Pleural lavage cytology: Where do we stand?

Although a malignant pleural effusion is considered a manifestation of an advanced stage disease not amenable to curative resection in patients with non-small cell lung cancer, the same is not true in the case of the presence of malignant cells in the pleural cavity without an accompanying effusion, discovered incidentally during the operation with pleural lavage cytology (PLC). PLC is a diagnostic technique used to detect tumor cells and translate this finding to a prognostic index. Various reports have attempted to utilize the results of PLC and draw inferences regarding the origins of malignant cells in the pleural cavity, the association of these results with various disease characteristics and, most importantly, their impact on disease recurrence and survival. However, due to non-consistent techniques and protocols used to acquire the samples for cytological evaluation and assess their significance, results are inhomogeneous. Nevertheless, the entrance of malignant cells in the pleural cavity follows the rules posed by the natural disease process when discovered before pulmonary resection takes place, while surgical manipulations certainly play an important role in the case malignant cells are checked over after pulmonary resection. In addition, although the prognostic significance of a positive PLC result is indisputable and significantly decreases long-term survival in the majority of studies, this factor has not yet been incorporated into the TNM staging system. Lastly, some authors have advocated the use of some form of adjuvant treatment for those patients found with positive PLC results, based on the assumption that a curative resection followed by multiple pleural washings will not remove the entirety of the population of malignant cells present in the pleural space.     

What Is the Role of Radiotherapy in Malignant Pleural Mesothelioma?

Objective.

A review of the evidence supporting the use of radiotherapy in patients with mesothelioma was performed.

Methods.

Relevant publications were searched for on Medline.

Results.

In a Medline search on radiotherapy and mesothelioma, 611 hits were obtained. A limited number of prospective phase II trials of radiotherapy as part of trimodality protocols for early disease and in the palliation of pain were found, along with three small randomized controlled trials of port-site prophylaxis.

Conclusion.

No randomized data exist to support the use of radiotherapy after radical surgery, although there are a large number of publications describing its use as an integral part of therapy, including seven phase II studies. One ongoing trial is randomizing patients to radiotherapy or not after extrapleural pneumonectomy. None of these studies provided any assessment of radiotherapy independent of the other modalities investigated, nor did any formally assess intensity-modulated radiotherapy. There have been several reports of excessive toxicity with this technique, and its use should be limited to phase I studies until the basis of this toxicity is better understood. Three trials have looked at port-site prophylaxis, one supporting its use and two showing no evidence of benefit. Two studies addressed pain control prospectively, one showing definite but short-lived benefits.

Implications.

Radiotherapy is widely used in treating mesothelioma with little supporting evidence. More randomized trials are required to justify this use in all three common settings for its use.     

Progress in the Management of Malignant Pleural Mesothelioma in 2017

Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1–deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.     

Spontaneous Pneumothorax and Lung Carcinoma: Should One Consider Synchronous Malignant Pleural Mesothelioma?

We describe the clinical and pathologic findings of a 68-year-old smoker with previous asbestos exposure who presented with spontaneous hydropneumothorax and was diagnosed with synchronous undifferentiated lung carcinoma and incidental malignant pleural mesothelioma. The synchronous occurrence of these two neoplasms is an extremely rare event with fewer than 20 reported cases in the English literature. The accurate diagnosis of synchronous tumors can be extremely challenging and the identification of a concomitant mesothelioma in our case was not made until an extensive immunohistochemical analysis was done on the resection specimen. Spontaneous pneumothorax occurs much more commonly in patients with malignant mesothelioma than with primary lung carcinomas. Consequently, although synchronous pleural mesotheliomas and lung carcinomas are infrequent, this diagnosis should be considered when a patient with a lung mass and a history of asbestos exposure presents with spontaneous pneumothorax and pleural thickening on imaging. Identification of synchronous tumors is of critical importance for determining the patient's stage and management and can have significant medicolegal implications should the patient seek compensation.     

