myasthenia Gravis (MG) was present in 629 patients (35%). Different clinical-pathologic characteristics were analyzed for their impact on survival and recurrence. Primary outcome was overall survival (OS); secondary outcomes were the proportion of incomplete resections, disease-free survival (DFS) and the cumulative incidence of recurrence (CIR). Results: Ten-year OS and DFS rates were 73% and 70%. The risk of mortality increased with age and with the stage. It also increased in the presence of TC, NETT and incomplete resection. Ten-year CIR was 12%. Predictors of incomplete resection included male gender, tumor size, the absence of MG, non-thymoma categories (TC and NETT) and high-risk thymomas (B2-B3). The risk of recurrence increased with tumor size, increased stage and NETT. Finally, our analysis indicates that the overall effect of adjuvant therapy after complete resection on OS was significantly beneficial (p=0.05) using a propensity score. Conclusions: Masaoka stages III-IV, incomplete resection and non-thymoma histology showed a significant impact in increasing recurrence and in worsening survival. The administration of adjuvant therapy after complete resection is associated with improved survival.

Abstract
Thymic epithelial tumors represent a wide range of anatomical, clinical, histological, and molecular malignant entities, which may be aggressive and difficult to treat. The histopathological classification distinguishes thymomas from thymic carcinomas. Chemotherapy may be used in two clinical scenarios in thymic epithelial tumors: 1) chemotherapy may constitute primary part of the multimodal curative-intent treatment of locally-advanced tumors, and is subsequently combined with surgery or radiotherapy; the main objective is to achieve long-term survival with no evidence of tumor recurrence; 2) chemotherapy may be delivered as the sole treatment modality in unresectable, advanced, metastatic, or recurrent tumors; then a palliative-intent treatment, the aim is to improve tumor-related symptoms through achievement of tumor response, while no prolonged survival is expected. Several chemotherapy regimens have been used in the curative-intent setting, mostly consisting of adriamycin- and/or platin-based multi-agent combinations. Usually 2-4 cycles of chemotherapy are administered before imaging reassessment. Aiming at increasing the response rate to primary treatment, and thus complete resection rate, chemotherapy may be combined with radiotherapy; however, retrospective data available do not provide with interpretable figures to compare chemotherapy to chemo-radiotherapy in the pre-operative setting. Response rates to curative-intent chemotherapy ranged from 70% to 80% in the largest studies. Patients for whom R0 resection was thought to be feasible undergo surgery, and complete resection is achieved in about 50% of cases. Postoperative radiotherapy is then frequently delivered. When the patient is not deemed to be a surgical candidate - either because R0 resection is not thought to be achievable or because of poor performance status or co-existent medical condition, definite radiotherapy, as reported above, is delivered. If radiotherapy is not feasible, either because of a large tumor burden that precludes safe delivery of appropriate doses or because of co-morbidities increasing the risks of radiation-induced toxicity, treatment is chemotherapy alone, in a strategy that may ultimately be considered palliative. In the reported literature, 10-21% of patients with locally-advanced thymic tumors receiving upfront chemotherapy did not receive either surgery or radiation therapy or other local treatment. Survival of these patients is frequently limited. Overall, the major challenge in interpreting data about pre-operative chemotherapy in thymic malignancies is the wide variation in the number of patients subsequently treated with surgery, radiotherapy, or chemotherapy alone, which suggests significant heterogeneity in the inclusion criteria among series. Response has been evaluated based on elusive criteria in some studies published before CT scan was largely available. In most studies, thymomas and thymic carcinomas, as well as newly diagnosed and recurrent tumors, were not analyzed separately. Ultimately, the majority of studies are retrospective, with uncontrolled design. Finally, one should consider the potential effect of corticosteroids, that have been known for a long time to have a “lympholytic” effect. Palliative chemotherapy is given as the sole treatment modality for thymic tumors, usually in the setting of stage IV, unresectable, recurrent disease. Prolonged disease control is possible, but tumor eradication is not expected. Several studies - both prospective and retrospective - described several regimens for definite chemotherapy, but because there are no randomized studies, it is unclear which are best; multi-agent combination regimens and anthracycline-based regimens appear to have improved response rates compared to others, especially the etoposide, ifosfamide and cisplatin combination. In general, combination regimen is recommended, for at least 3 and no more than 6 cycles. Overall, response rates are 20-40%, lower than that observed in the preoperative setting. Progression-free and overall survival of patients ranges from 12 to 66 months, and 37 to 72 months, respectively; such variability may be related to the various settings in which chemotherapy was delivered in those studies. In the palliative-intent setting, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. It is estimated that 50-70% of patients with thymoma recurrence are eligible to chemotherapy. Strategy may consist of the re-administration of a previously effective regimen, especially in case of previous response, late occurring recurrence, and for anthracyclins, a patient in a good medical condition and not having received cumulative doses precluding the safe delivery of at least 3 additional cycles. In case of recurrence, the strategy may actually primarily consist of a similar multimodal management to that conducted at time of first diagnosis, with surgery and radiotherapy in eligible cases. Complete re-resection remains a major prognostic factor in this setting. In patients not eligible to receive additional chemotherapy, octreotide may represent a valuable option; as a single agent, octreotide produced objective tumor responses rates, and of more relevance in this setting, disease control rates. Novel treatment strategies are needed, especially for refractory, recurrent tumors, and thymic carcinomas, which carry a poor prognosis despite multimodal treatment. Potentially druggable targets are emerging, laying the foundations to implement personalized medicine for patients. Given the currently available targeted agents outside of a clinical trial, the signaling pathways that are relevant in the clinical care of patients, are the KIT and the Vascular Endothelial Growth Factor (VEGF)-R (Receptor) pathways. Promising new targets in thymoma and thymic carcinoma include IGF-1R and histone-deacetylase. Cixutumumab, an IGF1-R directed monoclonal antibody was recently reported to produce a promising 90%-disease control rate in refractory thymomas. Belinostat, a histone deacetylase inhibitor was evaluated in thymic malignancies in a recently completed phase II trial enrolling 41 patients (25 thymomas and 16 thymic carcinomas). Response and 2-year survival rates were 8% and 77% in thymomas. mTOR inhibitors, in the setting of phase I trials, have been reported to produce significant control rates in thymoma and thymic carcinoma. Along with the large variety of questions relative to the treatment strategy, thymic epithelial tumors represent a model of therapeutic implementation and achievement in orphan thoracic oncology, showing how the advent of new results induces new questions, as well as diversifies further clinical research directions; in this setting, regional and international collaborative initiatives are mandatory to progress both in the understanding of the biological mechanisms underlying the development of thymic malignancies, and in the identification and validation of new targets with prognostic and predictive value.

