The Thoracic Mini Oral Competition opened with a paper on genetic mutations found in malignant pleural mesothelioma.
David S. Schrump, MD, presented a study that he and his colleagues performed to examine the ability of a human Double Minute-2 inhibitor (RG7388) to affect malignant pleural mesothelioma cells in vitro and in vivo.
Dr. Schrump, of the National Cancer Institute, Bethesda, Md., discussed how, in contrast to many other human cancers, malignant pleural mesotheliomas (MPM) rarely exhibit p53 mutations. In these neoplasms, p53 signaling is frequently dysregulated by over-expression of the p53 target gene Human Double Minute 2 (HDM2) – the human homologue of Murine Double Minute 2 (MDM2) which encodes a negative regulator of p53 transcriptional activity and stability. This is problematic, as therapeutic drugs that activate p53 signaling (such as mithramycin (MM), a repurposed chemotherapeutic agent currently in clinical trials) have the potential to trigger p53-mediated G0/G1 arrest, senescence, and apoptosis of MPM cells in vitro and in vivo.
Dr. Schrump and his colleagues initiated their study in order to determine if RG7388 (Idasanutlin; RG), a pharmacologic inhibitor of HDM2-p53 interaction could enhance the potential efficacy of MM for mesothelioma therapy.
They used Affymetrix micro-arrays, qRT-PCR, immunoblot, and immunofluorescence techniques to examine expression levels of p53, HDM2, and related genes/proteins regulating senescence, autophagy and apoptosis in MPM cells and xenografts following treatment with MM, RG, or sequential MM/RG. In addition, MTT, immunohistochemistry, immunoblot, and ApoBrdu techniques were used to examine viability and apoptosis in cultured cells and xenografts.
Dr. Schrump and his colleagues found that, under exposure conditions potentially achievable in clinical settings, MM markedly upregulated HDM2 expression in cultured MPM cells and xenografts with wild type (wt)-p53 . This coincided with a senescent and autophagic phenotype as evidenced by upregulation of HDM2, CDKN1A (p21), and MAPLC3B, downregulation of EZH2, SP1/MTOR, and ATG10, induction of LC3 puncta proteins and p-AMPK, and depletion of p-S6 kinase.
RG mediated dose-dependent increases in p53 as well as HDM2 and p21 expression that coincided with modest growth inhibition in MPM cells with wt-p53; this phenomenon was not observed in MPM cells with mt-p53 (a mutation that abrogates the tumor-suppressive role of p53). Subtherapeutic doses of MM for 24 hrs followed by RG for 48 hr mediated supra-additive growth inhibitory and apoptotic effects in MPM cells with wt-p53 but not mt-p53 as detected by ApoBrdU analysis as well as immunoblot assessment. Intraperitoneal MM followed by RG significantly reduced growth of subcutaneous wt-p53 MPM xenografts in athymic nude mice without apparent systemic toxicity as evidenced by physical appearance/activity and preserved body mass.
The antitumor effects of sequential MM/RG treatment were comparable to those produced by MM alone at a cumulative dose three times higher than that used in the combination regimen, according to Dr. Schrump.
“Our study showed that the Human Double Minute-2 inhibitor (RG7388) significantly enhanced mithramycin-mediated growth arrest and apoptosis of malignant pleural mesothelioma cells in vitro and in vivo. These findings provide the preclinical rationale for evaluation of MM in combination with HDM2 inhibitors for mesothelioma therapy,” Dr. Schrump concluded.
The next presentation turned to lung transplantion.
Several studies have suggested worse outcomes with single lung transplantation compared to double lung transplantation for COPD. However, those results may reflect selection bias by including patients exclusively listed for single or double transplantation, according to Neel K. Ranganath, MD. “If a clinician, or more likely a team of clinicians, decides at the time of listing that a patient is only appropriate to receive a single lung transplantation or only appropriate to receive a double lung transplantation, this introduces an innate selection bias that is difficult to account for in a retrospective registry analysis.”
Dr. Ranganath and his colleagues from NYU Langone Health, New York, performed a study that analyzed patients deemed appropriate for either procedure at time of listing to eliminate the inherent selection bias associated with exclusively listed patients.
In his presentation, Dr. Ranganath discussed the results of their study that retrospectively reviewed all consecutive adult lung transplants for COPD/emphysema provided by the Scientific Registry of Transplant Recipients over the period 2007 to 2017. Isolated lobar transplants, or patients listed only for single or only for double lung transplantation were excluded. The groups were stratified based on the ultimate procedure (single vs double) and propensity matching was performed using 24 recipient/donor characteristics.
Kaplan-Meier curves and log-rank tests compared survival between single and double transplantation from time of listing and separately from time of transplant, according to Dr. Ranganath. In addition, survival analysis was repeated for propensity-matched oversized single lung transplantation patients (donor TLC/recipient TLC > 1.15) vs. double lung transplantation.