Pleural and peritoneal mesotheliomas in SEER: age effects and temporal trends, 1973–2005

We analyzed mesothelioma incidence in the Surveillance, Epidemiology, and End Results (SEER) database over the period 1973–2005 using extensions of the age–period–cohort (APC) models. In these analyses, the usual non-specific age effects of the conventional APC models were replaced by hazard functions derived from two multistage models of carcinogenesis, the Armitage–Doll model and the two-stage clonal expansion (TSCE) model. The extended APC models described the incidence data on pleural and peritoneal mesotheliomas well. After adjustment for temporal trends, the data suggest that the age-specific incidence rates of both pleural and peritoneal mesotheliomas are identical in men and women. Driven largely by birth cohort effects, age-adjusted rates of pleural mesothelioma among men rose from about 7.5 per million person-years in 1973 to about 20 per million person-years in the early 1990s and appear to be stable or declining thereafter. Age-adjusted rates of pleural mesothelioma among women have remained more or less constant at about 2.5 per million person-years over the period 1973–2005. Age-adjusted rates for peritoneal mesothelioma in both men (1.2 per million person-years) and women (0.8 per million person-years) exhibit no temporal trends over the period of the study. We estimate that approximately 94,000 cases of pleural and 15,000 cases of peritoneal mesothelioma will occur in the US over the period 2005–2050. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

Efficacy of Recombinant Adenoviral Human p53Gene in Treatment of Malignant Pleural or Peritoneal Effusions

Background and objective Once the malignant pleural or peritoneal effusion is developed it is difficult to control.This report presents a new method for controlling the malignant effusions.Methods Forty-eight patients,29 males and 19 females with an average age of 61.2 years old,who were satisfied with the study inclusion criteria,were recruited in this study.Twenty-seven and 21 patients had a malignant pleural and peritoneal effusion,respectively.After draining most of fluids,these patients received intra-cavity infusion of rAd-p53 once per week for 4 weeks,at dose of 2×1012 viral particles(VP) diluted into 200 mL of saline solution for pleural effusions,and 4×1012 VP diluted into 500 mL of saline solution for peritoneal effusions.Results Participants were followed up for a median time of 13.6 month.A total of 11 cases,7 with pleural effusions and 4 with peritoneal effusions achieved a complete response(CR),and 20 cases(12 pleural effusions and 8 peritoneal effusions) had a partial response(PR).The overall response rate is 64.6%.Patients’ quality of life,assessed by using Karnofsky performance scale(KPS) scores,was improved by an average of 26.4.The one-year of overall survival rate was 54.2% with a median survival time of 12.5 months.There were no serious side effects observed except for self-limited fever found in 79.8% of the cases.Conclusions Intra-cavity infusion of rAd-p53 is an effective and safe treatment for the patients with malignant pleural or peritoneal effusions,especially for those patients who can’t tolerate the standard treatments.     

Utility of Integrated Computed Tomography—Positron Emission Tomography for Selection of Operable Malignant Pleural Mesothelioma

BackgroundMalignant pleural mesothelioma (MPM) is a primary malignancy characterized by local invasion of the pleura and metastasis. Despite advances in computed tomography (CT) and magnetic resonance imaging (MRI), accurately staging patients remains challenging. Recent studies have examined the use of integrated CT—positron emission tomography (PET) for staging patients.Materials and MethodsMayo Clinic databases were queried to identify cases with a histologic diagnosis of MPM from 2000 to 2006. Inclusion criteria were a diagnosis of MPM, an available CT scan, and an initial staging integrated CT-PET scan. A total of 35 patients were identified who met the inclusion criteria. Computed tomography and integrated CT-PET scans were reviewed by experienced radiologists. Laboratory parameters were reviewed. The Mayo Clinic tumor registry and Social Security database were queried for survival data in patients in which no follow-up was available.ResultsFindings on integrated CT-PET excluded 14 of 35 patients from surgical intervention. Extrapleural pneumonectomies (EPPs) were performed in 8 patients, and partial pleurectomies were performed in 2 patients. Upstaging from integrated CT-PET occurred in 70% of the patients when surgical pathology was available, 2 cases to an inoperable stage. Although not statistically significant, median survival was 20 months for patients undergoing an EPP and 12 months for patients excluded from surgical intervention by integrated CT-PET.ConclusionMalignant pleural mesothelioma is a difficult disease to accurately stage. The most common reason for upstaging in our series was an increase in T (tumor; tumor-node-metastasis staging system) disease. Our data suggest that integrated CT-PET is excellent for detecting nodal and distant metastases. However, the ability of this imaging modality to correctly stage locoregional disease is not superior to the combination of CT and MRI as reported in the literature.     

