Pleural mesothelioma (PM) is a rare, incurable cancer. Surgery for PM is an investigational, palliative procedure associated with increased morbidity/mortality. Dyspnea is a common symptom experienced by patients with PM before and after surgery. Dyspnea contributes to patient outcomes, including quality of life (QOL). The focus of this scoping review was to describe the evidence of the factors contributing to QOL, including a focus on dyspnea as a known contributor, before and after lung-sparing surgery for PM. The methodological framework of Arksey and O'Malley was used for this scoping review. The Theory of Unpleasant Symptoms informed the framework for key findings about the physiological, psychological, and situational concepts related to QOL and dyspnea. The search identified 293 studies, of which 15 met inclusion criteria. Most of the studies were prospective (57%), 28% were retrospective, and 14% were randomized control trials. Dyspnea was quantified in 78% of the studies and individually measured in 14% of the studies. Physiological and psychological concepts were identified. Given the magnitude and the palliative, investigational nature of the surgery, it is critical to consider the impact the procedure has on a patient's symptom burden and QOL. While the current literature has yielded valuable information, it highlights the gap that exists regarding the patient's lived experience and perceived QOL and dyspnea following lung-sparing surgery. The findings of this review suggest that future research requires qualitative and mixed-method studies to gain a more in-depth understanding of the PM patient's lived experience and perceived dyspnea and QOL before and after lung-sparing surgery.

Circulation of perfluorocarbon (PFC) through corporeal cavities has received interest by virtue of its potential to supplement oxygenation via mechanical ventilation. However, the technology is not mature enough for clinical application, due to the knowledge gaps regarding the limiting factors hampering oxygen transport from PFC to blood. In this paper, we investigate a novel hypothesis that hypothermic peritoneal perfusion of cold oxygenated may improve oxygenation of blood by facilitating the diffusion of oxygen from PFC to blood. Our hypothesis originates from physics-inspired insights that both hypothermia and PFC cooling may increase PFC-to-blood oxygen tension gradient: (i) hypothermia may decrease venous oxygen tension while (ii) cooling PFC may increase oxygen tension therein by increasing its oxygen solubility. Using a physics-based mathematical model capable of simulating oxygen tension responses to mechanical ventilation and peritoneal PFC perfusion under normothermic and hypothermic conditions, we analyzed the effect of hypothermic peritoneal cold PFC perfusion on blood oxygenation. The results predicted that peripheral oxygen saturation may be improved by 5-10%by peritoneal perfusion of oxygenated 15 degrees C PFC at 32 degrees C body temperature compared with peritoneal perfusion of oxygenated 37.5 degrees C PFC at 37.5 degrees C body temperature. The results also predicted thatcooling PFC may play a more meaningful role than hypothermia. Pending the investigationof adverse impact of hypothermia and cold PFC on homeostasis, hypothermic cold PFCperfusion may improve peritoneal oxygenation by facilitating diffusion

Supplemental Figure 1. Immunoblots of Patient Serum before and after Therapy Supplemental Figure 2. Distribution of 1/Nab Titers for the 40 Patients Supplemental Figure 3. Distribution of the Day 2 serum levels of Interferon-alpha Supplemental Figure 4. Lack of Correlation of lymphocyte or macrophage infiltration with survival. Supplemental Figure 5. Lack of Correlation of PDL1 staining with survival. Supplemental Figure 6. Correlation of the mRNA immunoscore with survival.

Supplemental Tables 1-6 Supplemental Table 1. Results of some recent trials of chemotherapy in MPM. Supplemental Table 2. Post-Trial Therapies Supplemental Table 3. Characteristics of Patients Selected for Flow Cytometry Analysis Supplemental Table 4. List of Immune Response Genes assayed by Nanostring Supplemental Table 5: Correlation of Antibody Response to MOS or Radiographic Response Supplemental Table 6. Flow Cytometry Results

Surgery for malignant pleural mesothelioma (MPM) remains unstandardized and highly variable. The significant morbidity associated with surgery has continued to limit its application and currently surgery is not the standard of care for many patients. A lung-sparing approach is now the most common technique, with many surgeons advocating 100% surgical resection of all pleural surfaces. However, resection of the entire visceral pleura is associated with the highly morbid complication of prolonged airleak.

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Purpose: Pleural mesothelioma (PM) is an aggressive tumor still considered incurable, in part due to the lack of predictive biomarkers. Little is known about the clinical implications of molecular alterations in resectable PM tissues and blood. Here, we characterized genetic alterations to identify prognostic and predictive biomarkers in patients with resected PM.Experimental Design: Targeted next-generation sequencing was performed in retrospective pleural tumor tissue and paired plasma samples from stage IB-IIIB resected PM. Association between prognosis and presence of specific mutations was validated in silico. Results: Thirty PM tissues and paired blood samples from 12 patients were analyzed. High tissue tumor mutational burden (TMB) (>10 mutations/Mb), tissue median minor allele frequency (MAF) (>9 mutations/Mb), and blood TMB (>6 mutations/Mb), tissue KMT2C, PBRM1, PKHD1,EPHB1 and blood LIFR mutations correlated with longer disease-free survival and/or overall survival. High concordance (>80%) between tissue and blood was found for some mutations.Conclusions: Tissue TMB and MAF, blood TMB, and specific mutations correlated with outcomes in patients with resected PM and should be further studied to validate their role as prognostic biomarkers and potentially predictive factors for combinations with immune-checkpoint inhibitors. This suggest that molecular profiling could identify longer survivors in patients with resected PM.

