Virtual Library

Abstract:
In the United States, almost 50% of lung cancer patients are 70 years of age or older. Moreover, shifting demographics in the United States -- indeed, across the world -- suggest that oncologists will be seeing many more older patients with lung cancer in years to come. With cancer therapy, older patients often suffer higher and more severe rates of adverse events than their younger counterparts, yet many derive benefit from therapy. The challenges of treating older patients remain notable largely because enrollment in cancer clinical trials tends to show an underrepresentation of older patients. In this context, this talk with discuss 1) the ongoing challenges faced in treating older patients with lung cancer; 2) the relevant and instructive data derived to date from clinical trials; 3) the role of the comprehensive geriatric assessment; and 4) general recommendations on approaches to treating elderly lung cancer patients.

Abstract:
Non-small cell lung cancer is a disease of the elderly. In Australia in 2010, 84% of new lung cancers in men and 81% in women were diagnosed in people aged 60 years and older. The definition of “elderly” in the lung cancer radiotherapy literature varies with the lower limit ranging from 65 years (1) up to 85 (2). Older patients are not only more likely to develop toxicities of intensive treatment, but also to have less physiologic reserve to tolerate these toxicities. They include fatigue, pneumonitis, esophagitis and myelosuppression. Although older patients may have good performance status (ECOG 0-1), and be judged suitable for radical treatment, they may become deconditioned and harmed by treatment. Identification of these patients pre-treatment is challenging. An instrument to measure “frailty”, such as that devised by Fried et al (3) to predict post surgery complications would be useful in the radiotherapy setting. Frailty should be distinguished from performance status, which is only one measure of physiologic reserve; Fried’s frailty score includes measures of weight loss, grip strength and walking speed as well. Given the above, it is not surprising that older patients have worse survival than younger patients (4). Partly this may be due to a higher likelihood of suboptimal treatment (radiotherapy alone rather than concomitant chemoradiotherapy), and partly to the competing risks of non-neoplastic comorbidities. Once survival is adjusted for these effects, age is no longer associated with increased risk of death (4). It is generally agreed that functional rather than chronological age is a more important consideration in patient selection for radical treatment (2, 5). Age is certainly not a contraindication to treatment with SABR for stage I disease (6). The choice of chemotherapy to accompany radiotherapy in pateints with locally advanced disease is unclear because of a lack of trials performed specifically in a geriatric population. Carboplatin is usually preferred to cisplatin in patients over 70 because of its more favorable toxicity profile. The evidence for two drugs rather than one is limited. In a study of the Japan Clinical Oncology Group limited to patients 70 years and older, daily carboplatin added to 60 Gy of radiotherapy improved median survival from 16.9 to 22.4 months (p=0.02) compared with radiotherapy alone (7). Performance status, in the absence of a validated frailty score, remains a critical determinant of suitability for (chemo)radiotherapy. Patients with performance status ECOG 2 or worse seem not to benefit from treatment intensification, including when the intent of treatment is palliation (8). Comorbidity scores (Charlson, Colinet) appear to be closely linked to performance status, but there is insufficient evidence to support their use in clinical decision making. Diminished pulmonary function is sometimes thought to be a contraindication to radical radiotherapy - yet patients who are unfit for surgery, usually because of diminished cardiopulmonary reserve, are the very patients most likely to be referred for stereotactic ablative body radiotherapy (SABR). In fact, some studies suggest that patients developing symptomatic radiation induced lung injury were more likely to have a higher FEV1(9). However caution should be exercised in treating patients with pre-existing interstitial lung disease, including with SABR (10). Our approach is to judge a patient’s suitability for treatment based on their biological age. In older patients with locoregional disease and performance status ECOG 0-1 who are suitable for radical treatment, we would recommend full dose SABR for patients with peripheral stage I disease, and chemoradiation for locally advanced disease, 60 Gy with concomitant carboplatin and paclitaxel. Patients who are not fit for chemotherapy are treated with radiotherapy alone. If there is concern regarding the patient’s capacity to undergo a six week course, we either review the patient at 40 Gy , and if there is evidence of diminished tolerance, cease at that point. If there is concern that a patient will not tolerate a risk of grade 3 esophagitis, but the aim is improved local control rather than paliiation, we would offer a split course to allow for mucosal recovery (20 Gy in 5 fractions, followed by a 4 week break, then another 20 Gy). Although thought to be suboptimal because of the risk of repopulation, a split course schedule is less likely to produce high grade esophagitis than 36 Gy in 12 continuous fractions. For older patients with diminished performance status (ECOG 2 or greater) and for whom palliation is the objective, 20 Gy in five fractions is a reasonable option, and little more demanding on resources and patient inconvenience than a large single dose. References 1. Sigel K, Lurslurchachai L, Bonomi M, Mhango G, Bergamo C, Kale M, et al. Effectiveness of radiation therapy alone for elderly patients with unresected stage III non-small cell lung cancer. Lung Cancer. 2013;82(2):266-70. 2. Khor RC, Bressel M, Tedesco J, Tai KH, Ball DL, Duchesne GM, et al. Tolerability and outcomes of curative radiotherapy in patients aged 85 or more years. Med J Aust. 2015;202(3):153-5. 3. Makary MA, Segev DL, Pronovost PJ, Syin D, Bandeen-Roche K, Patel P, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg. 2010;210(6):901-8. 4. Aridgides PD, Janik A, Bogart JA, Duffy S, Rosenbaum P, Gajra A. Radiotherapy for stage III non-small-cell lung carcinoma in the elderly (age >/= 70 years). Clin Lung Cancer. 2013;14(6):674-9. 5. Wanders R, Steevens J, Botterweck A, Dingemans A-MC, Reymen B, Baardwijk Av, et al. Treatment with curative intent of stage III non-small cell lung cancer patients of 75 years: A prospective population-based study. European Journal of Cancer. 2011;47(18):2691-7. 6. Palma D, Visser O, Lagerwaard FJ, Belderbos J, Slotman B, Senan S. Treatment of stage I NSCLC in elderly patients: a population-based matched-pair comparison of stereotactic radiotherapy versus surgery. Radiother Oncol. 2011;101(2):240-4. 7. Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, et al. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012;13(7):671-8. 8. Strom HH, Bremnes RM, Sundstrom SH, Helbekkmo N, Aasebo U. How Do Elderly Poor Prognosis Patients Tolerate Palliative Concurrent Chemoradiotherapy for Locally Advanced Non-Small-Cell Lung Cancer Stage III? A Subset Analysis From a Clinical Phase III Trial. Clin Lung Cancer. 2015;16(3):183-92. 9. Kong FM, Wang S. Nondosimetric risk factors for radiation-induced lung toxicity. Semin Radiat Oncol. 2015;25(2):100-9. 10. Ueki N, Matsuo Y, Togashi Y, Kubo T, Shibuya K, Iizuka Y, et al. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J Thorac Oncol. 2015;10(1):116-25.

Abstract:
It is difficult to define what an elderly or truly “high risk” patient is in regards to offering surgical treatment of lung cancer. The World Health organization defines an elderly patient as being over age 65 although most practitioners of thoracic surgery would likely define an elderly patient as someone over age 70 (1) . Likewise the definition of a truly high-risk patient is difficult to determine. These patients are often described as having significant cardiopulmonary or other organ dysfunction that could be potentially worsened by the surgical event. In developed countries the average population age is increasing and the incidence of lung cancer is also increasing in elderly patients. Combined with the natural decline in lung and cardiac function these data suggests that there will likely be a steady and significant increase in elderly and high-risk patients who present for consideration of resection for localized lung cancer. Clinical data in the elderly and high-risk patients is hard to come by, as many of these patients are not represented in clinical trials despite the high proportion of these patients in the lung cancer population. The data that is available is often retrospective in nature but it suggests that treatment decisions in these patient groups should not solely be based on chronological age but should take into account the patient’s life expectancy, quality of life desires, presence of comorbidities, and estimated risks and benefits of the procedure (2). Several studies have demonstrated the feasibility of surgically treating lung cancer in elderly patients including octogenarians. Likewise several studies evaluating patients with compromised lung function and other comorbidities have suggested that surgery is feasible in these patients (3,4). What is not clear is what the true limits of age and underlying organ dysfunction is that represent absolute contraindications to surgery. It is likely that improvements in anesthesia and surgical care have allowed older and more high-risk patients to be operated on safely. The use of video assisted thoracoscopy has greatly enhanced our ability to perform surgical resections on these elderly and high-risk patients. The gold standard operation of lobectomy for these patients can potentially be modified in high risk and elderly patients. Several retrospective studies suggest that in the elderly a lesser resection can be equivalent or superior to lobectomy in survival and perioperative morbidity (5). In addition the use of pneumonectomy in these patients should be avoided as the morbidity and mortality is increased significantly (6). It is clear that treatment with stereotactic radiotherapy will play an emerging role in the therapy if these patients. Long-term follow up is needed to truly understand the utility of radiotherapy in high risk and elderly patients. References 1) World Health Organization. Health statistics and health information systems. Available from URL http://www.who.int/healthinfo/survey/ageingdefnolder/en/index.html. 2) Pallis AG, Gridelli C, Wedding U, Faivre-Finn C, Veronesi G, Jaklitsch M, Luciani A, O'Brien M. Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology. Ann Oncol. 2014 Jul;25(7):1270-83. 3) Rivera C, Dahan M, Bernard A et al. Surgical treatment of lung cancer in the octogenarians: results of a nationwide audit. Eur J Cardiothorac Surg 2011; 39: 981–986. 4) Zhang R, Ferguson MK. Video-Assisted versus Open Lobectomy in Patients with Compromised Lung Function: A Literature Review and Meta-Analysis. PLoS One. 2015 Jul 6;10(7) 5) Cheng YD, Duan CJ, Dong S et al. Clinical controlled comparison between lobectomy and segmental resection for patients over 70 years of age with clinical stage I non-small cell lung cancer. Eur J Surg Oncol 2012; 38: 1149–1155. 6) Zuin A, Marulli G, Breda C et al. Pneumonectomy for lung cancer over the age of 75 years: is it worthwhile? Interact Cardiovasc Thorac Surg 2010; 10: 931–935.

Abstract not provided

Abstract:
Non-small-cell lung cancer (NSCLC) is the leading cause of brain metastases. The development of brain metastases in this group of patients represents an important public health issue, as 20-40% of NSCLC patients present with or will develop brain metastasis during the course of their treatment. The prognosis of NSCLC patients with brain metastases is generally extremely poor and brain metastases have a major impact on quality of life. The incidence of brain metastases has been increasing over time as a consequence of better neuroimaging modalities and also prolonged survival in the locally advanced and metastatic setting with improved therapies. This is particularly relevant in the group of patients with somatic aberrations within driver oncogenes, such as epidermal growth factor receptor (EGFR) as targeted therapy using tyrosine kinase inhibitors (TKIs) are producing high response rates and progression free survival. Patients with EGFR mutations therefore represent a population at higher risk of brain metastases than the overall NSCLC population, with a risk of developing intra-cranial disease as the first site of progression in approximately 20-30%, and a lifetime risk >50%. Of note, brain metastases in this group of patients present more and more in the context of well controlled systemic disease and are more likely to be treatable than in the historic paradigm where brain metastases developed in concert with progressive multi-organ metastatic disease.Furthermore, there is a suggestion that the prognosis of EGFR mutated patients and brain metastases is better compared to wild type . In the context of stable thoracic and systemic disease treatment options for oligometastatic brain disease include; surgery, stereotactic radiotherapy, whole brain radiotherapy, and systemic treatments. Surgery can play an important role in patients with brain metastases and particularly patients with mass effect from a large symptomatic lesion. Randomised controlled trials with single brain metastases have demonstrated that the addition of surgery to WBRT improves survival. Stereotactic radiosurgery (SRS) is increasingly used as the sole treatment rather than as a ‘booster therapy’ in addition to WBRT to improve local control. Typically, SRS is reserved for patients with controlled extracranial disease and life expectancy >6 months, 1 to 4 brain metastases less than 3cm in maximum diameter. Treatment with EGFR TKIs is generally considered in patients with EGFR mutations but the evidence to support the optimal sequencing with local therapies is limited. In my talk I will discuss the following points: • Risk of developing brain metastases in EGFR mutated NSCLC • Prognostic factors (including EGFR mutation) • The role of local treatment (SRS, WBRT and neurosurgery) • The role of prophylactic cranial irradiation • The role of systemic treatment • Future directions

Abstract:
Leptomeningeal disease is a severe neurologic complication that can be seen in up to 5% of patients with cancer and it is more commonly seen in patients with lymphoma, breast cancer, melanoma and lung cancer. It usually presents in approximately 70% patients with metastatic and progressive disease but may also be the first manifestation of cancer in 10% of cases. With improved diagnostic methods and longer survival of patients with advanced stage non-small cell lung cancer (NSCLC), the incidence of leptomeningeal disease has increased. The diagnosis of leptomeningeal disease is usually established by cytological examination of the cerebrospinal fluid (CSF) or by characteristic changes seen on gadolinium enhanced magnetic resonance imaging (MRI). Furthermore MRI provides anatomic information that may be useful in identifying sites for local radiotherapy treatment. Prognosis is generally poor, especially in patients with poor performance status, multiple, serious or major neurological deficits, bulky CNS disease, and CSF block. Factors associated with a better prognosis include good performance status, absence of major neurological deficits, minimal systemic disease, absence of CSF block and the availability of reasonable systemic therapies. Management principles include early diagnosis and achieving systemic control with the aim of preserving or improving neurological status, improving quality of life and prolonging survival, taking into account the burden of systemic disease, intracranial metastasis and the expected prognosis. Currently there is no standard treatment for leptomeningeal disease in patients with NSCLC and options include intra-thecal chemotherapy, systemic chemotherapy, molecular targeted therapy, and radiotherapy. Although the benefit of intra-thecal chemotherapy has not been proven in randomized controlled studies, it is commonly used as it provides local therapy with minimum systemic toxicity and high drug concentrations can be achieved. It has been noted that intra-thecal chemotherapy is ineffective for bulky meningeal disease as intra-CSF agents can only penetrate 2-3mm into such lesions. Retrospective studies in patients with NSCLC harboring sensitizing mutations in the epidermal growth factor receptor (EGFR) gene or rearrangement in anaplastic lymphoma kinase (ALK) gene suggest EGFR or ALK tyrosine kinase inhibitors is an attractive treatment option. Radiotherapy is used to in the treatment of bulky disease and in patients with CSF flow abnormalities. Radiotherapy is also indicated in symptomatic sites and also in the treatment of cauda equine syndrome and cranial neuropathies. Craniospinal irradiation is rarely administered, as it is associated with significant systemic toxicities and leucoencephalopathy. Several case examples will be presented and the clinical presentation, diagnostic assessment and management will be discussed. The role of molecular targeted agents such as the EGFR and ALK tyrosine kinase inhibitors will also be reviewed. The development of novel systemic agents especially molecular targeted agents with improved CNS penetration and anti-tumor activity is urgently required.

Abstract:
For patients with lung cancer, choices of systemic therapy are informed by clinical research. These guide the patient and clinician as to the gold standard options when facing their disease. However many patients seen day to day in the clinic are not eligible for clinical trials due to one factor or another, and therefore the applicability of standard of care options has a less solid evidence base. In a recent analysis of 528 newly diagnosed stage 4 NSCLC patients seen in consultation by medical oncologists, only 55% received systemic treatment [1]. Further, when simple and limited generic clinical trial inclusion criteria were applied to these patients, only 27% would have been ‘trial eligible’ [2]. In a review of selected recent practice changing chemotherapy, targeted therapy and immunotherapy trials, patients with significant renal impairment, hepatic impairment or cardiac impairment would have been excluded [3-6]. Therefore how should clinicians and patients approach making decisions about systemic therapy in the presence of organ failure, given the lack of available evidence? This abstract seeks to provide guidance on a reasonable approach to patients with lung cancer and organ failure. These issues should be discussed in a multi-disciplinary format, with specific interaction with specialists related to the particular organ failure (nephrology, hepatology, cardiology etc.), in addition to a specialist oncology pharmacist if the decision is made to proceed with therapy. Patients should be fully informed regarding relative benefits and harms from therapy, the consequences of declining therapy, and that proceeding with treatment will almost certainly not be based on level one evidence. Consideration should be given to early palliative care specialist input, and advance care planning. Understanding the cause and prognosis of the organ failure is self-evidently important. This abstract restricts discussion to patients with pre-existing organ failure, rather than organ failure secondary to the malignancy. In a recent review of clinical indicators of 6-month mortality in advanced non-cancer illnesses, Salpeter and colleagues evaluated heart failure, dementia, geriatric failure-to-thrive syndrome, hepatic cirrhosis, chronic obstructive pulmonary disease and end-stage renal disease. This list represented approximately 70% of the non-cancer diagnoses on admission to hospice [7]. Clearly not all patients with these conditions die within 6 months, and the authors identified common and disease specific prognostic indicators, including poor PS, malnutrition, comorbid illness and organ dysfunction. In the cancer clinic, the clinician must understand the natural course of the organ failure pathology. For patients with liver, kidney or heart failure who may be waiting for organ transplantation, the diagnosis of lung cancer makes them ineligible for the transplant program. Regarding prognosis of advanced organ failure, the United States Renal Data System (USRDS) Annual Report for patients receiving hemodialysis for end-stage renal disease, describes 3-year survival as 52%, and 61% for patients receiving peritoneal dialysis. The risk of death is particularly high in the first year of hemodialysis, with rates reported up to 25%. The Canadian Organ Replacement Register Annual Report describes a 5-year survival for patients on dialysis of approximately 43% (www.cihi.ca/corr ). For patients with end-stage heart failure, the 1-year survival is approximately 50% [8], which is not dramatically different to patients with stage 4 NSCLC receiving 1[st] line chemotherapy. The prognosis of patients with liver cirrhosis is variable, depending on severity, etiology and the presence or absence of complications. The MELD score (Model for End-Stage Liver Disease) is used to assess the severity of chronic liver disease [9], as an alternative to the Child-Pugh scoring system. Salpeter et al reported patients with decompensated liver failure (the presence of complications of cirrhosis) may have a median survival <6 months if associated with high MELD scores. An understanding of competing morbidities therefore clearly plays an important role in understanding the role systemic therapy plays in lung cancer. In assessing the need for adjuvant chemotherapy in patients with early stage disease, for patients with organ failure it is highly likely that any benefit from chemotherapy (approximately 5%) will be outweighed by the competing risks of the comorbid condition. After assessing patients with lung cancer, in the multi-disciplinary context and taking into account the issues discussed, the decision may still be to proceed with therapy. This should be on the understanding of the relative lack of data, and then a choice of regimen based on an understanding of the drug metabolism, with appropriate dose adjustments after dialogue with an oncology pharmacist. Table 1 outlines common lung cancer drugs and their route of elimination, and recommendations on use in renal or hepatic impairment. For patients receiving dialysis, there is variation in advice as to timing of adminstration relative to dialysis. This information and tabular information is taken from product monographs and selected references [10,11]. Data on efficacy for these drugs in these scenarios is largely limited to case reports. In conclusion, lung cancer patients with organ failure represent a population excluded from clinical trials and with a limited evidence base. The competing morbidity and mortality significantly mitigate against potential benefits from anti-cancer systemic therapy. The newer generations of targeted therapies and immunotherapies may be easier to deliver, but again limited data exists. Clinicians should discuss these cases in a multi-disciplinary environment, and early intervention from palliative care specialists may be particularly appropriate.

