Epithelioid Histology Research Articles

Association of BAP1 alterations with malignant pleural mesothelioma treated with trimodality therapy.

8552 Background: Trimodality therapy with pleurectomy/decortication, cytotoxic chemotherapy, and adjuvant pleural intensity modulated radiation therapy (IMPRINT) is an emerging standard of care for locally advanced epithelioid mesothelioma (Rimner, Zauderer et al. JCO 2016). Some patients, however, progress rapidly and we therefore sought to identify potential predictive markers of response to this treatment. Given the putative role of BAP1 in DNA damage repair, we hypothesized that alteration in BAP1 would be associated with improved local control after radiation therapy. Methods: We identified patients previously treated at our institution with IMPRINT to a median dose of 4680cGy in 26 fractions. Targeted next generation sequencing was performed with MSK-IMPACT on archival tissue samples. Chart review was undertaken for clinicopathologic features and outcome data. Results: MSK-IMPACT testing was successfully performed on 58 patients who completed IMPRINT. The majority were male with a median age of 70 years. Ninety-seven percent had epithelioid subtype while 3% were biphasic with predominantly epithelioid histology. Median overall survival was 30.2 months with a median follow-up of 45.3 months, consistent with prior reports. Somatic BAP1 mutations were identified in 34% of the specimens. Those with BAP1 mutant tumors had a median time to local failure of 22.4 months (IQR 10.9 – 36.9 months) while those with BAP1 wild type tumors only had a median of 12.1 months (IQR 8.7-15.85 months) to local failure (p = 0.057). We identified a trend towards improved overall survival among those with BAP1 altered tumors compared to those with BAP1 wild type (HR = 0.61, p = 0.14). Conclusions: BAP1 alteration may be associated with improved duration of local control and improved overall survival after IMPRINT therapy. Further analysis and validation in a large data set is needed and a platform for identifying and validating predictive biomarkers should be included in the planned NRG randomized trial of IMPRINT.

Randomized phase 2 study of maintenance pemetrexed (Pem) versus observation (Obs) for patients (pts) with malignant pleural mesothelioma (MPM) without progression after first-line chemotherapy: Cancer and Leukemia Group B (CALGB) 30901 (Alliance).

8517 Background: Standard front-line chemotherapy for advanced MPM is (Pem and a platinum; optimal treatment duration is unknown. We performed a randomized phase 2 trial (NCT01085630) to determine if continuation of single-agent Pem after 4-6 cycles of Pem-platinum would improve progression-free survival (PFS). Methods: Eligible pts had histologically confirmed unresectable MPM, and performance status (PS) 0-1. Pts with at least stable disease following 4-6 cycles of Pem-platinum were stratified by first-line regimen (cis- or carboplatin) and histology (epithelioid versus other) and randomized 1:1 to Obs or continuation of Pem until progression. The primary endpoint was PFS. We assumed that Obs produced a median (m) PFS of 3 months (mo) and Pem would yield a 100% improvement in mPFS to 6 mo; 60 eligible pts (30 per arm) were to be randomized. Results: 72 pts from 30 sites registered 12/10-6/16. The study closed early due to slow accrual once 53 pts were randomized; 49 eligible pts (22 Obs, 27 Pem) are included in the efficacy analysis. Pt characteristics (Obs/Pem): age: median (range) 70 (39-85)/70 (52-87); male 68%/78%; PS 0 27%/33%; epithelioid histology 77%/70%; first-line cisplatin 27%/26%. A median of 4 cycles of Pem (range 1-33) was delivered; 22% of pts required dose modification. mPFS was 3 mo on Obs and 3.4 mo on Pem (hazard ratio (HR) 0.99; 95% CI: 0.51-1.90; p=0.9733). Median overall survival (mOS) was 11.8 mo for Obs, and 16.3 mo for Pem (HR 0.86; 95% CI 0.44-1.71; p=0.6737). Toxicities ≥ grade 3 on Pem included anemia 8%, lymphopenia 8%, neutropenia 4%, and fatigue 4%; there were no grade 5 toxicities. A higher baseline level of serum mesothelin related peptide (SMRP) was associated with worse PFS (HR 1.861, p=0.049). Baseline osteopontin did not significantly affect PFS (p=0.3630). Conclusions: Although it was well tolerated, maintenance Pem following initial Pem/platinum doublet chemotherapy does not improve PFS in MPM patients. High baseline SMRP was associated with shorter PFS. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01085630.

Extra-pleural pneumonectomy in the era of image-guided intensity-modulated radiotherapy.