Abstract
Although the predominant approach in the treatment of thymoma and thymic carcinoma is surgery, radiation therapy also has an important role, either as postoperative therapy to reduce the risk of mediastinal recurrence or as part of definitive treatment for patients that who cannot undergo surgery. We present here a review of radiation therapy for thymic malignancies and briefly discuss the potential benefits from novel technologies for such treatment. Thymic carcinoma is a rare but more aggressive tumor which has a tendency to fail locally and distantly. Thymic carcinoma has more frequent EGFR and/or HER2 abnormalities compared to thymoma., and the outcome of thymic carcinoma is usually worse than invasive thymoma. Postoperative Radiation Therapy: Indications R0 (Completely Resected) Thymic Malignancies In general, radiation should be considered more strongly as the risk of recurrence increases. Therefore, for patients with the lowest likelihood of recurrence (i.e. completely resected Masaoka stage I thymoma), radiation can be safely omitted. For those at intermediate risk of local recurrence after complete resection, i.e. those with aggressive tumor histologies (such as thymic carcinoma) or Masaoka stage II and stage III disease, retrospective evidence exists both to support and contradict claims of benefit from adjuvant radiotherapy after complete resection. In general, our institutional practice includes postoperative radiation for completely resected Masaoka-Koga stage III thymoma and stage II or III thymic carcinoma. Risk assessment and stratification is usually done in a multidisciplinary setting and drives the choice of adjuvant treatment. The International Thymic Malignancy Interest Group (ITMIG) published a set of definitions and reporting guidelines for the use of radiation therapy for thymic malignancies in 2011. Pertinent recommendations for postoperative therapy are as follows. First, the term “postoperative” should be used for situations in which the tumor is resected and no residual disease is evident on imaging. If gross disease is present on postoperative imaging, then the disease should be defined as “recurrent” and the intent as “radiation for postoperative disease.” Second, the minimum acceptable dose for postoperative R0 disease is 50 Gy in 5 weeks. Finally, radiation to elective nodal regions not recommended, and the extent of malignancy before surgery should be used as a guide for designing the treatment fields. Microscopic Positive Margins (R1) and Gross Disease (R2) Radiation for R1 or R2 thymic malignancies should be started within 3 months of surgical resection. Doses between 40 Gy and 64 Gy are most appropriate for microscopically positive margins, whereas doses of 54 Gy or higher should be used for gross disease; both given in standard fractions of 1.8- to 2.0-Gy. Patients with positive margins should be considered for concurrent chemotherapy and radiotherapy, especially among patients with thymic carcinoma. Definitive Radiation Therapy Definitive radiation therapy is generally used for patients who are not candidates for surgery because of either the extent of disease at diagnosis or medical comorbidities. Because chemotherapy is a known radiation sensitizer, the combination of chemotherapy and radiation is considered most likely to control disease in these circumstances. In this setting, which is analogous to recurrent disease after surgical resection, we recommend radiation doses of 60 Gy -66 Gy to encompass gross disease plus a margin for microscopic regions at risk. Thymic carcinoma behaves more like non-small cell lung cancer arising from the thymus. Therefore, unresectable thymic carcinoma needs to be treated based on the histology or molecular biomarkers of expression e.g. EGFR, HER2 c-KIT and BCL-2. Approximately 50% of thymic carcinoma has squamous histology which can be treated with cisplatin based chemotherapy and radiotherapy. If unresectable thymic carcinoma has atypical carcinoid histology, etoposide and cisplatin plus radiotherapy might be the best option. For recurrent thymic carcinoma, molecular targeted agents e.g EGFR-TKI, c-KIT inhibitors and VEGFR inhibitors can be delivered in the protocol setting with or without radiotherapy. Techniques Because of the central location of thymic malignancies and the relatively high doses used in radiation therapy, we strongly recommend the use of conformal techniques, such as three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or, if available, proton beam therapy owing to the physical properties of the particles (i.e., the Bragg peak) which produce lower doses both proximal and distal to the target volume. In addition, because tumors can show substantial changes in shape or size over the course of several weeks of radiation therapy, we recommend that when radiation is to be used as definitive therapy, adaptive planning should be considered. Long-Term Consequences of Radiation on the Heart and Vasculature An abundance of evidence exists to show that long-term survivors of mediastinal radiation therapy can develop both acute and chronic cardiac sequelae. With regard to acute effects, the dose and fractionation of the radiation and the volume of heart irradiated all affect the risk of pericarditis and pericardial effusion. Given the close physiologic association between perfusion and ventilation, one might expect that radiation to the heart could affect lung function and vice versa. In a clinical study, investigators found that several heart dose-volume variables predicted radiation pneumonitis and that the fit of a model predicting pneumonitis was improved by the incorporation of heart variables. In conclusion, considerable evidence has shown that irradiation of the heart and vasculature can lead to increased acute and long-term toxicity and that these side effects are related to the dose, volume, and exact location of the irradiated field. Short-term surrogates of long-term toxicity such as findings on cardiovascular imaging or biomarker correlates would be helpful for identifying which patients at greatest risk for cardiac events. In the meantime, we recommend the continued use of advanced radiation therapy technologies such as IMRT, proton beam therapy, 4D imaging and treatment planning, and adaptive planning whenever possible to minimize the dose to mediastinal structures for patients with thymic disease, many of whom will survive for several decades and thus will live to see the long-term consequences of irradiation of these vital organs.

