Diagnostic Laparoscopy Improves Staging of Malignant Pleural Mesothelioma With Routine Positron Emission Tomography Imaging.

BACKGROUND: With a multimodal treatment strategy, cytoreductive surgery extends survival in malignant pleural mesothelioma. Improving the accuracy of staging can refine patient selection. Our objective was to determine whether diagnostic laparoscopy (DL) improves staging for patients with malignant pleural mesothelioma with the routine use of positron emission tomography (PET). METHODS: We performed a retrospective review of our prospectively maintained database from February 2014 to May 2019. Inclusion criteria were patients who had disease in the chest that was deemed potentially resectable by radiographic criteria and who underwent DL as part of the staging evaluation before surgery. RESULTS: Of 187 patients (71% men, 80% epithelial) who underwent DL during staging, 76% proceeded to surgery; 22% were unresectable at exploratory thoracotomy and 78% underwent resection (pleurectomy and decortication, 68%; extrapleural pneumonectomy, 32%). Also, 89% had a PET computed tomography (CT), and 11% had a preoperative CT without PET. DL revealed peritoneal disease in 17%. Among patients with pathologically proven disease at DL, 77% had negative PET-CT imaging. Based on the pathologic findings at DL the sensitivity, specificity, positive predictive value, and negative predictive value of PET-CT were 23%, 78%, 17%, and 83%, respectively. The accuracy of PET-CT was 68%. CONCLUSIONS: PET-CT has low sensitivity and diagnostic accuracy to identify peritoneal disease in malignant pleural mesothelioma. DL as part of the preoperative staging defines an important subset of patients with bicavitary disease. We recommend DL as a component of staging before surgery.

Therapeutic Synergy in Esophageal Cancer and Mesothelioma Is Predicted by Dynamic BH3 Profiling.

Approximately 20,000 patients per year are diagnosed with esophageal adenocarcinoma (EAC) and malignant pleural mesothelioma (MPM); fewer than 20% survive 5 years. Effective therapeutic strategies are limited although patients receive a combination of chemotherapeutics. These tumors harbor thousands of mutations that contribute to tumor development. Downstream of oncogenic driving mutations, altered tumor mitochondria promote resistance to apoptosis. Dynamic Bcl-2 homology-3 profiling (DBP) is a functional assay of live cells that identifies the mitochondrial proteins responsible for resistance to apoptosis. We hypothesized that DBP will predict which protein to target to overcome resistance thereby enhancing combinatorial therapy.DBP predicted that targeting either Mcl-1 or Bcl-xL increases the efficacy of the chemotherapeutic agent, cisplatin, whereas targeting Bcl-2 does not. We performed these assays by treating EAC and MPM cells with a combination of Bcl-2 homology-3 (BH3) mimetics and cisplatin. Following treatments, we performed efficacy assessments including apoptosis assays, IC50 calculations, and generation of a combinatorial index. DBP confirmed that targeting mitochondria with BH3 mimetics alters the threshold of apoptosis. These apoptotic effects were abolished when the mitochondrial pathway was disrupted. We validated our findings by developing knockdown models of antiapoptotic proteins Mcl-1, Bcl-xL, and the mitochondrial effector proteins Bax/Bak. Knockdown of Mcl-1 or Bcl-xL recapitulated the results of BH3 mimetics. In addition, we report an approach for BH3 profiling directly from patient tumor samples. We demonstrate that the DBP assay on living tumor cells measures the dynamic changes of resistance mechanisms, assesses response to combinatorial therapy, and provides results in a clinically feasible time frame.