Tumor-infiltrating myeloid cells (TIMs) comprise monocytes, macrophages, dendritic cells, and neutrophils, and have emerged as key regulators of cancer growth. These cells can diversify into ...a spectrum of states, which might promote or limit tumor outgrowth but remain poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to map TIMs in non-small-cell lung cancer patients. We uncovered 25 TIM states, most of which were reproducibly found across patients. To facilitate translational research of these populations, we also profiled TIMs in mice. In comparing TIMs across species, we identified a near-complete congruence of population structures among dendritic cells and monocytes; conserved neutrophil subsets; and species differences among macrophages. By contrast, myeloid cell population structures in patients’ blood showed limited overlap with those of TIMs. This study determines the lung TIM landscape and sets the stage for future investigations into the potential of TIMs as immunotherapy targets.
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•Human dendritic cell and monocyte subsets show one-to-one equivalence in mouse•Neutrophils exhibit tumor-associated phenotypes that are conserved across species•Myeloid subsets in patient blood only partially overlap with those in their tumors•Unique markers define myeloid cell subsets and associate with clinical prognosis
Tumor-infiltrating myeloid cells (TIMs) have emerged as key cancer regulators and potential next-generation immunotherapy targets, yet they remain incompletely understood. Using scRNA-seq, Zilionis et al. map the TIM landscape in human and murine lung tumors and systematically compare cell states, revealing conserved myeloid populations across individuals and species.
Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, ...thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .
Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from ...developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high‐resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1‐asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.
Pleural mesothelioma (PM) is a rare and aggressive disease that arises from the mesothelial cells lining the pleural cavity. Approximately 80% of PM patients have a history of asbestos exposure. The ...long latency period of 20–40 years from the time of asbestos exposure to diagnosis, suggests that multiple somatic genetic alterations are required for the tumorigenesis of PM. The genomic landscape of PM has been characterized by inter- and intratumor heterogeneity associated with the impairment of tumor suppressor genes such as CDKN2A, NF2, and BAP1. Current systemic therapies have shown only limited efficacy, and none is approved for patients with relapsed PM. Advances in understanding of the molecular landscape of PM has facilitated several biomarker-driven clinical trials but so far, no predictive biomarkers for targeted therapies are in clinical use. Recent advances in the PM genetics have provided optimism for successful molecular strategies in the future. Here, we summarize the molecular mechanism underlying PM pathogenesis and review potential therapeutic targets.
BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural mesotheliomas (51 epithelioid, 27 ...biphasic, 6 sarcomatoid) by a hybrid-capture next-generation sequencing (NGS) panel including complete coverage of coding and splicing regions for BAP1, CDKN2A/MTAP, NF2, and TP53 and correlated molecular findings with diagnostic immunostains for BAP1, MTAP, Merlin, and p53, respectively. Fifty-seven reactive mesothelial proliferations served as benign comparators. Loss of BAP1, MTAP, and Merlin protein expression were, respectively, 54%, 46%, and 52% sensitive and 100% specific for mesothelioma. Two-marker immunopanels of BAP1 + MTAP, BAP1 + Merlin, and MTAP + Merlin were 79%, 85%, and 71% sensitive for mesothelioma, while a three-marker immunopanel of BAP1 + MTAP + Merlin was 90% sensitive. Diffuse (mutant-pattern) p53 immunostaining was seen in only 6 (7%) tumors but represented the only immunohistochemical abnormality in 2 cases. Null-pattern p53 was not specific for malignancy. An immunopanel of BAP1 + MTAP + Merlin + p53 was 93% sensitive for mesothelioma, and panel NGS detected a pathogenic alteration in BAP1, MTAP, NF2, and/or TP53 in 95%. Together, 83 (99%) of 84 tumors showed a diagnostic alteration by either immunohistochemistry or panel NGS. Adding Merlin to the standard BAP1 + MTAP immunopanel increases sensitivity for mesothelioma without sacrificing specificity. p53 immunohistochemistry and panel NGS with complete coverage of BAP1, CDKN2A/MTAP, TP53, and NF2 may be useful in diagnostically challenging cases.
•Some sugarcane hybrids combine high sucrose yields and low lignocellulose recalcitrance.•The internodes from the top to the base of the culm revealed progressive maturation stages.•Sugarcane ...digestibility decreases significantly with internode maturation.•Chemical composition conveys internode digestibility.•The initial levels of lignification are critical for internode recalcitrance.