Abstract
Whenever a major alteration in histopathologic classification occurs, important ramifications for cytopathology follow. Furthermore, the recent recognition that associations of specific types of epithelial malignancies of the lung are associated with different prognoses and therapeutic complications also directly impacts diagnostic cytology. One important question is: how well can we distinguish adenocarcinoma, squamous cell carcinoma, and other nonsmall cell carcinomas (NSCLC) from each other in cytologic preparations? The answer is very well, with most recent data emanating from aspiration samples. Based purely on routine cytomorphology, approximately 90% of all specimens with NSCLC can be rendered by strict adherence to classic well indoctrinated cellular features. When the distinction cannot be rendered by morphology alone, the addtion of a small battery of immunochemical reactions raises the proportion of correct cell typing to nearlly 100%. Recommendations emphasize using a limited array of antibodies, eg. targets such as TTF-1, cytokeratin 5/6, and synaptophysin. In the infrequent case in which this does not make clear the cell type, a diagnosis of NSCLC, NOS is preferred over large cell carcinoma. Once a tumor is interpreted as adenocarcinoma, how well do we do in determining the predominant histologic subtype from the 2011 classification? The answer is poorly. This is related to both the small sample size with the recognition of the histologic heterogeneity within a sizeable tumor mass and the concept that the rather uniform manners in which neoplastic cells aggregate and present themselves in aspiration and exfoliative smears is typical of all types of adenocarcinomas and thus not representative of the histologic subtype. Current data supports the general notion that the predominant histologic subtype correlates with prognosis, and thus may serve as a morphologic grading surrogate. As just stated, it does not appear that cytology will permit such a parallel assessment. However, there is some evidence that certain nuclear attributes of adenocarcinoma cells in cytologic specimens are associated with prognosis and, hence, nuclear grading may be of value in this regard. Features which include nuclear contour, chromatin pattern, and the prominence of nucleoli can be used to formulate a meaningful nuclear grading system. This is likely better performed with alcohol-fixed Papanicolaou stained specimnes compared to air-dried Romanowsky stained samples. Note that mitotic figure counting is not a component of this proposal. It is crucial to recognize that cytologic samples provide a substrate for the molecular testing of therapeutically important mutations in adenocarcinoma cells which seem to be equal to histologic specimens. Thus, it is very relevant that sufficient cytologic material be collected at the very time of sampling and that it be utlized in an extremely judicious manner.

Abstract
There has been very little improvement in outcome from lung cancer over the last two decades but the identification of actionable mutations and structural rearrangements in subsets of patients with lung adenocarcinoma holds hope for the near future, particularly if these agents successfully move into the adjuvant setting. Detection of key molecular targets is central to this new understanding of lung adenocarcinoma and targeted therapy but poses significant challenges for implementation into routine clinical diagnostics. The importance of molecular testing in lung adenocarcinoma has been emphasized not only in the updated classification of adenocarcinoma but also in the recently released molecular testing guidelines for selection of lung cancer patients for EGFR and ALK Tyrosine Kinase Inhibitors produced by the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology this year with a central recommendation that tissue should be prioritized for EGFR and ALK testing. Recent molecular and genomic studies of lung adenocarcinoma in particular has resulted in the identification of other low incidence, novel driver mutations including structural rearrangements in ROS1 and RET-KIF5B as well as recognition of point mutations in BRAF and HER2 among others. It is apparent that “profiling” lung cancers for a range of important and potentially treatable driver mutations may offer significant advantages such as cost effective, rapid identification of actionable changes and efficient triage for clinical trials of novel agents. However performing molecular testing in lung cancer can be challenging given the majority of patients present with inoperable disease. This means histological and molecular diagnosis is generally performed on small biopsies including cytological specimens often with very limited material for testing. Furthermore much of this tissue has undergone formalin fixation and paraffin processing with subsequent DNA cross-linkage and fragmentation. There are additional problems of contamination with non-malignant tissue elements including stroma and inflammatory cells. There are also time pressures with the need for rapid results with current recommendations for results to be available within 10 working to allow appropriate triage for therapy. It is important to direct testing to appropriate clinical groups likely to benefit. While there are strong demongraphic associations of actionable mutations in lung adenocarcinoma, including non-smoking status, younger age, female sex and Asian ethnicity, these criteria are insufficiently robust to exclude patients without these characteristics from testing. Current recommendations in limited specimens are that molecular testing for EGFR or ALK gene changes be primarily undertaken in adenocarcinoma or cases with a component of adenocarcinoma. Fortunately cytology is emerging as a robust method for classification of lung cancer and these specimens are increasingly utilized for mutation testing. Large cell or histologically undifferentiated carcinomas with features suggestive of adenocarcinoma differentiation eg TTF-1 expression are also suitable for molecular testing. Molecular testing of limited biopsies may also be considered in cases showing squamous or small cell histology guided by clinical features such as ethnic background and non-smoking status among others. There is good concordance between primary and metastatic sites for EGFR mutational status and specimens from either site are acceptable for testing with choice based on morphological assessment of optimal specimens for molecular testing There are a wide variety of molecular techniques available to assess for the presence of key driver mutations in lung adenocarcinoma, each with their own limitations and advantages, but there is no perfect technology that fulfills all clinical and laboratory needs, especially on the limited material usually available in lung cancer mutation testing. Virtually all techniques for EGFR testing depend on PCR amplification, which is a major issue where limited DNA template is present raising the possibility of both false negative (due to sensitivity issues) and false positive results (eg due to amplification of formalin artifacts). In our own practice we have found that standard methods for DNA quantification such as spectrophotometry significantly overestimates the amount of DNA available for testing in comparison to more specific methods such as DNA fluorometry or estimates of amplifiable DNA copy number. We currently perform routine diagnostic mutation testing via multigene mutation profiling using a commercial panel, Oncocarta v1.0, on the massARRAY Sequenom platform in combination with fragment analysis for EGFR exon 19 and 20 insertions and deletions. This allows simultaneous determination of key mutations in EGFR and KRAS status as well as identifying rare but potentially actionable changes in BRAF, PIK3CA and HER2. In parallel, we perform immunohistochemistry for ALK and ROS1 to allow rapid triage for FISH testing if mutation profiling is negative. However not all cases have sufficient material for this approach and we are currently validating a new custom panel which can be performed reliably with less DNA. While cytological specimens are problematic in the generally small amount of tumour material available for testing, they have the advantage of often containing a relatively pure population of tumour cells, with a marked reduction in stromal contamination especially in FNAB specimen. Earlier studies suggested cytological specimen were less preferred to small tissue biopsies but a number of more recent publications have highlighted the suitability of these specimens. While the most recent recommendations suggest that cell block specimens allowing pretest morphological assessment are preferred to fresh smears, fresh material offers generally better quality and quantity of DNA. FISH testing for ALK gene rearrangement on cytological specimens is feasible and increasingly widely performed. Generally FISH testing requires less cellular material than mutation testing and the direct visualization of the molecular assay in tumor cells gives greater confidence that a negative result is far less likely to reflect problems with sensitivity as for EGFR testing. Expert morphological assessment is critical to ensure malignant cells are being assessed in this setting. In summary, cytology specimens are a commonly tested lung cancer diagnostic specimen and offer a number of advantages over more invasive small biopsies. Expert cytological assessment of specimens should be undertaken prior to molecular testing to maximize the quality and accuracy of testing.