Drug	Elimination	Liver	Renal
Cisplatin	Renal	N/A	↓ depending on CrCl
Caboplatin	Renal	N/A	Calvert Formula
Docetaxel	Liver	Adjust	N/A
Pemetrexed	Renal	Caution in severe dysfunction	avoid if CrCl <45
Paclitaxel	Liver	Adjust	N/A
Gemcitabine	Urine (inactive)	Adjust by Bilirubin	Caution
Vinorelbine	Liver	Adjust by Bilirubin	N/A
Gefitinib	Liver	Caution	Caution if CrCl <20
Erlotinib	Liver	Caution	N/A
Afatinib	Liver	Caution	Caution if CrCl <30
Crizotinib	Liver	Adjust	Caution if CrCl <30
Ceritnib	Liver	Adjust	Caution if CrCl <30
Bevacizumab	Reticulo-endothelial system	Not involved	Not involved
Nivolumab	Biochemical degradation	No effect in mild impairment	no effect if CrCl>/=15

References : 1. Brule S, Al-Baimani K, Jonker H, et al: Palliative chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC): Investigating disparities between patients who are treated versus those who are not. J Clin Oncol 33, 2015 2. Al-Baimani K, Jonker H, Zhang T, et al: Are clinical trial eligibility criteria an accurate reflection of a real world population of advanced lung cancer patients, World Conference on Lung Cancer. Denver, 2015, pp Abstract 1398 3. Gettinger SN, Horn L, Gandhi L, et al: Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 33:2004-12 4. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-57, 2009 5. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-8, 2002 6. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-94 7. Salpeter SR, Luo EJ, Malter DS, et al: Systematic review of noncancer presentations with a median survival of 6 months or less. Am J Med 125:512 e1-6 8. Friedrich EB, Bohm M: Management of end stage heart failure. Heart 93:626-31, 2007 9. Kamath PS, Kim WR: The model for end-stage liver disease (MELD). Hepatology 45:797-805, 2007 10. Janus N, Thariat J, Boulanger H, et al: Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 21:1395-403 11. Brandes JC, Grossman SA, Ahmad H: Alteration of pemetrexed excretion in the presence of acute renal failure and effusions: presentation of a case and review of the literature. Cancer Invest 24:283-7, 2006

Abstract not provided

Background:
Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFR.

Methods:
This open-label multicentre phase II trial enrolled consenting adult patients with advanced, histologically-confirmed MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Patients were ECOG PS < 2 and had adequate end-organ function. Dovitinib was administered orally at 500 mg/day for 5 days on, 2 days off; cycle length was 28 days. Two dose reductions (to 300 mg) for toxicity were permitted. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. Pre- and cycle 1 day 15 on-treatment diffusion-weighted pleural MRI was evaluated for its potential as an early marker of drug effect. The primary end-point was the proportion of patients progression-free at 3 months (PF3). A two-stage design was used: H0: 3-month PFS=40% versus HA: 3-month PFS=65% (roughly corresponding to a median PFS of 4.5 months), with α=0.05, β=0.20. If 6 of 12 PF3 in stage I, an additional 14 patients would be enrolled, with dovitinib of interest if > 15 of 26 PF3.

Results:
12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1-8). Commonly observed and / or grade 3 at least possibly related adverse events (any grade / grade 3, %): diarrhea (67 / 0%) vomiting (50 / 0%) fatigue (42 / 8 %), nausea (42 / 8 %), rash (0 / 17 %), syncope / generalized muscle weakness / elevated ALT (0 / 8 % each). No hyperphosphatemia was observed. 7 patients had at least one dose interruption (5 in cycle 1) and 5 had a dose reduction (1 to 300 mg); median dose intensity during cycles 1 and 2 was 80 %. 3 patients discontinued due to clinical progression by day 1 cycle 2. Best response: 1 unconfirmed PR, 4 SD, 2 PD and 4 inevaluable (3 with clinical PD; 1 intercurrent illness). The median PFS was 2.6 months and the median OS was 4 months. PF3 was 50%; although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population.

Conclusion:
Dovitinib has minimal activity and a toxicity profile comparable to other VEGFR inhibitors in previously-treated MPM; it is not clear if FGFR is effectively targeted. Correlative studies are ongoing and may help to clarify the role of the FGFR in MPM. [NCT01769547].

Background:
To observe the efficacy and safety of intra-thoracic chemotherapy of recombinant human endostatin (Endostar) combined with cisplatin in the treatment of malignant pleural effusion.

Methods:
A total of 84 patients with malignant pleural effusion were randomly divided into intra-thoracic chemotherapy of Endostar combined with cisplatin group (combination group) and single cisplatin group (single group). Before treatment, pleural effusion was completely resolved. Combination group was treated with intra-thoracic injection of 40～50 mg cisplatin and 60 mg Endostar twice a week, and 4 times were as a cycle at most. Single group was only treated with cisplatin, and other operations were the same as the combination group. RECIST1.0 hydrothorax evaluation criteria and NCI-CTC AE 3.0 version classification criteria were applied to evaluate the efficacy and adverse reactions, respectively.

Results:
The response rates of initially-treated patients in combination group and single group were 63.6% and 40.6%, respectively, and significant difference was presented (X[2]＝2.737, P＝0.022). The response rates of all patients in combination group and single group were 58.1% and 36.6%, respectively, and the difference was significant (X[2]＝4.877, P＝0.019). The progression-free survival (PFS) in combination group was dramatically longer than in single group (95 d vs. 53 d; X[2]＝3.872, P＝0.039). No adverse reactions at degree Ⅳ were observed in all groups. Incidences of adverse reactions including neutropenia, anemia, fatigue and increase of blood pressure in combination group were all higher than in control group, but there was no statistical significance (P＞0.05).

Conclusion:
Intra-thoracic injection of cisplatin alone is effective for treating patients with malignant pleural effusion, and its efficacy is better in combination with Endostar. Cisplatin combined with Endostar has a synergistic effect and better safety, being worthy of further popularization in clinic.

Background:
Malignant pleural mesothelioma (MPM) is usually a fatal neoplasm, and current therapeutic interventions are far from satisfactory. Naftopidil, an α1-adrenoceptor antagonist, is used clinically for the treatment of benign prostate hypertrophy, and has been found to reduce the incidence of prostate cancer and to inhibit prostate cancer cell proliferation via G1 cell cycle arrest. Recently, naftopidil has been demonstrated to induce apoptosis in mesothelioma cells by activating caspase-8 and the effector caspase-3 independently of α1-adrenoceptor suppression. Hence, a more potent naftopidil analogue, HUHS1015, was synthesized. The current study evaluates the inhibitory effect of HUHS1015 on malignant mesothelioma cell proliferation in preclinical models and assesses whether HUHS1015 can be the basis for new drug for the treatment of MPM.

Methods:
We treated the human MPM cell lines MSTO-211H, NCI-H28, NCI-H2052 and NCI-H2452 with HUHS1015, and evaluated cell viability using the MTT method. Additionally, NCI-H2052 tumor xenograft models in BALB/c-nu/nu mice were utilized to investigate anti-mesothelioma activity in vivo.

Results:
HUHS1015 reduced the viability of MPM cells more potently than cisplatin or paclitaxel at concentrations higher than 30 μM, and the drug induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. The effect of HUHS1015 on the expression of Bcl-2 family mRNAs in MSTO-211H and NCI-H2052 cells was tested using real-time RT-PCR. Puma, Hrk, and Noxa mRNAs were up-regulated in both cell lines. In the NCI-H2052 mouse xenograft models, HUHS1015 strongly suppressed tumor growth.

Conclusion:
These results indicate that HUHS1015 may be an effective anticancer drug candidate for the treatment of MPM. HUHS1015 induces apoptosis of MPM cells through modulation of a mitochondrial pathway, and future clinical investigations with this drug are warranted for mesothelioma.

Background:
Sarcomatoid lung cancer (SLC) is an aggressive subset of poorly differentiated non-small cell lung carcinoma (NSCLC), comprising just one percent of all NSCLC. Further elucidation of this unique histological entity has been hampered by a lack of large-scale clinical trial evidence. The National Comprehensive Cancer Network (NCCN) contains no clear direction regarding optimal management. The purpose of this study, therefore, is to identify potential therapeutic options for this disease using a multiplatform, biomarker-directed approach.

Methods:
In total, 48 SLC specimens analyzed via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH) were retrospectively evaluated.

Results:
High rates of PD-L1 (83.3%, 5/6) and PD-1 (80.0%, 4/5) protein expression by IHC imply benefit to recently-approved compounds. EGFR amplification by ISH (18.8%, 3/16) and MET amplification (9.5%, 2/21) were independent of EGFR mutation in this group. No ALK, HER2 or ROS1 ISH abnormalities were detected. Mutational analysis shows the highest mutation rates in TP53 (50.0%, 7/14), KRAS (44.4%, 16/36), cKIT (5.3%, 1/19), EGFR (5.1%, 2/39) and BRAF (4.8%, 1/21). The two EGFR mutations detected were L858R and exon 20 insertion.

Conclusion:
Multiplatform profiling identified multiple potential actionable targets with various approved therapies. PD-1 and PD-L1 overexpression rate was comparable to that published in sarcomatoid renal cell carcinoma. Therefore, new immunotherapies should be prospectively tested in sarcomatoid disease specific trials based on high PD-1/PD-L1 overexpression. Our finding of low EGFR mutational frequency is consistent with previous, published findings in this disease. Lower rates of ALK, ROS1, and EGFR are not surprising given SLC’s association with smoking. Clinical trials evaluating the benefit of imatinib and vemurafenib in subgroups with cKIT or BRAF mutations may be worthwhile.

Abstract not provided

Background:
Controversy over adjuvant radiation of thymoma has raged on among experts for decades. 20-30% thymoma patients present with myasthenia gravis (MG). The co-existence of MG and thymoma makes the surgical treatment and adjuvant radiation more complicated. The aim of this article is to investigate whether patients with MG and thymoma should receive mediastinal radiation therapy and when after extended thymectomy.

Methods:
Between 2002 and 2012, 159 patients with MG and thymoma underwent extended thymectomy. These patients were subdivided into 3 groups: Group 1 (n=89), patients having mediastinal radiotherapy within one month after surgery; Group 2, having mediastinal radiotherapy over three month after surgery (n = 49); and Group 3, without adjuvant radiation (n = 21).

Results:
152 patients underwent extended thymectomy by VATS, and 7 undergoing the trans-sternal approach due to thymoma invading great vessels. The resection was extended to the pericardium in 23 patients, the lung in 17 patients, and the innominate vein in 11 patients. There were no inoperable cases. The proportions of type A, AB, B1, B2, B3, and thymic carcinoma in this data were 0.6%, 19.5%, 25.8%, 32.7%,21.4%, and 0%, respectively. 146 patients were followed for 15 months to 12 years: 82 in Group 1, 45 in Group 2, and 19 in Group 3. Postoperative myasthenic crisis occurred in 38 cases: 16 cases in Group 1, 14 in Group 2, and 8 in Group 3. There was a significant difference in occurrence of postoperative myasthenic crisis between Group 1 and Group 3 (P=0.045). The rates of reaching CSR were 31.7% in Group 1, 22.2% in Group 2, and 21.1% in Group 3, respectively. The overall survival of Group 1, Group 2, and Group 3 were 90.2%, 86.7%, and 78.9%, respectively. 6 patients in Group 1 recurred, while 4 patients in Group 2 and 4 in Group 3 recurred. There was no lymph node metastasis detected. Kaplan-Meier survival curves demonstrate that there is no significant difference in overall survival among 3 groups. However, Cox regression analysis made by entering some factors including sex, age, and adjuvant radiation, revealed that adjuvant radiation might have significant influence in prognosis in thymoma patients ( P = 0.047). Figure 1



Conclusion:
Adjuvant radiation within one month after extended thymectomy may help decrease possibility of postoperative myasthenic crisis, raise the cumulative probabilities of reaching CSR, and might have significant influence in prognosis in thymoma patients with MG. In recurrence cases, no lymph node metastasis was detected

Background:
Thymic epithelial tumours are rare malignancies for which there is no standard treatment for patients with advanced disease progressing on or after chemotherapy. Despite the lack of identified targets in thymic malignancies, several studies demonstrated that VEGFR and KIT pathways are the most relevant targets for therapeutic intervention. Lucitanib is an oral, potent, selective inhibitor of the tyrosine kinase activity of FGFR1-3, VEGFR1-3, and PDGFR α/β, all key targets involved in pro-angiogenic and proliferative pathways leading to tumour progression. Therefore, lucitanib could be a potential therapeutic alternative for patients with recurrent or refractory disease.

Methods:
This first in human study is currently evaluating oral lucitanib as monotherapy in various solid tumours. The escalation phase used a 3+3 design in patients with advanced solid tumours to establish the recommended phase II dose. Safety and efficacy were further evaluated in patients whose tumours were determined to be FGF aberrant (FGFR1 and/or 11q amplification) or in patients with tumours known to be anti-angiogenesis-sensitive such as thymic epithelial tumours. In addition, different doses and administration schedules were investigated.

Results:
Of the 134 patients treated in the study, 3 had B-type Thymoma (T) and 12 had Thymic Carcinoma (TC). Among these patients, median age was 54 years [range 37-72], 7 were males and 8 females. Twelve patients (80%) were treated at 12.5mg on daily basis. The other 3 patients (T) received 5, 15 and 20mg respectively. Patients had received a median of 2 previous anti-cancer treatments [range: 0-6]. Median duration of treatment with lucitanib was 7 cycles [range 2-44]. All patients were evaluable for anti-tumour activity according to RECIST v1.1. Two patients had confirmed partial response (1T / 1TC) lasting at least 7 months (TC patient is still ongoing) and 10 patients had a stable disease with 6 of them lasting at least 6 months. To date, 4 patients are still ongoing and receiving benefit from lucitanib independently of the number of previous regimens. The most common adverse events related to lucitanib in this population (all grades, all doses) were hypertension (80%), hypothyroidism (53%), proteinuria (53%) and diarrhoea (40%). There was no major bleeding event reported. These findings were in line with the overall safety profile of lucitanib already described.

Conclusion:
The results of this tumour cohort analysis suggest that lucitanib has signs of clinical activity in patients with advanced thymic epithelial tumours, and should be further investigated in dedicated studies.

Background:
RYTHMIC (Réseau tumeurs THYMiques et Cancer) is the French nationwide network for thymic malignancies. Starting 2012, all patients diagnosed with thymic tumor had to be enrolled, as recommended by the French National Cancer Institute, part of good clinical practice.

Methods:
RYTHMIC prospective database is hosted by the French Thoracic Cancer Intergroup (IFCT), and collects clinical, imaging, treatment, and follow-up data of patients discussed at the reference national multidisciplinary tumor board (MTB). Data cutoff was April 1[st], 2015 for this analysis.