To assess the outcome of malignant pleural mesothelioma patients treated with extra-pleural pneumonectomy (EPP) and adjuvant radiotherapy (RT), using the most advanced radiotherapeutic techniques, namely image-guided intensity-modulated RT (IG-IMRT). Fifty-four patients were analyzed. Minimum radiation dose was 50Gy (2Gy/fr). Planning target volume encompassed the entire hemithorax, including the ipsilateral mediastinum if interested by disease, the pericardium and diaphragm, and any drain sites. The study endpoints included loco-regional control (LRC), distant metastases free survival (DMFS), and overall survival (OS), as well as radiation-related toxicity. Major patients and treatment characteristics were the following: median age 62years, epithelioid histology in 51 (94%) cases, locally advanced disease in 41 (90%) cases, and metastatic mediastinal lymph nodes in 27 patients (50%). Only 7 patients (13%) had gross residual disease after surgery. Chemotherapy was administered in 38 patients (70%). Median follow-up was 16months (range 0-73months). Median and 2-year OS were 21months and was 43.8%, respectively. The predominant pattern of failure was distant: 34 patients (62.9%) developed some component of distant failure, and only 5 patients (9.2%) developed an isolated loco-regional recurrence. The estimates of LRC and DMFS at 2years were 63.4% and 43.4%, respectively. Three fatal pneumonitis were documented. Other major toxicities included: Grade 2 and 3 pneumonitis in 1 and 2 cases, respectively, 1 case of bronchial fistula, pleural empyema, and Grade 3 esophagitis, respectively. Although executed in the era of high-technology radiotherapy (IG-IMRT), EPP should not be routinely performed.

196O - STELLAR: Final updated results of a phase II trial of TTFields with chemotherapy for unresectable malignant pleural mesothelioma

Background: Tumor Treating Fields (TTFields), an anti-mitotic, regional treatment approved for glioblastoma utilizes low intensity, alternating electric fields delivered non-invasively to the tumor using a portable medical device. In-vitro, human mesothelioma cells were highly susceptible to TTFields. Methods: The trial accrued 80 patients with unresectable, previously untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin. Inclusion criteria included ECOG PS of 0-1 and pathologically proven mesothelioma. The primary endpoint was overall survival (OS). A visual analog scale was used to assess EOCG performance status and cancer-related pain assessed until disease progression. The sample size provided 80% power with two-sided alpha of 0.05 to detect an increase in median OS of 5.5 months compared to historical controls (Vogelzang, JCO 2003). Results: All 80 patients had a minimum follow up of 12 months. Median age was 67 (range 27-78), 84% were male and 44% (35 patients) had an ECOG PS of 1. 66% (53 patients) had epithelioid histology, similar to the Vogelzang study. Median OS was 18.2 months (95% CI 12.1-25.8) versus 12.1 months in the historical control. Median OS for epithelioid patients was 21.2 months (95% CI 13.2-25.8). ECOG score was stable during the first year of follow up. Median time to deterioration in performance status was 13.1 months. Average score of pain was lower compared to baseline during the first 7 months of the treatment and was higher later on the study, with a median time to a clinical significant 33% increase in pain of 8.4 months. No device-related serious adverse events (AEs) were reported. Expected TTFields-related dermatitis was reported in 46% (37 patients). Four patients (5%) had grade 3 dermatitis. Conclusions: The study met primary endpoint of significant extension of overall survival in previously untreated mesothelioma patients. TTFields was not associated with a decrease in performance status or an increase in pain for the duration of TTFields use. TTFields in combination with chemotherapy is efficacious in malignant pleural mesothelioma compared to historical data.

Does histoid leprosy represent a locally hyperimmune variant of lepromatous leprosy?

Histoid leprosy is a subtype of leprosy with distinct clinical presentation and histologic features. It accounts for <4% of leprosy cases. The exact location of histoid leprosy along the immune spectrum and its relation to other subtypes is unclear. To evaluate the local immune phenomenon which define histoid leprosy. Parallel skin biopsies from histoid lesions and from unremarkable skin in patients with histoid leprosy were evaluated and the histologic findings compared. Formalin fixed, paraffin embedded tissue sections from lesional and non-lesional biopsies were assessed for changes in epidermis and dermis; type and extent of infiltrate, presence or absence of pseudocapsule and associated reactions. Bacillary index was evaluated using Wade Fite stain for lepra bacilli. Amongst 208 leprosy cases, six cases of histoid leprosy were identified (2.88%). The cases showed presence of nodules, patches and plaques overlying clinically unremarkable skin. Fourteen skin biopsies were evaluated of which the lesional biopsies showed equal proportion of fusocellular, fusocellular epithelioid and fusocellular-vacuolated histology. A greater circumscription was noted in lesional biopsies; however the cellular content of the infiltrate was similar in lesional and non-lesional biopsies. A case of erythema nodosum leprosum in histoid leprosy was also seen. Ours is the first study comparing normal and lesional skin in histoid leprosy. Though the histoid lesions appear to have a derivation from lepromatous leprosy, the local histologic and clinical alterations may be a result of heightened local immunity or reactive local modifying factors.

