A preclinical model to investigate the role of surgically-induced inflammation in tumor responses to intraoperative photodynamic therapy.

OBJECTIVE: Inflammation is a well-known consequence of surgery. Although surgical debulking of tumor is beneficial to patients, the onset of inflammation in injured tissue may impede the success of adjuvant therapies. One marker for postoperative inflammation is IL-6, which is released as a consequence of surgical injuries. IL-6 is predictive of response to many cancer therapies, and it is linked to various molecular and cellular resistance mechanisms. The purpose of this study was to establish a murine model by which therapeutic responses to photodynamic therapy (PDT) can be studied in the context of surgical inflammation. MATERIALS AND METHODS: Murine models with AB12 mesothelioma tumors were treated with either surgical resection or sham surgery with tumor incision but no resection. The timing and extent of IL-6 release in the tumor and/or serum was measured using enzyme-linked immunosorbent assay (ELISA) and compared to that measured in the serum of 27 consecutive, prospectively enrolled patients with malignant pleural mesothelioma (MPM) who underwent macroscopic complete resection (MCR). RESULTS: MPM patients showed a significant increase in IL-6 at the time MCR was completed. Similarly, IL-6 increased in the tumor and serum of mice treated with surgical resections. However, investigations that combine resection with another therapy make it necessary to grow tumors for resection to a larger volume than those that receive secondary therapy alone. As the larger size may alter tumor biology independent of the effects of surgical injury, we assessed the tumor incision model. In this model, tumor levels of IL-6 significantly increased after tumor incision. CONCLUSION: The tumor incision model induces IL-6 release as is seen in the surgical setting, yet it avoids the limitations of surgical resection models. Potential mechanisms by which surgical induction of inflammation and IL-6 could alter the nature and efficacy of tumor response to PDT are reviewed. These include a wide spectrum of molecular and cellular mechanisms through which surgically-induced IL-6 could change the effectiveness of therapies that are combined with surgery. The tumor incision model can be employed for novel investigations of the effects of surgically-induced, acute inflammation on therapeutic response to PDT (or potentially other therapies). Lasers Surg. Med. 50:440-450, 2018. © 2018 Wiley Periodicals, Inc.

Genomic profiling of tissue and blood predicts survival outcomes in patients with resected pleural mesothelioma.

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.

Laying the Foundation for a Mesothelioma Patient Registry: Development of Data Collection Tools.

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.

A trial of intrapleural adenoviral-mediated Interferon-α2b gene transfer for malignant pleural mesothelioma.

New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe "flu-like" symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor. Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).

Examining the impact of physical function performance in predicting patient outcomes after lung-sparing surgery for malignant pleural mesothelioma.

PURPOSE: 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.

CT for detection of malignant posterior intercostal lymph nodes in patients undergoing pre-operative staging for malignant pleural mesothelioma.

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.

Nursing and Allied Health Research Priorities in the Care of Patients With Thoracic Malignancies: An International Cross-Sectional Survey.

BACKGROUND: There is currently no evidence of research priorities from nurses and allied health professionals working in the field of thoracic malignancies, which could provide strategic directions for funders, policy makers, and researchers. OBJECTIVE: The aim of this study is to identify the priorities for lung cancer and other thoracic malignancies research and practice in nurses and allied health professionals. METHODS: Descriptive cross-sectional web-based international survey conducted through international societies' membership lists. RESULTS: Participants included 152 nurses and allied health professionals. Key priority categories were related to developing and evaluation interventions; symptom management interventions; health care system issues; treatment-related research (immunotherapy; targeted therapies); persistent/late effects management (fatigue; pulmonary toxicity); risk reduction, and screening research. The specific topic with the highest endorsement (80.9%) was the development of interventions to improve quality of life. Symptom management interventions, particularly for pain, dyspnea, and fatigue, were also highly endorsed. Health care system topics were related to delivery of care and included nurse-/allied health-led care (67.5%), working with the multidisciplinary team (67.5%), continuity of care (69.2%), and access to care (67.5%). Topics around screening/early detection research were highly endorsed too. CONCLUSION: A clear focus (and need) for research in interventions to improve quality of life and symptom management, particularly for pain, dyspnea, and fatigue was also established, alongside healthcare system issues and screening research. IMPLICATIONS FOR PRACTICE: International societies and funding bodies could consider these topics in their funding decisions and in shaping their strategic directions in the care of patients with thoracic malignancies.

Posterior Intercostal Lymph Nodes Double Recurrence and Death Risk in Malignant Pleural Mesothelioma.