Results:
1089 questions were raised at the MTB about the management of 888 patients with thymic epithelial tumor. Among assessable cases, Masaoka-Koga stage III-IV tumors accounted for 42% of cases; histology was thymoma in 82% of cases, and thymic carcinoma in 18% of cases. First-line treatment of locally advanced disease, and management (diagnosis and treatment) of recurrent disease led to raise 227 (21%), and 234 (21%) questions at the MTB, respectively, 312 (68%) of which were about the modalities of systemic treatment. Figure 2 shows the proposed regimens for primary (A) and exclusive (B) chemotherapy in treatment-naïve patients, and chemotherapy (C) and targeted agents (D) for recurrent tumors. Combination of cisplatin, adriamycin, and cyclophosphamide and carboplatine, paclitaxel were the most frequently proposed regimens as first- and second-line treatment, respectively. Figure 1 Figure 2





Conclusion:
RYTHMIC is an exhaustive registry of thymic malignancies, which provides unique insights in the management of advanced and recurrent tumors with systemic agents. Meanwhile, limited data have been made available in the literature so far, as clinical trials were conducted in small numbers of patients, and existing databases enrolled a majority of surgically resected, early-stage tumors. Through the use of targeted agents, RYTHMIC allows the rapid implementation of new results in clinical practice, while ensuring patients an equal access to therapeutic innovation. Supported by Institut National du Cancer

Background:
Percutaneous cryoablation (PC) is an ablative technique, being used for local treatment of recurrent mesothelioma in patients following surgical lung sparing decortication and pleurectomy, and occasionally for palliative control of tumor extension to vital structures or pain control. The purpose of this study was to evaluate the safety and efficacy of PC in local control of recurrent mesothelioma.

Methods:
With IRB approval, patients with recurrent mesothelioma following lung sparing pleurectomy and decortication with at least one PC were identified from a database containing ablation information. Intra procedural and immediate post procedural hospital information was assessed for complications and follow up imaging was used to asses for late complications and recurrence. Patients were followed with CT and and PET/CT scans for 6 and some up to 12 months. Local recurrence determined by increased regional metabolic activity or increased size of post ablation zone at 6 months. A stepwise multiple logistic regression model was used to assess predictors of local recurrence after ablation, considering clinical variables including: stage at diagnosis, chemotherapy, radiation, recurrence time lag following surgery, and number of lesions at time of recurrence presentation, And PC variables including: size of the lesion, edge of ice ball beyond the tumor, number of probes, size of probes, number of cryo cycles, maximum and total freeze and thaw time.

Results:
From the database, 25 patients were identified who underwent a total of 117 outpatient cryoablations (range of 1-25). 4 ablations in 3 patients were performed for palliative and pain control indications. Lesions measured a mean of 32.5 mm (range 9-113) by 18.0 mm (range 6-60) in diameter. At 6 months 110/117 (94.0%) of ablations showed no recurrence. No major, but minor complications including hematoma, small pneumothorax and hemoptysis in one patient each and erythema in 3 chest wall subcutaneous lesions (5/117 =4.2%). Late complications in 4/117 (3.4%) ablations. Considering the clinical and cryoablation variables no recurrence was seen in patients having the edge of iceball more than 7 mm beyond the tumor.

Conclusion:
PCT can be used for management of recurrent mesothelioma following surgery with low recurrence rate of 6%, and limited procedural complications 4.2% and late complications of 3.4%. When performing PCT, at least 7 mm of the of iceball is needed to extend beyond the edge of tumor to limit local recurrence.

Abstract not provided

Background:
High dose lung-sparing pleural radiotherapy for malignant pleural mesothelioma (MPM) is difficult. Given the steep dose gradient with volumetric modulated arc therapy (VMAT), accurate target delineation is critical. The optimal imaging modality to define radiotherapy target volumes has not been studied in depth. This is the aim of the present study.

Methods:
Twelve consecutive patients with a histopathological diagnosis of stage I-IV MPM (6 left-sided and 6 right-sided) were included. CT scans with intravenous (IV) contrast, [18]F-FDG PET/CT scans, MRI scans (post-contrast T1-weighted and T2-weighted) and diffusion-weighted images (DWI) were obtained and downloaded from the institutional database onto a standalone image fusion workstation (MIM Software Inc., Cleveland, OH, USA) for image registration and contouring. CT scans were rigidly co-registered with ~18~FDG-CT-PET, with MRI scans and with DWI scans. Four sets of pleural GTVs were defined: 1) a CT-based GTV (GTV~CT~); 2) a PET/CT-based GTV (GTV~CT+PET/CT~); 3) a T1/T2-weighted MRI-based GTV (GTV~CT+MRI~); 4) a DWI-based GTV (GTV~CT+DWI~). Only the pleural tumor was contoured; mediastinal nodes were excluded. In each of the 4 co-registrations, a “quantitative” and a “qualitative” (visual) evaluation of the volumes were performed. “Quantitative” evaluation was carried out through the coefficient of variation (COV; the ratio between the standard deviation [SD] and the mean: a measure of the dispersion of a distribution) and the Jaccard index (the ratio between the union and the intersection between two volumes: a measure of overlap). “Qualitative” evaluation consisted of a visual identification of any additional tumor site in each of the 4 obtained co-registrations.

Results:
Compared to CT-based GTV definition, PET/CT identified additional tumour sites in 12/16 patients. Compared to either CT or PET/CT, MRI and DWI identified additional tumour sites in 15/16 patients. Additional tumour sites were mainly the parietal pleura, the diaphragm and the chest wall. Mean GTV~CT~, GTV~CT+PET/CT~, GTV~CT+MRI~ and GTV~CT+DWI~ (+SD) were respectively 630.1 mL (+302.81), 640.23 (+302.83), 660.8 (+290.8) and 655.2 mL (+290.7). Mean Jaccard index was lower in MRI-based contours versus all the others.

Conclusion:
To the best of our knowledge, this is the first study showing that the integration of the MRI (T1/T2-weighted) and DWI into the target volume definition in lung-sparing hemi-thoracic VMAT in MPM may allow to improve the accuracy of target delineation and reduce the likelihood of geographical misses.

Background:
Although extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) provide similar survival in malignant pleural mesothelioma (MPM), we sought to compare the two procedures in terms of another important outcome" hospital resource utilization (RU).

Methods:
With IRB approval, we retrospectively reviewed our prospective database to determine RU (ICU and hospital stay, mechanical ventilation, and central line use, etc) and Kaplan-Meier median survival (MS) for patient undergoing P/D. Our results are compared with similar findings for EPP reported in the literature.

Results:
We identified 121 pts on an "intent to treat" basis from 1997-2011. 94 (77.7%) were male. Mean age was 65.9 yrs (range 27-84). Comorbidities included hypertension 45.5%, coronary artery disease 11.6%, diabetes 10.7%, and vascular disease 6.2%. Mean surgical time was 7 hrs 57 mins (range 3 hrs 15 min–14 hrs 21 min). R1 resection was achieved in 116 (95.9%). Microscopic "margins" were assessed in 63 with 40 (63.5%) positive. Pathologic T- and N-staging is shown in Table 1. Morbidity was mostly limited to air leaks >10 days 41 (33.9%) and atrial arrhythmias 38 (31.4%). Three patients (2.5%) died. Relevant RU data included: intraoperative CVP lines 3 (2.5%), OR extubation 113 (93.4%), no ICU stay 99 (81.7%), and mean hospital stay 10 (range 5-103) days. RU data with P/D + RTx is compared to EPP as reported by others (figure 1). MS was 13.8 mos for all patients and 17.8 mos for epithelioid histology, which was better than biphasic (10.3 mos) and sarcomatoid (2.1 mos) subtypes (p<0.01). MS for 85/121 patients (70.2%) who completed P/D + RTx was 19.7 mos. MS for similar groups of EPP patients is reportedly 16.8-19 mos (eg, Thorac Cardiovasc Surg 1999;117(1):54-65 and J Clin Oncol 2009;27(18):3007-13).

Conclusions: P/D +RTx provide essentially the same outcomes as EPP with less use of hospital resources

	T Stage	N Stage
0	0	57(47.1%)
1	0	3(2.5%)
2	24(19.8%)	58(47.9%)
3	70(57.9%)	0
4	27(22.3%)	-

Figure 1



Conclusion:
P/D provides essentially the same outcomes as EPP with less use of hospital resources.

Background:
Surgical resection for pulmonary metstasis of osteosarcoma has been considered as the treatment of choice, however, it was not feasible to predict the benefit of metastasectomy for patients with multiple poor prognostic parameters. Survival prediction model can be very helpful for this purpose, so we made a nomogram based on parametric survival model(PSM) and regression trees from recursive partitioning analysis(RPA).

Methods:
We reviewed the clinical variables of patients who underwent single or multiple surgical resection for pulmonary metastasis of osteosarcoma between 1994 and 2012. Prognostic parameters were incorporated into PSM and RPA to build a nomogram and regression trees for the prediction of survival after single or multiple metastasectomy. The ‘rms’ and ‘rpart’ package of R(version 3.2.0) were used for this procedure. PSM was validated with C-index calculated by bootstrap method and then the parameters of PSM were used for RPA.

Results:
We analyzed 186 patients who received 294 metastasectomies. The number of second, third, and forth metastasectomy cases were 62, 28, and 11 respectively. Overall 5-year survival rate after first metastasectomy was 47%. Age, gender, number of metastatic nodules, frequency of metastasectomy, disease free interval before metastasectomy, size, subtype and resection margin of primary tumor were affecting overall survival. Nomogram and regression trees were displayed in figures. C-index of PSM was 0.71. Figure 1 Figure 2





Conclusion:
Our prediction model using a nomogram and regression trees can be easily employable for calculating survival benefits. Nomogram and RPA are complementary to each other. RPA displays comprehensive grouping of patients who have similar prognosis, while nomogram is useful for predicting hazard ratio of individual patient. In this study, our combined model constitutes a useful tool for predicting prognosis of patients who undergo repeated metastasectomy for osteosarcoma.

Background:
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder characterized by proliferation of neuroendocrine cells in the bronchial wall and considered to be pre-invasive lesion for lung carcinoid tumors [1]. There is increasing rate of diagnosis of this condition due to widespread availability and use of cross sectional imaging. DIPNECH is reported as an incidental finding in approximately 5.4% of patients undergoing resection for lung neoplasms [2]. The optimal management of this condition is currently not well-established. The limited data regarding the clinicopathologic characteristics and long term outcome for patients with DIPNECH provided a strong rationale for this study.

Methods:
We employed medical records to obtain demographic, clinical characteristics and survival for patients diagnosed with DIPNECH at our institution between January 1990 to December 2014. A review of archival diagnostic material was conducted by expert pulmonary pathologists to confirm the original diagnosis. Differences in clinical characteristics and survival was assessed between patient groups defined by race, gender, age, smoking status, body habitus and treatment received. Survival was computed using the Kaplan–Meier method while univariate and multivariate models were employed to assess for significant association between patient survival and variables of interest.

Results:
A total of 27 patients were included in this analysis. The majority of patients were females (89%) and predominantly of Caucasian (66.7%) or Black (14.8%) race. The median age at diagnoses was 63 years (range: 20-77) and 61.5% of patients were non-smoker. Approximately 52% underwent surgical resection. The median overall survival (OS) was 151 months (95%CI: 39-165) while 1-year and 5-year survival rates were 95.2% and 73.2% respectively. Nineteen patients (71%) remain alive at the time of this analysis. Male patients (HR: 4.58, 95%CI: 0.76-27.67, p=0.098) and smokers (HR: 23.79; 95%CI: 0.98-579.54; p<0.052) appeared to have an inferior survival. No statistically significant difference in survival was recorded in patient subgroups defined by age, race, surgical intervention or body weight.

Conclusion:
DIPNECH is a rare condition with increasing rate of diagnosis. The overall prognosis is good in comparison to other lung neoplasms but up to a quarter of the patients do not survive beyond five years post diagnosis. Male gender and associated use of tobacco products may be associated with poor outcome. References: 1. Chassagnon, G., et al., DIPNECH: when to suggest this diagnosis on CT. Clin Radiol, 2015. 70(3): p. 317-25. 2. Ruffini, E., et al., The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms. Eur J Cardiothorac Surg, 2004. 26(1): p. 165-72.

Abstract not provided

Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung and peritoneum with median overall survival with standard of care (SOC) chemotherapy only 12 months from diagnosis. This poor prognosis may be attributed at least in part to cancer stem cells (CSCs) that are resistant to chemotherapy and can mediate cancer recurrence and progression. Focal adhesion kinase (FAK) plays an essential role in the survival, self-renewal and tumor-initiating capability of CSCs. The FAK inhibitor VS-6063 (defactinib) is currently being tested in patients with MPM following disease control on standard pemetrexed/platinum chemotherapy (COMMAND, ClinicalTrials.gov NCT01870609).

Methods:
An Aldefluor assay, previously validated as a CSC assay (Shapiro et al., 2014), was used to assess the effects of chemotherapy or VS-6063 on CSCs in vitro. Tumor initiating potential of MPM cells after treatment with SOC agents, and VS-6063 alone or in combination with pemetrexed was measured in vivo. CSC marker expression in MPM patient tumor samples was measured by IHC, Q-PCR and RNASeq analysis. Novel CSC markers were validated in an in vivo limiting dilution assay.

Results:
Treatment of a human MPM cell line with pemetrexed or cisplatin, the SOC therapy for mesothelioma, resulted in a 6-fold enrichment of ALDH-positive CSCs. In direct contrast, the FAK inhibitor VS-6063 markedly reduced the proportion of CSCs. Control and pemetrexed-treated MPM cells showed robust tumor initiation in vivo, while cells treated with VS-6063 alone or VS-6063 plus pemetrexed had decreased tumor initiating capacity. FAK inhibitor was found to selectively induce apoptosis in CSCs, indicating that the mechanism of their elimination is cell death. In addition to ALDH, several new mesothelioma CSC markers were validated in in vivo limiting dilution assay and their clinical utility was assessed. An increase in CSC markers, including ALDH1, CD133 and CXCR2, was observed in tumor samples from 11 patients following first line pemetrexed-cisplatin chemotherapy. In tumor biopsies from MPM patients treated for 12 days with VS-6063, tumor pFAK (Y397) and expression of CSC markers was reduced. Interestingly, gene expression analysis of these samples revealed an inhibition of CSC pathways after VS-6063 administration. VS-6063 maintained the effect of chemotherapy in patient-derived xenograft (PDX) mouse model. Treatment with pemetrexed/cisplatin resulted in tumor growth inhibition followed by rapid tumor re-growth upon cessation of the treatment. Tumor re-growth was substantially delayed when FAK inhibitor was administered after chemotherapy.

Conclusion:
These data provide a strong rationale for the current clinical testing of VS-6063 following treatment with pemetrexed plus platinum to potentially prolong time to progression in patients with mesothelioma.

Background:
Efforts to elucidate tumorigenic mutations in mesothelioma are essential to advance therapy. Prior efforts to characterize the molecular heterogeneity of this disease have been limited by sample condition and testing platforms. Herein, we describe efforts to prospectively test patients using next-generation sequencing with matched patient germline controls.

Methods:
Sequential mesothelioma patients were approached for consent to our IRB protocol NCT01775072 to perform MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a comprehensive molecular profiling platform based on solution-phase exon capture and next generation sequencing to detect somatic genetic alterations in FFPE tumor specimens. MSK-IMPACT involves hybridization capture and deep sequencing of all protein-coding exons of 341 key cancer-associated genes, including all genes that are druggable by approved therapies or are targets of experimental therapies being investigated in clinical trials at MSKCC.

Results:
51 patients with mesothelioma underwent MSK-IMPACT testing (see Table 1). 12 samples had low tumor content. Among 39 samples with reliable results, BAP1 was the most common alteration (46%). Another 3 samples had changes also thought to inactivate BAP1 (2 samples had gene copy number changes just below the cutoff for whole gene deletions and 1 had an inversion of LIMD-BAP1 thought to inactivate BAP1), making the incidence of BAP1 alterations possibly as high as 56%. In 4 samples with sufficient tumor content, no alterations were identified. Table 1

	N=39 (%)
Gender M/F	26/13 (67/33)
Primary site of disease * Pleural * Peritoneal * Testicular	32 (82) 6 (15) 1 (3)
# identified alteration, average	3
Alterations present in >6% * BAP1 * NF2 * CDKN2Ap16INK4A * SETD2 * CDKN2Ap14ARF * LATS1 * CREBBP * WT1 * CDKN2B * PI3KCA * PBRM1 * TP53	18 (46) 8 (21) 5 (13) 5 (13) 4 (10) 4 (10) 4 (10) 4 (10) 3 (8) 3 (8) 3 (8) 3 (8)

Conclusion:
Using MSK-IMPACT, BAP1 inactivation is the most common alteration. Other aberrations previously reported at high frequency were identified but albeit at lower frequencies (NF2 and p16, previously reported as 40% and 75% respectively). For multiple samples with deep coverage, no alterations were identified. The high incidence of BAP1 mutations in this systematic testing makes this pathway ideal for developing and testing targeted therapies.

Background:
Thymic epithelial tumours (TETs) are rare intrathoracic cancers that can be invasive and very difficult to treat. There is currently a huge gap in the understanding of the basic science behind their development as well as great clinical need for development of effective treatments. Recently a missense mutation (T>A, at the same position on chromosome 7, 74146970) was identified in GTF2I at high frequency (78%) in the more indolent type A and AB thymomas. We examined the frequency of this alteration in an independent cohort of well clinically characterized patients from the UK.