Mesothelioma, a cancer of mesothelial cells that line the chest, lungs, heart, and abdomen, is a relatively rare disease. In the United States, approximately 3000 individuals are diagnosed with mesothelioma annually. The primary risk factor for mesothelioma is occupational asbestos exposure which can occur decades prior to disease development, though in approximately 20% of cases, known asbestos exposure is lacking. While several other countries have developed mesothelioma registries to collect key clinical and exposure data elements to allow better estimation of incidence, prevalence, and risk factors associated with disease development, no national mesothelioma registry exists in the U.S. Therefore, as part of a larger feasibility study, a patient exposure questionnaire and a clinical data collection tool were created using a series of key informant interviews. Findings suggest that risk factor and clinical data collection via an on-line questionnaire is feasible, but specific concerns related to confidentiality, in the context of employer responsibility for exposure in the unique U.S. legal environment, and timing of enrollment must be addressed. Lessons learned from piloting these tools will inform the design and implementation of a mesothelioma registry of national scope.

This paper presents an experimentally parameterized model of the dynamics of oxygen transport in a laboratory animal that simultaneously experiences: (i) a reduction in inspired oxygen plus (ii) an increase in intra-abdominal pressure. The goal is to model the potential impact of elevated intra-abdominal pressure on oxygen transport dynamics. The model contains three compartments, namely, the animal’s lungs, lower body vasculature, and upper body vasculature. The model assumes that intra-abdominal pressure affects the split of cardiac output among the two vasculature compartments and that aerobic metabolism in each compartment diminishes with severe hypoxia. Fitting this model to a laboratory experiment on an adult male Yorkshire swine using a regularized nonlinear least-squares approach furnishes both physiologically plausible parameter values plus a reasonable quality of fit.

Additional Trial related information and methods

This paper estimates the parameters of a model of hypoxia in large animals (specifically, Yorkshire swine) from experimental data. The paper adopts a simple, control-oriented model of oxygen transport and consumption dynamics. The model uses three state variables to represent oxygen concentrations and/or partial pressures in the animal's alveolar, arterial, and venous compartments. Hypoxia is induced in a laboratory animal by placing the animal on mechanical ventilation and reducing the fraction of inspired oxygen. The resulting dataset is used for the optimal estimation of key parameters governing the animal's oxygen transport, oxygen consumption, and hemoglobin dissociation. In this nonlinear system identification exercise, the optimization objective is a weighted sum of the mean square errors in predicting (i) blood oxygen saturation and (ii) end-tidal oxygen fraction. The resulting model fits the experimental hypoxia data reasonably well, and is intended as a baseline for ongoing research on the treatment of respiratory failure.

This paper examines the problem of modeling the dynamics of the filling, drainage, and pressurization of the peritoneal cavity of a laboratory animal during perfusion. The paper is motivated by the potential of the peritoneal perfusion of an oxygenated perfluorocarbon (PFC) to provide a pathway for gas exchange in patients suffering from respiratory failure. Modeling cavity mechanics is important for avoiding excessive intracavity pressures that could potentially cause abdominal compartment syndrome during perfusion. Previous research in the literature examines elastic cavity behavior, but the problem of experimentally identifying models that couple this behavior with suction-assisted discharge remains relatively unexplored. Towards this goal, we performed large animal (namely, swine) experiments where we measured variables including peritoneal intracavity pressure, suction pressure, and PFC inflow. A simple state-space model fits data from the above experiment well. This model helps elucidate important preliminary insights into: (i) the role of active suction in facilitating discharge, (ii) the stiffening of the peritoneal cavity with perfusion, (iii) the linearity of cavity discharge behavior, (iv) the potential need to examine the impact of paralytics on cavity pressure dynamics as future work.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that rarely develop distant metastasis but often invade surrounding areas. Due to the limited therapeutic options available, the prognosis of these patients is poor, particularly in those with sarcomatoid histology. Moreover, trimodality treatment of resectable MPM is still controversial with high heterogeneity of clinical outcomes among resected patients and the lack of predictive biomarkers. Genomic studies have showed that MPM tumors are characterized by poor mutational landscapes characterized by minute mutations, rather than driver mutations, that are often missed in comparative genomic hybridization and next-generation sequencing studies. Thus, we aimed to further characterize the genetic background of these tumors and to identify predictive biomarkers in these MPM patients.