During the study period, 46% (637/1393) and 54% (756/1393) of patients that were listed for both procedures ultimately received single and double lung transplantation, respectively. After propensity matching, 296 matched patients remained in each group. Overall patient survival since time of listing was 94.3% vs 93.8% at 1 year, 57.7% vs 67.1% at 5 years, and 17.8% vs 29.5% at 10 years for single and double lung transplantation, respectively.
Patient survival curves were not significantly different between single and double transplantation, whether analyzed by time of listing or time of transplant, but trended toward favoring double transplantation with absolute survival advantages at 5 and 10 years of 9.4% and 11.7%, respectively.
When comparing oversized single lungs to double lungs, patient survival since time of listing was 92.0% vs. 92.9% at 1 year, 60.2% vs 65.8% at 5 years, and 22.4% vs 28.9% at 10 years. Patient survival curves remained statistically similar, and the trend favoring double lung transplantation diminished almost entirely.
“In this cohort of concurrently listed COPD lung transplant recipients, overall survival was similar regardless of ultimately undergoing single lung transplantation or double lung transplantation, though there was a trend favoring the double lung procedure at 5 and 10 years. However, this potential advantage appeared to be mitigated with oversized single lung transplantation, suggesting that oversizing single lungs may be an appropriate alternative in well-selected lung transplant recipients with COPD,” Dr. Ranganath concluded.
“These findings are increasingly relevant when considering the scarcity of donor lungs as a resource. If we can identify the subset of COPD lung transplant recipients who would receive equivalent benefit from a single lung transplantation as a double lung transplantation, it would dramatically increase the number of recipient beneficiaries from a limited number of donor lungs.”
With the scarcity of organs available for transplant, the use of older donors could be of potential benefit. Ben Dunne, MD, and his colleagues from Toronto General Hospital performed a study to determine evaluate whether lung transplantation using organs from donors over the age of 70 can be performed with survival and freedom from chronic lung allograft dysfunction (CLAD) equivalent to organs from younger donors.
Dr. Dunne presented the results of their retrospective single-center study, which reviewed their institutional database between the years 2002 and 2017 to assess overall survival and freedom from CLAD in recipients of lungs from donors who were less than 18 years, 18-55 years, 56-69 years, and 70+ years of age.
A total of 1,526 lung transplants were performed in the time period, with 105 donors less 18 years of age, 948 between 18 and 55 years, 374 between 56 and 69 years, and 99 donors aged 70+ years.
There were significantly fewer smokers in the less than 18 years donor group than the other three groups and there was a trend toward more urgent recipients in the older donor group. However, there were no significant differences in last donor pO2, DCD vs NDD, single lung transplant, or the use of ex vivo lung perfusion between the four groups. Nor were there statistically significant differences in the median hospital length of stay, ICU length of stay, or 30-day mortality.
Dr. Dunne reported that post-transplant absolute FEV1 was best from donors less than 18 years of age and declined significantly with donor age (2.73, 2.68, 2.48, 2.47L/s) [P less than 0.01]. After multivariable analysis there was no difference in survival or freedom from CLAD between any of the age groups.
“Our study showed that lungs from donors over 70 years of age, despite a slightly lower peak post-transplant FEV1, have similar survival and freedom from CLAD as donors from the “traditional” (less than 55 years) age group and the commonly accepted “extended criteria” (56-69 years) age group,” Dr. Dunne stated. “In this cohort, lungs from older donors were more commonly used for more urgent recipients. After thorough analysis, the long-term outcome for recipients of older donor lungs appears to be just as good as for recipients of younger lungs,” he concluded.
Samuel Freyaldenhoven, MD, Brigham & Women’s Hospital, Boston, presented a study that he and his colleagues performed that aimed to characterize patterns of whole chromosome alterations (WCAs) in malignant pleural mesothelioma (MSM) and to correlate them to clinicopathologic data and gene expression signatures. Dr Freyaldenhoven and his colleagues used single nucleotide polymorphism (SNP) arrays to profile DNA copy numbers from 95 MPM paired tumor-normal samples from patients who underwent resection at Brigham and Women’s Hospital (BWH). WCAs were also analyzed in an independent cohort of 87 paired MPM samples profiled using the Affymetrix SNP6 SNP array (The Cancer Genome Atlas). Cases in which both arms of a chromosome had the same copy number change were classified as WCAs. An overall WCA burden was determined using the total number of WCAs observed in each sample. They stratified samples into two groups (low and high) by WCA burden using the bottom quartile as a cutoff.
“Our study suggests that WCA is a common feature in MPM. In addition, it provides evidence that the WCA burden is an independent prognostic indicator, and is associated with DNA repair mechanisms, cell proliferation, and tumor immune infiltration. Additional analyses are in progress to further elucidate the role of WCA in MPM,” Dr. Freyaldenhoven concluded.