Correlation of programmed death ligand 1 expression with overall survival, clinical, and pathological features in patients with malignant plural mesothelioma

Background and aim Recent studies have proposed high expression of programmed death ligand 1 (PD-L1) in pleural tumors. Thus, we conducted the present study to examine the expression of PD-L1 in malignant pleural mesothelioma (MPM), to analyze the association between PD-L1 expression and clinicopathological features, and to correlate PD-L1 expression with overall survival (OS).Materials and methods A retrospective study on 54 cases of pleural mesothelioma was conducted. Using an automated stainer (BenchMark Ventana), the sections were stained with the following antibodies according to the standard protocol and the manufacturer’s recommendations for each antibody: PD-L1 and Ki-67. Tumors were deemed positive for PD-L1 if membranous and/or cytoplasmic staining was present in more than 1% of tumor cells.Results The median age was 65 years (range, 45–87 years), and 81.5% of the patients were men. PD-L1 was expressed on the cell membrane and cytoplasm of tumor cells in 23 (42.6%) cases. PD-L1 expression was significantly associated with the histopathological type (P<0.001). In addition, positive PD-L1 expression in tumor cell was associated with advanced stage (P<0.001) and high Ki-67 (P=0.031). Kaplan–Meier analysis demonstrated that PD-L1 expression in tumor cells was significantly associated with OS. Cases with positive PD-L1 expression had a shorter OS (median, 12 vs. 30 months with negative PD-L1 expression) (P=0.001). In univariate Cox regression analysis, high PD-L1 expression was confirmed to be associated with OS (hazard ratio, 0.24; 95% confidence interval, 0.1–0.57; P=0.001). Patients with epithelioid histology had a significantly longer OS than the other histopathological subtypes (P<0.001).Conclusion In conclusion, PD-L1 expression is associated with poor OS in MPM. Further, this study confirms the better prognostic profile of epithelioid MPM, compared with other histologic subtypes.

1807P - STELLAR: Final results of a phase II trial of TTFields with chemotherapy for first-line treatment of pleural mesothelioma

Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, using low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. In vitro, human mesothelioma cells were highly susceptible to TTFields. TTFields have been shown to extend survival of patients with glioblastoma when added to chemotherapy. Methods: The trial accrued 80 patients with unresectable, untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields in combination with pemetrexed and platinum. Inclusion criteria included ECOG 0-1 and at least one measurable lesion according to modified RECIST. Patients were followed q3w (CT scan q6w) until disease progression. The primary endpoint was overall survival (OS). This single arm study assumed historical control with a median survival of 12.1 months (Vogelzang et al. 2003). The sample size provided 80% power with a two-sided alpha of 0.05 to detect an increase in median OS of 5.5 months. Results: All patients had a minimum follow up of 12 months. Median age was 67 (range 27-78), 84% were male and 56% smokers. 16% (13 patients) had metastatic disease and 44% (35 patients) had an ECOG PS of 1. 66% (53 patients) had epithelioid histology. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy. Median OS was 18.2 months (95% CI 12.1-25.8) compared to 12.1 months in historical controls. Median PFS was 7.6 months (95% CI 6.7-8.6) compared to 5.7 months in historical controls. Partial responses were seen in 40.3% of patients and clinical benefit (PR+SD) was seen in 97.2% of patients. No device-related serious adverse events (AEs) were reported. Expected TTFields-related dermatitis was reported in 46% (37 patients). Only 4 patients (5%) had grade 3 dermatitis. Conclusions: The study met its primary endpoint of significant extension of survival for previously untreated mesothelioma patients. Secondary efficacy endpoints were also improved compared to historical control. The study demonstrated no safety concerns for the combination of TTFields to the thorax with chemotherapy. These results support the addition of TTFields to chemotherapy in the first-line treatment of malignant pleural mesothelioma. Clinical trial identification: NCT02397928. Legal entity responsible for the study: Novocure. Funding: Novocure. Disclosure: J.G. Aerts: Advisory boards: BMS, MSD, Roche, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Amphera; Stock owner: Amphera. R. Ramlau: Consultant: Novocure. All other authors have declared no conflicts of interest.