PD-L1 Expression of Tumor Cells,Macrophages, and Immune Cells in Non–Small Cell Lung Cancer Patients with Malignant Pleural Effusion

Introduction

Whether immunohistochemical staining of programmed death ligand 1 (PD-L1) on cells of pleural effusion could be used to predict response to immunotherapy treatment has not been reported.

Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non–Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis

Background

Pemetrexed is a folate analog inhibitor for the treatment of non–small-cell lung cancer (NSCLC) and malignant pleural mesothelioma. Folic acid and vitamin B12 supplementation before initiating pemetrexed is necessary because of high rates of cytopenias without supplementation. However, the timing of supplementation has not been thoroughly investigated.

ERCC1, MLH1, MSH2, MSH6, and βIII-Tubulin: Resistance Proteins Associated With Response and Outcome to Platinum-based Chemotherapy in Malignant Pleural Mesothelioma

IntroductionPlatinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for “tailoring” chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy.Material and MethodsPre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and βIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data.ResultsERCC1, MLH1, MSH2, MSH6, and βIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P ≤ .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between βIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1 C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group.ConclusionsEnzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted.     

Rationale and Design of a Phase II Trial of Osimertinib Combined With Bevacizumab in Patients With Untreated Epidermal Growth Factor Receptor-mutated Non–small-cell Lung Cancer and Malignant Pleural and/or Pericardial Effusion (SPIRAL II Study)

Progression-free survival (PFS) of patients with non–small-cell lung cancer with pleural or pericardial effusion is expected to be prolonged with combination use of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor plus bevacizumab compared with that with an EGFR-tyrosine kinase inhibitor alone. Phase I clinical trial data have been reported for combined treatment with osimertinib plus bevacizumab and demonstrated their safety, but the efficacy remains unclear, particularly in patients with pleural or pericardial effusion. This is an ongoing single arm, prospective, open-label, multicenter, phase II trial to evaluate the efficacy and safety of osimertinib plus bevacizumab combination therapy in EGFR mutation-positive patients with untreated or recurrent non–small-cell lung cancer and pleural and/or pericardial effusion. Osimertinib will be administered orally once daily at a dose of 80 mg. One cycle consists of 21 days. Bevacizumab 15 mg/kg will be administered by drip infusion on Day 1 of each cycle. Treatment will be continued until progressive disease or any of the discontinuation criteria are met. The primary endpoint will be the 1-year PFS rate. Secondary endpoints are response rate, PFS, overall survival, survival not requiring pleural/pericardial drainage, and safety. Osimertinib plus bevacizumab combination therapy is expected to prolong PFS and reduce adverse events.Trial registration numberUMIN000028071     

Radiologic Considerations and Standardization of Malignant Pleural Mesothelioma Imaging Within Clinical Trials: Consensus Statement from the NCI Thoracic Malignancy Steering Committee – International Association for the Study of Lung Cancer – Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting

Detailed guidelines pertaining to radiological assessment of malignant pleural mesothelioma are currently lacking due to the rarity of the disease, complex morphology, propensity to invade multiple planes simultaneously, and lack of specific recommendations within the radiology community about assessment, reporting, and follow-up. In March 2017, a multidisciplinary meeting of mesothelioma experts was co-sponsored by the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and the Mesothelioma Applied Research Foundation. One of the outcomes of this conference was the foundation of detailed, multidisciplinary consensus imaging and management guidelines. Here, we present the recommendations for radiologic assessment of malignant pleural mesothelioma in the setting of clinical trial enrollment. We discuss optimization of imaging parameters across modalities, standardized reporting, and response assessment within clinical trials.