Methods:
Tumour samples were collected from 94 patients from a single tertiary cardiothoracic centre in the UK, the Royal Brompton & Harefield NHS Foundation Trust (London). These were subject to histological assessment by expert Consultant Histopathologists to confirm the diagnosis and determine tumour abundance. DNA was extracted with Quiagen’s QIAamp DNA FFPE Tissue Kit (Catalogue No. 56404). PCR and Sanger sequencing was performed with semi-nested primers.

Results:
We assessed the frequency of the GTF2I mutation in a total of 94 TETs with a tumour abundance of at least 70%. The mean age for all patients was 57 and the male: female ratio was 1:1.25 The GTF2I mutation was seen in 25 of 87 evaluable TETs (29%) and was present more commonly in type A (85%) and AB (46%) thymomas. The frequency decreased to 9% in type B1 (1/11) and 5% in type B2 thymomas (1/19). In our cohort the mutation was not detected in any B3 thymomas or carcinomas, including neuroendocrine tumours or two cases of thymic hyperplasia. Interestingly all AB thymomas with the mutation had a much lower percentage of mutant alleles compared to the majority of the A thymomas. Twenty-three of the 25 patients (92%) with the mutation had Stage I – II disease at presentation and had complete resection of their thymoma.

Conclusion:
Our results confirm the presence of the GTF2I mutation at a high frequency in type A and AB thymomas in an entirely different patient cohort. Although the frequency of the mutation in type A thymomas in our cohort is very similar to what was reported originally (85% and 82% respectively) it was lower in the AB thymomas (46% and 74% respectively). Explanations for this include the smaller sample number in our cohort and a higher percentage of the lymphocytic component in our samples than that in the original series. The lower mutation frequency in the B subtypes and carcinomas compared to the original series could be due to the smaller numbers in our cohort. We aim to address these issues by expanding our validation series to over 200 samples. Whole exome and RNA sequencing of TETs is ongoing and will allow us to further confirm and extend this finding.

Background:
There is currently no licenced second line therapy for mesothelioma patients upon relapse after pemetrexed cisplatin. The vinca alkaloid spindle poison, vinorelbine, exhibits useful activity in mesothelioma, warranting evaluation in a new UK randomised clinical trial, VIM. However the molecular determinants of efficacy are unclear. We have reported that BRCA1 is an essential regulator of vinorelbine-induced apoptosis, and loss of detectable BRCA1 occurs in 39% of mesotheliomas. However the mechanisms governing BRCA1 dependent lethality has been lacking. We have utilized a functional genetic approach to uncover critical genes required for vinorelbine efficacy.

Methods:
Apoptosis was analysed by PARP cleavage and caspase 3/7 activity assay. Focused RNAi targeting Caspase 8, BAX and BAK was conducted to delineate critical death activators. Mouse embryonic fibroblasts (MEFs) wild type (WT) or double knockout (DKO) for BAX/BAK cells were also used. MAD2L1 expression was studied by western blot and qRT-PCR. Tumour explants were derived from 10 MPM patients.

Results:
Mitochondrial and caspase-8 dependent apoptosis pathways were shown by triple knockdown of BAX, BAK and Caspase 8 to be required to rescue completely from vinorelbine-induced apoptosis. Loss of BRCA1 recapitulated this apoptosis block and was associated with loss of Oct1 dependent MAD2L1 associated transcriptional upregulation. RNAi mediated silencing of MAD2L12 phenocopied BRCA1 loss. In cells selected for resistance to vinorelbine, MAD2L1 failed to upregulate, secondly to constitutive downregulation of BRCA1. Using mesothelioma explants derived at extrapleural decortication, exhibited either marked resistance or sensitivity to vinorelbine induced apoptosis; correlation with regulation of BRCA1/Oct1/MAD2L is ongoing and will be presented.

Conclusion:
BRCA1 functions through an Oct1/MAD2L1-dependent activation of both mitochondria dependent and independent pathways to induce apoptosis. This implicates a requirement for a functional spindle assembly checkpoint, with implications for expanding the biomarker repertoire governing vinorelbine efficacy in mesothelioma

Abstract not provided

Background:
GSK3052230/FP1039 is a soluble fusion protein with the ECD of FGFR1c linked to the hinge and Fc regions of human IgG1 and acts as a ligand trap by sequestering FGFs involved in tumor growth and angiogenesis. In contrast to small molecule FGFR kinase inhibitors, GSK3052230 spares the hormonal FGF ligands, namely FGF19, 21 and 23. GSK3052230 combined with chemotherapy was efficacious in xenograft models of FGFR1-amplified NSCLC and malignant pleural mesothelioma (MPM) with FGF2 mRNA overexpression. A phase I monotherapy study determined 20mg/kg weekly as the maximum feasible dose (MFD) achieving the desired blood concentration, with no maximum tolerated dose (MTD) reached.

Methods:
This study (NCT01868022 funded by GSK) will evaluate the safety and efficacy of GSK3052230 weekly infusion in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic sqNSCLC that has progressed after at least 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Each arm involves a dose escalation phase utilizing the 3+3 design, followed by an expansion phase up to 30 patients (pts). Key endpoints include the MTD/MFD of GSK3052230 with chemotherapy, safety, response rates and duration.

Results:
Thirty-four pts have been dosed with GSK3052230 at dose levels ranging from 5mg/kg to 20mg/kg in combination with chemotherapy across three Arms, n=15 (A), n=6 (B) and n=13 (C). Baseline characteristics: males/females 29/5; mean age 68.5 years; ECOG PS 0 (n=20), 1 (n=13), 2 (n=1). Most common AEs were: Arm A: asthenia, neutropenia; Arm B: neutropenia, diarrhea, rash; Arm C: decreased appetite, nausea, infusion reaction. Infusion reactions were seen in 8/34 (24%) pts (n=3 Grade (Gr)1, n=3 Gr2, n=2 Gr3). Serious AEs included: Arm A- neutropenia (n=4), fatigue (n=1), asthenia (n=1), fever (n=1), respiratory infection (n=1); Arm B- neutropenia (n=1), abdominal pain (n=1); Arm C-bowel perforation/ischemia (n=1), infusion reaction (n=1), elevated creatinine (n=1). No DLTs have been observed in sqNSCLC pts (Arms A and B). Three DLTs were reported in mesothelioma pts (Arm C 20mg/kg): Gr5 bowel perforation/ischemia, Gr4 elevated creatinine levels and Gr3 infusion reaction. MFD for Arm A is determined at 20mg/kg. Dose escalation is ongoing for Arms B and C. Preliminary PK results revealed no drug-drug interactions. At time of data-cutoff, 10 PR were observed among 23 patients evaluable for efficacy (ORR = 43%) and a clinical benefit rate of 78% with two ongoing subjects on study >300 days. Preliminary efficacy is as follows: Arm A (6 PR, 2 SD, 1 PD, 6= not-yet-evaluable (NE)), Arm B (4 SD, 1 PD, 1 NE), and Arm C (3 PR, 3 SD, 3 PD, 4 NE).

Conclusion:
GSK3052230 is in general well tolerated in combination with chemotherapy. The MFD for GSK3052230 is 20mg/kg in combination with paclitaxel + carboplatin in first line sqNSCLC patients. Toxicities typically associated with small-molecule FGFR inhibitors, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. The initial activity and safety profile of GSK3052230 ​warrant further study.

Background:
Malignant pleural mesotheliomas (MPM) are relatively rare tumors for which there are no effective treatment options. Previously we reported that mithramycin (MM) dramatically inhibits growth and tumorigenicity of MPM cells in part via depletion of Specificity Protein 1 (SP1) and activation of p53 signaling. We also demonstrated that 24h MM treatment induces G0/G1arrest and senescence with subsequent apoptosis of MPM cells. The present study was undertaken to examine the effects of RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis- a p53 activator and MDM2 inhibitor) with or without MM in cultured MPM cells in vitro and in vivo.

Methods:
NCI-SB-MES1 and NCI-SB-MES7 (MES1 and MES7, respectively) with wild-type p53 were cultured in the presence of mithramycin (24h) and/or RITA (48h). DNA damage, senescence and autophagy were assessed by immunoblot/immunofluorescence analysis of g-H2A-X phosphorylation and foci formation, ß-gal staining, and immunoblot/immunofluorescence analysis of LC3 proteins. Propidium iodide and APO-BrdU techniques were used to determine cell cycle kinetics and quantify apoptosis. qRT-PCR and immunoblot techniques were used to examine signal transduction, cell cycle-related and apoptosis-related protein levels in MPM cells. Murine subcutaneous xenograft models were used to evaluate the combinatorial antitumor effects of RITA and MM in-vivo.

Results:
MM treatment (10-100nM x 24h) mediated dose-dependent depletion of SP1 and markedly increased p53 levels in MPM cells; these effects coincided with DNA damage, G0/G1 arrest, senescence and an autophagy phenotype as evidenced by induction of LC3 puncta/proteins and p-AMPK and inhibition of p-S6 kinase. Senescence or autophagy phenotype coincided with up-regulation of CDKN1A, MDM2/TP53INP1, MAPLC3B, and down-regulation of EZH2, SP1/MTOR. RITA (100-1000nM x48h) alone mediated low-level, dose-dependent growth inhibition in MPM cells. However treatment with subtherapeutic doses of MM for 24h followed by RITA for 48h resulted in synergistic growth inhibition and apoptosis in MPM cells, detected by flow cytometry, as well as immunoblot analysis of cleaved PARP and cleaved caspase 3. Sequential intraperitoneal treatment with MM (1mg/kg/week) followed by RITA (2 mg/kg/3d/week) significantly reduced volumes/masses of subcutaneous MES1 xenografts in athymic nude mice.

Conclusion:
Sequential mithramycin/RITA treatment significantly reduces mesothelioma tumor burden via induction of apoptosis. These findings provide preclinical rationale for evaluation of this drug regimen in MPM patients.

Background:
The CALGB and EORTC have previously developed prognostic scoring systems for patients with MPM, but these included patients managed surgically and predated the use of pemetrexed. We sought to identify prognostic factors in a contemporary cohort of patients with unresectable MPM.

Methods:
We retrospectively reviewed the charts of patients with histologically proven MPM managed non-surgically at MSKCC from 2000-2012. Variables analyzed and correlated with overall survival (OS) included: sex, age at diagnosis, smoking history, asbestos exposure, tumor laterality, initial performance status (PS), tumor histology, clinical TNM, initial PET maximum Standardized Uptake Value (SUVmax), hemoglobin level, platelet, lymphocyte and neutrophil counts, treatment type (chemotherapy and/or radiotherapy), and response to treatment. OS was analyzed by Kaplan-Meier method, and significance (p<0.05) of prognostic factors was analyzed by log-rank test and Cox regression.

Results:
191 patients met study criteria: median age 71 years (range 46-90), 147 (77%) male, 128 (67%) epithelioid , 20 (10.5%) biphasic, and 28 (14.6%) sarcomatoid. 34 patients were stage I-II at presentation and 157 (82%) stage III-IV. First line chemotherapy included pemetrexed in 159 (90.3%) patients. Median time from diagnosis to treatment was 1.2 months. With a median follow-up of 13.2 months, median OS for all patients was 13.4 months. By univariate analysis, histology (p<0.001), platelet count (≤450 vs. >450, p<0.001), initial PS, maximum PET SUV (> or ≤8.1, p=0.037) were significant. Clinical staging (I/II vs III/IV) did not correlate with OS (p=0.35). By multivariable analyses, only histology, platelet count and PS were independent prognostic factors. 1-year OS was 69% (95%CI 62%-78%) for epithelioid versus 30% (95%CI 15%-59%) and 29% (95%CI 16%-51%) for biphasic and sarcomatoid tumors, respectively. Patients with PS 0-1 had a 1-year OS of 64% (95%CI 56%-73%) versus 42% (95%CI 31%-57%) for PS 2 or greater. Epithelioid histology, PS 0-1 and elevated neutrophil count at diagnosis were significantly associated with response to first line chemotherapy. Patients with response or stable disease after the first two cycles of chemotherapy had significantly better OS, median OS was 16.8 (95% CI 14.8 – 20.1) versus 6.5 (95% CI 5.4-8.5) months (p<0.001). Patients receiving more than one line of chemotherapy had better OS, median OS 14.2 (95% CI 12.1 – 16.8) versus 8.7 (95% CI 6.6 – 11.0 ) months (p=0.013). There was no significant association between use of radiotherapy and OS (p=0.058), but patients who received radiotherapy showed a 1-year OS of 60.5% vs 44.0% of patients who did not receive radiotherapy.

Conclusion:
This analysis in patients with unresectable MPM confirms that some elements of the CALGB and EORTC prognostic scoring systems (platelet count, PS, histology) correlate with OS, and identifies factors (PS, elevated neutrophil count, histology) associated with response to chemotherapy. Our analysis emphasizes the impact of histology and response to first-line chemotherapy on outcomes, but also the lack of predictability with the use of clinical staging.

Background:
The staging of malignant pleural mesothelioma (MPM) remains undetermined. But it is still important for informing prognosis and selection for high risk surgery. The specific lymphatic drainage of the pleura implies that nodal staging based on that used in lung cancer may not be accurate for MPM. We have evaluated an alternative nodal staging strategy.

Methods:
We retrospectively analysed the pathology and outcome of 282 patients who survived for over 30 days following radical surgery for MPM: 190 extended pleurectomy decortication(EPD), 92 extrapleural pneumonectomy(EPP). All patients underwent intraoperative systematic nodal dissection. Nodal stations were assigned to all nodes, and patients were staged according to the current UICC system. The status and number of nodes in each station were recorded. Survival was calculated for the standard nodal stages (N0, N1, N2). We derived nodal groups Na, Nb, Nc based on the percentage of sampled nodes containing tumour, irrespective of nodal station: Na = N0, Nb ≤ median %, Nc > median %.

Results:
The type of surgery did not influence median survival; EPD 12.3 vs. EPP 14.5 months, p=0.46. The median survival of the standard nodal stages were: N0(113 patients), 16.5 months; N1(13 patients), 13.0 months; N2(156 patients), 11.8 months. There was no significance difference in survival between N1 and N2, p=0.65 but there was between N0 and N1/N2, p=0.04. The median percentage of nodal metastases was 43%. There were significant differences in median survival between Na, Nb and Nc, p=0.03. There were significantly more positive N2 nodes in group Nc (98%), than in group Nb (86%) p=0.001.

Nodal stage	No of patients	Median survival (months)
N0	113	16.5
N1	13	13.0
N2	156	11.8
Na - no metastases	113	16.5
Nb -	86	13.5
Nc - > 43% metastases	83	9.9

Figure 1



Conclusion:
There appears to be greater accuracy in a nodal staging system based on the nodal burden of metastases rather than an anatomically based system. There may be less accuracy in nodal staging in lung sparing radical surgery for MPM due to less extensive nodal sampling.

Abstract not provided

Background:
Maximal cyto-reductive surgery with adjuvant therapy provides survival advantage in selected patients with malignant pleural mesothelioma (MPM). Extended pleurectomy and decortication (EPD), a lung sparing procedure, provides an opportunity to measure the tumor volume. We hypothesized that tumor volume is a better predictor of survival than the T and N, because it represents tumor burden more accurately. Currently the significance of epithelioid differentiation in the biphasic histology also remains poorly understood. We report our experience with patients undergoing EPD and the implication of tumor volume and epithelioid differentiation in overall survival.

Methods:
We evaluated 116 patients who underwent EPD for MPM. The following variables were assessed: age, gender, histology, tumor volume and pathological T and N stage. The tumor volume of resected specimens was measured using a water displacement method. All histological examinations were performed by a single pathologist, and the percent epithelioid histology was estimated in all patients. A Cox regression model was used to identify significant predictors of survival. Kaplan-Meier was used to summarize overall and subgroup survival.

Results:
There were 95 males and 21 females with a median age of 68 years (range 43-88 years). Epithelioid differentiation was 100% in 60 patients, 50-95% in 35 patients, and less than 50% in 21 patients (no patient with pure sarcomatoid histology was included in this report). Mean tumor volume was 642+/- 400ml. Tumor volume was between 100-299cc in 20 patients, between 300-599cc in 37 patients, and >600cc in 54 patients. In 5 patients the volume was not estimated. Six patients (5%) died within 30 days. Two-year survival from EPD was 28%. Median survival was 15.7 months. Percent epithelioid differentiation (p=0.0004) and tumor volume (p=0.001) were significant predictors of survival. T (p=0.05) stage, but not N stage, was a significant predictor of survival. Tumor volume was a predictor of T stage (p=0.05). No relationship between N stage and either tumor volume or histology was observed.

Conclusion:
Percent epithelioid differentiation and tumor volume are independent predictors of survival in MPM patients undergoing EPD.

Background:
Malignant mesothelioma (MM) is a universally lethal disease, which develops in the pleura, peritoneum, pericardium, and tunica vaginalis. MM is commonly associated with a prominent inflammatory reaction, including extensive macrophage infiltration. Early reports indicate presence of tumor infiltrating lymphocytes (TILs), PD-L1 expression (Kindler et al ASCO 2014), and activity of anti-PD-1 therapy (Alley et al AACR 2015). However, quantitative evaluation of multiple immune markers in a large mesothelioma cohort and evaluation of prognostic and biologic implications has not been reported.