Sugarcane hybrids acquired several characteristics through plant breeding, including high sucrose and lignocellulose production. Recently, biomass-based industries designed to produce high-value chemicals and fuels from whole plant biomass encouraged new breeding efforts to develop plants with high sucrose yields and low lignocellulose recalcitrance. The present study utilized four experimental sugarcane hybrids to evaluate the dynamics of sucrose and lignocellulose accumulation, lignocellulose composition, and enzymatic digestibility during internode development. During the internode maturation stages, the sucrose content increased while the lignocellulose fraction presented an increased lignin and decreased glucan content. Enzymatic digestibility and lignin content of the lignocellulose fraction displayed an inversely related pattern, and the first internode was two-fold more digestible than mature internodes, indicating that digestibility decreases significantly with internode maturation and tissue lignification. Some sugarcane hybrids (H89 and H58) combined desirable phenotype characteristics (high sucrose yield and low lignocellulose recalcitrance) that were not detected in H140 and H321. Proper molecular markers discriminating these samples will help to further design breeding steps to produce sugarcane modern hybrids combining high sucrose yields and low lignocellulose recalcitrance.
Malignant peritoneal mesothelioma is a rare aggressive tumor that arises from the peritoneal lining. While recurrent BAP1 mutations have been identified in a subset of mesotheliomas, molecular ...characteristics of peritoneal mesotheliomas, including those lacking BAP1 alterations, remain poorly understood. Using targeted next-generation sequencing, we examined the molecular features of 26 diffuse malignant peritoneal mesotheliomas. As part of an exploratory analysis, we analyzed an additional localized peritoneal mesothelioma and one well-differentiated papillary mesothelioma with invasive foci. Genomic characterization identified categories of diffuse malignant peritoneal mesotheliomas: The first group included 18 (69%) tumors with recurrent BAP1 alterations, with eight (31%) having more than one BAP1 alterations, and concomitant alterations in PBRM1 (46%) and SETD2 (35%). All tumors with complete loss of BAP1 expression by immunohistochemistry harbored BAP1 molecular alterations. PBRM1 alterations were significantly enriched in the BAP1-altered cohort. Frequent copy number loss of BAP1, ARID1B, PRDM1, PBRM1, SETD2, NF2, and CDKN2A was noted. The second group included eight (31%) BAP1-wild-type tumors: two with TP53 mutations, one with a TRAF7 activating mutation, one with a SUZ12 inactivating mutation, and three with ALK rearrangements that we previously published. One TP53-mutant biphasic mesothelioma showed evidence of genomic near-haploidization showing loss of heterozygosity of all chromosomes except 5, 7, 16, and 20. The localized peritoneal mesothelioma harbored a nonsense CHEK2 mutation, and the well-differentiated papillary mesothelioma with invasive foci harbored no reportable variants. In conclusion, we described the genetic categories of diffuse malignant peritoneal mesotheliomas, with BAP1-mutant and BAP1-wild-type groups. Our findings implicated DNA repair, epigenetics, and cell cycle regulation in the pathogenesis of peritoneal mesotheliomas, with identification of potential therapeutic targets.
Objective Successful pulmonary wedge resection for early-stage non–small cell lung cancer requires a pathologically confirmed negative margin. To date, however, no clear evidence is available ...regarding whether an optimal margin distance, defined as the distance from the primary tumor to the closest resection margin, exists. Toward addressing this gap, we investigated the relationship between the margin distance and local recurrence risk. Methods We reviewed all adult patients who had undergone wedge resection for small (≤2 cm) non–small cell lung cancer from January 2001 to August 2011, with follow-up through to December 31, 2011. The exclusion criteria included other active noncutaneous malignancies, bronchoalveolar carcinomas, lymph node or distant metastases at diagnosis, large cell cancer, adenosquamous cancer, multiple, multifocal, and/or metastatic disease, and previous chemotherapy or radiotherapy. Using Cox regression analysis, we examined the relationship between the margin distance and interval to local recurrence, adjusting for chronic obstructive pulmonary disease, forced expiratory volume in 1 second, smoking, diabetes, tumor size, tumor location, surgeon, open versus video-assisted thoracoscopic surgery, and whether the lymph nodes were sampled. Results Of 557 consecutive adult patients, 479 met our inclusion criteria. The overall, unadjusted 1- and 2-year local recurrences rate was 5.7% and 11.0%, respectively. From the adjusted analyses, an increased margin distance was significantly associated with a lower risk of local recurrence ( P = .033). Patients with a 10-mm margin distance had a 45% lower local recurrence risk than those with a 5-mm distance (hazard ratio, 0.55; 95% confidence interval, 0.35-0.86). Beyond 15 mm, no evidence of additional benefit was associated with an increased margin distance. Conclusions In wedge resection for small non–small cell lung cancer, increasing the margin distance ≤15 mm significantly decreased the local recurrence risk, with no evidence of additional benefit beyond 15 mm.
Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has ...been essentially limited to three histologic subtypes.
A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification.
Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 BAP1, and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome.
These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.
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