Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer.

Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable. However, functional studies show a strikingly constrained tumorigenic pathway underlying heterogeneous genetic variants. These results suggest that although the mutation-specific routes that cells take during oncogenesis are stochastic, genetic trajectories may be constrained by selection for functional convergence on key signaling pathways. Our findings highlight the robust evolutionary pressures that simultaneously shape the expansion and constraint of genomic diversity, a principle that holds important implications for understanding tumor evolution and optimizing therapeutic strategies.Across cancer types tumor heterogeneity has been observed, but how this relates to tumor evolution is unclear. Here, the authors sequence multiple synchronous lung cancers, highlighting the evolutionary pressures that simultaneously shape the expansion and constraint of genomic heterogeneity

Peripheral Blood Lymphocyte Subsets Predict the Efficacy of Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer

BackgroundNon–small cell lung cancer (NSCLC) has entered the era of immunotherapy. However, only partial patients were able to benefit from immune checkpoint inhibitors (ICIs). Currently, biomarkers for predicting patients’ response to ICIs are primarily tumor tissue dependent and have limited accuracy. There is an urgent need to explore peripheral blood-based biomarkers to predict the efficacy and safety of ICI therapy.MethodsTo explore the correlation between lymphocyte subsets and the efficacy and safety of ICIs, we retrospectively analyzed peripheral blood lymphocyte subsets and survival prognosis data of 136 patients with stage IV NSCLC treated with ICIs.ResultsThe two factors that had the greatest impact on the prognosis of patients with NSCLC treated with ICIs were CD4+CD45RA− T cell (HR = 0.644, P = 0.047) and CD8+ T/lymphocyte (%) (HR = 1.806, P = 0.015). CD4+CD45RA− T cell showed excellent predictive efficacy (AUC = 0.854) for ICIs monotherapy, with a sensitivity of 75.0% and specificity of 91.7% using CD4+CD45RA− T cell >311.3 × 106/L as the threshold. In contrast, CD8+ T/lymphocyte (%) was only associated with the prognosis but had no predictive role for ICI efficacy. CD4+ T cell and its subsets were significantly higher in patients with mild (grades 1–2) immune-related adverse events (irAEs) than those without irAEs. CD8+CD38+ T cell was associated with total irAEs and severe (grades 3–4) irAEs but was not suitable to be a predictive biomarker.ConclusionPeripheral blood CD4+CD45RA− T cell was associated with the prognosis of patients with NSCLC applying ICIs, whereas CD8+CD38+ T cell was associated with irAEs and severe irAEs

Clinical Predictive Factors associated with First Line EGFR-TKI Efficacy in Advanced NSCLC Patients with EGFR Mutations

Background and objective Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated some dramatic efficacy in advanced non-small-cell lung cancer (NSCLC) patients with activating EGFR mutation. However, progression-free survivals (PFS) among those patients who were treated with first line EGFR TKIs were inconsistent. The aim of this study is to explore the association of clinical prognostic factors with EGFR-TKI efficacy in advanced NSCLC patients. Methods The demographic and clinical characteristics of 203 patients with activating EGFR mutation treated with first generation TKI as a first-line therapy were retrospectively reviewed. Results Of the 203 patients enrolled in this study, 139 patients had progression of disease and 63 patients died. The subjects had a median follow up duration of 21.1months and a median PFS of 14.3 months. Partial response (PR) was achieved in 127 (66.1%) patients and stable disease (SD) rate was achieved in 55 (28.6%) patients. In univariate analysis, patients with 2 or higher ECOG score (5.1 vs 16 months, P=0.033), SD as best overall response (9.5 vs 17.9 months, P=0.030), extrathoracic metastasis (11.7 vs 27.5 months, P=0.004), liver metastasis (4.1 vs 16.0 months, P=0.000), bone metastasis (13.3 vs 21.5months, P=0.027) and pulmonary embolism (5.5 vs 16.6 months, P=0.005) had shorter PFS than those without the listed factors. Multivariable Cox regression analysis showed best overall response (HR=1.825, 95%CI: 1.107-3.008, P=0.018) and liver metastasis (HR=1.694, 95%CI: 1.146-5.756, P=0.022) were independent predictive factors of shorter PFS. Conclusion Despite the high efficacy of EGFR-TKI, SD as best overall response and liver metastasis predicts poorer PFS in advanced NSCLC patients with EGFR gene mutations receiving first-line therapy treatment

MIMO-aided nonlinear hybrid transceiver design for multiuser mmWave systems relying on Tomlinson-Harashima precoding