Abstract 1557: Analysis of angiogenic and stromal biomarkers in a large malignant mesothelioma cohort

Abstract Background: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other serosal membranes originating from mesothelial cells. Agents targeting vascular endothelial growth factor (VEGF) receptor such as bevacizumab; and multi-kinase inhibitors such as nintedanib [angiokinase inhibitor of VEGF, platelet-derived growth factor (PDGF) receptor and fibroblast growth factor receptor (FGFR)] have recently demonstrated efficacy in MM. In the setting of these new therapeutic agents, it is important to evaluate VEGF, PDGF and CD31 (angiogenesis marker) in MM to assess their associated prognostic implications. Methods: Tissue microarrays (TMAs) were created from formalin-fixed, paraffin-embedded tissue samples obtained from 326 patients who underwent surgical resection or biopsy for MM between 1988 and 2014. The expression of PDGF-C, VEGF and CD31 were analysed by immunohistochemical (IHC) staining. The H-score method assigned a score of 0-300 to each sample, based on the percentage of cells stained at different intensities viewed at various magnifications by a pathologist and an investigator. The discriminatory threshold was set for each IHC stain (usually the median score) and the samples were classified as low (below median score) or high expression (above median score) for each of stain. CD31 was evaluated via Chalkley's method (objective method of measuring vascularity) to evaluate microvessel density. We evaluated the association between expression of the biomarkers, clinicopathological factors and outcomes, in patients with MM. Results: The histological subtypes comprised of 203/325 (62.5%) epithelioid; 72/325 (22.2%) biphasic; 42/325 (12.9%) sarcomatoid, or indeterminate. The median age was 67 (range 24-88) with Male: Female ratio of 266: 53. CD31 high (≥5) was seen in only 31/302 (10.3%) irrespective of histology (13/31 (42%) epithelioid; 10/31 (32%) sarcomatoid; 7/31 (23%) biphasic; 1/31 indeterminate). PDGF-C high IHC (≥150) was seen in 203 /310 (65%) of all samples but was higher in epithelioid histology (129/203 (64%) epithelioid; 45/203 (22%) biphasic and 28/203 (13.8%) sarcomatoid; 1/203 indeterminate). VEGF high (≥200) was seen in 219/322 (68%) of all MM and was also higher in epithelioid histology [143/209 (68%)]. There was no association of VEGF IHC with survival nor differences between histological subtypes. There was a non-significant trend towards poorer survival in epithelioid tumours with increased PDGFC expression (HR 0.7928; 95% CI 0.5958 to 1.055, P=0.0434). High CD31 score was associated with significantly poorer survival (OS 12 vs 8.6 months; HR 0.48; 95% CI 0.2873 to 0.7941, P=0.0044). Of the 31 patients with high CD31 scores; 23/31 (74%) were also high for PDGF-C and 20/31 (64%) with high VEGF scores. Conclusions: High PDGF-C expression and CD31 scores are associated with poor survival in MM. Abrogating these pathways may have prognostic implications. Citation Format: Puey Ling Chia, Prudence Russell, Carmel Murone, Marzena Walkiewicz, Ulf Eriksson, Andrew Scott, Thomas John. Analysis of angiogenic and stromal biomarkers in a large malignant mesothelioma cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1557.

Malignant Peritoneal Mesothelioma: National Practice Patterns, Outcomes, and Predictors of Survival.

This study of a large, contemporary national database evaluated management patterns, outcomes, and prognostic factors of malignant peritoneal mesothelioma (MPM) in the USA. The National Cancer Data Base was queried for newly diagnosed nonmetastatic MPM. Patients were divided into five cohorts: observation, chemotherapy alone, cytoreductive surgery (CRS) alone, CRS/chemo [referring to any non-hyperthermic intraperitoneal chemotherapy (HIPEC) chemotherapy], and CRS/HIPEC. Statistics included multivariable logistic regression, Kaplan-Meier analysis, and Cox proportional hazards modeling. Of 1514 patients, 379 (25%) underwent observation, 370 (24%) received chemotherapy only, 197 (13%) CRS alone, 352 (23%) CRS/chemo, and 216 (14%) CRS/HIPEC. No major temporal trends in management were noted. Factors predictive of CRS administration included younger age, female gender, insurance status, residence in educated areas, living farther from treating institutions, and treatment at academic centers (p < 0.05 for all). Compared with epithelioid histology, those with sarcomatoid and biphasic histology were less and more likely to undergo CRS, respectively (p < 0.05 for both). In all CRS patients, 30- and 90-day mortality rates were 0.8 and 1.2%, respectively. At median follow-up of 50months, median OS in the respective groups was 6, 17, 21, 52, and 61months (p < 0.001). Poor prognostic factors included advanced age, male gender, uninsured/Medicaid insurance, and sarcomatoid/biphasic histology (p < 0.05 for all). In the USA, MPM is treated using a wide variety of strategies. Many factors impact the type of treatment delivered, including age, sociodemographics, geography, histology, and facility type. Although these data do not imply causation, combined-modality management seems associated with the longest OS.

Prognostic factors and treatment outcomes of malignant pleural mesothelioma in Eastern Asian patients - A Taiwanese study.

