Prolonged survival and novel prognostic factors in women with pleural mesothelioma treated with extended pleurectomy decortication.

Background: Pleural mesothelioma (PM) is an uncommon and extremely aggressive malignancy associated with past exposure to asbestos. The low representation of women among PM patients is likely due to differences in occupational asbestos exposure. Due to the controversial role of female sex as a prognostic factor in PM, the study aims to evaluate the survival of females treated with lung-sparing surgery. We present a cohort of 114 consecutive female patients with PM who underwent intended extended pleurectomy decortication (ePD) over 11 years in a high-volume single institution. Methods: All women from 2007-2017 who underwent intended ePD were enrolled in the study. Data on clinical, operative, and outcome were collected. Kaplan-Meier estimators and log-rank tests were employed to assess the overall survival, and Cox regression models were utilized to analyze prognostic factors. Results: During the study period, 454 patients underwent thoracotomy with intended ePD in a single institution. There were 114 females (25%), and macroscopic complete resection (MCR) was achieved in 97 (85.1%). The median age was 65 years, histology was epithelioid in 81 (71.0%), biphasic in 31 (27.2%), and sarcomatoid in 2 (1.8%). The 30- and 90-day mortality were 3.5% and 6.1%, respectively. Median survival in females was 38 months, and 5-year survival was 28.2%. The median survival and 5-year survival rate for patients with epithelioid histology and MCR were 44.4 months and 36.4%, respectively. In a univariate analysis, several factors were found to be associated with patient overall survival including MCR [hazard ratio (HR): 0.3, P<0.001], early T status (HR: 1.6, P=0.03), adjuvant therapy (HR: 0.5, P=0.006), intraoperative heated chemotherapy (IOHC) (HR: 0.8, P=0.03), age (HR: 1.02, P=0.03) and epithelioid histology (HR: 0.5, P=0.009). Conclusions: For women with epithelioid PM undergoing intended ePD within a multimodal setting, prolonged survival is anticipated.

The Role of Surgery in Pleural Mesothelioma.

Surgery plays a central role in the diagnosis, staging, and management of pleural mesothelioma. Achieving an accurate diagnosis through surgical intervention and identifying the specific histologic subtype is crucial for determining the appropriate course of treatment. The histologic subtype guides decisions regarding the use of chemotherapy, immunotherapy, or multimodality treatment. The goal of surgery as part of multimodality treatment is to accomplish macroscopic complete resection with the eradication of grossly visible and palpable disease. Over the past two decades, many medical centers worldwide have shifted from performing extra-pleural pneumonectomy (EPP) to pleurectomy decortication (PD). This transition is motivated by the lower rates of short-term mortality and morbidity associated with PD and similar or even better long-term survival outcomes, compared to EPP. This review aims to outline the role of surgery in diagnosing, staging, and treating patients with pleural mesothelioma.

A Single-Center Experience in Combined Oncological-Surgical Treatment for Resectable Locally Advanced Non-Small Cell Lung Cancer (NSCLC).

Non-small cell lung cancer (NSCLC) is the most common pulmonary malignancy, frequently diagnosed at an advanced stage (III/IV). Patients in the Locally Advanced Stage Subgroup (IIIA) are relatively few, yet compose heterogenic phenotypes, posing a diagnostic and treating challenge, leading to a lack of clinical guidelines regarding the optimal standard of care. Several approaches exist, with a general agreement that a combined oncological and surgical modality approach is required. In this current retrospective descriptive study, patients with operable stage IIIA NSCLC who underwent surgery between 2013 and 2020 were evaluated on several aspects, including the initial diagnosis, neoadjuvant regimens, outcomes of surgical intervention, and overall survival at 2 years and 5 years following treatment. A total of 35 patients had neoadjuvant oncological treatment (mostly chemoradiation therapy) prior to surgery, out of which 28 patients were diagnosed with stage IIIA NSCLC. In post-operative assessment of pathological staging, downstaging was reported in 19 patients, of which 25% of cases were defined as a complete pathological response. The 2-year overall survival rate was 65% and the 5-year overall survival rate was 62%. The main pattern of disease recurrence was distant metastasis.