Hybrid analog-digital (A/D) transceivers designed for millimeter wave (mmWave) systems have received substantial research attention, as a benefit of their lower cost and modest energy consumption compared to their fully-digital counterparts. We further improve their performance by conceiving a Tomlinson-Harashima precoding (THP) based nonlinear joint design for the downlink of multiuser multiple-input multipleoutput (MIMO) mmWave systems. Our optimization criterion is that of minimizing the mean square error (MSE) of the system under channel uncertainties subject both to realistic transmit power constraint and to the unit modulus constraint imposed on the elements of the analog beamforming (BF) matrices governing the BF operation in the radio frequency domain. We transform this optimization problem into a more tractable form and develop an efficient block coordinate descent (BCD) basedalgorithm for solving it. Then, a novel two-timescale nonlinear joint hybrid transceiver design algorithm is developed, which can be viewed as an extension of the BCD-based joint design algorithm for reducing both the channel state information (CSI) signalling overhead and the effects of outdated CSI. Moreover, we determine the near-optimal cancellation order for the THP structure based on the lower bound of the MSE. The proposed algorithms can be guaranteed to converge to a Karush-Kuhn-Tucker (KKT) solution of the original problem. The simulation results demonstrate that our proposed nonlinear joint hybrid transceiver design algorithms significantly outperform the existing linear hybrid transceiver algorithms and approach the performance of the fully-digital transceiver, despite its lower cost and power dissipation

A Retrospective Study of 42 Lung Cancer Patients with Pancreatic Metastases

Background and objective A number of patients with lung cancer have distant metastases at the time of diagnosis. The most common sites for metastases are liver, brain, etc. However pancreatic metastasis is relatively rare, with an insidious onset and poor prognosis. There are no sufficient recognition and attention of lung cancer with pancreatic metastasis. The aim of this study was to summarize the pathological characteristics, clinical manifestations, therapies and prognosis of pancreatic metastases of lung cancer, thus further exploring better managements for the best prolonged survival or quality of life. Methods 42 patients of lung carcinoma with confirmed pancreatic metastases hospitalized at the Peking Union Medical College Hospital from January 1998 to December 2018 were identified. We reviewed all medical documentations for complete information including diagnosis, treatment, prognosis features. Results 24 (57%) patients were asymptomatic or presented with non-specific symptoms. 18 (43%) patients had symptoms related to pancreatic metastases, such as acute pancreatitis, obstructive jaundice or pain of lumber back. The median overall survival (OS) was 8.8 months. Multivariate analysis suggested patients with symptoms had a poor prognosis compared with patients without pancreatic symptoms [(hazard ratio, HR)=2.645, 95%CI: 1.013-6.910, P=0.047]. Patients received chemotherapy had better prognosis versus those who did not [HR=0.158, 95%CI: 0.049-0.512, P=0.002]. Conclusion Pancreatic metastasis of lung cancer is rare and the prognosis is poor. Chemotherapy can prolong survival significantly. Local radiotherapy of the pancreas may alleviate local symptoms, improve quality of life, facilitate further systemic chemotherapy for patients to prolong survival. Patients with symptoms related to pancreatic metastases can benefit from the comprehensive treatment of chemotherapy combined with local pancreatic radiotherapy

Clinical Features of Intradural Extramedullary Spinal Cord Metastases in Primary Lung Cancer

Background and objective Intradural extramedullary spinal cord metastases in lung cancer is rare, and it leads to severe neurological damage. The aim of this study is to identify the clinical features of intradural extramedullary spinal cord metastases in primary lung cancer patients. Methods The 8 cases of lung cancer with intradural extramedullary metastases, who were hospitalized in Peking Union Medical College Hospital (PUMCH) during May 2013 to May 2016, were enrolled in the retrospective study. Medical charts of the 8 patients were reviewed systematically. Results Intradural extramedullary spinal cord metastases was diagnosed in 7 cases with non-small cell lung cancer (NSCLC) and 1 case with small cell lung cancer (SCLC). Cauda equina syndrome was the most common clinical manifestation. Malignant cells in cerebrospinal fluid were positive in all the 5 cases (100%) who underwent lumbar puncture. Contrast-enhanced magnetic resonance imaging (MRI) of spine manifested as diffuse abnormal enhancement of pial lining of spinal cordin 3 cases, intradural extramedullary nodules in 4 cases, and both of them in 1 case. Neurological symptoms were improved or stable in 4 cases who underwent targeted therapy and/or radiotherapy. The median overall survival was 5.8 months. Conclusion Intradural extramedullary spinal cord metastases can be diagnosed with caution according to its neurological symptoms and contrast-enhanced MRI presentation.Targeted therapy and/or radiotherapy may be effective for symptoms control

EGFR Gene Mutation Statuses in Advanced Non-small Cell Lung Cancer Patients and Their Influence on Effect of Gefitinib