Abstract
Most lung cancers are readily diagnosed by using light microscope without attaining special stains [1], but at least 30% of NSCLC could benefit from immunohistochemistry (IHC) to unveil the cell differentiation lineages, especially when dealing with cytology and biopsy specimens [2]. Molecular methods, including micro-RNA expression analysis [3], are cumbersome and unlikely to be directly transferred into the everyday diagnostic workflow [2, 4]. IHC is not a perfect mathematic model, since there is a small (<5%) subset of NSCLC with ambiguous co-expression of glandular and squamous cell differentiation markers or negative reaction for any marker [5, 6]. a) What is the best combination of biomarkers to use? The coordinated expression for TTF-1 for adenocarcinoma and p40 for squamous carcinoma is currently emerging as the most reasonable and reliable biomarker duet in terms of sensitivity and specificity [2, 7-9]. Other promising biomarkers include napsin A for adenocarcinoma [10] and desmocollin-3 for squamous carcinoma [11, 12]. While TTF1 is the best marker for adenocarcinoma and p40 equivalent to p63 for squamous carcinoma, p40 is by far superior in terms of specificity since only rare adenocarcinomas are focally positive in comparison with p63 [2, 7-9]. b) Be aware of antibody clones and other technical issues. The monoclonal antibody 8G7G3/1 for TTF1 seems to be more specific for adenocarcinoma than other clones (such as SPT24) [8, 13], but it has also been recorded in gynecologic [14] and breast [15] carcinomas. Monoclonal antibody to napsin A for adenocarcinoma is less sensitive, but more specific than polyclonal antiserum [16]. The single best marker for squamous carcinoma is a polyclonal rabbit antiserum against p40 [7-9][,17], but very recently a monoclonal antibody has been made commercially available. c) Practical hints to surgical pathologists. NSCLC-NOS upon morphology with negativity for p40 and some TTF-1 positivity should be equated to poorly differentiated adenocarcinomas, once large cell neuroendocrine carcinoma (LCNEC) by relevant markers (e.g., synaptophysin) has been excluded. NSCLC-NOS upon morphology showing double negativity or with only erratic labeling for p40 in < 5% tumor cells in absence of TTF-1 should be considered as poorly differentiated non-squamous carcinomas corresponding, in most instances, to poorly differentiated adenocarcinoma once metastatic cancer has been reasonably excluded, keeping in mind however that the same immunoprofile may be shared by sarcomatoid carcinomas (excludible by morphology and vimentin IHC) [17] and LCNEC (excludible by synaptophysin IHC). Poorly differentiated squamous carcinomas are instead highlighted by strong and diffuse p40 expression and TTF-1 negativity, hence lack of p40 exclude by definition this tumor according to the axiom “no p40, no squamous” [9]. When morphology fails to conclusively subtype NSCLC, it is recommended specifying in the pathology report the real contribution of IHC to render the final diagnosis according to the relevant cell differentiation lineages (e.g., NSCLC-NOS, favor adenocarcinoma or squamous carcinoma by IHC) [6]. References 1. Travis W, Brambilla E, Muller-Hermelink H, Harris C. Tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. 2. Rossi G, Pelosi G, Barbareschi M, et al. Subtyping non-small cell lung cancer: relevant issues and operative recommendations for the best pathology practice. Int J Surg Pathol 2013;21:326-36. 3. Lebanony D, Benjamin H, Gilad S, et al. Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. J Clin Oncol 2009;27:2030-7. 4. Rossi G, Papotti M, Barbareschi M, Graziano P, Pelosi G. Morphology and a limited number of immunohistochemical markers may efficiently subtype non-small-cell lung cancer. J Clin Oncol 2009;27:e141-2; author reply e3-4. 5. Travis W, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85. 6. Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 2013;137:668-84. 7. Bishop JA, Teruya-Feldstein J, Westra WH, et al. p40 (DeltaNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 2012;25:405-15. 8. Pelosi G, Fabbri A, Bianchi F, et al. DeltaNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol 2012;7:281-90. 9. Pelosi G, Rossi G, Cavazza A, et al. DeltaNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol 2013;21:229-39. 10. Turner BM, Cagle PT, Sainz IM, et al. Napsin A, a new marker for lung adenocarcinoma, is complementary and more sensitive and specific than thyroid transcription factor 1 in the differential diagnosis of primary pulmonary carcinoma: evaluation of 1674 cases by tissue microarray. Arch Pathol Lab Med 2012;136:163-71. 11. Monica V, Ceppi P, Righi L, et al. Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung. Mod Pathol 2009;22:709-17. 12. Righi L, Graziano P, Fornari A, et al. Immunohistochemical subtyping of nonsmall cell lung cancer not otherwise specified in fine-needle aspiration cytology: a retrospective study of 103 cases with surgical correlation. Cancer 2011;117:3416-23. 13. Rekhtman N, Ang DC, Sima CS, Travis WD, Moreira AL. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol 2011;24:1348-59. 14. Siami K, McCluggage WG, Ordonez NG, et al. Thyroid transcription factor-1 expression in endometrial and endocervical adenocarcinomas. Am J Surg Pathol 2007;31:1759-63. 15. Robens J, Goldstein L, Gown AM, Schnitt SJ. Thyroid transcription factor-1 expression in breast carcinomas. Am J Surg Pathol 2010;34:1881-5. 16. Bishop JA, Sharma R, Illei PB. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol 2010;41:20-5. 17. Pelosi G, Melotti F, Cavazza A, et al. A modified vimentin histological score helps recognize pulmonary sarcomatoid carcinoma in small biopsy samples. Anticancer Res 2012;32:1463-73.

Abstract
According to the recent trend of increased frequency of CT screening for lung cancer, earlier stage of lung cancer is being detected and removed surgically. In applying the new classification to such lesions, it always becomes problematic to make a differential diagnosis among the three categories: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant adenocarcinoma. AIS is defined by a pure lepidic growth pattern with a continuous growth of neoplastic cells along the alveolar septa without disruption of the alveolar structures. MIA is defined as an adenocarcinoma with predominant lepidic growth with less than or equal to 0.5 cm area of sromal invasion. The definitions are summarized in Table. When the invasive area is more than 0.5 cm and lepidic growth is predominant, the tumor is diagnosed as lepidic predominant adenocarcinoma. The distinction is clinically important because AIS and MIA have been shown to have 100%5 year recurrence free-survival, whereas lepidic predominant adenocarcinoma can recur. However, the major difficulty for the differential diagnosis has in roots in the identification of stromal invasion and measurement of the invasive area. Histological stromal invasion is determined by tumor cell and stromal factors. Because the area where the tumor cells show invasive structure is regarded as an invasive area, it is important to recognize the differentiation of lepidic pattern from papillary or acinic pattern. However, the distinction is often difficult in practice. In terms of the stromal factor, it is also difficult to differentiate an invasive scar (myofibroblastic stroma) from a scar due to collapse. Physicians should know this room for discussion, and practical solutions should be shared with pathologists. Figure 1