Methods:
We performed multiplex immunofluorescence (IF) staining and automated, quantitative density assessments in a clinically annotated cohort of 109 malignant mesotheliomas (58 epithelioid, 43 biphasic, 8 sarcomatoid). Staining for PD-1, PD-L1 (immune checkpoint), FOXP3 (T-regulatory cells), and CD8 (TILs) was performed using a quantitative, multiplex IF system (TissueFax), and a multi-tumor-validated, quantitative StrataQuest analysis algorithm in order to identify specific immune cells and respective densities. Gene expression data (TCGA) was analyzed to confirm individual correlations. Staining for CD206 (macrophages) is ongoing.

Results:
PD-L1 density correlated with more aggressive histology, and was highest in sarcomatoid (median density score of 3016), and biphasic (2720) tumors compared with epithelioid tumors (1740). Using a cutoff of 5% PD-L1 density by area 19% of epithelioid, 38% of sarcomatoid, and 44% of biphasic tumors were deemed PD-L1 positive. PD-L1 expression exhibited a bimodal distribution (peaks at both high and low PD-L1 densities). Also with the biphasic tumor cohort expression of PD-L1 correlated with worse outcome (P=0.02), while PD-1 and CD8 did not have prognostic implications (and could not distinguish histologic subtypes). By contrast in epithelioid MM CD8 infiltration density showed a trend towards improved prognosis (P=0.06) (and correlated with PD-1 expression), while PD-L1 expression was not prognostic. Interestingly, PD-1/CD8 and PD-L1 expression did not correlate regardless of histology (R=0.02-0.08), suggesting macrophage-driven PD-L1 expression. Gene expression data supported this hypothesis and staining for M2-related macrophage markers is ongoing. In epithelioid tumors FOXP3 T-regulatory cell density showed a trend towards worse prognosis (P=0.07). In biphasic and sarcomatoid tumors prognosis was poor regardless of FOXP3 expression. Data on stromal versus tumor expression patterns is being processed.

Conclusion:
In mesothelioma CD8, PD-1, PD-L1 and FOXP3 are widely expressed, with 19% of epithelioid, and 38-44% of sarcomatoid and biphasic tumors showing elevated PD-L1 density. PD-L1 expression correlates with a worse prognosis by subtype and in the biphasic tumor population. In epithelioid tumors PD-1 may indicate better outcome. PD-1 and PD-L1 expression do not correlate with each other in malignant mesothelioma, which relates to pro-tumorigenic macrophages leading to potentially interferon gamma independent PD-L1 expression.

Background:
The value of surgical treatment for malignant pleural mesothelioma is still an open question. We analysed a surgical series of MPM patients undergoing surgery for MPM in a single institution

Methods:
A retrospective analysis was carried out of all surgical patients treated in our Department from 2000 to February 2015. Selection criteria were age<75, performance status 0-1, non-sarcomatoid histology, pretreatment stage I-III, and fit for major surgery. The procedure of choice was extrapleural pneumonectomy (EPP) until 2010 and radical pleurectomy/decortication (PD) thereafter. Patients that were found to be unresectable underwent palliative pleurectomy. The IMIG system was used for pathological staging, complications were scored based on WHO-derived criteria and the Charlson Co-morbidity Index was used to stratify patients.

Results:
Radical surgery was attempted in 163 patients: 91 received EPP, 47 underwent PD (1 with macroscopic residual disease) and 25 a palliative pleurectomy. Their main features and survival outcomes are summarized in table 1. Mean age and Charlson score were higher in PD than in EPP patients. A mixed histology was more prevalent in those who received palliative pleurectomy. Complications were equally frequent after EPP and PD but less frequent after palliative surgery. However, EPP patients had a high frequency of early- and late-occurring (30-600+ days postop) pleural sepsis (p=0.002) that had an unfavorable effect on OS (p=0.035). Induction chemotherapy was associated with better outcomes in PD but not in EPP. At multivariate analysis, epithelial histology (p=0.0419, grade 3+ complications (p=0.001) and Charlson index (p=0.001) were associated with better overall survival (OS). PD was associated with better OS compared with palliative pleurectomy (p=0.05), while EPP was not. Figure 1

EP (%) P/D (%) R2 (%) N° 91 47 25 Mean Age (95% CI) 60 (58 - 61) 65 (62 - 67) 63 (60 - 66) Males 66 (72) 31 (66) 22 (88) Trimodal** 28 (30.77) 33 (70.21) 6 (24.00) Epithelioid 81 (89.01) 46 (97.87) 20 (80.00) p-Stage 0-II 18 (19.8) 18 (38.3) - p-Stage III 68 (74.73) 20 (42.55) 2 (8.00) p-Stage IV 5 (5.49) 9 (19.15) 21 (92.00) Grade 3+ Complications 25 (25.47) 12 (25.53) 2 (8.00) 30-Day Mortality 3 (3.30) 1 (2.13) - Median OS (IQI) 19.0 (9.3 - 35.6) 29.9 (13.7 - 35.2) 13.3 (4.7 - 31.6) Median DFS (IQI) 11.5 (7.1 - 21.8) 12.1 (6.4 - 19.2) -

Title table: Patients' features and survival outcomes in surgical MPM patients * Surgery + either chemo or RT, **induction + Surgery + Postoperative radiotherapy, IQI= Interquartile Interval



Conclusion:
EPP does not offer a significant benefit while PD may offer an advantage over palliative pleurectomy. The Charlson index is a major independent prognosticator in patients undergoing surgery for MPM.

Background:
Surgery has a controversial role in the treatment of malignant pleural mesothelioma (MPM) as no trial has demonstrated independent survival benefit of surgery. Likewise, there is lack of consensus regarding the role of radiation in MPM. We evaluated whether cancer-directed surgery and/or radiation independently influenced MPM survival in a large population-based dataset.

Methods:
The Surveillance, Epidemiology, and End Results database was explored from 1973 to 2009 to identify all cases of pathologically-proven MPM. Age, sex, race, diagnosis year, stage, cancer-directed surgery, radiation, and vital status were analyzed (chemotherapy data not available). The association between prognostic factors and survival was estimated using a Cox proportional hazards model.

Results:
There were 14,228 patients with pathologic diagnosis of MPM. On multivariable analysis, female gender, younger age, localized stage, and cancer-directed surgery were independently associated with longer survival (Table). Survival was longer for patients who underwent surgery or surgery and radiation but not for those who underwent radiation only (Figure).

Table. Association between Patient and Disease Characteristics and Survival
Variable	Category	Adjusted HR (95% CI) *
Sex	Male	1 (Ref)
	Female	0.78 ( 0.75-0.82)
Race	White	1 (ref)
	Black	1.07 (0.98-1.16)
	Other	0.99 (0.89-1.09)
Age (years)	continuous	1.24 (1.22-1.26)
Stage	Localized	1 (ref)
	Regional	1.30 (1.21-1.40)
	Distant	1.34 (1.26-1.42)
Diagnosis year	1973-1989	1 (ref)
	1990-1994	0.91 (0.85-0.97)
	1995-1999	0.86 (0.81-0.92)
	2000-2004	0.86 (0.81-0.91)
	2005-2009	0.80 (0.75-0.84)
Therapy	No radiation or surgery	1 (ref)
	Radiation only	1.17 (1.10-1.25)
	Surgery only	0.65 (0.62-0.68)
	Radiation and surgery	0.69 (0.63-0.75)

Figure 1



Conclusion:
In this study of 14,228 patients over 36 years, cancer-directed surgery was associated with better survival in MPM, independent of other forms of therapy, including radiation. These data support the role of surgery-based therapy as the cornerstone for treatment in this challenging disease.

Abstract not provided

Abstract not provided

Abstract:
The deubiquitinase (DUB) BAP1 recently emerged as a major tumor suppressor inactivated in several malignancies notably mesothelioma. With the aim of defining the BAP1 mechanism of action, we previously conducted a tandem affinity immunopurification of BAP1-associated proteins and found that most of the interacting partners are transcription factors and cofactors. Notably, BAP1 forms a complex with the Host Cell Factor (HCF-1), the O-linked N-acetyl-Glucosamine Transferase (OGT), the Lysine Specific Demethylase KDM1B, the Additional Sex Comb Like proteins ASXL1 and ASXL2 (ASXL1/2), the Forkhead Box transcription factors FOXK1 and FOXK2 as well as the zinc finger transcription factor Yin Yang 1 (YY1). We found that BAP1 regulates the expression of genes involved in cell proliferation and is recruited to gene regulatory regions to activate transcription. BAP1 is also recruited to the site of DNA double strand breaks to promote repair by homologous recombination. Moreover, this DUB appears to be also finely regulated by post-translational modifications including phosphorylation and ubiquitination. Interestingly, the ortholog of BAP1 in drosophila, named Calypso, deubiquitinates histone H2A on lysine 119 (H2Aub). H2Aub is a critical epigenomic modification involved in transcriptional and DNA repair, and is associated with stem cell function, development, cell proliferation and cancer. Calypso associates with Additional Sex Comb (ASX) and forms the Polycomb Repressive DUB (PR-DUB) complex. Recently, we provided insights into the importance of BAP1-interacting partners, ASXL1 and ASXL2 (two orthologs of ASX) in promoting H2A deubiquitination. We found that BAP1 forms two mutually exclusive complexes with ASXL1 and ASXL2. ASXL1 and ASXL2 use their highly conserved ASXM domain to interact with the C-terminal domain (CTD) of BAP1, and these factors regulate each other’s protein stability. Significantly, through mutational analysis, we found that ASXM enhances BAP1 binding to ubiquitin and stimulates its DUB activity. Importantly, these functions require intramolecular interactions in BAP1 that generate a Composite Ubiquitin Binding Interface (CUBI). Gain and loss of function studies indicated that BAP1, ASXL1 and ASXL2 play critical roles in the coordination of cell cycle progression. Notably, overexpression of BAP1 or ASXL2 trigger the p53/p21 DNA damage response and cellular senescence, and these effects are abolished by mutations of the CTD or ASXM interaction domains. Furthermore, we showed that cancer-associated inactivation of BAP1/ASXL1/2 DUB activity disrupts coordination of cell proliferation. Altogether, our results indicate that the mammalian BAP1 is an authentic DUB for H2A that regulates chromatin function and exerts a tight control on cell cycle progression. Moreover, our studies provide a mechanistic link between H2A deubiquitination, BAP1 interacting partners and tumor suppression.

Abstract:
Background: BRCA1 associated protein-1 (BAP1) is a tumor suppressor gene that encodes a deubiquitinase involved in cell cycle regulation, cellular differentiation, and cell death (Carbone et al., 2013; Murali, Wiesner, & Scolyer, 2013). BAP1 is recruited to double-stand DNA breaks and promotes error-free DNA-repair (Yu et al., 2014). Germline BAP1 mutations have been identified in around 40 families with accumulation of mesothelioma, uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC) (Carbone et al., 2013; Wadt et al., 2014; Wiesner et al., 2011). Speculation exists as to whether BAP1 germline mutation carriers with mesothelioma, UM or RCC have different prognosis compared to non-carriers with the same types of cancer. Somatic BAP1 mutations have been identified in approximately 20% of pleural malignant mesotheliomas (Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M, 2013), with most studies reporting no significant differences in the histopathological features or survival of patients with BAP1 mutant compared to wild-type tumors. A recent study of Portuguese siblings discovered a germline BAP1 mutation as the possible cause of the only known familial clustering of well-differentiated papillary mesothelioma (WDPM), a rare subtype of epithelioid mesothelioma (Ribeiro et al., 2013), and there has since been another report of WDPM in a carrier of a germline BAP1 mutation (Pilarski et al., 2014). Previously, some patients with germline BAP1 mutations and malignant mesotheliomas have been reported as long-term survivors, which is very rare for mesotheliomas, raising the possibility that such tumors may be associated with more favorable prognosis (Ribeiro et al., 2013; Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, 2014). In contrast, somatic BAP1 mutations or loss of BAP1 have been associated with high-grade tumors or disseminated disease in sporadic RCC and UM patients, which could indicate a worse prognosis for carriers of germline BAP1 mutations with these tumor types. Clearly, further studies are necessary to clarify whether BAP1 germline mutation carriers with various cancers have altered prognosis relative to individuals who acquire somatic mutations in BAP1. Here, we sought to determine the frequency of germline BAP1 mutations in cancer prone families with accumulation of mesothelioma, UM, CM and RCC. Methods: Families were collected through the Danish melanoma registry and through Clinical Genetic Departments in Denmark. Families, who previously had received genetic counselling regarding mesothelioma, CM, UM, and RCC, were contacted. Results: In total we analysed 152 Danish families and found five with BAP1 mutations, which are described in Table 1. We analysed 127 CM patients, who were either young onset (<40 years), had multiple primary CM, or had a family history of melanoma, and found no BAP1 mutation. We analysed 22 sporadic cases of UM or familial cases of CM, with one case of UM in the family and found no BAP1 mutation. However, in 6 melanoma families with two cases of UM, we found 4 families with BAP1 mutation, and 2 of 3 families analysed with 2 or more cases of mesothelioma carried BAP1 mutations. We found that the strongest indicator of a germline BAP1 mutation, were families with two or more cases of mesotheliomas or UM. In 40% of families with the occurrence of mesothelioma and CM we also found BAP1 mutations but did not find BAP1 mutations in families with only CM or RCC, or families with CM and RCC. Table 1: Characterization of Danish BAP1 mutation-positive families

Family	Mutation	Cases of UM/No. of mutation carriers	Cases of mesothelioma/ No. of mutation carriers	Cases of CM/No. of mutation carriers	Other types of cancer in mutation carriers
A	c.1708C>G p.L570V	3/14	2/14	1/14	Paraganglioma, Sarcoma
B	c.581-2A>G Splice defect	7/9	0/9	1/9	Lung
C	c.1209_1210dupT p.D404X	0/8	3/8	2/8	BCC, Breast, unknown primary
D	c.178C>T p.R60X	3/10	0/10	2/10	BCC, ovary
E	c.178C>T p.R60X	2/4	1/4	0/4	BCC
Total		15/45(33%)	6/45(13%)	6/45(13%)

13% of BAP1 mutation carries developed mesothelioma, 33% developed UM, and 13% developed CM. There were no cases of RCC in the 5 Danish BAP1 mutation-positive families. Conclusion: In the Danish BAP1 mutation carriers we observed rare tumor types (pericardial paraganglioma and malignant fibrous histiocytoma) and three cases of unknown primary tumors. At present there is no international consensus about a surveillance program for BAP1 mutation carriers. Since BAP1 contributes to a rare, recently discovered cancer syndrome, there is as yet no documented reduction of morbidity or mortality to persons following surveillance. To obtain such empirical data we offer persons carrying a pathogenic BAP1 mutation a surveillance program consisting of yearly ophthalmological and dermatological examination from the age of 15. In addition, from the age of 25, we offer ultrasound examination of the kidneys every second year. We inform the patient and their general practitioners of the increased cancer risk, and signs which should prompt further symptom-related investigations. At the moment, we have not established a surveillance program for mesothelioma. References: Carbone, M., Yang, H., Pass, H. I., Krausz, T., Testa, J. R., & Gaudino, G. (2013). BAP1 and cancer. Nature Reviews. Cancer, 13, 153–9. doi:10.1038/nrc3459 Murali, R., Wiesner, T., & Scolyer, R. a. (2013). Tumours associated with BAP1 mutations. Pathology, 45, 116–26. doi:10.1097/PAT.0b013e32835d0efb Pilarski, R., Cebulla, C. M., Massengill, J. B., Rai, K., Rich, T., Strong, L., … Abdel-Rahman, M. H. (2014). Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes and Cancer, 53, 177–182. doi:10.1002/gcc.22129 Ribeiro, C., Campelos, S., Moura, C. S., Machado, J. C., Justino, A., & Parente, B. (2013). Well-differentiated papillary mesothelioma: Clustering in a Portuguese family with a germline BAP1 mutation. Annals of Oncology, 24, 2147–2150. doi:10.1093/annonc/mdt135 Wadt, K. A. W., Aoude, L. G., Johansson, P., Solinas, A., Pritchard, A., Crainic, O., … Hayward, N. K. (2014). A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clinical Genetics. doi:10.1111/cge.12501 Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, S. M. (2014). J OURNAL OF C LINICAL O NCOLOGY Toward an Improved Definition of the Tumor Spectrum Associated With BAP1. Journal of Clinical Oncology, 30(32), 2012–2015. Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., … Speicher, M. R. (2011). Germline mutations in BAP1 predispose to melanocytic tumors. Nature Genetics, 43(10), 1018–21. doi:10.1038/ng.910 Yu, H., Pak, H., Hammond-Martel, I., Ghram, M., Rodrigue, A., Daou, S., … Affar, E. B. (2014). Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America, 111, 285–90. doi:10.1073/pnas.1309085110 Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M. (2013). Clinical Characteristics of Patients with Malignant Pleural. Journal of Thoracic Oncology, 8(11), 1430–1433.

