Clinical Features and Surgical Treatment of Synchronous Multiple Primary Lung Adenocarcinomas With Different EGFR Mutations

BackgroundWith the popularity of lung cancer screening and advances in imaging technology, more and more synchronous multiple primary lung adenocarcinomas (SMPLA) are being diagnosed clinically, however, the clinical characteristics and prognosis of SMPLA with different EGFR mutations remains unclear. We aimed to explore clinical features and surgical outcomes of these patients to aid in the diagnosis and treatment of SMPLA.MethodsMedical records of patients with different EGFR mutations who have been diagnosed as SMPLA and underwent surgical resection from March 2015 to December 2019 were retrospectively analyzed. Clinical characteristics, surgical outcomes, recurrence-free survival (RFS) and overall survival (OS) were investigated.ResultsA total of 70 patients (68.6% female and 77.1% non-somkers) were included. Total of 161 lesions in all patients, 84.4% were ground-glass opacity (GGO) lesions. EGFR mutations were detected in 108 lesions, most of which were L858R (35.4%) and 19Del (20.5%). The mutation rate of mixed GGO is significantly higher than that of pure GGO and solid nodules (SN); the mutation rate of invasive adenocarcinoma is significantly higher than that of other histology subtypes; the mutation rate of lesions >20 mm was significantly higher than that of ≤20 mm. However, there is no significant difference in the mutation rate of specific driver gene between different radiological features, pathological characteristics and sizes. After a median follow-up time of 29 months, the 3-year OS and RFS were 94.4% and 86.0%, respectively.ConclusionsA high discordance of EGFR mutations were identified between tumors in patients with SMPLA. Synchronous multiple lung adenocarcinomas with predominantly multiple GGO should be considered as SMPLA, and surgery may be aggressively performed for these patients due to a good prognosis.

Clinical and Genetic Characteristics of Thymoma Patients With Autoimmune Hepatitis and Myocarditis

BackgroundOur study investigated a special series of thymoma with autoimmune hepatitis and myocarditis and tried to reveal the gene expression profiles of this series of thymoma.MethodsFrom 2011 to 2019, a total of 13 special thymoma patients presented with autoimmune hepatitis and myocarditis, accounting for about 1.26% of thymoma patients undergoing surgery in Beijing TongRen Hospital. Clinical data were retrospectively collected. All samples were harvested during surgical procedures, and analyzed to identify changes in gene expression using the CapitalBio mRNA microarray analysis, the Whole exome sequencing analysis (WES), qPCR and immunohistochemistry (IHC) tools.ResultsAfter surgery, patient symptoms were relieved gradually. Levels of lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), aspartate transaminase (AST), and alanine amiotransferase (ALT) increased to some extent within 1 to 3 months after surgery, and fluctuated, and then, gradually decreased close to normal within 6 months after surgery. Enrichment analysis of Kyoto Genome and Genome Encyclopedia (KEGG) pathway was performed and enrichment results were visualized. It indicated that gene expression of 5 signaling pathways, including cell cycle and p53 signaling pathway, were generally abnormal. P53 expression was up-regulated in all tumor tissues. However, IHC and qPCR analysis showed that there was no significant difference in p21 expression between normal and tumor tissue. Results of WES showed that only one driver gene-MDM4 amplified 4 fold in 53.2% thymoma cells. Further qPCR and IHC analysis confirmed the up-regulation of the expression of p53 and mdm4 in 13 thymoma patients with autoimmune hepatitis and myocarditis.ConclusionOur study reveals the clinical and genetic characteristics of thymoma patients with autoimmune hepatitis and myocarditis. For this special category of thymoma, the up-regulation of p53 and mdm4 plays an important role in the occurrence of thymoma and autoimmune hepatitis/myocarditis.

Case Report: Tumor Microenvironment Characteristics in a Patient With HER2 Mutant Lung Squamous Cell Carcinoma Harboring High PD-L1 Expression Who Presented Hyperprogressive Disease