Abstract
Background: The development of high-resolution chest imaging techniques and screening of smokers for lung cancer resulted in increased detection of multiple lung cancers. The challenge for pathologists and treating physicians is to determine whether multiple lung cancers represent separate primary tumors or metastasis, as this affects the stage, treatment and prognosis. The clinical and pathological criteria used to define multiple lung tumors were initially published by Martini and Melamed in 1975. These criteria are based on tumor morphology and location and may not predict prognosis. The AJCC 7[th] edition staging of lung adenocarcinoma recognized shortcomings of this proposal and incorporated changes in the staging of multiple lung cancer, but molecular genetic analysis was not recommended as a standard approach. Methods: PubMed available peer-reviewed original articles and experience of the author. Results: Distinction between primary tumors and intrapulmonary metastasis becomes challenging when tumors are morphologically similar. Since the original Martini and Melamed proposal, many molecular approaches have been utilized in the evaluation of clonal relationships between multiple lung nodules including DNA microsatellite analysis, PCR assays for common somatic mutations, aCHG, and gene expression analysis. Molecular classification of multiple lung cancers is concordant with pathological classification in about two-thirds of the cases. It is difficult to determine the precise percentage because of the relatively small number of analyzed cases, mixed analysis of synchronous and metachronous tumors, and use of different methods and interpretation criteria. Early studies used two types of clonality assays: a panel of variable number of polymorphic microsatellite markers and X-chromosome inactivation analysis (Am J Surg Pathol 2005; 29(7):897;Ann Diagn Pathol 2001;5(6):321; Clin Cancer Res 2000; 6(10):3994; J Natl Cancer Inst 2009;101:560) . Tumors with largely concordant results were considered clonal in origin (metastases), and those with discordant findings were considered to be independent primary tumors. The main weakness of earlier studies was a limited number of analyzed genes. Recently, more comprehensive approaches analyzing a large number of single nucleotide polymorphic loci in a single assay or large-scale DNA sequencing of tumors were used (Clin Cancer Res 2009; 15(16):5184; Lung Cancer 2012;77:281). Although more comprehensive molecular approaches were used, a proportion of cases with discordant molecular and morphological results remained similar. Furthermore, molecular profiling only slightly improved prognostic classification of multiple lung tumors. Standard practice is to test non-resectable adenocarcinomas for common actionable somatic mutations (e.g. EGFR) and gene rearrangements (e.g. ALK) as predictors of response to targeted therapies. This information can also be used for improved staging of multiple lung nodules (Eur Resp J 2012; 39:1437; Lung Cancer 2012; 77:281). Based on similar or different mutational profile synchronous tumors may be classified as independent primaries or intrapulmonary metastases. It is very likely that surgically non-resectable tumors with different mutational profiles such as EGFR and KRAS will show different treatment responses, further emphasizing the need for separate analysis of multifocal tumors. In contrast to morphologic classification, molecular profiling can be performed on the cytology specimens. This approach can be used in adenocarcinoma only, and currently no standard molecular testing in squamous cell carcinoma is in practice. Conclusions: Molecular approaches to classification of multiple lung tumors have not been standardized, and their performance in routine clinical practice remain to be established. Testing for common activating oncogenic mutations and translocations is likely to provide information about clonal relationship between multifocal lung tumors. Implementation of molecular information to current histologic staging could improve the accuracy of staging in patients with multifocal tumors and improve therapeutic decision making.

Abstract not provided

Abstract
Although recent development of minimally invasive procedures contributed significantly to reduce of postoperative complications, as the population continues to age, as more patients receive induction therapies, and as more patients are immunocompromised, complications will continue to increase. Although many complications can be treated medically, some complications require another round of surgery. Postoperative complications after lung cancer surgery can take place both in early and late postoperative periods. As a matter of fact, major surgical errors during the surgery can result in mortality or major morbidity. Hence, the surgery for complications of surgery should begin with prevention of the intraoperative event during the initial surgery. Intraoperative complications During the major lung resection, various kinds of errors can take place. Poor surgical technique can cause injuries of the pulmonary vasculature as well as of the bronchus. The risk of intraoperative technical complication can occur either during VATS or thoracotomy procedures. However, it is more difficult to control in VATS. Minor bleeding can be easily controlled trough VATS. However, once a major vascular injury occurs, the bleeding focus should be compressed, and a prompt thoracotomy should be made. Any bronchial injuries should be detected during the surgery and appropriately fixed. Bleeding can also occur from the pulmonary parenchyma, especially after wedge resection in patients whose pulmonary arterial pressure is increased. For such patients, the staple lines should be oversewed meticulously as the elevated pulmonary arterial pressure may cause postoperative bleeding. Sometimes, lack of understanding of variations of intrathoracic anatomy can cause serious complications. Such structural variations should be acknowledged preoperatively by carefully reviewing the CT scans. According to a report from a dedicated thoracic surgical center, the catastrophic complications took place in 1% of patients, including main pulmonary arterial and main pulmonary venous transection requiring reanastomosis, unplanned pneumonectomies, unplanned bilobectomy, tracheoesophageal fistula, membranous airway injury to the bronchus intermedius, complete staple line disruption of the inferior pulmonary vein, injury to the azygos/superior vena cava junction, and splenectomy. The third and perhaps the most important cause of intraoperative complication is negligence. Thus, establishment of standardized surgical protocol is mandatory in training hospital. Postoperative complications Common postoperative complications such as prolonged air leak, atrial fibrillation, aspiration and pneumonia can be treated by medical methods. The early postoperative course is often compromised by chylothorax. The initial treatment is to give nothing by mouth and wait until the chest tube drainage decreases. However, if the chylothorax persists, reoperation with duct ligation should be considered. Empyema is an uncommon complication after pulmonary resection. The key treatment principle is control of the pleural space, which can be established by lung expansion. If there is any question of a BPF, repeat thoracotomy with muscle or omental harvesting is mandatory to drain the empyema and to decorticate the lung, and to buttress the open bronchus. Superficial wound infections are managed with antibiotics, drainage, and local wound care. Management options of deep sternal infection include sternal debridement or sternectomy, prolonged open wound care or irrigation, muscle flap reconstruction, or some combination of these. Postpneumonectomy bronchopleural fistula (BPF) is difficult-to-manage. Management is determined by the timing of complication, the condition of the patient, and the presence or absence of empyema. Patients should be positioned with their operated side down. Chest tube drainage of the empyema should be performed. For repair of the bronchus, a long stump can be resected and closed primarily if the BPF took place in the early postoperative period. In some cases, primary closure of postpneumonectomy BPF may not be tenable. In such situations, the bronchial leak point can be closed with a vascularized flap. Sterile or minimally contaminated cavities can be irrigated, filled with antibiotic solution, and then closed. Eloesser flaps are ideal for long-term open drainage and irrigation. Alternatively, after the pleural cavity is granulating and healthy, it can be filled with antibiotic solution and closed. Rarely, BPFs have been managed nonoperatively with endoscopic techniques combined with antibiotics. Residual space after lobectomy can also occur. Intraoperative maneuvers to lessen the risk for space problems include pleural tents, phrenic nerve crush, muscle or omental transposition, thoracoplasty, and pneumoperitoneum. If a patient is clinically well, continued observation and antibiotics are appropriate while the space fills. Lobar torsion is one of the most serious complications and commonly affects the right middle lobe after right upper lobectomy. Visual confirmation of anatomic position and proper lung inflation allows detection of twisted or ischemic lung before closure. The lung may be salvageable if the torsion is recognized early, before infarction occurs. However, usually the diagnosis is late, and resection is required. Postpneumonectomy syndrome is caused by displacement and rotation of the mediastinum into the operated chest. The remaining main stem bronchus is stretched and compressed over the spine or aorta. Surgical treatment principle is to reposition the mediastinum by placing intrathoracic prosthetic implants, which will relieve the airway compromise. Sleeve lobectomy or other bronchoplastic procedures may result in late airway stenosis. Repeated dilations sometimes stabilize strictures but usually the effect is temporarily. In some cases, reoperation is necessary. If the stenosis resulted from kinking of the anastomosis, resection and re-anastomosis may fix the problem. Usually, a completion pneumonectomy may be necessary. A fistula between the airway and pulmonary artery occur after bronchoplasty or tracheal resection. If a fistula is apparent, emergency surgery should be performed. The mortality rate of bronchovascular fistulas is high. Tracheoesophageal fistula can develop with prolonged intubation and mechanical ventilation. Surgical repair should be attempted after the patient's condition is optimized, and the patient is breathing spontaneously. Chest wall graft infection can happen even several years after chest wall resection and reconstruction. When chronic, often times, soft tissue flap support may be sufficient to obviate skeletal reconstruction. Conclusions An appropriate patient selection and meticulous surgery are the best prophylaxis against postoperative surgical complications. When complications arise, they require an experienced surgeon for identification and correction. Furthermore, training of surgical techniques, sound knowledge of anatomical variations, as well as stringent observances of surgical principle are mandatory to overcome intraoperative complications.