Arabidopsis LSH10 transcription factor and OTLD1 histone deubiquitinase interact and transcriptionally regulate the same target genes.

Histone ubiquitylation/deubiquitylation plays a major role in the epigenetic regulation of gene expression. In plants, OTLD1, a member of the ovarian tumor (OTU) deubiquitinase family, deubiquitylates histone 2B and represses the expression of genes involved in growth, cell expansion, and hormone signaling. OTLD1 lacks the intrinsic ability to bind DNA. How OTLD1, as well as most other known plant histone deubiquitinases, recognizes its target genes remains unknown. Here, we show that Arabidopsis transcription factor LSH10, a member of the ALOG protein family, interacts with OTLD1 in living plant cells. Loss-of-function LSH10 mutations relieve the OTLD1-promoted transcriptional repression of the target genes, resulting in their elevated expression, whereas recovery of the LSH10 function results in down-regulated transcription of the same genes. We show that LSH10 associates with the target gene chromatin as well as with DNA sequences in the promoter regions of the target genes. Furthermore, without LSH10, the degree of H2B monoubiquitylation in the target promoter chromatin increases. Hence, our data suggest that OTLD1-LSH10 acts as a co-repressor complex potentially representing a general mechanism for the specific function of plant histone deubiquitinases at their target chromatin.

ToBRFV Infects the Reproductive Tissues of Tomato Plants but Is Not Transmitted to the Progenies by Pollination.

Tomato brown rugose fruit virus (ToBRFV), a newly identified Tobamovirus, has recently emerged as a significant pathogen of tomato plants (Solanum lycopersicum). The virus can evade or overcome the known tobamovirus resistance in tomatoes, i.e., Tm-1, Tm-2, and its allele Tm-22. ToBRFV was identified for the first time only a few years ago, and its interactions with the tomato host are still not clear. We investigated ToBRFV's presence in the reproductive tissues of tomato using fluorescent in situ hybridization (FISH) and RT-PCR. In infected plants, the virus was detected in the leaves, petals, ovary, stamen, style, stigma, and pollen grains but not inside the ovules. Fruits and seeds harvested from infected plants were contaminated with the virus. To test whether the virus is pollen transmitted, clean mother plants were hand pollinated with pollen from ToBRFV-infected plants and grown to fruit. None of the fruits and seeds harvested from the pollinated clean mother plants contained ToBRFV. Pollen germination assays revealed the germination arrest of ToBRFV-infected pollen. We concluded that ToBRFV might infect reproductive organs and pollen grains of tomato but that it is not pollen transmitted.

Outcomes of pleurectomy decortication in patients with biphasic mesothelioma.

OBJECTIVE: There are limited small, single-institution observational studies on the role of surgery in patients with biphasic mesothelioma. Herein we report a series of 147 consecutive patients with biphasic mesothelioma treated over 11 years in a high-volume single institution with intended pleurectomy decortication (PDC). METHODS: All patients with biphasic mesothelioma from 2007 to 2017 who underwent PDC in our institution were included and clinical, pathologic, and surgical information was retrieved. Kaplan-Meier estimators and log rank test were used to compare the overall survival, and Cox regression models were used to analyzed prognostic factors. RESULTS: There were 117 men (80%), 99 right-sided operations (67%), and median age was 70 (range, 36-86) years. Neoadjuvant therapy was given to 36 (24.5%) and 108 (73.5%) received intraoperative heated chemotherapy. Macroscopic complete resection was achieved in 126 (86%). Tumors were assigned to stages IA (23; 18.8%), IB (60; 47.5%) II (15; 11.5%), IIIA (17; 13.1%), and IIIB (11; 9%) according to the eighth edition of the tumor-node-metastasis classification of malignant tumors. The 30- and 90-day mortality were 1.3% and 6.1%, respectively. The median overall survival in the macroscopic complete resection group was 16.7 months and 24 months in patients younger than 70 years. In a univariate analysis, factors that were associated with patient overall survival included age (P = .001), preoperative percentage forced expiratory volume in 1 second (P = .019), and adjuvant therapy (P < .001). No correlation was found between sex, neoadjuvant therapy, and nodal status to overall survival. CONCLUSIONS: In selected patients with biphasic mesothelioma and good prognostic factors prolonged survival after PDC is expected.

