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Introduction: Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce. Methods: We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing. Results: Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFR exon 21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0–17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2–29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0–5.9 mo). Conclusions: SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.

Abstract This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab–chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA–IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9–81.0%). For patients with ctDNA– vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

Summary: Pulmonary nodules with part-solid imaging features manifest during the progression from preinvasive to invasive lung adenocarcinoma. To define the spatial composition and evolutionary trajectories of early-stage lung adenocarcinoma, we combined spatial transcriptomics (ST) and pathological annotations from 20 part-solid nodules (PSNs), four of which were matched with single-cell RNA sequencing. Two malignant cell populations (MC1 and MC2) were identified, and a linear evolutionary relationship was observed. Compared to MC2, the pre-existing malignant MC1 exhibited a lower metastatic signature, corresponding to the preinvasive component (lepidic) on pathology and the ground glass component on PSN imaging. Higher immune infiltration was observed among MC1 regions in ST profiles, and further analysis revealed that macrophages may be involved in this process through the CD74 axis. This work provides deeper insights into the evolutionary process and spatial immune cell composition behind PSNs and highlights the mechanisms of immune escape behind this adenocarcinoma trajectory.

Abstract Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC.

Abstract Major pathological response (MPR) is a potential surrogate for overall survival. We determined whether the dynamic changes in 18F‐labeled fluoro‐2‐deoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) were associated with MPR in patients receiving neoadjuvant immunotherapy. Forty‐four patients with stage II–III non‐small cell lung cancer (NSCLC) who received neoadjuvant immunotherapy and radical surgery were enrolled. Moreover, 18F‐FDG PET/CT scans were performed at baseline and within 1 week before surgery to evaluate the disease. All histological sections were reviewed to assess MPR. The detailed clinical features of the patients were analyzed. The reliability of the clinical variables was assessed in differentiating between MPR and non‐MPR using logistic regression. Receiver‐operating characteristic (ROC) curve analysis identified the SUVmax changes threshold most associated with MPR. Most of the patients were pathologically diagnosed with squamous cell carcinoma and received anti‐PD‐1 antibodies plus chemotherapy. The immunotherapy regimens included nivolumab, pembrolizumab, and camrelizumab. MPR was observed in more than half of lesions. Tumors with MPR had a higher decrease in the longest dimension on dynamic PET/CT than those without MPR. Furthermore, the decline in SUVmax was significantly different between MPR and non‐MPR diseases, and MPR lesions had a prominent mean reduction in SUVmax. SUVmax reduction was independently associated with MPR in the multivariate regression. On ROC analysis, the threshold of SUVmax decrease in 60% was associated with MPR. Dynamic changes in SUVmax were associated with MPR. The tumors with MPR showed a greater PET/CT response than those without MPR. A SUVmax decrease of more than 60% is more likely to result in an MPR after receiving neoadjuvant immunotherapy.

Multiple primary lung cancer (MPLC) remains a tough challenge to diagnose and treat. Although neoadjuvant immunotherapy has shown promising results in early stage non-small cell lung cancer, whether such modality can benefit all primary lesions remains unclear. Herein, we performed integrated multiomics analysis in one patient with early stage MPLC with remarkable tumor shrinkage in a solid nodule and no response in two subsolid nodules after treatment with three cycles of neoadjuvant pembrolizumab. Genomic heterogeneity was observed among responding nodules with high levels of infiltrating CD8+ and CD68+ immune cells. Substantially downregulated human leukocyte antigen (HLA)-related genes and impaired T lymphocyte function were observed in non-responding nodules. A larger proportion of infiltrating tissue resident memory T cells (Trm) along with high T cell receptor repertoire clonality in responding nodules were validated as predictive and prognostic biomarkers in multiple cancer types using external public datasets. These results suggested that neoadjuvant programmed death 1 (PD-1)/programmed death ligand 1 inhibitors alone may not be an optimal therapeutic strategy for MPLC due to disparities in genomic alterations and immune microenvironment among different lesions. Additionally, we postulate that increased infiltration of Trm may be a unique marker of early immune responses to PD-1 blockade.

Abstract Background Hepatocellular carcinoma (HCC) often arises in the setting of chronic inflammation with multiple inhibitory immune signals. V-domain Ig suppressor of T cell activation (VISTA) is identified as a novel negative checkpoint regulator. This study sought to determine the expression and prognostic value of VISTA in HCC and classify tumor microenvironments (TMEs) based on VISTA and CD8+ tumor-infiltrating lymphocytes (TILs). Methods The expression of VISTA and CD8 proteins was assessed in 183 HCC tissue microarrays (TMAs) by immunohistochemistry (IHC). VISTA and CD8A mRNA extracted from 372 patients with HCC in The Cancer Genome Atlas (TCGA) database was included as a validation cohort. Associations between the VISTA, clinicopathological variables, and survival were analyzed. Results VISTA expression was detected in 29.5% HCC tissues, among which 16.4% tissues were positive for tumor cells (TCs), and 16.9% tissues were positive for immune cells (ICs). VISTA expression was significantly associated with tissues with a high pathological grading (p = 0.038), without liver cirrhosis (p = 0.011), and with a high density of CD8 + TILs (p