Abstract
Treatment of Cancer Cachexia over the next 5 years. The focus of this session will be on the emerging evidence for therapeutic approaches, outside anti-cancer treatments, that help clinicians care for patients and their families with anorexia cachexia syndrome. An overview of the basic pathophysiology will be presented to enable understanding of the diverse interventions studied as well as those that are currently under investigation. The challenge and importance of defining the syndrome will be discussed. It will also be important to discuss the drivers that are moving the sector towards the concept of categorising patients into pre-cachexia, established cachexia and refractory cachexia. This has implications about when to intervene and how the goals of interventions may change over time. This may help design better matched cohorts for clinical trials, influence design of service models and alert us to the possibility of previous false negative studies. There will be a review of the prevalence of anorexia cachexia in various tumour streams and at different time points over the illness trajectory. The scope and scale of the clinical impact will be discussed in detail including the potential importance of symptom clusters, association with total symptom burden, links to fatigue and the evolving picture of the psycho-social distress that is common for suffers and their families or carers. Significant time will be dedicated to summarising the evidence base for pharmacological, nutritional and exercise approaches. The author will share his own experience in leading a dedicated inter-disciplinary cancer cachexia clinic over the last 9 years in Victoria and why he feels a multi-modality approach should be adopted. Lastly an outline of what might represent best practice for the management of this syndrome over the next five years will be presented for open discussion.

Background
Carboplatin (CBDCA) is used widely against various tumors,including non-small cell lung cancer, small cell lung cancer, which is classified a moderate emetic risk. 5-HT~3~ antagonist and corticosteroid had a great efficacy in patients (pts) treated with CBDCA containing chemotherapy. This randomized trial was conducted to evaluate the efficacy and safety of aprepitant (APR) compared with corticosteroid, based on granisetron (GRA) plus corticosteroid at the first day, in pts treated with CBDCA containing chemotherapy.

Methods
Pts treated with CBDCA (AUC 5 or 6) containing chemotherapy were entered on this trial. Major eligible criteria included more than 20 years old, and ECOG PS 0-2. Patients were randomized either A group (GRA 3 mg, iv, day 1, dexamethasone [DEX] 3.3 mg, iv, day 1, APR 125 mg , po, day 1, and APR 80 mg, po, days 2,3) or D group (GRA 3 mg, iv, day 1, D EX 6.6 mg, iv, day 1, and DEX 8 mg, po, days 2, 3). Randomization was stratified by gender and CBDCA AUC 5 or 6. Study period was 120 hours from administration of CBDCA. During this period, pts recorded the time and date of emetic episodes and severity of nausea by themselves in a survey form. Primary endpoint was complete response rate (CRR), defined as no emetic episodes and no rescue medications during the overall study period. Secondary endpoints included CRR during the acute (0-24 h) and the delayed (24-120 h) phases, no nausea rate, severity of nausea and safety. The planned sample size of 128 provided 80% power to detect a 20% improvement in the CRR at overall period with two-sided α of 0.1. This study was approved by the institutional review board in our institution. All pts provided written informed consent prior to enrollment.

Results
From October 2010 to August 2012, 128 pts were entered in this phase III trial. Three quarters of entered pts were male, and 63% were received CBDCA AUC 6. Baseline factors, such as age, gender, AUC of CBDCA, chemotherapy regimen, and PS, were well balanced between the two groups. The CRR during overall study period were 61.3% and 68.8% in A and D group, respectively (p=0.3799). There was no difference of CRR during both the acute phase (98.4% vs 98.4%) and the delayed (61.3% vs 68.8%). There was no adverse event due to the antiemetic therapy in both groups during the overall study period.

Conclusion
This randomized phase III trial failed to demonstrate that APR was superior to DEX for emesis induced by CBDCA containing chemotherapy which was classified a moderate emetic risk. Combination APR with DEX on days 2 and 3, or more was likely to increase an antiemetic efficacy during delayed phase. Further study was warranted.

Background
Patients with cancer have varying preferences for involvement in decision-making between active, collaborative and passive roles. Previous studies suggest that many patients prefer a more active role than they experienced, and a more active role over time[MSA(1] . We sought the preferred and actual level of involvement in decision-making among patients considering ACT after resection of early NSCLC.