There are scarce reports on the prognostic factors and treatment outcomes of patients with malignant pleural mesothelioma (MPM) in Asia. This study aimed to address these matters in a real-world setting. Medical records of patients with histologically proven MPM diagnosed between 1977 and 2016 at the National Taiwan University Hospital were reviewed. Variables including age, gender, performance status, asbestos exposure, smoking history, histology subtype, staging, and treatment received were recorded. All patients were followed until death or March 1st, 2017. Survival and prognostic factors were analyzed by the Kaplan-Meir method and the Cox proportional hazard model. A total of 93 patients was identified, including 65 men and 28 women. An increasing trend of MPM cases diagnosed was observed in the past 40 years. Stage I/II disease (HR 0.24, 95% CI 0.13-0.46) and epithelioid histology (HR 0.42, 95% CI 0.23-0.75) were associated with favorable prognosis, whereas age ≥70 years (HR 2.66, 95% CI 1.36-5.22) and ECOG ≥2 (HR 5.03, 95% CI 2.69-9.4) were poor prognostic factors. After adjustment for prognostic factors, surgery in stage I-III MPM (HR 0.36, 95% CI 0.15-0.83) and systemic therapy in stage III/IV disease (HR 0.42, 95% CI 0.19-0.94) conferred a survival benefit. This is one of the largest case series of MPM reported in Asia outside of Japan. Prognostic factors in the study population included age, performance status, stage, and histology subtype. Surgery in potentially resectable disease and systemic therapy in advanced MPM confer a survival benefit in Asian patients.

Macroscopic complete resection is not associated with improved survival in patients with malignant pleural mesothelioma

ObjectiveMacroscopic complete resection (MCR) is the recommended surgical strategy in malignant pleural mesothelioma. Our objective was to analyze whether MCR influences survival in malignant pleural mesothelioma. MethodsBetween 2002 and 2016, 154 patients underwent pleurectomy decortication (n = 90), extrapleural pneumonectomy (n = 42), or exploratory/diagnostic procedures (n = 22) in a single institution. Patient data were recorded in a prospective database. Patients who underwent surgical resection (n = 132) were analyzed according to MCR as a whole group and after propensity score matching based on gender, age, histology, clinical T and N status, adjuvant chemotherapy, and trimodality treatment. Kaplan-Meier survival and univariate and multivariate analyses were performed. ResultsMedian age was 56 years (range, 26 to 80 years) and 62 were women. One hundred ten had epithelioid histology. MCR was achieved in 75 patients (49%). In-hospital mortality was seen in 7 patients (4.5%). Preoperative chemotherapy was applied in 32 patients. One hundred thirty-three patients underwent adjuvant treatment (45 had chemoradiation). Mean follow-up was 21 ± 19 months. Overall median survival, 2-year, and 5-year survivals were 18.1 months, 36%, and 16%, respectively. There was no difference in median survival between patients who underwent MCR (21.4 months) and who did not (16.3 months) (P = .6). Following propensity score matching (23 patients in each group), median survivals were similar (13.3 vs 14.2 months; P = .63). ConclusionsMCR was not associated with improved survival in malignant pleural mesothelioma. We need to clearly define MCR and identify subgroups of patients who would benefit from this principle because minimal versus extensive and location of gross residual disease may have different influences on survival.

Clinicopathologic and genetic characteristics of young patients with pleural diffuse malignant mesothelioma

Pleural diffuse malignant mesothelioma typically presents during the seventh decade of life and has poor prognosis. Recent epidemiologic studies have shown differences between young and older mesothelioma patients, but the biology of pleural mesothelioma in young patients is poorly understood. We studied the clinicopathologic and genetic characteristics in pleural mesothelioma patients aged 35 years and younger. Thirty-six consecutive pleural mesothelioma patients aged 35 years and younger were compared with 48 older patients. We examined demographic and clinical characteristics, histologic type, growth patterns, mitotic index, and nuclear grade on hematoxylin and eosin-stained slides, BAP1 protein expression by immunohistochemistry, and CDKN2A and NF2 deletions by fluorescence in situ hybridization. Clinicopathologic and cytogenetic results were compared between young and older groups, and correlated with overall survival. Young patients were more frequently women, reported less asbestos exposure, and had a greater frequency of prior therapeutic radiation and family history of breast cancer than older patients (P<0.05 each). There were no histologic differences between young and older patients (all P>0.05). CDKN2A deletion was less prevalent in young patients (P=0.01), loss of BAP1 protein expression less frequent in young patients (P=0.06), and NF2 deletion rates similar between groups (P>0.05 each). Median overall survival was 40 vs 26 months (P=0.10) in young and older patients, respectively, and 47 vs 31 months (P=0.04) when comparing patients with epithelioid histology only. High mitotic index and non-epithelioid histology were the only characteristics associated with a poor overall survival in young patients. Young patients with pleural mesothelioma have an equal sex distribution and are more likely to have a history of mantle radiation, family history of breast cancer, and lower rates of CDKN2A deletion than older patients. Our results suggest that pleural mesothelioma in young patients has distinctive clinical and genetic characteristics, despite some similarities to pleural mesothelioma in older patients.