BackgroundHigh PD-L1 expression in non-small cell lung cancer (NSCLC) is evident to predict elevated immunotherapy efficacy, to which NSCLC with onco-driver gene mutations is probed with poor responsiveness. Thus, it is of great interest to investigate how effective immune monotherapy is in the presence of concurrent high PD-L1 expression and driving gene mutation.Patients and methodsWe present a case of squamous lung cancer with high PD-L1 expression and HER2 exon 20 insertion (20Ins) who presented hyperprogressive disease (HPD) after being treated with PD-1 inhibitor.ResultsA 71-year-old female was diagnosed with advanced squamous lung cancer with 98% tumor proportion score of PD-1 and 20ins. She benefited from first-line docetaxel cisplatin followed by 2 months second-line afatinib. Third-line pembrolizumab monotherapy was then given. Unfortunately, she rapidly progressed with dramatically enlarged primary site as well as mediastinal lymph nodes and pleural effusion only 2 weeks later, presenting severe dyspnea and dysphagia. Re-biopsy was conducted, and we found that compared with the baseline, CD8+ T cells were largely recruited only in tumor stroma but not in tumor parenchyma. Tumor-associated macrophages were notably increased in both tumor stroma and parenchyma. Concomitantly, CD56dim NK cells in tumor parenchyma were decreased.ConclusionsApplication of immune monotherapy in patients with positive driver genes demands extreme caution, even harboring high PD-L1 expression. Abnormality of tumor microenvironment might be critically involved in immune checkpoint inhibitor-induced HPD. Further study in greater depth is required.

Case Report: A Case of Sintilimab-Induced Cystitis/Ureteritis and Review of Sintilimab-Related Adverse Events

Immune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). Here, we first report a case of sintilimab-related cystitis/ureteritis. A 53-year-old man with driver gene-negative pulmonary adenocarcinoma (cT1cN3M1c, Stage IVB) was being treated with sintilimab in combination of paclitaxel-albumin and bevacizumab as second-line treatment. He was hospitalized for haematuria, pollakiuria, painful micturition and low back pain after three courses. Urinalysis showed red blood cells (RBCs) and white blood cells (WBCs) were obviously increased, and serum creatinine (sCr) level was also significantly elevated. Urine culture and cytology were both negative, and cystoscopy revealed diffused redness of bladder mucosa. Urinary ultrasonography showed mild hydronephrosis and dilated ureter. The patient was diagnosed as immunotherapy-related cystitis/ureteritis after a multidisciplinary team (MDT) meeting. Once the diagnosis was made, corticosteroid therapy was given, which rapidly resolved the patient’s symptoms and signs. Computer tomography angiography (CTA) and CT urography (CTU) was conducted after sCr level was back to normal and demonstrated ureter dilation and hydroureter. Once symptoms relieved, bladder biopsy was performed and confirmed the bladder inflammation. The patient was subsequently switched to maintenance dose of methylprednisolone and tapered gradually. Since sintilimab has been used in advanced malignancies, we first reported a rare case of sintilimab-induced cystitis/ureteritis and summarized sintilimab-related adverse events to improve the assessment and management of irAEs.

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls.

The treatment of advanced pulmonary sarcomatoid carcinoma

Pulmonary sarcomatoid carcinoma (PSC) is a pathological subtype of non-small cell lung cancer. Although the incidence of PSC in lung cancer is very low, it is an aggressive cancer, leading to a poor prognosis. Currently, there is no standard treatment for advanced PSC. Targeted therapy can be used for patients with MET exon 14 mutations and patients with other driver gene mutations may also benefit from treatment. The emergence of immune checkpoint inhibitors also provides potential options for advanced PSC treatment, but more clinical data is needed. Additionally, more research may be warranted to explore the effects of chemotherapy, radiotherapy and antiangiogenic therapy. In this review, the authors summarize the research regarding the treatment of advanced PSC.

Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers

BackgroundDiagnosing and treating patients with multiple primary lung cancers (MPLCs) bring challenges to the clinic, and the preliminary evidence has revealed unsatisfying outcomes after targeted therapy and immunotherapy. Therefore, we surveyed genomic profiles of MPLCs and their possible associations with tumor mutation burden (TMB), programmed death-ligand 1 (PD-L1), and the immune cell infiltration landscape.Materials and methodsA total of 112 patients with MPLCs with surgically resected 294 tumors were eligible, and 255 tumors were sequenced using a 1021-gene panel. Immunohistochemistry staining was performed to evaluate the levels of PD-L1 and the density of CD3+/CD8+ tumor-infiltrating lymphocytes (TILs), and CD68+/CD163+ tumor-associated macrophages (TAMs) at the central tumor and invasive margin, and immunotypes were generated based on those variables.ResultsMPLCs often occur simultaneously in non-smoker women younger than 60 years and manifest as ground-glass opacities, adenocarcinoma, and stage I lung lesions. The most frequently mutated genes in the 255 tumors were EGFR (56%), ERBB2 (12%), TP53 (12%), BRAF (11%), RBM10 (11%), and KRAS (9%). We found 87 (77.7%) patients with diverse genomic profiles, and 61 (54.5%) who shared at least one putative driver gene between different tumors presented more aggressive tumors. The median TMB was 1.92 mutations/Mb, and high-TMB (≥3) lesions often harbored EGFRL858R/KRASG12C/RBM10/TP53/LRP1B mutations or wild-type ERBB2. Only 8.1% of patients and 3.9% of lesions were positive for PD-L1 on tumor cells, and this positivity was more frequent in LRP1B/TP53-mutant tumors. EGFRL858R/RBM10/TP53 mutations were positively associated with specific immune cells and an inflamed immunotype, but ERBB2 mutations were negatively correlated. TMB, CD3+TILs, and CD68+/CD163+ TAMs presented with significant heterogeneity among paired tumors (all kappa <0.2), but PD-L1 and CD8 +TILs were more uniformly present in tumor pairs.ConclusionMPLCs are driven by different molecular events and often exhibit low TMB, low PD-L1, and a heterogeneous immune infiltration landscape. Specific genomic profiles are associated with TMB and the tumor immune microenvironmental landscape in MPLCs. Our findings can help to guide MPLCs diagnoses and to identify patient populations that may benefit from immunotherapy and targeted therapy.

Landscape of Driver Gene Events, Biomarkers and Druggable Targets Identified by Whole Genome Sequencing of Glioblastomas

Background The survival of glioblastoma patients is poor. Median survival after diagnosis is 15 months, despite treatment involving surgical resection, radiotherapy and/or temozolomide chemotherapy. Identification of novel targets and stratification strategies of glioblastoma patients to improve patient survival is urgently needed. Whole genome sequencing (WGS) is the most comprehensive means to identify such DNA-level targets. We report a unique set of WGS samples along with comprehensive analyses of the glioblastoma genome and potential clinical impact of WGS. Methods Our cohort consisted of 42 glioblastoma tumor tissue and matched whole-blood samples, which were whole-genome sequenced as part of the CPCT-02 study. Somatic single-nucleotide variants, small insertions/deletions, multi-nucleotide variants, copy-number alterations (CNAs) and structural variants were analyzed. These aberrations were harnessed to investigate driver genes, enrichments in CNAs, mutational signatures, fusion genes and potential targeted therapies. Results Tumor mutational burden (TMB) was similar to other WGS efforts (1-342 mutations per megabase pair). Mutational analysis in low TMB samples showed that the age-related CpG demethylation signature was dominant, while hyper- and ultramutated tumors had additional defective DNA mismatch repair signatures and showed microsatellite instability in their genomes. We detected chromothripsis in 24% of our cohort, recurrently on chromosomes 1 and 12. Recurrent non-coding regions only resulted in TERT promoter variants. Finally, we found biomarkers and potentially druggable changes in all but one of our tumor samples. Conclusions With high quality WGS data and comprehensive methods, we identified the landscape of driver gene events and druggable targets in glioblastoma patients.

A Network-Centric Framework for the Evaluation of Mutual Exclusivity Tests on Cancer Drivers

One of the key concepts employed in cancer driver gene identification is that of mutual exclusivity (ME); a driver mutation is less likely to occur in case of an earlier mutation that has common functionality in the same molecular pathway. Several ME tests have been proposed recently, however the current protocols to evaluate ME tests have two main limitations. Firstly the evaluations are mostly with respect to simulated data and secondly the evaluation metrics lack a network-centric view. The latter is especially crucial as the notion of common functionality can be achieved through searching for interaction patterns in relevant networks. We propose a network-centric framework to evaluate the pairwise significances found by statistical ME tests. It has three main components. The first component consists of metrics employed in the network-centric ME evaluations. Such metrics are designed so that network knowledge and the reference set of known cancer genes are incorporated in ME evaluations under a careful definition of proper control groups. The other two components are designed as further mechanisms to avoid confounders inherent in ME detection on top of the network-centric view. To this end, our second objective is to dissect the side effects caused by mutation load artifacts where mutations driving tumor subtypes with low mutation load might be incorrectly diagnosed as mutually exclusive. Finally, as part of the third main component, the confounding issue stemming from the use of nonspecific interaction networks generated as combinations of interactions from different tissues is resolved through the creation and use of tissue-specific networks in the proposed framework. The data, the source code and useful scripts are available at: https://github.com/abu-compbio/NetCentric.