Methods
98 patients completed a self-administered questionnaire at baseline (before ACT, if they were having it) and at 6 months (after ACT, if they had it). Preferred and actual level of involvement in decision-making were assessed by the Control Preferences Scale (CPS) and trichotomised into active, collaborative, and passive roles. Health-related quality of life (HRQL) data were assessed by the Patient DATA Form. Differences on the original CPS scale between preferred and actual roles and between preferred roles over time were assessed with the Wilcoxon signed-rank test. Determinants of preference for an active role were assessed with chi-square tests of association in 2x2 tables, summarising by odds ratios (ORs). Wilcoxon rank-sum (WRS) tests were used to assess differences in survival benefits required to make ACT worthwhile between patients preferring active and less active roles.

Results
Most patients were male (55%) with a median age of 64 years (range, 43-79 years), married (74%) and previous smokers (82%). The majority had had a lobectomy (85%), adenocarcinoma histology (63%), and half (46%) had stage II disease. 83 patients decided to have ACT (85%), 15 declined ACT (15%). ACT was most commonly 4 cycles (71%) of cisplatin/ vinorelbine (73%). Preferred role in decision-making at baseline (n=98) was active in 26 (27%), collaborative in 46 (47%), and passive in 26 (27%); and at 6 months (n=73) was active in 15 (21%), collaborative in 37 (51%) and passive in 21 (29%). Preferred decision-making roles were stable over time (p=0.5). Actual decision-making roles at baseline (n=98) were active in 24 (24%), collaborative in 47 (48%), and passive in 27 (28%). There was concordance between preferred and actual decision-making roles at baseline (p=0.4). Preferring a more active role was associated with university education (p=0.02, OR 2.9) and worse HRQL during ACT: physical well-being (p=0.05, OR 4.4), overall well-being (p=0.02, OR 5.5), sleep (p=0.03, OR 8.4) and shortness of breath (p=0.01, OR 7.6). Patients who preferred an active decision-making role judged larger survival benefits to make ACT worthwhile than patients who preferred a passive role (eg extra survival time of 1 year v 6 months, WRS p=0.03; extra survival rate of 17.5% v 2.5%, WRS p <0.01).

Conclusion
Patients with recently resected NSCLC varied in their preferred roles in decision-making about ACT with most patients preferring a collaborative role. Their preferences were stable over time, and were concordant with their perceived actual role in decision-making at baseline. Preferences for an active role in decision-making were associated with judging larger survival benefits necessary to make ACT worthwhile. Clinicians should elicit and consider patients’ preferences for involvement in decision-making when discussing ACT for NSCLC.

Background
Lung cancer, the leading cause of cancer-related death, is associated with poor survival, painful, life-threatening disease attributes, and greater associated economic burden compared with other cancers. The disease also presents multiple challenges for the caregivers of patients with lung cancer, including increased distress, significant impact on social and health-related quality of life (HRQoL), and costs associated with loss of income and time spent on patient care. Little information exists on the extent of this caregiver burden. The current study aims to investigate the HRQoL and the comorbidity burden of caregivers of patients with lung cancer in several European (EU) countries.

Methods
Data were provided from the 2010 and 2011 EU National Health and Wellness Survey (NHWS), an annual, stratified, random, cross-sectional, self-administered Internet-based survey of healthcare attitudes and behaviors among adults in France, Germany, Italy, Spain, and the United Kingdom (n=114,962). Respondents who reported providing care for a patient with lung cancer ("caregivers") were compared with respondents not providing care ("non-caregivers") on measures of HRQoL and self-reports of diagnosis with conditions known to be caused or exacerbated by psychological stress. HRQoL was assessed using the 12-Item Short Form Survey (SF)-12v2, which included Mental (MCS) and Physical (PCS) Component Summary scores; mental and physical functioning subscales; and SF-6D health state utilities (with higher scores indicating better health status and minimally important differences [MIDs] of 3 points in PCS/MCS scores, and 0.03 points in health utilities).The self-reported diagnoses of interest included depression, anxiety, insomnia, headache, migraine, and gastrointestinal (GI) illnesses (ie, gastroesophageal reflux disease, heartburn, and/or irritable bowel syndrome). Regression models were used to predict health outcomes as a function of caregiving vs non-caregiving, controlling for demographics (age, gender, education, income, marital status, employment, body mass index category), health risk behaviors (exercise, smoking), and the Charlson Comorbidity Index (reflecting mortality risk).

Results
No significant differences between caregivers (n=107) and non-caregivers (n=103,868) on sociodemographic and health characteristics were observed. Caregivers and non-caregivers were on average 44.1 and 46.3 years old, respectively, and employed (55.1% and 57.4%, respectively), suggesting care given by children rather than by spouse/partner. Adjusting for covariates, caregivers reported significantly worse HRQoL than non-caregivers, including PCS (-1.91 points, P=.017), MCS (-3.52 points, P <.001, exceeding MID), health utilities (-0.049 points, P <.001, exceeding MID), and all subscales, except vitality (-1.83 to -4.87, all P <.03). In addition, caregivers had about twice the odds of non-caregivers of diagnosis with depression (OR=1.885, P =.018), insomnia (OR=2.190, P =.002), headache (OR=1.997, P =.008), and GI problems (OR=1.970, P =.002).

Conclusion
Adjusting for confounders, caregivers for patients with lung cancer reported significantly lower mental and physical health status, lower health utilities, and higher depression, insomnia, headache, and GI problems than non-caregivers. In addition to confirming and extending knowledge of the caregiver burden of lung cancer in EU, this study highlights a need for increased personalized support for caregivers. Research on other aspects of caregiver burden, such as healthcare resource utilization and work productivity, will help refine estimation of the financial impact of lung cancer on society.

Abstract not provided

Background
Lung cancer affects nearly 40,000 patients per year in the UK of which 5000 (12%) will undergo major lung resection for primary lung cancer. Approximately 15% of patients will have complications post operatively. Once the patient develops a post surgical pulmonary complication mortality increases from 0.5% to 12%, ITU admission rate increases from 1.5% to 26% and the length of stay increases from 5 to 14 days. A Lack of preparedness prevents patients immediately engaging in post operative activities successfully and can result in an increase in patient’s anxiety, post operative complications and length of stay in hospital. The United Kingdom National Lung Cancer Forum for Nurses Thoracic Surgical Group (TSG) has produced this Guideline to aid health care professionals in the preparation and support of patients undergoing a lung resection with an aim to promote patient self management.