Diaphragm and lung–preserving surgery with hyperthermic chemotherapy for malignant pleural mesothelioma: A 10-year experience

BackgroundThe best surgical treatment for malignant pleural mesothelioma is still under a debate, but recent evidence points toward a less-invasive approach to reduce morbidity and mortality. We reported our 10-year experience of a limited surgical approach associated with hyperthermic intrathoracic chemotherapy (HITHOC). Material and MethodsBetween 2005 and 2014, patients with epithelioid or biphasic malignant pleural mesothelioma were treated with lung–diaphragm–pericardium-sparing pleurectomy associated with double-drug HITHOC; at least 3 cycles of adjuvant chemotherapy were then administered. The primary outcome examined was the feasibility of the procedure, whereas secondary outcomes were overall survival and disease-free interval. ResultsAmong 49 patients, 41 were male. Median age was 68 years (35-76 years). Histology was epithelioid in 43 cases. Pathologic stage I, II, III, and IV occurred in 12, 14, 20, and 3 cases, respectively. No intraoperative complications or postoperative mortality occurred, whereas morbidity rate was 46.9%. Median hospital stay was 8 days (5-45 days). Actuarial median overall survival was 22 months and a 1-, 2-, and 5-year survival accounted for 79.6%, 45.7%, and 9.9%, respectively. Disease-free survival after surgery was 62%, 37.5%, and 18.5% at 1, 2, and 5 years, respectively. Risk factors analysis for overall survival confirmed a significant role for early stages, epithelioid histology, and fibrinogen serum levels. ConclusionsCytoreductive surgery associated with HITHOC and adjuvant chemotherapy appears feasible and safe, with no mortality and low morbidity. Preserving lung and diaphragmatic function might warrant an acceptable long-term outcome.

Orbital recurrence of iris melanoma 21 years after enucleation

We present the case of a 56-year-old man who developed a neoplasm of epithelioid histology in his anophthalmic left orbit 21 years after he underwent enucleation for a spindle cell...

Extrapleural pneumonectomy (EPP) vs. pleurectomy decortication (P/D).

Surgical techniques for treatment of malignant pleural mesothelioma (MPM) have improved over the decades. The main surgical principle was accepted as macroscopic complete resection. This principle was achieved with extrapleural pneumonectomy (EPP) and extended pleurectomy/decortication (P/D). Mortality and morbidity are higher following EPP with supraventricular arrhythmias, pulmonary embolism, bronchopleural fistula and pulmonary failure being the most common, while prolonged air leak is frequent following P/D. Completion of multimodality treatment was also shown to be a prognostic factor. Many different neoadjuvant and adjuvant protocols were applied with limited effect on prognosis. While locoregional recurrence is more common following P/D, EPP patients typically recur in contralateral hemithorax and abdomen. Hemithoracic radiation following EPP was the only effective technique shown to decrease locoregional recurrence. However, neither surgical technique (EPP vs. P/D), nor types of multimodality treatment protocols were found to be prognostic in MPM. Epithelioid histology, metastasis to extrapleural lymph nodes and completion of multimodality treatment were prognostic in most of the series. In conclusion, based on the current evidence, the choice of a less morbid and mortal procedure (P/D) seems to be the logical choice in the treatment of MPM.

Determining the prevalence of germline BAP1 mutations in malignant mesothelioma (MM).

e13118 Background: Somatic BAP1 mutations are very common in MM tumors (Bueno et al. Nat Genet 2016, Bott et al. Nature Genet 2011) and germline BAP1 mutations have also been shown to segregate in numerous families with clusters of malignancies including MM (Testa et al. Nat Genet 2011). However, the prevalence of germline BAP1 alterations in an unselected population of MM patients remains unknown. Methods: Unselected patients with MM were enrolled on a prospective trial (NCT01773655) to collect germline DNA, detailed family history, exposure questionnaires, and tumor tissue if available. De-identified germline DNA sequencing was performed to evaluate for the presence of BAP1 mutations. Patients with prespecified high-risk criteria (age &lt; 50 yrs, no asbestos exposure, personal/family history of choroidal nevus, uveal melanoma, melanoma, or mesothelioma, or cancer in ≥ two 1st degree relatives) were contacted by Clinical Genetics and offered counseling and identified BAP1 testing. Results: 120 patietns with MM were enrolled. The majority are male (63%) with pleural mesothelioma (78%) and mostly epithelioid histology (75%). Sixty-seven percent met high-risk criteria for identified testing and 27 patients have consented for identified testing. Both deidentified and identified testing is ongoing. To date, among 17 patients tested, 3 have been identified with germline pathogenic BAP1 alterations. Two of those three patients had a personal history of an associated malignancy. Additional testing results will be reported at the meeting. Conclusions: Germline BAP1 mutations may be more common than previously thought among MM patients. Further work is needed to clarify those at high risk for germline mutation so they and their at-risk family members may receive testing and genetic counseling regarding their risk of malignancy. Additionally, ongoing work to define associations between genotype and phenotype should continue so that the full scope of diseases and risks are outlined for this new BAP1 associated cancer predisposition syndrome.