Abstract not provided

Abstract:
Introduction Cancer mortality continues to decline in the US and the number of cancer survivors continues to rise, currently estimated at 14.5 million in 2014 and predicted to reach 19 million by 2024 (ACS and NCI). The percent of adult cancer survivors who are current smokers has not changed dramatically over the past 10 years, and is comparable to the general population, except in the youngest age group, 18-44, where it is significantly higher (2000-2010 NHIS). The 2014 Report of the Surgeon General, "The Health Consequences of Smoking - 50 Years of Progress," cited 20,830,000 premature deaths caused by smoking and exposure to secondhand smoke (1965-2014). Smoking–related cancers accounted for 6,587,000 and lung cancers caused by exposure to secondhand smoke accounted for 263,000. Between 2005 and 2009, over 480,000 US deaths annually were attributable to cigarette smoking. Lung cancer accounted for almost 138,000 (29%). In 2015, the estimate is 158,040 lung cancer deaths – 86,380 (28%) in men and 71,660 (26%) in women, still the leading cause of cancer death in the US. The 2014 SGR concluded that there is a causal relationship between cigarette smoking and adverse health outcomes, and that quitting smoking improves the prognosis of cancer patients. In cancer patients and survivors, a causal relationship was concluded between smoking and all-cause mortality, cancer-specific mortality, and increased risk for second primary cancers known to be caused by smoking. The relationship is considered suggestive but not causal between cigarette smoking and risk of recurrence, poorer response to treatment and increased treatment-related toxicity. Among chronic disease populations (NHIS 2006 vs 2012), 15.2% of lung cancer survivors continue to smoke, compared to 20.9% in 2006. Among other smoking-related cancers, 33.8% of survivors continue to smoke, compared to 38.8% in 2006. Among persons with no chronic disease, the comparable percents of current smokers were 16.6% in 2012 and 19.3% in 2006. These elevated rates of current smoking among chronic disease survivors are truly alarming. Clearly, the need for tobacco cessation intervention is great among cancer patients and survivors. Addiction to cigarette smoking (and all tobacco use) is challenging to treat in both healthy individuals and in those with serious diseases. Nearly 70% of smokers say they want to quit, and nicotine dependence is considered a chronic relapsing disorder. Negative affect, particularly symptoms of depression or negative mood, is strongly related to higher smoking prevalence and relapse rates. MD Anderson’s Tobacco Treatment Program (TTP) In response to the great need to assist cancer patients and survivors in their efforts to stop using tobacco, in 2006 the Tobacco Treatment Program was established at MD Anderson, underwritten by funds from the State of Texas settlement with the tobacco industry. The program continues to be funded from that source, at no cost to participants. The Mission of the TTP is to implement a comprehensive tobacco-cessation and relapse prevention program for all MD Anderson patients and employees (including family members). The program is led by three faculty Directors, members of the Department of Behavioral Science: Paul Cinciripini, Ph.D., Program Director; Janice Blalock, Ph.D., Assistant Director; and Maher Karam-Hage, MD, Associate Medical Director. The program is staffed by a counseling team, a medical team, a data team and a number of research and administrative staff. The TTP provides a range of treatment options that become progressive more intense, to match the needs of each participant. Multiple options for service delivery include: Self-help educational packet and follow-up call; Motivational intervention, education and follow-up call; Telephone counseling only; and Comprehensive, individualized counseling involving in-person counseling and both in-person and telephone follow-up. This component includes pharmacotherapy and the assessment and treatment of psychiatric co-morbid disorders. In 2012, MD Anderson began automatic referral to the TTP of all patients who currently smoke or recently quit smoking for proactive assistance. The number of referrals/day more than quadrupled, from ~10/day to between 40-50/day (2012-2014 data). Recently, there has been an expansion of service to the Regional Care Centers via a Telemedicine Platform. In FY 14, 4,613 patients had a motivational interaction with program staff, including 3,639 current smokers and 974 recent quitters. The three top clinic sources were GU (16.8%), Head & Neck (14.6%) and Thoracic (14.3%). The data below are based on the subset of patients who participated in the “in-person” option. In terms of demographics: Ethnicity – 75.3% non-Hispanic white; 12.9% black/African-American; 6.9% Hispanic; and 4.9% other; Gender – 52.0% female and 48.0% male; Location – 56.1% Houston Metro area; Mean age – 55.7 years; Mean number of cigarettes smoked/day – 15.1; number of years smoked – 32.7. Psychiatric co-morbidity – 12% alcohol abuse, 13% major depression, 11% other depression, 13% anxiety, and 8% panic disorder; 61% no psychiatric disorder. Between 2006 and 2013, a cohort of 3404 individuals reached the 9 month time point since completing their initial individual consultation with TTP providers. Self-reported 7 day point prevalence abstinence information was determined for two analyses - Intent–To-Treat (ITT, all patients, excluding deceased) and Respondent-Only (RO, only those patients who responded to follow-up). Response rates for the RO analysis were high – 89% at 3 months, 83% at 6 months, and 76% at 9 months). The RO analysis was undertaken because patients cannot be reached at follow-up for reasons other than relapse to smoking, including illness, successful cessation, and other personal concerns. The ITT analysis utilized the traditional conservative approach of representing missing data as smoking. The 7 day point prevalence abstinence rates for ITT and RO analyses, at follow-up, were: 3 months – ITT 41.1%, RO 46.0% 6 months – ITT 39.1%, RO 47.2% 9 months – ITT 35.1%, RO 46.2% These data compare favorably with those of smoking cessation studies in the general population, using both pharmacotherapy and counseling. In conclusion, the MD Anderson Cancer Center seeks to reduce tobacco use and its adverse consequences in its own patient and employee population and in a set of new initiatives to extend its expertise throughout the Texas university system and institutions that serve vulnerable populations who consume tobacco (to be presented at IASLC).

Abstract:
Better understanding of tobacco control assists clinicians with individual patient care and with opposition to an industry wtih resources and motivation to undermine health policy. Modern tobacco control is anchored in the WHO Framework Convention on Tobacco Control[1] which advocates effective policies including plain packaging legislation, widespread smoking bans and control of advertising. Tobacco control policies, despite apparent simplicity, are complex to implement and vulnerable to attack. The tobacco industry anticipates and undermines much policy change. To match this, tobacco control needs to be sophisticated, robust and anticipate the tobacco industry. Article 5.3 of the FCTC calls for protection of tobacco control against attack. Clinicians may improve smoking cessation with an understanding of current tobacco control. Many tobacco control strategies are effective, particularly tobacco taxes, plain packaging and smoking bans[2]. Tobacco taxes can have a rapid, demonstrable and predictable effect on smoking rates, both over time and in comparisons between countries[3][,][4 ][5]. Taxes have recently been increased in China[6]. Tobacco taxation can be complex and multilayered, with different tax structures having varying impact on the price of cigarettes and therefore smoking rates[4]. Plain packaging, now in place in Australia, the UK and Ireland, has emerging effects on smoking rates and attitudes to smoking[7]. Smoking bans can have a marked effect on smoking rates[2]. Keeping tobacco “out-of-sight” has had an impact; recent Australian data (where post-plain packaging smoking rates have fallen by almost 3%[8]) show discernible changes in cigarette pack display and active smoking at outdoor venues[9]. Tobacco control strategies are complex to implement. Local strategies, while relatively straightforward conceptually, can be vulnerable to opposition from the tobacco industry. The globalization of the tobacco epidemic, with internationalization of tobacco companies, makes the effects of trade liberalisation, trade agreements and foreign investment very influential on tobacco control and regulation[10]. Strategies which appear to be locally driven, such as smoking bans, advertising bans and modifications in packaging can suffer from intervention at a global level, such as challenges to Australia’s plain packaging legislation, a domestic health policy challenged by Phillip Morris Asia to the High Court of Australia[11]. The tobacco industry uses complex strategies to oppose tobacco control. The industry anticipates legislation and exploits international legal processes to oppose health policy implementation, as exemplified by Ukraine’s incongruous opposition to Australia’s introduction of plain packaging, now abandoned[12]. Trade agreements may facilitate this sort of legal exploitation; the planned TPPA, an agreement under negotiation between 12 Pacific Rim countries including the USA and Australia, includes investor state dispute settlement (ISDS) provisions that assist foreign investment to oppose policy that adversely affects their interests[10]. The tobacco industry can be difficult to separate from the modern economy, with wide infiltration of financial systems such as superannuation[13] and governments compromised by ownership of tobacco industries as in China[14] and Vietnam[15]. Tobacco control strategies require thought, tenacity, political will and flair to match the efforts of an industry powerfully motivated towards profit. Clinicians may benefit from understanding tobacco control. Tobacco cessation, a component of which is prevention of uptake, can be understood in this context. Tobacco tax increases have been shown to predict quitline use which gives clinicians an opportunity to intensify tobacco cessation treatment[16]. The FCTC divides tobacco control into reduction of demand (tobacco cessation) and reduction in supply. Reduction in demand results most clearly from tobacco cessation, addressing nicotine dependence and habit. Reduction in supply can have an impact on demand too, with evidence that advertising bans, smoking bans and plain packaging change the attitudes of smokers[17]. Placing tobacco cessation in the context of tobacco control may give the smoker and the physician more control and may enhance quit rates and reduce uptake. Tobacco control is much more complex than it first appears. The context of the WHO FCTC is the best basis on which build an understanding of the modern paradigm of control. Local strategies are essential to reduce demand. Global control strategies are pivotal in reducing supply. Individual cessation strategies, particularly the duration and intensity of the treatment of nicotine addiction may be more successfully implemented with an understanding of tobacco control. References: 1. WHO | WHO Framework Convention on Tobacco Control. WHO at 2. Levy, D. T., Chaloupka, F. & Gitchell, J. The effects of tobacco control policies on smoking rates: a tobacco control scorecard. J. Public Health Manag. Pract. JPHMP 10, 338–353 (2004). 3. Van Hasselt, M. et al. The relation between tobacco taxes and youth and young adult smoking: What happened following the 2009 U.S. federal tax increase on cigarettes? Addict. Behav. 45, 104–109 (2015). 4. Shang, C., Chaloupka, F. J., Zahra, N. & Fong, G. T. The distribution of cigarette prices under different tax structures: findings from the International Tobacco Control Policy Evaluation (ITC) Project. Tob. Control 23, i23–i29 (2014). 5. Hill, S., Amos, A., Clifford, D. & Platt, S. Impact of tobacco control interventions on socioeconomic inequalities in smoking: review of the evidence. Tob. Control 23, e89–e97 (2014). 6. China hikes cigarette tax in anti-smoking drive. Reuters (2015). at 7. Wakefield, M. et al. Australian adult smokers’ responses to plain packaging with larger graphic health warnings 1 year after implementation: results from a national cross-sectional tracking survey. Tob. Control 24, ii17–ii25 (2015). 8. Ageing, A. G. D. of H. and. Tobacco key facts and figures. at 9. Zacher, M. et al. Personal pack display and active smoking at outdoor café strips: assessing the impact of plain packaging 1 year postimplementation. Tob. Control 24, ii94–ii97 (2015). 10. Faunce, T. A. & Townsend, R. The Trans-Pacific Partnership Agreement: challenges for Australian health and medicine policies. Med. J. Aust. 194, (2011). 11. Department, A.-G. Tobacco plain packaging—investor-state arbitration. at 12. seatca. Ukraine drops lawsuit against Australia over plain-packaging tobacco laws, WTO says. Southeast Asia Tobacco Control Alliance at 13. Walsh, R. A., Tzelepis, F. & Stojanovski, E. Australian superannuation funds and tobacco investments: Issues for DAR readers. Drug Alcohol Rev. 28, 445–446 (2009). 14. Lv, J. et al. Implementation of the WHO Framework Convention on Tobacco Control in mainland China. Tob. Control 20, 309–314 (2011). 15. Higashi, H., Khuong, T. A., Ngo, A. D. & Hill, P. S. The development of Tobacco Harm Prevention Law in Vietnam: stakeholder tensions over tobacco control legislation in a state owned industry. Subst. Abuse Treat. Prev. Policy 6, 24 (2011). 16. Keller, P. A., Greenseid, L. O., Christenson, M., Boyle, R. G. & Schillo, B. A. Seizing an opportunity: increasing use of cessation services following a tobacco tax increase. BMC Public Health 15, (2015). 17. Wakefield, M. A. et al. Time series analysis of the impact of tobacco control policies on smoking prevalence among Australian adults, 2001–2011. Bull. World Health Organ. 92, 413–422 (2014).

Abstract:
Dr. Cummings is currently a Professor in the Department of Psychiatry & Behavioral Sciences at the Medical University of South Carolina (USA) and co-leader of the Hollings Cancer Center Tobacco Research Program. He is widely recognized for his international research on smoking behavior, product marketing and consumer perceptions, and the influence of cigarette design on smoking behavior. He is the co-chair of the International Association for the Study of Lung Cancer’s (IASLC) sub-committee on tobacco control and smoking cessation and helped IASLC develop its policy statement on electronic cigarettes (1). This session will describe the evolution of the nicotine delivery market, especially with the explosive growth of vaporized nicotine products (referred to throughout this application as VNPs which includes e-cigarettes, also referred to here as ENDS – Electronic Nicotine Delivery Systems, pressurized aerosol nicotine products, and heat no-burn tobacco products), which may represent a new paradigm for tobacco control by ostensibly offering smokers an opportunity to obtain nicotine in ways that do not cause the extreme risks for such a broad spectrum of smoking-caused diseases that make tobacco smoke the leading cause of premature death in high-income nations (2-4). The rapidly growing demand for VNPs seen in many countries suggests that these products are already having an impact on cigarette consumption today (5-6). Despite this unpromising history of harm reduction products, VNPs, of which e-cigarettes are the best know, represent a new generation of alternatives that show some promise for eventually displacing cigarettes and possibly offering real harm reduction (7). This presentation will provide an overview of e-cigarettes and other VNP products, will present data on who is using these products, whether the products can help smokers quit, and discuss safety concerns (8-9). Finally, the presentation will also provide some practical advice on how to talk to your patients about e-cigarettes (10). References 1) Cummings KM, Dresler CM, Field JK, Fox J, Gritz ER, Hanna NH, et al. E-cigarettes and cancer patients. Journal of Thoracic Oncology. 2014;9(4):438-41. 2) Abrams DB. Promise and peril of e-cigarettes: can disruptive technology make cigarettes obsolete? JAMA 2014;311(2):135-6. 3) Cahn Z, Siegel M. Electronic cigarettes as a harm reduction strategy for tobacco control: a step forward or a repeat of past mistakes? Journal of Public Health Policy.2011;32(1):16-31. 4) Fiore MC, Schroeder SA, Baker TB. Smoke, the chief killer--strategies for targeting combustible tobacco use. NEJM. 2014;370(4):297-9. 5) Gravely S, Fong, GT., Cummings, KM., Yan, M., et al. Awareness, trial, and current use of electronic cigarettes among 10 countries: Findings from the ITC Project IJERPH. 2014;11:11691-704. 6) Yong HH, Borland R, Balmford J, McNeill A, et al. Trends in E-Cigarette Awareness, Trial, and Use Under the Different Regulatory Environments of Australia and the United Kingdom. Nicotine Tob Res (2014) doi: 10.1093/ntr/ntu231 7) Sweanor D, Yach D. Looking for the next breakthrough in tobacco control and health. South African Medical Journal. 2013;103(11):810-1. 8) McRobbie H, Bullen C, Hartmann-Boyce J, Hajek P. Electronic cigarettes for smoking cessation and reduction. The Cochrane database of systematic reviews. 2014; 12:CD010216. 9) Hajek P, Etter JF, Benowitz N, Eissenberg T, McRobbie H. Electronic cigarettes: review of use, content, safety, effects on smokers and potential for harm and benefit. Addiction. 2014;109(11):1801-10. 10) Borderud SP, Li L, Y, Burkhalter JE, Sheffer CE, Ostroff JS. Electronic Cigarette Use Among Patients With Cancer. Cancer, 2014; 120(22):3527-35.

Abstract:
The cancer anorexia-cachexia syndrome (CACS) is a significant clinical problem, affecting upwards of half of all patients with cancer, and causing at least 20% of deaths in the general cancer population. An international expert consensus grouprecently defined cancer anorexia-cachexia as “a multifactorial syndrome characterized by an ongoing loss of skeletal mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment” [1]. Its impact is particularly significant in lung cancers, where it is present in 60% of patients at diagnosis; in all stages of NSCLCa patients, 5 kg of weight loss reduced survival rates by more than 40%. Systemic inflammation, reduced food intake and altered metabolism contribute to loss of muscle mass and body weight reduction [2,3]. CACS is associated with fatigue and a reduction in physical functioning, quality of life (QoL), tolerance and response to anticancer therapy, and survival [1,4,5,6]. The condition is further compounded by its under-recognition, with CACS often present even in the absence of weight loss and at times obscured by obesity [5]. CACS may be preceded by muscle loss and may be exacerbated by anticancer therapies. It is the final common pathway in people with advanced cancer leading to death unless some other process supervenes. The most prominent feature of CACS is its nonresponsiveness to existing treatment approaches, which have included unsuccessful use of nutritional supplements, appetite stimulants, 5-hydroxytryptamine-3 (5-HT3) antagonists and cyclooxygenase-2 (COX-2) inhibitors [2]. American guidelines are aimed at the delivery of optimal nutrition management [7], with those of organizations such as the National Comprehensive Cancer Network lacking specific guidance on pharmacologic treatments [8]. The European Palliative Care Research Collaborative (EPCRC) offers clinical guidance on drug treatments for cancer cachexia [9], but is limited in available advice due to the lack of widely effective and safe agents. There is a vast unmet medical need for this debilitating syndrome. While CACS continues to be an issue that impacts many cancer patients, headway is being made in the development of drugs that can significantly improve quality of life. Some investigational agents have shown potential in completed Phase II or III studies of patients with CACS. During this session we will review recent clinical trial evidence for these agents. Other developmental headway is being made in rapid identification of people at risk for CACS and/or requiring treatment, and point of care clinical decision support to optimize treatment approach. The use of aggregating clinical, biological and patient-reported data and development of specific predictive models are leading to personalized symptom control. In totality, the industry is making progress in the treatment of CACS, and there continues to be vast opportunity to further improve in the future. 1 Fearon K, Strasser F, Anker SD et al.Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 12(5), 489–495 (2011). 2 Suzuki H, Asakawa A, Amitani H, Fujitsuka N, Nakamura N, Inui A. Cancer cachexia pathophysiology and translational aspect of herbal medicine. Jpn. J. Clin. Oncol. 43(7), 695–705 (2013). 3 Dodson S, Baracos VE, Jatoi A et al. Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies. Annu. Rev. Med. 62, 265–279 (2011). 4 Kumar NB, Kazi A, Smith T et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr. Treat. Options Oncol. 11(3–4), 107–117 (2010). 5 Fearon K, Arends J, Baracos V.Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. Oncol. 10(2), 90–99 (2013). 6 Ross PJ, Ashley S, Norton A et al. Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br. J. Cancer. 90(10), 1905–1911 (2004). 7 August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. J.P.E.N. J. Parenter. Enteral. Nutr. 33(5), 472–500 (2009). 8 National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Palliative Care 2013. www.nccn.org/professionals/physician_gls/pdf/palliative.pdf (Accessed 14 November 2013). 9 European Palliative Care Research Collaborative. European Clinical Guidelines: Clinical practice guidelines on cancer cachexia in advanced cancer patients with a focus on refractory cachexia 2010.