Postoperative Empyema After Pleurectomy Decortication for Malignant Pleural Mesothelioma.

BACKGROUND: Postoperative empyema after pleurectomy decortication (PDC) for malignant pleural mesothelioma (MPM) is a serious complication that necessitates prolonged hospitalization. This study determined the incidence, risk factors, and prognosis in patients when postoperative empyema develops after PDC. METHODS: The background, type of PDC, neoadjuvant treatment, date of empyema, pleural fluid cultures, treatment after empyema, and prognosis from a series of consecutive 355 patients treated over 9 years at a single high-volume center were investigated. Fisher exact test, Kaplan-Meier estimators, and log-rank test were used to identify significant risk factors for postoperative empyema and compare the overall survival. RESULTS: During the 9-year period, 355 patients (263 men) underwent PDC for MPM at a median age of 69 years. Neoadjuvant therapy was given to 87, and 282 received intraoperative heated chemotherapy. During the study, empyema developed in 24 patients (6.8%). The length of stay of patients with postoperative empyema was significantly longer. Median survival was 11.7 months for patients with postoperative empyema and 21.3 months for patients without empyema (hazard ratio, 1.78; P = .009). Postoperative empyema was associated with male sex, prolonged air leak, and use of prosthetic mesh. CONCLUSIONS: Postoperative empyema after PDC is associated with prolonged length of stay and higher mortality. The rates of this serious postoperative complication might decrease by developing better strategies to avoid prolonged air leak after PDC.

Pleurectomy Decortication in the Treatment of Malignant Pleural Mesothelioma: Encouraging Results and Novel Prognostic Implications Based on Experience in 355 Consecutive Patients.

OBJECTIVE: We report a series of 355 consecutive patients treated over 9 years in a single institution with intended PDC. BACKGROUND: Surgery for MPM has shifted from extra-pleural pneumonectomy to PDC with the goal of MCR. METHODS: Clinical and outcome data were reviewed. Kaplan-Meier estimators and log rank test were used to compare the overall survival, and logistic regression models were used. RESULTS: MCR was achieved in 304. There were 223 males, median age was 69 and histology was epithelioid in 184. The 30 and 90-day mortality were 3.0% and 4.6%.Most complications were low grade. Prolonged air leak in 141, deep venous thrombosis in 64, Atrial fibrillation in 42, chylothorax in 24, Empyema in 23, pneumonia in 21, Hemothorax in 12 and pulmonary embolus in 8. Median/5-year survival were 20.7 months/17.9% in the intent-to-treat cohort and 23.2months/21.2% in the MCR group. The survivals were best for patients with Tlstage and epithelioid histology (69.8months/54.1%). In a multivariable analysis, factors that were found to be associated with longer patient overall survival included epithelioid histology, T stage, quantitative clinical stage/tumor volume staging, adjuvant chemotherapy, intraoperative heated chemo, female sex, and length of stay shorter than 14 days. CONCLUSIONS: PDC is feasible with low mortality and is associated with manageable complication rates. 5-year survival of patients undergoing PDC with MCR in multi-modality setting is approaching 25% depending on quantitative and clinical stage, sex and histological subtype and is better than PDC without- MCR.

Leaf Plasmodesmata Respond Differently to TMV, ToBRFV and TYLCV Infection.

Macromolecule and cytosolic signal distribution throughout the plant employs a unique cellular and intracellular mechanism called plasmodesmata (PD). Plant viruses spread throughout plants via PD using their movement proteins (MPs). Viral MPs induce changes in plasmodesmata's structure and alter their ability to move macromolecule and cytosolic signals. The developmental distribution of a family member of proteins termed plasmodesmata located proteins number 5 (PDLP5) conjugated to GFP (PDLP5-GFP) is described here. The GFP enables the visual localization of PDLP5 in the cell via confocal microscopy. We observed that PDLP5-GFP protein is present in seed protein bodies and immediately after seed imbibition in the plasma membrane. The effect of three different plant viruses, the tobacco mosaic virus (TMV), tomato brown rugose fruit virus (ToBRFV, tobamoviruses), and tomato yellow leaf curl virus (TYLCV, begomoviruses), on PDLP5-GFP accumulation at the plasmodesmata was tested. In tobacco leaf, TMV and ToBRFV increased PDLP5-GFP amount at the plasmodesmata of cell types compared to control. However, there was no statistically significant difference in tomato leaf. On the other hand, TYLCV decreased PDLP5-GFP quantity in plasmodesmata in all tomato leaf cells compared to control, without any significant effect on plasmodesmata in tobacco leaf cells.

Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM).

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM. METHODS: KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways. RESULTS: Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth. CONCLUSIONS: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.

Identification and Mapping of Tomato Genome Loci Controlling Tolerance and Resistance to Tomato Brown Rugose Fruit Virus.

Tomato brown rugose fruit virus (ToBRFV) was identified in Israel during October 2014 in tomato plants (Solanum lycopersicum). These plants, carrying the durable resistance gene against tomato mosaic virus, Tm-22 , displayed severe disease symptoms and losses to fruit yield and quality. These plants were found infected with a tobamovirus similar to that discovered earlier in Jordan. This study was designed to screen and identify tomato genotypes resistant or tolerant to ToBRFV. The identified resistance and tolerance traits were further characterized virologically and genetically. Finally, DNA markers linked to genes controlling these traits were developed as tools to expedite resistance breeding. To achieve these objectives, 160 genotypes were screened, resulting in the identification of an unexpectedly high number of tolerant genotypes and a single genotype resistant to the virus. A selected tolerant genotype and the resistant genotype were further analyzed. Analysis of genetic inheritance revealed that a single recessive gene controls tolerance whereas at least two genes control resistance. Allelic test between the tolerant and the resistant genotype revealed that these two genotypes share a locus controlling tolerance, mapped to chromosome 11. This locus displayed a strong association with the tolerance trait, explaining nearly 91% of its variation in segregating populations. This same locus displayed a statistically significant association with symptom levels in segregating populations based on the resistant genotype. However, in these populations, the locus was able to explain only ~41% of the variation in symptom levels, confirming that additional loci are involved in the genetic control of the resistance trait in this genotype. A locus on chromosome 2, at the region of the Tm-1 gene, was finally found to interact with the locus discovered on chromosome 11 to control resistance.

Novel Therapeutic Targets and Immune Dysfunction in Malignant Pleural Mesothelioma.

Advances in the treatment of malignant pleural mesothelioma (MPM) have been disappointing, despite the apparent need for new therapeutic options for this rare and devastating cancer. Drug resistance is common and surgical intervention has brought benefits only to a subset of patients. MPM is a heterogenous disease with a surprisingly low mutation rate and recent sequencing efforts have confirmed alterations in a limited number of tumor suppressors that do not provide apparent insights into the molecular mechanisms that drive this malignancy. There is increasing evidence that epigenetic regulation leads to immune evasion and transformation in MPM. Further, the low efficacy of immune checkpoint inhibitors is consistent with a suppression of genes involved in the anti-tumor immune response. We review three promising emerging therapeutic targets (STAT3, KDM4A, heparanase) and highlight their potential effects on the immune response.

Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM).

Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression, using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response, including upregulation of ICOSLG (Inducible T-Cell Costimulator Ligand or B7H2). Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.

Routine surveillance for diagnosis of venous thromboembolism after pleurectomy for malignant pleural mesothelioma.