Background and objective It has been proven that the status of epidermal growth factor receptor (EGFR) gene mutation was related to effects of gefitinib in patients with advanced non-small cell lung cancer (NSCLC). The aim of this study is to reports distribution of EGFR gene mutations in advanced NSCLC and their influence on effect of gefitinib. Methods From Jan 2007 to Dec 2009, 160 patients with advanced non-squamous NSCLC received EGFR mutation tests, and EGFR exon 19 and 21 were amplified by mutant-enriched PCR and analyzed by sequencing. Among those patients, 111 received gefitinib therapy. Overall survival (OS) and progression free survival (PFS) were calculated using the Kaplan-Meier method and a Cox regression analysis was used to detect differences between strata. Results The percentage of EGFR mutation in advanced non-squamous NSCLC was 55%, and it was only significantly related with pathological type. OS of the patients with or without EGFR gene mutations were 29.0 months (95%CI: 24.2-33.8) and 21.0 months (95%CI: 14.7-27.3) respectively, and the difference was not significant. PFS of patients with or without EGFR gene mutations were 17.0 months (95%CI: 5.6-17.6) and 11.6 months (95% CI 8.6~25.4), and the difference was significant (P=0.022). Multivariate analysis shows that OS was significantly related with ECOG status, pathological type and EGFR mutation statuses, and PFS was significantly related to ECOG status, former regimens number and EGFR mutation statuses. There were no significant differences in OS and PFS between patients with EGFR exon 19 deletions and those with exon 21 point mutation. Conclusion PFS of patients with EGFR mutations was better than those without EGFR mutations, but OS was similar. There were no significant differences in OS and PFS between patients with EGFR exon 19 deletions and those with exon 21 point mutation

Concurrent Driver Gene Mutations as Negative Predictive Factors in Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung CancerResearch in context

Background: Tyrosine kinase inhibitors (TKIs) are clinically effective in non-small cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) oncogene mutations. Genetic factors, other than EGFR sensitive mutations, that allow prognosis of TKI treatment remain undefined. Methods: We retrospectively screened 423 consecutive patients with advanced NSCLC and EGFR 19del or 21L858R mutations. A total of 71 patients whose progression-free survivals (PFS) were shorter than 6 months or longer than 24 months were included and stratified into separate groups. Genetic background discrepancy was analysed in the two groups using next generation sequencing (NGS). Findings: Sensitive EGFR mutations of 19del or 21L858R were detected by NGS in all patients; the 21L858R mutation was the major type. The most frequent accompanying somatic mutations were TP53, RB1, MAP2K. ALK fusion, MET amplification, and BRAF V600E were found only in the short PFS group. Concurrent pretreament T790 M mutation was found in both groups, but was proportionally higher in the short PFS group. In the short PFS group, patients had significantly more driver gene mutations than in long PFS group (P = 0·018). The numbers of concomitant somatic mutations, EGFR pathway-related mutations, and tumor mutation burden (TMB) were not significantly different between the two groups. Interpretation: Co-occuring driver gene mutations were negative predictive factors of TKI therapy in EGFR-mutated patients. This study highlights the importance of exploring co-occuring genomic alterations before initiation of EGFR-TKIs. Keywords: Non-small cell lung cancer, Epidermal growth factor receptor tyrosine kinase inhibitor, Predictive factor, Co-occurring mutation

Next Steps after Negative Results Obtained by EBUS-TBNA from Patients Suspected Clinically Lung Cancer with Mediastinal Lymphnode Metastasis

Background and objective Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is well known as an important technique for diagnosis and staging of lung cancer. But a standard protocol to deal with patients who have a negative pathology result still needs to be defined. Herein, we describe the subsequent procedures of these patients in a single center. Methods A total of 1,412 patients with clinical suspected lung cancer and mediastinal metastasis who underwent EBUS-TBNA were collected between September 2010 and December 2016. Among them, 51 patients with nonspecific pathology result were included and retrospectively analyzed. Results The 51 patients were stratified into five groups by clinical characterize and follow-up procedures: (1) Diagnosed by other bronchoscopy procedures group (9 cases). Abnormalities of tracheobronchial tree were found during visual examination in the majority of patients (8 cases). Biopsy, endobronchial brushing, bronchoalveolar lavage, and transbronchial lung biopsy (TBLB) were used to get a specific diagnosis. (2) EBUS-TBNA re-biopsy group (11 cases). Patients in this group had normal mucosal appearance and airway lumen. Re-biopsy were performed on patients in this group. (3) Surgery group (6 cases). Patients underwent surgery after negative result of EBUS-TBNA. Five of them were confirmed with non-nodal metastasis after surgery. (4) Underwent other pathology diagnosis group (15 cases). patients in this group had other metastasis sites besides midiastinal lymph node. Computed tomography (CT)-guided fine-needle aspiration and lymph node biopsy were performed. (5) Follow-up group (10 cases). None invasive procedure was used in this group. The median follow up time was 38 months. One patient was diagnosed lymphoma during the follow up. Conclusion Diagnostic procedures should be chosen based on the clinical character in EBUS-TBNA negative patients with suspected lung cancer. Long time follow-up is very important in patients whose diagnosis is apparently unknown