Abstract Background Small hepatocellular carcinoma (sHCC) is a unique variant of HCC that is characterized by small tumor size (maximum tumor diameter ≤3 cm) and favorable long-term outcomes. The present study aimed to define clinicopathologic factors that predict survival in patients with sHCC. Methods The study population consisted of 335 patients who underwent hepatectomy for solitary sHCC between December 1998 and 2010. Prognostic factors were evaluated using Kaplan–Meier curves and Cox proportional hazard models. Results The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were 77.7% and 59.9%, respectively. Kaplan–Meier curves showed that tumor size and vascular invasion had prognostic significance within this relatively selected cohort (P

[This corrects the article DOI: 10.1371/journal.pone.0104068.].

Patients with EGFR mutations showed unfavorable response to programmed cell death-1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between EGFR mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, 2 pool-analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression, and the association of EGFR status with response to anti-PD-1/L1 therapy. Pool-analysis of 15 public studies suggested that patients with EGFR mutations had decreased PD-L1 expression (odds ratio: 1.79, 95% CI: 1.10–2.93; P = 0.02). Analysis of The Cancer Genome Atlas (TCGA) and the GCLI cohort confirmed the inverse correlation between EGFR mutation and PD-L1 expression. Furthermore, patients with EGFR mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1+/CD8+ TIL (P = 0.034). Importantly, patients with EGFR mutations, especially the sensitive subtype, showed a significantly decreased mutation burden, based on analysis of the discovery and validation sets. Finally, a pool-analysis of 4 randomized control trials confirmed that patients with EGFR mutation did not benefit from PD-1/L1 inhibitors (Hazard ratio [HR] = 1.09, P = 0.51) while patients with EGFR wild-type did (HR = 0.73, P < 0.00001). This study provided evidence of a correlation between EGFR mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity, which caused an inferior response to PD-1 blockade in NSCLCs.

Recent studies provide convincing evidence that a combined immunohistochemical or fluorescence in situ hybridization (FISH) score of MYC, BCL2, BCL6 proteins and MYC translocations predicted outcome in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, by far, all these researches are based on Western populations. Therefore, we investigate the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression by immunohistochemistry and FISH from 336 de novo DLBCL, NOS treated with CHOP or R-CHOP. Breaks in MYC and BCL6, and fusion in IGH/BCL2 were detected in 9.7%, 20.0%, and 11.1% of the cases, respectively, and were not significantly associated with clinical outcomes. Protein overexpression of MYC (≥40%), BCL2 (≥70%) and BCL6 (≥50%) was encountered in 51%, 51% and 36% of the tumors, respectively. On the basis of MYC, BCL2 and BCL6 expression, double-hit scores (DHSs) and triple-hit score (THS) were assigned to all patients with DLBCL. Patients with high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS had multiple adverse prognostic factors including high LDH level, poor performance status, advanced clinical stage, high International Prognostic Index (IPI) score, and non-germinal center B-cell. In univariate analysis, high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS were associated with inferior OS and PFS in both CHOP and R-CHOP cohorts (P0.05). These data together suggest that the immunohistochemical DHSs and THS defined a large subset of DLBCLs with double-hit biology and was strongly associated with poor outcome in patients treated with R-CHOP or CHOP.

The role of microRNA-155 (miR-155) has been associated with oncogenesis of several human tumors. However the expression pattern of miR-155 has not been investigated in nasopharyngeal carcinoma (NPC). The present study was to assess miR-155 expression pattern and its possible function in NPC, to identify its targets and evaluate their clinical applications in NPC. MiR-155 was found to be upregulated in two Epstein-Barr virus (EBV) negative NPC derived cell lines CNE1 and TW03, as well as in NPC clinical samples by quantitative Real-time PCR and in situ hybridization detection. EBV encoded LMP1 and LMP2A could further enhance the expression of miR-155 in NPC CNE1 and TW03 cells. JMJD1A and BACH1 were identified as putative targets of miR-155 in a bioinformatics screen. Overexpression of miR-155 downregulated a luciferase transcript fused to the 3'UTR of JMJD1A and BACH1. MiR-155 mimic could downregulate the expression of JMJD1A and BACH1, while miR-155 inhibitor could upregulate JMJD1A expression in NPC cell lines. Moreover, downregulation of JMJD1A was significantly correlated with N stage in TNM classification (p = 0.023), a lower five-year survival rate (p = 0.021), and a lower five-year disease-free survival rate (p = 0.049) of NPC patients. Taken together, up-regulation of miR-155 in NPC is partly driven by LMP1 and LMP2A, and results in downregulation of JMJD1A, which is associated with N stage and poor prognosis of NPC patients. The potential of miR-155 and JMJD1A as therapeutic targets in NPC should be further investigated.