Abstract:
An international consensus group has defined cancer cachexia as “a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment”.[1] Fifty percent of patients with lung cancer have muscle wasting at diagnosis and this muscle loss increases throughout their disease course. Metabolic changes associated with cachexia lead to decreased protein stores, altered metabolism, and impaired immunity which clinically can be associated with anorexia and fatigue, weakness, and decreased physical performance. Cancer patients with muscle wasting are less able to tolerate chemotherapy, have worse treatment outcomes, loss of independence and overall shorter survival. Effective prevention and treatment strategies are needed. Although muscle wasting is central to the process of cachexia, our clinical diagnostic criteria are largely based on weight. Standard definitions for cancer cachexia include either weight loss > 5% of body weight or a body mass index (BMI) of < 20 kg/m[2] with 2% weight loss. More exact measurements of muscle and muscle wasting can be made through imaging techniques assessing lean body mass (LBM). Dexascan has been used to evaluate LBM, but is not routinely used in clinical practice currently. A very promising technique involves the use of standard computerized tomography in conjunction with a software program which accurately delineates skeletal muscle from adipose tissue, with excellent correlation with other techniques.[2] Application of this technique to a large population of patients with advanced lung and GI cancer has demonstrated a high prevalence of muscle wasting (sarcopenia) in patients with a BMI <20, but also documents a prevalence of sarcopenia of 40-60% in patients with normal BMI. At least 20% of patients with an elevated BMI also have muscle wasting (sarcopenic obesity). Studies in this population with sarcopenia regardless of baseline weight have shown increased toxicity of chemotherapy treatments, shorter time to tumor progression and decreased overall survival. Despite the frequency and severity of cancer cachexia, broad based accepted clinical practice guidelines are limited. The European Palliative Care Research Collaborative consensus recommendations[3 ]include enteral nutritional therapy, nutritional counseling, physical therapy, and psychotherapeutic interventions for quality of life benefit. However, specific pharmacologic therapies, to date, have had little established benefit. For example, Megesterol stimulates appetite and weight gain in some patients, but without an increase in muscle mass, and has significant toxicity regarding venous thromboembolic events. The most effective strategy would be effective anticancer therapy. However, in advanced cancer where our treatments may only be partially effective or ineffective, toxicities are frequent and add to the overall wasting syndrome. Improved biologic understanding of muscle wasting has led to new therapeutic approaches that are under development. One category of agents interferes with biologic signaling and cytokines that may lead to muscle atrophy, including myostatin/activan inhibitors, anti-TNFa and anti-IL6 agents, among others. Several of these agents are in early phase clinical trials. A second approach has been to target pathways that directly stimulate hypertrophy of muscle. Two of these agents have been studied in phase 3 trials in advanced lung cancer patients, enobosarm and anamorelin. Enobosarm, a selective androgen receptor modulator, has been developed to have direct action on muscle, but without androgenic effects on prostate or virilization. Phase 2 trials have shown a clear increase in LBM and physical function, leading to two randomized phase 3 trials in patients with advanced lung cancer receiving chemotherapy. These studies have shown a clear impact on improvement in LBM in both trials, but an inconsistent effect on function as measured by stair climb power between the 2 studies.[4] As predicted by the mechanism of action, no change in appetite or body weight was noted. A second approach for muscle hypertrophy is Anamorelin, a ghrelin receptor agonist. Ghrelin stimulates appetite, increase in body weight and body mass and metabolism. Randomized phase 3 trials of Anamorelin in advanced lung cancer patients have demonstrated an increase in body weight, along with LBM, but no improvement in functional assessment as measured by hand grip strength.[5] Quality of life improvements have also been seen in the study population with Anamorelin. Clinical trial results of both enobosarm and Anamorelin will be reviewed and compared in more detail, as well as potential implications for future development of these and other agents, leading to more effective therapeutic interventions for patients with cancer cachexia in the future. References Ferron K, et al. Lancet Oncol. 12:485-495, 2011. Prado C, et al. Lancet Oncol. 9:629, 2008. European Palliative Care Research Collaborative, 2011, www.epcrc.org. Crawford, J. J Clin Oncol 32:5s, 2014 (suppl; abstr 9618). Temel J, Abernethy A, et al. ASCO Proceedings, Abstract 9500, 2015.

Background:
MPM median overall survival (OS) did not exceed 13 months with pemetrexed-platinum doublet, with virtually no surviving patients at 5 years. Vascular endothelial growth factor is a potent mitogen for MPM cells.

Methods:
In this French multicenter randomized phase 3 trial, eligible patients had unresectable, histologically proved MPM, age < 76, no prior chemo, PS 0-2, no thrombosis, nor bleeding. Randomized patients (1:1) received pem 500 mg/m2, CDDP 75 mg/m2 at D1, with (arm B) or without bevacizumab (arm A), 15 mg/kg Q21D, for 6 cycles. Arm B non-progressive patients received bevacizumab maintenance therapy until progression or toxicity. Primary endpoint was OS. 445 patients were to be randomized, and 385 events observed, to show a significant OS improvement, with 80% statistical power, 5% a-risk.

Results:
From Feb. 2008 to Jan. 2014, 448 patients were included in 73 centers. Males: 75.4%, median age: 65.7 years (range 34.7-75.9), PS 0-1: 96.7%. The IDMC recommended a second interim analysis after 85% of events. On 01-Jan-2015, the duration since last news was < 30 days in 105 out of 106 still living patients. Overall survival was significantly longer in the experimental arm (median: 18.8 months, 95%CI[15.9-22.6] vs. 16.1 months, 95%CI[14.0-17.9] for the reference arm, (adj.HR = 0.76, 95%CI[0.61; 0.94], p = 0.012). With only 46/448 non-progressive patients at the date of analysis, median PFS was 9.6 months, 95%CI[8.5-10.6] in bevacizumab arm vs. 7.5 months, 95%CI[6.8-8.1] (adj.HR = 0.62, 95%CI[0.50-0.75], p < 0.0001). G3-4 hematological toxicities did not significantly differ in the two arms (49.5% vs. 47.3%). Significantly more G3 proteinuria (0.0 vs. 3.1%), G3 hypertension (0.0 vs. 23%), G3-4 arterial thrombotic events (0.0 vs. 2.7%) were observed in bevacizumab arm. QOL and exploratory biomarkers studies will be also presented at time of the meeting.

Conclusion:
Bevacizumab addition to pemetrexed/cis-platin provides a significantly longer survival in pts with MPM, with acceptable toxicity, making this triplet a new treatment paradigm.

Background:
Anetumab ravtansine (BAY 94-9343) is a novel fully humanized anti-mesothelin IgG1 antibody conjugated to a ravtansine, a maytansine derivative DM4 antitubulin cytotoxic agent. We report results from a phase I study evaluating the safety, PK and tumor response in patients (pts) with advanced solid tumors treated with anetumab, with a particular focus on patients with mesothelioma.

Methods:
Anetumab was given IV every 21 days (q3w) in 77 pts: 45 pts in 10 dose escalation cohorts from 0.15 to 7.5 mg/kg (21 mesothelioma, 9 pancreatic, 5 breast, 4 ovarian, 6 other), and 32 pts in 2 expansion cohorts (12 mesothelioma and 20 ovarian); 38 pts were treated at MTD in escalation and expansion cohorts (16 mesothelioma, 21 ovarian, 1 breast). Clinical and laboratory safety assessments were made on D1, D8 and D15 in C1-C3 and on D1 in subsequent cycles. Tumor assessments were made q6wks up to C8 and q12wks thereafter. Mesothelin expression in archival tumor samples was assessed retrospecively by IHC (SP74, Ventana).

Results:
Thirty-two males and 45 females were treated [mean age 62 yrs (range, 18-84 yrs), body weight 77 kg (44-113 kg), ECOG ≤1, median prior cytotoxic regimens: overall 4 (1-9), mesothelioma 1 (1-4)]. Non-tolerated anetumab dose was 7.5 mg/kg (DLTs: 1 pt with G2 keratitis and G3 neuropathy, 1 pt with G4 keratitis and G2 neuropathy). Anetumab MTD was 6.5 mg/kg (DLT: G3 AST increase). Only one DLT occurred at doses below MTD (G3 hyponatremia, 5.5 mg/kg). No drug-related deaths and few drug-related SAEs (7 total and 5 at MTD) were reported. Seventeen of 38 (45%) pts total or 7 of 16 (44%) mesothelioma pts at MTD had drug-related AE requiring dose reduction (G1-4 keratitis, G2-3 neuropathy, G3 fatigue, anorexia, asthenia, diarrhea, N&V, AST increase). LFT increases were the most common drug-related laboratory abnormality at MTD: AST in 7 pts (2 G3), ALT in 6 pts (no G3), alkaline phosphatase in 4 pts (one G3) and bilirubin increase in 1 pt (no G3). There were no drug-related G3 hematological abnormalities at any dose. Fourteen of 38 (37%) pts total or 4 of 16 (25%) mesothelioma pts at MTD had G1-4 keratitis (worst G3-4 in 3 pts, blurred vision in 10, dose reduction in 8, dose delay in 11, all fully reversible). Anetumab at the MTD showed a PR in 6 pts (19%) and SD in 18 pts (47%) overall. Five of 16 (31%) mesothelioma pts at the MTD had durable PR (>600 days in 4 pts) and 7 (44%) had SD. Five PRs occurred in 11 mesothelioma pts who received anetumab as second line treatment (45% response rate).

Conclusion:
Anetumab at the MTD (6.5 mg/kg) showed encouraging efficacy with durable PR in pts with advanced mesothelioma. At the MTD, all drug-related AEs were reversible and non-life-threatening but required dose reduction in about half of pts, most commonly due to G1-4 keratitis and G2-3 peripheral neuropathy. Given this benefit-risk ratio, the recommended phase II dose of anetumab in second line treatment of advanced mesothelioma is 6.5 mg/kg IV q3w.

Background:
Targeting the programmed death receptor 1 (PD-1) pathway is a valid therapeutic target in a variety of solid tumors and hematologic malignancies. Pembrolizumab (MK-3475) is a potent, highly selective humanized monoclonal antibody against PD-1 and is approved in the United States for the treatment of advanced melanoma that progressed following ipilimumab and, if BRAF[V600] mutant, a BRAF inhibitor. We have previously reported preliminary antitumor response and safety data for pembrolizumab in patients with MPM enrolled in the KEYNOTE-028 study. Here we present updated safety and efficacy data, including survival, for these patients.

Methods:
KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Other key eligibility criteria included measurable disease, failure of standard therapy, ECOG PS 0-1, adequate organ function, and no autoimmune disease or interstitial lung disease. PD-L1 positivity was defined as expression in ≥1% of tumor cells by IHC at a central laboratory. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end point was the ORR. Secondary end points included safety and tolerability and PFS.

Results:
Of the 84 patients with MPM screened for PD-L1 expression, 38 (45%) patients had PD-L1–positive tumors. Of these 38 patients, 25 met the eligibility criteria and were treated with pembrolizumab. As of March 20, 2015, ORR is 28% (n = 7); 12 (48%) patients had stable disease, resulting in a disease control rate of 76%. In the 15 patients with only 1 prior line of therapy, ORR and DCR are 20% and 73%, respectively. Responses are durable, and 10 (40%) patients remain on treatment (duration, 24+ to 36+ weeks). With a median follow-up duration of 8.6 months, median PFS is 5.5 months (95% CI, 3.4-NR), and the 6-month PFS rate is 49.4%. No new safety signals were observed. 15 (60%) patients experienced a drug-related adverse event (DRAE), including 3 (12%) who experienced grade 3-4 DRAEs. Only 2 patients required dose interruption because of immune-related adverse events (transaminitis and uveitis [n = 1 each]). There was no treatment-related mortality, and no patients discontinued because of DRAEs.

Conclusion:
Single-agent pembrolizumab has significant clinical activity in patients with PD-L1–positive MPM. The durability of responses and the 49.4% 6-month PFS rate in this pretreated patient population warrants further investigation. Updated safety and survival data, as well as the correlation of antitumor activity with the level of PD-L1 expression, will be available at the time of presentation.

Abstract not provided

Background:
Limited treatment options exist for patients with thymic malignancies (TM), and chemotherapy efficacy is often restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). Single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, was investigated in TM pts in this trial.

Methods:
This was an open-label single drug trial at 2 institutions. Eligible pts had TM (thymoma (T) or thymic carcinoma (TC)) with progression or relapse after at least 1 prior chemotherapy regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m[2] IV days 1-3 repeated in 3-week cycles.

Results:
From 7/11 to 4/14, a total of 33 patients (14T/19TC) were enrolled. There were 14 women and 19 men; age range of 30-81 years; 9 Asian, 1 African-American, 1 Hispanic and 22 non-Hispanic White pts. A high rate of febrile neutropenia (FN) led to an amended starting dose of 35 mg/m[2] days 1-3 repeated in 3-week cycles. In total, 7 pts experienced FN with 1 related death. Other grade 3/4 related events included: thrombocytopenia (n=2), neutropenia without fever (n=3), hyponatremia (n=2), hypokalemia (n=2), anemia (n=7), lethargy/fatigue (n=7), perirectal abscess (n=2), palmar-plantar erythrodysesthesia (n=3), syncope (n=2), venous embolism (n=2), and 1 pt each with sepsis, oral abscess, mucositis, chest pain, and epigastric pain. Other toxicities were generally mild and well tolerated. No significant changes in LVEF were noted on serial echocardiograms. There were 6 partial responses (4T/2TC), 21 with stable disease, and 4 with progressive disease (PD) or death at or before first assessment for a response rate (RR) of 18% and a disease control rate (DCR) of 88% (29%/11% RR in T vs TC and 100%/78% DCR in T vs TC). All but 5 patients received at least 4 cycles, and 15 tolerated >10 cycles, with 36 cycles as the highest number to date. Five patients remain on therapy.

Conclusion:
Amrubicin, at 35 mg/m[2 ]IV days 1-3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with thymoma and thymic carcinoma with an 18% RR and no unexpected toxicity. Response rate and disease control rate was higher in the thymoma patients compared to the thymic carcinoma patients. Further exploration of amrubicin as a single drug or in combination is warranted in thymic malignancies.

Background:
We conducted a prospective phase II study of cisplatin plus Cremorphor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors (TETs) in order to determine the efficacy and tolerability of the combination.

Methods:
Patients were treated with cisplatin (70 mg/m[2]) and Genexol-PM (230 mg/m[2]) every three weeks for a maximum of six cycles. The primary end point of this study was objective response rate (ORR), and secondary end points included toxicity, progression-free survival (PFS), overall survival (OS), correlation between early [18]F-FDG PET/CT response and PFS, and correlation between baseline FDG uptake and histology.

Results:
Forty-two patients with unresectable thymoma (n=14) or thymic carcinoma (n=28) were enrolled. The median age was 59 years (range, 25-77) and 30 (71%) patients were male, and 39 (93%) had an ECOG PS of 1. The median number of treatment cycles was six (range 1-6). For 40 assessable patients, the ORR was 62.5% (95% confidence interval [CI] 47.6-77.4) with rates of 46% (95% CI 23.3-76.9) for advanced thymoma (n=13) and 70% (95% CI 52.0-82.1) for thymic carcinoma (n=27). With a median follow-up of 15.5 months, the median PFS was 9.8 months (11.4 months for thymoma vs. 8.1 months for thymic carcinoma, with median follow-ups of 16.1 vs. 15.5 months, respectively). The two-year OS was 77.9% for thymoma and 65.9% for thymic carcinoma. There were no treatment-related deaths. The most common grade 3 and 4 treatment-related adverse event was neutropenia in 11 patients (26%). Sixteen (38%) patients experienced grade 2 hypersensitivity reactions. There was no correlation between early PET response and PFS, but tumor histology (thymoma vs. thymic carcinoma) was correlated with SUV~max~ before chemotherapy.