Mature overall survival (OS) results from the LUME-Meso study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) vs placebo (P) + PEM/CIS in chemo-naïve patients (pts) with malignant pleural mesothelioma (MPM).

8506 Background: LUME-Meso is a Phase (Ph) II/III, double-blind, randomized study. N targets MPM by inhibiting VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases. Primary analysis of the Ph II data demonstrated improved progression-free survival (PFS; hazard ratio [HR]=0.56; 95% confidence interval [CI] 0.34–0.91; p=0.017). Mature Ph 2 OS and updated PFS results are reported here. Methods: Pts with unresectable MPM (ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomized 1:1 to receive ≤6 cycles PEM (500 mg/m2)/CIS (75 mg/m2) Day 1 + N or P (200 mg bid, Days 2–21), followed by N or P monotherapy until progression or toxicity. The primary endpoint was PFS. The primary OS analysis and updated PFS analysis were performed as predefined. Results: 87 pts were randomly assigned (N=44, P=43). OS benefit favored N over P treatment (HR=0.77; 95% CI 0.46–1.29; p=0.319; 62 [71%] OS events) and was greatest in epithelioid pts (HR=0.70; 95% CI 0.40–1.21; p=0.197) with a median (m) OS gain of 5.4 months (mOS [95% CI]: 20.6 [16.2–28.8] N vs 15.2 [12.2–23.6] P). Updated PFS results (HR=0.54; 95% CI 0.33–0.87; p=0.010) also showed greatest benefit for epithelioid pts (HR=0.49; 95% CI 0.30–0.82; p=0.006) with a mPFS gain of 4.0 months (mPFS [95% CI]: 9.7 [7.2–12.4] N vs 5.7 [5.5–7.0] P). Improved forced vital capacity, objective response rates and duration of response were also observed with N treatment. Drug-related adverse events (AEs) in N- vs P-treated pts were 97.7% vs 97.6%. Grade ≥3 AEs of note included neutropenia (27.3% vs 4.9%), ALT (11.4% vs 0) and GGT (6.8% vs 0) elevations, and diarrhea (6.8% vs 0). AEs led to trial discontinuation in only 3 (6.8%) N vs 7 (17.1%) P pts. Conclusions: Mature Ph II OS data show that adding N to standard 1st-line treatment gives a strong signal towards improved OS. Updated PFS confirmed the primary analysis; AEs were manageable. The greatest clinical benefit was observed in pts with epithelioid histology. Median survival of 20.6 months in epithelioid pts treated with N is unprecedented in advanced MPM trials. Ph III is actively recruiting in this pt population. Clinical trial information: NCT01907100.

RETRACTED: OA02.03 Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study

Malignant pleural mesothelioma (MPM) is a rare but devastating malignancy. Despite the search for new promising treatment approaches, the outcome for most MPM patients remains dismal. Therefore, the identification of novel biomarkers is urgently needed in order to identify patients with a better prognosis and to support personalized therapeutic decisions. In our previously published study, we were able to show that fibroblast growth factor 18 (FGF18) is overexpressed in MPM tissue specimens and cell models. The objective of this study was the evaluation of FGF18 as a circulating biomarker in MPM. Plasma was collected from 107 MPM patients at the time of diagnosis or before surgical resection. Samples were included from the Medical University of Vienna, University Hospital Center in Zagreb and from The Concord Repatriation General Hospital and Strathfield Private Hospital in Sydney. Samples from 49 healthy volunteers and from 8 patients with non-malignant pleural diseases served as controls. Circulating FGF18 was measured by enzyme-linked immunosorbent assay and correlated to clinical, pathologic and radiologic parameters. Plasma FGF18 level was significantly elevated in MPM patients vs. healthy controls (P<0.0001). A slight increase of circulating FGF18 level was also detected in patients with pleuritis or fibrosis (vs. control, P=0.0067). Sarcomatoid (n=7) morphology was associated with high FGF18 levels when compared to the epithelioid (n=77) histology (P=0.0064). Importantly, MPM patients presenting with FGF18 levels below the median had a significantly longer overall survival when compared to those with high FGF18 levels (median survival 625 versus 382 d, P=0.0038). Data on multivariate analysis, disease-free survival, correlation with other biomarkers and tumor volume will be presented at the conference. Our findings reveal that FGF18 is a promising blood-derived candidate biomarker in MPM. Furthermore FGF18 may support the histological classification of MPM and the identification of MPM patients with poor prognosis.