This paper identifies a state-space model of the impact of the peritoneal perfusion of an oxygenated perfluorocarbon (PFC) on the dynamics of carbon dioxide (CO 2 ) transport in a large laboratory animal. Previous research shows that such perfusion has the potential to enable the peritoneal cavity to serve as a "third lung" that supplements oxygenation during hypoxia. However, the effect of this potential treatment modality on CO 2 transport dynamics remains relatively unexplored. The paper addresses this gap by: (i) proposing a three-compartment model of CO 2 transport dynamics; (ii) utilizing time scale separation to simplify it into a residualized single-compartment model; and (iii) parameterizing the model using experimental data. Two experimental datasets are used for parameterization, involving the use of reduced minute ventilation to induce hypercarbia both (i) with and (ii) without PFC perfusion. Fisher analysis is used for quantifying the resulting model parameter uncertainties. The outcomes of this analysis strongly suggest a positive impact of perfusion on CO 2 clearance, with further validation experiments planned as future work.

This paper presents a novel mechatronic setup intended for providing respiratory support to patients suffering from pulmonary failure. The setup relies upon the circulation of an oxygenated perfluorocarbon (PFC) through the abdominal cavity. Such circulation provides a potential pathway for the transport of oxygen to the bloodstream. However, the viability of this technology for CO2 clearance has not been established. Moreover, there is a lack of experimental data enabling the modeling and identification of the underlying dynamics of this technology. To address these gaps, we develop a flexible experimental perfusion setup capable of monitoring and controlling key variables such as perfusate flowrate, temperature, pressure, and oxygenation. The paper (i) briefly summarizes the design of this setup; (ii) highlights the degree to which its data acquisition system enables the collection and cross-correlation of both perfusion-related and physiological variables; and (iii) discusses the development of flow, pressure, and temperature control algorithms for the setup. Experiments with large animals (swine) show that the setup is capable of successfully controlling the perfusion process, as well as gathering extensive data to support subsequent modeling and identification studies.

Introduction: Recent evidence suggests that patients with malignant pleural mesothelioma (MPM) undergoing extended pleurectomy/decortication (eP/D) with metastasis to the posterior intercostal lymph nodes (PILN) have a worse prognosis. In this study, we determine if MPM PILN metastasis can be reliably detected on computed tomography (CT). Materials and Methods: Preoperative staging CT exams were reviewed for the presence of PILN in MPM patients undergoing eP/D between 2007-2013 with surgical sampling of their PILN. CT images were reviewed by two thoracic radiologists blinded to clinical records, including operative pathology reports. The number and short axis size of PILN were recorded and correlated with surgical pathology. Statistical analysis examined the value of preoperative CT to detect metastatic PILN. Results: Of 36 patients that underwent eP/D with PILN sampling had preoperative CT images for review. At surgery, 22 of these patients had metastatic PILN and 14 had benign PILN. The positive and negative predictive values for one or more nodes seen on preoperative CT were 60 % and 38 % respectively. The number of PILN on preoperative CT did not predict metastasis (p = 0.40) with an average of 2 PILN seen, regardless of PILN pathology. The average nodal short axis size was 4.6 mm and 4.8 mm for benign and malignant PILN, respectively, and PILN short axis size did not predict metastasis (p = 0.39). There was little inter-observer variability between the size and number of nodes detected by each radiologist. Conclusions: CT does not reliably identify metastatic PILN on preoperative CT for patients with MPM undergoing extended pleurectomy/decortication.

Lung-sparing surgery for malignant pleural mesothelioma (MPM) is associated with a difficult and prolonged recovery due to the extensive nature of the procedure. For a select group of patients, prolonged survival rates have been reported. A clear understanding of which patients will benefit from lung-sparing surgery is currently unknown. Despite having favorable tumor histologies, limited tumor burden and being deemed physically fit for surgery, some patients will still experience increased morbidity and/or mortality.

ABSRACTPurpose The purpose of this study was to examine the impact of physical function performance and pulmonary function on patient outcomes after lung-sparing surgery for malignant pleural mesothelioma (MPM).Materials and methods A retrospective review of 54 patients with MPM from 2015 to 2020 was performed. The primary objective was to assess whether physical function, as measured by the Eastern Cooperative Oncology Group Performance Status (ECOG), and pulmonary function tests were predictive of postoperative patient outcomes (ventilator days, chest tube days, hospital length of stay). A secondary objective was to explore demographic and preoperative variables that best predict postoperative physical function and patient outcomes.Results Data include 54 patients who underwent extended pleurectomy-decortication. Preoperative ECOG was a significant predictor of postoperative patient outcomes while preoperative lung function lacked predictive ability. Preoperative ECOG was also predictive of preoperative lung function. Age on the day of surgery was the best predictor of postoperative physical function, which was significantly reduced postoperatively.Conclusions Preoperative physical function performance was a significant predictor of postoperative outcomes. The results of our study highlight the importance of physical function in patients with MPM and support the need for early rehabilitation and further research to determine optimal rehabilitation interventions.IMPLICATIONS FOR REHABILITATIONPreoperative physical function can predict outcomes after lung-sparing surgery for malignant pleural mesothelioma (MPM).Physical function in patients with MPM should be carefully examined.To accurately reflect patients' abilities, patient assessment should include both patient-reported outcomes and performance-based measures.Patients with MPM should receive rehabilitation early after diagnosis and throughout the continuum of care.