BACKGROUND: Posterior intercostal lymph nodes, previously undescribed for cancer staging, are part of the lymphatic drainage of the pleural space. This study assessed the impact of posterior intercostal lymph nodes on survival in patients undergoing extended pleurectomy/decortication for malignant pleural mesothelioma. METHODS: As part of the thoracic lymphadenectomy, posterior intercostal lymph nodes were accessed by incising the endothoracic fascia at the level of the rib heads. These nodes were systematically harvested in 56 consecutive patients undergoing extended pleurectomy decortication in a clinical trial. The impact of these nodes on progression-free (PFS) and overall survival (OS) was analyzed by multiple statistical methods. RESULTS: Median PFS and OS were 11.6 and 25.5 months, respectively. In 6 of 56 patients (11%), posterior intercostal lymph nodes were the only positive nodes, and overall, 48.2% had posterior intercostal lymph node metastases. Patients with N2 disease had significantly poorer prognosis if the posterior intercostal lymph nodes were involved: PFS (7.3 vs 14.9 months, P = .002) and OS (14.4 vs 26.1 months, P = .028). In the multivariable models, after adjustment for nodal stage and other prognostic factors, intercostal nodes remained associated with a 2.5-fold elevated risk of progression (P < .001) and a 2.3-fold elevated risk of death (P < .001). CONCLUSIONS: Metastases to posterior intercostal lymph nodes independently more than doubled the risk of progression and death and were the only site of nodal metastases in 11% of patients. These nodes warrant further investigation, including nonoperative techniques to identify and factor them into treatment decision making.

A Proposed System Toward Standardizing Surgical-Based Treatments for Malignant Pleural Mesothelioma, From the Joint National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Taskforce.

This article is a joint effort arising from a task force formed at a National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting, held at the NIH in March 2017. Malignant pleural mesothelioma remains one of the most virulent and recalcitrant malignancies, still considered incurable, and in desperate need of clinical trials in order to make progress for our patients. Although not standard of care, there is compelling evidence that a select subgroup of mesothelioma patients benefit from a surgery-based multimodal approach. As it is not possible to achieve a microscopically complete resection with mesothelioma, there appears to be no role for surgery alone. Thus, it is anticipated that significant strides in the surgery-based treatment of this cancer will require trials that determine which complementary treatments best augment the cytoreductive efficacy of surgery. Although lung-sacrificing surgery for mesothelioma is fairly standardized, approaches to lung-sparing surgery are highly variable and lung sparing surgery is emerging internationally as the dominant extirpative procedure for this cancer. It is not currently possible to rigorously assess the contribution of the adjuvant treatments combined with surgery because of the variability in procedures used to debulk this cancer, the extreme variability of the cancer itself, the variability in patient selection, the variability in treatment of the inevitable recurrence, and even the variability in follow up schedules. This article is an effort to address these problems by suggesting a more uniform approach to the surgical procedure and also proposing a series of data collection forms that could be adopted immediately, with any eye toward collecting the information that will be necessary to facilitate patient selection and determine which aspects of mesothelioma surgery can and should be standardized - with the goal being extension of life while maintaining quality of life as an equal priority. Furthermore, a completely original contribution in this manuscript is the proposal of a grading system that takes the information from the surgical procedure data forms and generates a completeness of resection score. This is the initial effort to establish a common denominator for mesothelioma surgery that will allow for more accurate comparison between surgical series and better assessment of the impact of the treatments combined with surgery.

Lymphangitic carcinomatosis: A common radiographic manifestation of local failure following extended pleurectomy/decortication in patients with malignant pleural mesothelioma.

INTRODUCTION: The lymphangitic carcinomatosis (LC) pattern of metastatic malignancy is associated with a poor prognosis but is currently not well defined in malignant pleural mesothelioma (MPM). Here, we report the incidence and prognostic significance of the radiographic development of LC in MPM following extended pleurectomy/decortication (EPD). METHODS: Consecutive patients with biopsy-proven MPM undergoing EPD with intraoperative photodynamic therapy (PDT) at our institution from 2008 to 2014 were included in this retrospective study. Patients without available post-surgical clinical or imaging data for direct review were excluded. CT images were reviewed by an experienced, board-certified thoracic radiologist and confirmed by consensus review. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan Meier methodology. Hazard ratios were compared with a cox proportional hazard model. RESULTS: 44 patients underwent EPD with PDT during the study period and had available clinical and imaging data. During the follow-up period (median 34 months), 17 patients (39%) developed LC at a median of 10 months after surgery (IQR 5-21 months). 16 of the 17 patients who developed LC (94%) died during the follow-up period, compared to 17 of the 27 who did not develop LC (63%). OS for the LC versus non-LC group was 53% versus 93% at 1 year and 18% versus 67% at 3 years. LC was significantly associated with a lower OS (HR 4.07; 95% confidence interval 1.44-11.48; p = 0.008). PFS for the LC group versus non-LC group was 8 months (IQR 5-9 months) compared to 17 months (IQR 11-24 months) (p < 0.001). CONCLUSION: LC is a common form of failure in MPM following EPD and is associated with a poor prognosis. Thus, further studies are warranted to determine if any evidence of preoperative LC should be an absolute contraindication to EPD and may warrant an EPP or no surgery at all.