Methods
Following a literature review and discussion amongst this specialist group the Guideline was developed focusing on key topic areas and interventions which included: poor nutrition, before and during the healing process is associated with poor wound healing risks of hospital death and pulmonary complications after lung cancer resection are increased by smoking patients who receive a multi-disciplinary rehabilitation and early mobilisation achieve earlier discharge from hospital and significantly reduce in hospital morbidities and complication rates patient’s satisfaction regarding pain management significantly correlates to the preoperative information they have received good quality patient information is vital in reducing patient’s anxiety and improving the overall patient experience

Results
The Guideline was developed to support any health professional involved in the provision of care for patients who are undergoing thoracic surgery. The Guideline includes information for health professionals providing examples of current best practice and information for patients. The aim of the Guideline is to support self management, support patients through the surgical pathway, and improve patient outcomes and patient experience. The full guideline can be found at http://www.nlcfn.org.uk/editorimages/Guidelines%20to%20Prepare%20etc.pdf

Conclusion
The Guideline is relevant to all patients who are undergoing a lung resection. The Guideline includes a series of broad statements and where necessary local procedures should be developed to complement the guidelines in each clinical area. The Guideline compliments the Surgical Follow Up Guideline also produced by the NLCFN Thoracic Surgical Group.

Background
The goal of any intervention in medicine is to return the patient to the “pre-clinical state”. Thoracic surgical intervention remains the most effective way to manage early stage lung cancer. Minimally invasive techniques have substantially reduced the morbidity associated with traditional open procedures and have returned patients to health faster. This has been achieved without compromising the oncologic validity of the operation and when done appropriately, has even proved superior. Our health system instituted a minimally invasive thoracic surgical program 5 years ago to realize these benefits. This was accomplished through the recruitment of minimally invasive trained, dedicated thoracic surgeons; service line focused team development; rigorous training of the team; systematic community awareness; and investment in technology and equipment. Seeing tremendous success in volumetric growth with our minimally invasive program, we began to focus on strategies to return patients to their pre-operative functional state more swiftly. We believed inherently that early post-operative ambulation had several clear benefits: 1) clearance of pulmonary secretions and reduction of atelectasis thereby preventing pneumonia, 2) avoidance of deep venous thromboses and subsequent pulmonary emboli, 3) reduced third space fluid shifts therefore reducing the risk of atrial fibrillation and myocardial infarction, 4) better pain control without narcotics, and 5) a general sense of well being. Therefore, we hypothesized that prompt initiation of ambulation should reduce morbidity and return patients to the pre-operative state expeditiously and with greater predictability.

Methods
Our limitations were pain, nursing motivation and culture. Pain is substantially reduced in minimally invasive approaches. Ambulation inherently reduces pain as the upright position takes tension off the intercostal spaces. Nursing motivation and culture proved to be a bigger challenge given limitations in the time available for “bedside nursing”. However, perhaps more relevant was the skepticism related to the safety of this endeavor. Given these realities, we created an environment to test our hypothesis seeking first to demonstrate safety and feasibility of an endeavor that we believed to be so pivotal. In July of 2010, with the support of nursing leadership, administration and our thoracic oncology team, we began a program of aggressive post-operative ambulation with one simple mandate: every patient must walk 250 feet within 1 hour of extubation.

Results
For this analysis we included all patients recovered in our dedicated unit after VATS, thoracotomy, robotic or laparoscopic interventions. We excluded patients undergoing bronchoscopy or mediastinoscopy as they were routinely discharged within two hours of extubation. From July 2010 through May 2013, a total of 720 patients were recovered in our unit. 553 (77%) were able to walk 250 feet or more. Of these, 328 (59%) were successful within 1 hour of extubation. 74 patients (10%) were unable to ambulate largely due to weakness and hypotension. There have been no adverse events since implementation (0% complication rate).

Conclusion
We conclude that early post-operative ambulation is feasible and safe. We have observed favorable responses from patients and families and have enjoyed a considerable decrement in our overall post-operative length of stay. Further investigation will be necessary to quantify these endpoints.

Background
Clinical trials (CT) are fundamental to improving outcomes in lung cancer. Recruitment to CT in the UK is poor. The National Cancer Research Interest Group, Clinical Studies Group (UK), identified that Lung Cancer Nurse Specialist (LCNS) may have a role in improving recruitment to CT. The National Lung Cancer Audit (England) 2010-2012 identified that patients who access a LCNS are more likely to recieve anti cancer treatment. Therefore could this correlation be applicable to the CT setting? A survey was conducted to understand the role of LCNS in relation to CT, and to investigate the views of LCNS regarding CT involvement of advanced stage patients.

Methods
A questionnaire was emailed to all registered members of the National Lung Cancer Nurses Forum NLCFN(UK) with an explanatory letter,during the month of April 2013. An e-survey was chosen, to facilitate a convenient route for response and to minimise costs. A custom excel database was built for the purposes of data collection and analysis. The audit was pilot tested by 10 LCNS prior to distribution.

Results
138 (50%) responses received. Results support that LCNS have a good understanding of CT availability (92%). Research nurses were regarded as key team members by all respondents, and 81% were dedicated to lung cancer CT. 85% of LCNS discussed CT in the course of treatment option consultations. The vast majority of technical aspects of CT recruitment, was deferred to the Research nurses. Benefits of CT participation identified by the LCNS's included: access to new drugs, closer follow up,benefit for future patients, additional support from Research nurses, a level of decision making regarding treatment. Disadvantages included: excessive time commitment, additional requirement for hospital appointments, travel distance to trial centre, patients deriving false hope, delays commencing therapy due to protocol requirements, increased number of invasive procedures, feeling they will let the doctor down by non-participation, psychological harm if they don’t responsed to therapy. 17% of respondents suggested that CT participation may be unethical. On further analysis concerns were information, selection and appropriate support levels. Responses confirmed that there is uncertainty in relation to the LCNS role in CT management generally. Little reference was made regarding non drug CT, such as radiotherapy or supportive care.

Conclusion
The LCNS community understand and supports the value of CT. This include patients in the advanced stages of the disease. The role of the LCNS is not clearly defined in relation to CT. Most LCNS are comfortable speaking to patients regarding CT and have a good working knowledge of CT availability. The finer detail in terms of recruitment and clinical trial management is seen as the remit of the research nurse. No expressions of serious concern in relation to trial participation or ethical concerns where derived from responses. LCNS’s have reported understanding of CT philosophy in the UK, and the requirement for CT to continue in this patient group, while at the same time demonstrating a strong advocacy role. LCNS’s in the UK support clinical trial recruitment in patients with lung cancer and regard them as ethical.

Abstract not provided