OBJECTIVE: The purpose of this study was to determine the incidence of venous thromboembolism and utility of a routine surveillance program in patients undergoing surgery for mesothelioma. METHODS: Patients undergoing pleurectomy from May 2016 to August 2018 were included. A standardized surveillance program to look for venous thromboembolism in this group included noninvasive studies every 7 days postoperatively or earlier if symptomatic. All patients received external pneumatic compression sleeves in addition to prophylactic heparin. If deep vein thrombosis or pulmonary embolus was discovered, heparin drip was initiated until conversion to therapeutic anticoagulation. RESULTS: A total of 100 patients underwent pleurectomy for mesothelioma. Seven patients were found to have preoperative deep vein thrombosis, and as such only 93 patients were included for analysis. The median age of patients at surgery was 71 years (30-85 years). During the study, 30 patients (32%) developed evidence of thrombosis; 20 patients (22%) developed only deep vein thrombosis without embolism, 3 patients (3%) developed only pulmonary embolism, and 7 patients (7%) developed both deep vein thrombosis and pulmonary embolus. Of the 27 patients who developed deep vein thrombosis, 9 (33%) were asymptomatic at the time of diagnosis, and none of these developed a pulmonary embolus or other bleeding complications. There were 2 (2%) events of major postoperative bleeding related to therapeutic anticoagulation. CONCLUSIONS: The incidence of venous thromboembolism is high (32%) among patients undergoing surveillance after pleurectomy for mesothelioma. Up to 33% of patients with deep vein thrombosis are asymptomatic at the time of diagnosis, and the incidence of complications related to anticoagulation is low. Routine surveillance may be useful to diagnose and treat deep vein thrombosis before it progresses to symptomatic or fatal pulmonary embolus.

Coordinate activation of a target gene by KDM1C histone demethylase and OTLD1 histone deubiquitinase in Arabidopsis.

Potential functional coordination between histone deubiquitinases and histone lysine demethylases represents one of the least studied aspects of epigenetic control of transcriptional outcomes. Here, this question was addressed using Arabidopsis histone modification erasers deubiquitinase OTLD1 and demethylase KDM1C known to interact with each other in plant cells. Characterization of gain- and loss-of-function mutants of OTLD1 and KDM1C showed that both enzymes associate with the promoter chromatin of their target gene AN3 and function as coactivators of its expression. This transcriptional outcome was underlain by demethylation of the H3K9 repression mark, presumably by the KDM1C histone demethylase activity. Association of KDM1C and OTLD1 with the target chromatin was interdependent such that OTLD1 was not detected at the AN3 in the absence of KDM1C and KDM1C displayed a different and non-functional pattern of association in the absence of OTLD1. Thus, OTLD1 and KDM1C may crosstalk with each other to assemble a functional coactivator complex at the AN3 promoter chromatin and set the KDM1C specificity for the methylated H3K9 to determine the correct transcriptional outcome.

Progress of malignant mesothelioma research in basic science: A review of the 14th international conference of the international mesothelioma interest group (iMig2018).

Here we summarize the most recent update of mesothelioma research in basic science presented at the 14th iMig2018 international conference. The symposium of basic science track mainly focused on the drivers of mesothelioma initiation and progression, molecular pathogenesis, and perspectives on potential therapeutic approaches. This review covers several promising fields including strategies efficiently inhibiting YAP/TAZ functions or their critical downstream targets, heparanase inhibitors, RAN depletion, and MIF/CD74 inhibitors that may be developed as novel therapeutic approaches. In addition, targeting mesothelioma stem cells by depleting M2-polarized macrophages in tumor microenvironment or blocking Tnfsf18 (GITRL)-GITR signalling might be translated into therapeutic modalities in mesothelioma treatment.

World Management of Geminiviruses.

Management of geminiviruses is a worldwide challenge because of the widespread distribution of economically important diseases caused by these viruses. Regardless of the type of agriculture, management is most effective with an integrated pest management (IPM) approach that involves measures before, during, and after the growing season. This includes starting with resistant cultivars and virus- and vector-free transplants and propagative plants. For high value vegetables, protected culture (e.g., greenhouses and screenhouses) allows for effective management but is limited owing to high cost. Protection of young plants in open fields is provided by row covers, but other measures are typically required. Measures that are used for crops in open fields include roguing infected plants and insect vector management. Application of insecticide to manage vectors (whiteflies and leafhoppers) is the most widely used measure but can cause undesirable environmental and human health issues. For annual crops, these measures can be more effective when combined with host-free periods of two to three months. Finally, given the great diversity of the viruses, their insect vectors, and the crops affected, IPM approaches need to be based on the biology and ecology of the virus and vector and the crop production system. Here, we present the general measures that can be used in an IPM program for geminivirus diseases, specific case studies, and future challenges.