Conclusion:
These data suggest that the combination of cisplatin and Genexol-PM is highly effective and tolerable for the treatment of unresectable TETs, especially in patients with thymic carcinoma.

Background:
Preoperative CT imaging assists in the management of thymic malignancies (TMs), discerning resectability and the need for neoadjuvant chemotherapy. Here, we examine preoperative CT imaging characteristics in relation to the newly proposed IASLC/ITMIG TNM pathologic staging system for TMs.

Methods:
Inclusion criteria for this retrospective study were as follows: 1) diagnosis of thymoma, thymic carcinoma, or thymic carcinoid, 2) definitive primary surgery performed at Stanford University, and 3) pretreatment CT imaging available for review. From 01/1997-03/2015, we identified 119 TM patients who had surgery, and 47 TM patients met all inclusion criteria. The most common reason patients were excluded was for either a missing pretreatment CT (outside imaging not routinely uploaded until 2008) or having surgery for biopsy or recurrent disease. The radiologist (D.T.) was blinded to clinical data, and examined baseline CT imaging per the International Thymic Malignancy Interest Group (ITMIG) standard report terms: contour, calcification, internal density, size of longest diameter, infiltration of mediastinal fat, abutment of mediastinal vessels, vascular endoluminal invasion, abutment/invasion of mediastinal structures, elevated hemidiaphragm, pleural nodules, pleural effusion, mediastinal lymph node enlargement. A univariate analysis and a Lasso regularized general transformation prediction model were performed with all variables to examine the association with pathologic IASLC/ITMIG TNM stage (p<0.05 significant; p<0.10 trend).

Results:
Of 47 TM patients, 9 received neoadjuvant chemotherapy. IASLC/ITMIG pathologic stage included 35 I, 1 II, 7 IIIA, 2 IIIB, 1 each of IVA and IVB. By T stage, there were 36 T1 (encapsulated or unencapsulated+extension into mediastinal fat or mediastinal pleura), 1 T2 (pericardium), 8 T3 (lung, brachiocephalic vein, SVC, chest wall, phrenic nerve, or hilar pulmonary vessels) and 2 T4 (aorta, arch, main pulmonary artery, myocardium, trachea, or esophagus). Only one patient each had N2 and M1a disease (separate pleural or pericardial nodule). Histologies included 5 A/micronodular thymoma, 13 AB, 5 B1, 14 B2, 5 B3, and 5 C/carcinoid. There was a significant positive association with aggressive histology and higher stage (OR=10.0;p=0.02). The following CT characteristics had a statistically significant positive association with higher stage (stage 1 vs. others, T1 vs. others) in a univariate analysis: lobulated contour, infiltration of mediastinal fat, invasion of mediastinal structures, vascular endoluminal invasion, elevated hemidiaphragm. There was a trend for higher stage with larger size and the presence of calcification. In a prediction model, vascular endoluminal invasion and elevated hemidiaphragm were the most important for predicting higher stage followed by invasion of mediastinal structures>abutment of mediastinal vessels>calcification>lobulated contour> mediastinal lymph node enlargement. When excluding clearly invasive CT characteristics, only abutment of mediastinal vessels was significantly associated with higher stage.

Conclusion:
Preoperative CT characteristics, especially those indicating clear invasion, are most useful in delineating more advanced stage disease by ITMIG/IASLC criteria in TMs. Other primary tumor characteristics including contour, calcification, and abutment of mediastinal vessels are moderately helpful. This study is limited by the small sample size, the predominance of stage I disease, the inclusion of patients who received neoadjuvant chemotherapy, and the inherent bias of a definitive surgically treated population.

Abstract not provided

Background:
Despite imaging advances, differentiating pleural malignancy (PM) from benign pleural disease (BPD) remains challenging, particularly early-stage Malignant Pleural Mesothelioma (MPM), which can look similar to benign asbestos-related pleural effusion (BAPE). We report the diagnostic performance of a novel Magnetic Resonance Imaging (MRI) biomarker of PM - Early Contrast Enhancement (ECE).

Methods:
24 patients with suspected PM were recruited prospectively (January 2013-November 2014). All underwent contrast-enhanced Computed Tomography (CT) scanning and Thoracoscopy. 3-T Pleural MRI was performed prior to Thoracoscopy (median 4 (IQR 4–8) days). Imaging methodology was developed using patients 1-6. In 18 patients, T1-weighted 3D-spoiled-gradient-echo sequences were acquired coronally at baseline, 40 and 80 seconds and 4.5, 9 and 13.5 minutes after intravenous Gadobutrol contrast. Mean signal intensity (SI) of parietal pleura at each time-point was derived from 15 regions of interest placed by two respiratory physicians. ECE on the resulting SI/time curve was defined objectively as an early peak (at/before 4.5 minutes) and/or late fall in mean SI (Figure 1). CT and MRI scans were assessed for morphological features of PM by two thoracic radiologists. All analyses were blinded. Diagnostic performance was assessed using contingency tables. Inter- and intra-observer agreement was assessed using Cohen’s kappa statistic. Figure 1



Results:
Median patient age was 73 (IQR 70–80) years. 75% (n=18) were asbestos-exposed. ECE was present in 10/11 patients with PM (MPM (10); lung cancer (1)). The false negative case had MPM. 1 MPM case was initially diagnosed with BAPE but reclassified as MPM after developing progressive PM, consistent with their initial MRI result (ECE present). ECE was absent in 6/7 patients with BPD (BAPE (4), fibrothorax (2), TB (1)). The false positive case had TB. Table 1 summarises diagnostic performance.

Table 1: Diagnostic performance and reproducibility of ECE, CT morphology and MRI morphology in pleural malignancy

	Sensitivity (%)	Specificity (%)	Negative Predictive Value (%)	Positive Predictive Value (%)	Inter-observer agreement	Intra-observer agreement
CT Morphology	90	50	80	69	0.753	Not done
MRI Morphology	91	71	83	83	0.727	Not done
MRI Early Contrast Enhancement	91	86	86	91	0.766	1.000

Conclusion:
ECE appears a sensitive and specific objective biomarker of PM, out-performing subjectively-defined CT and MR morphology. SI/time curves for ECE assessment can be generated reproducibly in patients with minimal pleural thickening, suggesting potential utility as a non-invasive biomarker for the early detection of MPM or low-volume metastatic PM.

Background:
There is no established diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein on the surface of many cell types that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 in patients with MPM.

Methods:
The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. Soluble CD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. To make a comparative review of the usefulness of sCD26, we determined serum and pleural fluid soluble mesothelin-related peptides (SMRP). SMRP was measured by the chemiluminescent enzyme immunoassay (CLEIA) based on 2-step sandwich method.

Results:
Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P=0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P=0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P=0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P=0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P=0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P=0.028). Median values of serum and pleural fluid SMRP in MPM patients were 0.43 and 15.37 mmol/l, respectively. Median value of pleural fluid SMRP in epithelioid MPM was 17.28 mmol/l. Median values of serum SMRP in SPE and pleural fluid SMRP in OPD were 0.90 and 0.43 mmol/l, respectively. Pleural fluid SMRP in MPM was significantly higher than in OPD (P=0.000) and serum SMRP in MPM was significantly higher than in SPE (P=0.000).

Conclusion:
Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM.

Background:
Identifying driver mutations assists with understanding molecular aspects of cancer and development of novel drugs. The genetics of malignant pleural mesothelioma (MPM) has primarily been to date described in terms of deletions of specific chromosomal regions with CDKN2A and NF2 most commonly mutated, and more recently, evidence for a role of BAP1. The current work suggests that activation of the Integrin Linked Kinase (ILK) pathway may be oncogenic in a subset of MPM.

Methods:
Whole-genome sequencing was accomplished for 10 tumor and matched normal genomic DNA samples using a Complete Genomics platform. Tumor and normal genomes were sequenced to at least 30-fold haploid coverage, with corresponding diploid coverage of at least 99.5%. Selected candidates single nucleotide variations (SNVs) were further characterized using PCR and Sanger sequencing to identify tumor-specific single nucleotide mutations. Potential driver genes were investigated in 147 additional MPM cases by targeted resequencing. Levels of transcripts were examined in an available expression data set (Affymetrix® Human Gene 1.1 ST Array). Association of mutation status and gene expression to clinicopathologic variables was explored statistically.

Results:
Among 146 single nucleotide variants (SNVs) mapping in amino acid coding regions of annotated exons and generating non-synonymous amino acid changes, 85 were confirmed to be tumor specific. Functional enrichments of genes affected by point mutations were performed utilizing Ingenuity Pathway Analysis to identify clusters of genes annotated in pathways potentially relevant to the biology of MPM. Mutations affecting genes involved in the Integrin Linked Kinase (ILK) pathway were the most significantly (p = 4.9e-5) enriched. Specifically, 5 of 10 sequenced MPM samples showed point mutations in at least one of 6 genes of this pathway (MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A). Re-sequencing analysis of 147 MPM tumors identified 40 SNVs in these genes among 31 MPM samples (21%). Thirty-five (88%) SNVs were present in both tumor and matching normal DNA samples. In 4 samples, tumor specific mutations were identified, 3 in MYH9 (1.4%) and 2 in RHOA (1.4%) both recently proposed as genes involved in tumorigenesis. Non-epithelioid tumors expressed significantly higher levels of MYH9 (p<0.001), RHOA (p<0.001), and MYH10 (p=0.001) compared to epithelioid tumors. RHOA was more highly expressed in men than women (p=0.001). The highest quartile of MYH9 and of RHOA expression was associated with higher gender-adjusted risk of death (HR=2.23 and HR=1.95, respectively) compared to the lower three quartiles (p<0.001) by multivariate analysis.

Conclusion:
Tumor specific mutations in MYH9 or RHOA were found in six of 157 (3.8%) MPM patients. Interestingly, both MYH9 (22q13.1) and RHOA (3p21.3) reside in two chromosomal regions frequently deleted in MPM. Additional analysis is in progress to investigate the role of ILK pathway activation in MPM. These observations suggest that a sub-class of MPM may respond to therapy targeting the ILK pathway.

Abstract not provided

Background:
Local tumor recurrence is very frequent after resection of malignant pleural mesothelioma (MPM). Intracavitary chemotherapy has been shown to be a promising approach to improve local tumor control. Here, we present the results of a phase-I-dose-escalation trial with intracavitary application of cisplatin-fibrin after surgical tumor resection.

Methods:
Altogether 12 patients (75% IMIG stage III-IV) were treated with 4 different dose levels of cisplatin (11, 22, 33 and 44mg/m[2] body surface area (BSA)). Eight patients of 22, 33 and 44mg/m[2] groups received previous induction treatment with intravenous cisplatin/pemetrexed. Cisplatin-fibrin was sprayed on the surface of chest wall, diaphragm, mediastinum and lung after pleurectomy/decortication (P/D). Blood was taken before surgery and at several time points after the treatment. Tissue sampling was conducted before and at 90 minutes after the administration. Cisplatin levels were measured by inductively coupled plasma sector field mass spectrometry.

Results:
Serum cisplatin kinetics and AUC0-120 are depicted in figure 1. Induction intravenous chemotherapy contributed to >50% of total serum cisplatin levels compared to cisplatin-fibrin (figure 1B). The median AUC0-24 of the 3 patients in the highest dose level (44mg/m[2]BSA) including predoses from induction chemotherapy reached 23h*µg/g, which is still below the suggested renal toxicity risk level, 25h*µg/g (Royer 2008). Our serum cisplatin AUC levels stayed far below levels reported after intrapleural perfusion (approx. 89h*µg/g (Ried 2013)). Local cisplatin concentration in tissues varied from 12-133 (median: 36.5µg/g) and did not seem to be dose dependent. No dose limiting toxicity due to cisplatin was observed. Major morbidity was observed in 4 patients (33%). 30day- and 90day-mortality was 0%. The median follow up after surgery was 11 months (range: 5-28 months). In 8 patients receiving 11, 22, 33 mg/m[2]BSA, relapse was detected after a median freedom from recurrence (FFR) of 8 months (95% confidence interval (CI): 1-14 months). In three patients with early IMIG stage (I and II), no sign of relapse was observed at 28, 8 and 6 months after the treatment (11, 44, 44 mg/m[2]BSA, respectively). The last patient (44mg/m[2]BSA) with IMIG stage III tumor currently shows no sign of recurrence at 5 months after surgery. Figure 1



Conclusion:
The administration of intracavitary cisplatin-fibrin as high as 44mg/m[2]BSA is safe after P/D, also in combination with induction chemotherapy. Tissue cisplatin concentration was high whereas no dose limiting toxicity due to systemic distribution was detected. A confirmation of the safety and efficacy of the highest dosage, 44 mg/m[2]BSA, in a phase II trial is warranted.

Background:
Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures (SOPs) to facilitate basic and translational research is very limited. MesobanK, funded by the British Lung Foundation and the Mick Knighton Mesothelioma Research Fund, is a UK based bioresource to collect fresh tissue, blood, pleural fluid and anonymised linked clinical data to strict SOPs from patients with malignant pleural mesothelioma.

Methods:
1) To construct a tissue microarray (TMA) from 1000 cases of formalin fixed paraffin embedded pleural mesothelioma tissue linked to a clinical data set. Each case will have several cores taken to allow for tumour heterogeneity. 2) To collect 300 cases of fresh pleural mesothelioma tissue (5 samples per case), blood (whole blood, serum, plasma and buffy coat) and pleural fluid (supernatant and cell pellet) linked to a clinical data set. Longer term follow up and survival data will be provided by the UK National Cancer Registration Service. 3) To develop at least 20 new fully characterised and annotated mesothelioma cell lines. Governance MesobanK abides by all relevant UK and EU legislation regarding the collection of tissue and data. Mesobank is a member of the UK Confederation of Cancer Biobanks. Prioritisation for access to samples will be based solely on scientific merit. The project is managed by a dedicated project manager and overseen by a Steering Committee; an independent Scientific Advisory Board reviews anonymised applications for samples.

Results:
All required ethical permissions have been obtained. A secure, web-based multi-user database has been constructed for data collection. As of April 2015, 730 of the 1000 cases for the TMA have been acquired from UK pathology departments and the first part of the TMA construction is underway at the Cancer Research UK Cambridge Institute. In the first year of operation, 100 prospective cases have been banked and quality control to assess tumour percentage and necrosis in each sample is underway. Figure 1 shows weight of sample versus tumour percentage from the QC of the first 144 samples. Twenty six new cell lines have been developed and are currently being characterised. Figure 1



Conclusion:
Procurement of formalin fixed tissue for the TMA and fresh biospecimens is progressing well and MesobanK is now open for investigators to apply for tissue samples. Enquiries about tissue availability should be directed to [email protected]. An application form is available at www.mesobank.com. A cost contribution model has been developed to support on-going funding of MesobanK.

Background:
Malignant pleural mesothelioma (MPM) is a devastating malignancy with still rising incidence worldwide. Its aggressive biological behavior and therapy resistance result in a median overall survival (OS) of 9 to 17 months only. Currently, platinum-based chemotherapy in combination with antifolate agents is the standard front-line therapy for MPM and to date no molecularly targeted therapeutic approaches have been approved in the clinics. Nintedanib is an indolinone derivative that has been demonstrated to efficiently inhibit the activity of VEGFR, PDGFR and FGFR tyrosine kinase isoforms and thus to be capable to suppress angiogenesis and tumor growth. Here, we report the antitumor activity of nintedanib in MPM.

Methods:
21 MPM cell lines were treated with nintedanib and SRB assays were performed to determine the IC50 values for each cell line. 4 sensitive cell models were selected for further in vitro analysis: BrdU, TUNEL and clonogenic assays were performed to investigate the impact of the drug on the proliferation, apoptosis and colony formation capacity of MPM cells, respectively. The migratory activity of MPM cells was analyzed with 2D videomicroscopy. The downstream signaling of the target receptors was investigated by Western blot analysis. Drug interactions with cisplatin were assessed in the p31 MPM cell line and in its cisplatin-resistant subline (p31cis) by using the CalcuSyn software. The in vivo anti-MPM activity of nintedanib was studied in an orthotopic human MPM xenograft model in SCID mice. Tumor-bearing animals were treated with 50 mg/kg nintedanib daily, per os (PO) or intraperitoneally (IP) and followed for survival.

Results:
Nintedanib exerted a growth inhibitory effect on MPM cell lines in both short- and long-term viability assays. The inhibition of proliferation was observed in all MPM cell models analyzed, whereas significant apoptosis induction was only found in half of them. Migratory activity strongly decreased upon nintedanib treatment. Down-regulation of Erk1/2 phosphorylation was evident within 10 min of treatment and was present even after 24h. Nintedanib, however, had no inhibitory effect on the activation of Akt or S6. Additive, but no synergistic effect on cell viability was detected in the p31 and p31cis MPM cells when nintedanib was combined with cisplatin. In vivo, survival of PO-treated animals showed favorable trend (vs. PO control, log-rank test, p=0.059). Nintedanib significantly prolonged the survival of mice when it was administered IP (vs. IP control, log-rank test, p=0.0008).

Conclusion:
Our data suggest that nintedanib exerts antitumor activity in MPM both in vitro and in vivo and thus may represent a promising novel therapeutic option in this malignancy.

Abstract not provided