P3.03-029 EPP Followed by Hemithoracic IMRT - A Multicenter Study on Behalf of the Italian Association for Radiation Oncology Lung Cancer Study Group: Topic: Mesothelioma Clinical

The treatment of MPM is not well defined. Although it has been shown that extrapleural pneumonectomy (EPP) followed by hemithoracic RT may improve survival in early-stage disease, this therapeutic approach is declining. This might be due to the recent publication of a randomized trial (SAKK 17/04) which assessed the effect of high-dose hemithoracic RT after EPP. The study reported poor outcomes and the results did not support the use of hemithoracic RT. The major weakness of the SAKK study is the heterogeneity of the radiation techniques and schedules, and that only 12 patients received IMRT. On this background we conducted the present study to assess the outcome of MPM patients treated with EPP and adjuvant IMRT. This is a retrospective multicenter study, including 5 academic centers in Italy. Seventy patients treated with EPP and adjuvant IMRT were enrolled. The majority (95%) of patients had an epithelioid histology. Sixty patients were affected by stage III-IVA disease. Fifty-four (77%) patients received neoadjuvant/adjuvant chemotherapy. The IMRT dose ranged between 50-60 Gy in 25-27 fractions. Radiation was interrupted in two patients due to systemic progression of disease. Median follow-up was 14 months (range, 0-83 months). Rates of local control, loco-regional control, distant-metastases free survival (DMFS) and overall survival (OS) at 2 years were 73%, 63%, 39%, and 63%, respectively. Patients with stage I-II had a better 2-year OS and DMFS than those with advanced disease: 60% vs. 40% (p=0.09), and 78% vs. 32% (p=0.03), respectively. Three fatal pneumonitis were reported. Other major toxicities were: Grade 2-3 pneumonitis in 2 cases, 1 bronchial fistula, and 1 Grade 3 esophagitis. This multicenter study showed that EPP followed by hemithoracic IMRT is associated with high rate of local and loco-regional control, and showed that long-term survival can be achieved, even if some patients may experience life-threatening lung toxicity. Distant metastasis represent the predominant pattern of failure.

P3.03-056 Retrospective Study Comparing Two Frontline Chemotherapy Schemes in Unresectable Malignant Mesothelioma: Topic: Mesothelioma Clinical

Standard treatment for mesothelioma is platinum-based combination chemotherapy. Selected patients can benefit from surgical procedures and / or radiotherapy. We retrospectively reviewed the results of different platinum doublets administered in clinical practice in our center. This is a single-center study of 64 patients with mesothelioma treated with first-line palliative chemotherapy between September 1999 and December 2015. Patients were divided into 2 groups according to the treatment received: (A) 55 patients who received platinum + pemetrexed and (B) 9 patients treated with platinum + gemcitabine. The characteristics of the groups are compared and the results obtained presented. Group A characteristics: 75.4% male, mean age 66.7 years. Origin: 91.2% pleural and peritoneal 5.3%. Histology: epithelioid 61.1%, 5.6% biphasic and 33% unknown. Clinical staging III and IV (50.9%) I and II (24.6%). They had PS0 = 31.6%, PS1= 57.9%, PS2 = 5.3%. Group 'B': 77.8% male, mean age 69.9 years. Origin: pleural 77.8% and 22.2% peritoneal. Epithelioid histology 44.4%, 22.2% sarcomatoid and 22.2% unknown. They had PS0 =11.1%, PS1 = 55.6%, PS2= 22.2%, PS3 = 11.1%. There were no significant differences between groups in either prognostic factors or in the indication of palliative pleurodesis. Progression-free survival (A) was 6.7 vs. (B) 2.53 months (p = 0.013). Overall survival (A) was 19.1 months vs. (B) 7.7 months (p = 0.046). The response rate was (A) 50% and (B) 11% (p = 0.19). They received second line: (A) 52.6% vs. (B) 1p (11.1%). G3-4 toxicities: (A) neutropenia and asthenia (14.1%), anemia (7%), diarrhea (3.5%), thrombocytopenia, nausea/vomiting, neuropathy, vascular, hearing and dysgeusia (1.8%). In (B) 2p anemia (22.2%), diarrhea 1p (11.1%). Median number of cycles (A) 6 vs. (B) 3 (p = 0.084). No significant differences in the number of delays and dose reductions between treatments were observed. A significant increase in PFS and OS was achieved with the combination of cisplatin and pemetrexed in our series. The toxicity profile is the expected one with a clinical benefit with cisplatin compared to gemcitabine.