Single-cell technologies have revealed the complexity of the tumour immune microenvironment with unparalleled resolution
. Most clinical strategies rely on histopathological stratification of tumour ...subtypes, yet the spatial context of single-cell phenotypes within these stratified subgroups is poorly understood. Here we apply imaging mass cytometry to characterize the tumour and immunological landscape of samples from 416 patients with lung adenocarcinoma across five histological patterns. We resolve more than 1.6 million cells, enabling spatial analysis of immune lineages and activation states with distinct clinical correlates, including survival. Using deep learning, we can predict with high accuracy those patients who will progress after surgery using a single 1-mm
tumour core, which could be informative for clinical management following surgical resection. Our dataset represents a valuable resource for the non-small cell lung cancer research community and exemplifies the utility of spatial resolution within single-cell analyses. This study also highlights how artificial intelligence can improve our understanding of microenvironmental features that underlie cancer progression and may influence future clinical practice.
To determine how patients with infiltrating lobular carcinoma (ILC) differ from patients with the more common infiltrating ductal carcinoma (IDC) with regard to patient and tumor factors, local ...treatment, and patterns of recurrence.
Twelve thousand two hundred six breast cancer patients entered onto 15 International Breast Cancer Study Group trials between 1978 and 2002 were categorized as having ILC, IDC, or other/mixed types.
Seven hundred sixty-seven tumors (6.2%) were classified as ILC, 8,607 (70.5%) were classified as IDC, and 2,832 (23.2%) were classified as other. The analysis is limited to the 9,374 patients categorized as either pure IDC or ILC. The median follow-up time was 13 years. Compared with IDC, ILC was associated with older age; larger, better differentiated, and estrogen receptor (ER)-positive tumors; and less vessel invasion. Mastectomy was used more frequently for ILC (P < .01). There was a significant (P < .01) early advantage in disease-free survival and overall survival for the ILC cohort followed by a significant (P < .01) late advantage for the IDC cohort after 6 and 10 years, respectively. Similar patterns were observed in cohorts defined by ER status. ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (all P < .01).
ILC is more than a histologic variant of breast cancer. The diagnosis of ILC carries distinct prognostic and biologic implications.
The purpose of this study was to determine outcomes of patients with node-negative medically inoperable non-small cell lung cancer (NSCLC) whose primary tumors exceeded 5 cm and were treated with ...stereotactic body radiation therapy (SBRT).
We surveyed our institutional prospective lung SBRT registry to identify treated patients with tumors >5 cm. Treatment outcomes for local control (LC), locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were assessed by Kaplan-Meier estimates. Toxicities were graded according to Common Terminology Criteria for Adverse Events version 4. Mean pretreatment pulmonary function test values were compared to mean posttreatment values.
From December 2003 to July 2014, 40 patients met study criteria. Median follow-up was 10.8 months (range: 0.4-70.3 months). Median age was 76 years (range: 56-90 years), median body mass index was 24.3 (range: 17.7-37.2), median Karnofsky performance score was 80 (range: 60-90), and median Charlson comorbidity index score was 2 (range: 0-5). Median forced expiratory volume in 1 second (FEV1) was 1.41 L (range: 0.47-3.67 L), and median diffusion capacity (DLCO) was 47% of predicted (range: 29%-80%). All patients were staged by fluorodeoxyglucose-positron emission tomography/computed tomography staging, and 47.5% underwent mediastinal staging by endobronchial ultrasonography. Median tumor size was 5.6 cm (range: 5.1-10 cm), median SBRT dose was 50 Gy (range: 30-60 Gy) in 5 fractions (range: 3-10 fractions). Eighteen-month LC, LRC, DFS, and OS rates were 91.2%, 64.4%, 34.6%, and 59.7%, respectively. Distant failure was the predominant pattern of failure (32.5%). Three patients (7.5%) experienced grade 3 or higher toxicity. Mean posttreatment FEV1 was not significantly reduced (P=.51), but a statistically significant absolute 6.5% (P=.03) reduction in DLCO was observed.
Lung SBRT for medically inoperable node-negative NSCLC with primary tumors larger than 5 cm is safe and provides excellent local control with limited toxicity. The predominant pattern of failure in this population was distant failure.
Vismodegib, an inhibitor of the Hedgehog signaling pathway, is an approved drug for monotherapy in locally advanced or metastatic basal cell carcinoma (BCC). Data on combined modality treatment by ...vismodegib and radiation therapy, however, are rare. In the present study, we examined the radiation sensitizing effects of vismodegib by analyzing viability, cell cycle distribution, cell death, DNA damage repair and clonogenic survival in three-dimensional cultures of a BCC and a head and neck squamous cell carcinoma (HNSCC) cell line. We found that vismodegib decreases expression of the Hedgehog target genes glioma-associated oncogene homologue (GLI1) and the inhibitor of apoptosis protein (IAP) Survivin in a cell line- and irradiation-dependent manner, most pronounced in squamous cell carcinoma (SCC) cells. Furthermore, vismodegib significantly reduced proliferation in both cell lines, while additional irradiation only slightly further impacted on viability. Analyses of cell cycle distribution and cell death induction indicated a G1 arrest in BCC and a G2 arrest in HNSCC cells and an increased fraction of cells in SubG1 phase following combined treatment. Moreover, a significant rise in the number of phosphorylated histone-2AX/p53-binding protein 1 (γH2AX/53BP1) foci in vismodegib- and radiation-treated cells was associated with a significant radiosensitization of both cell lines. In summary, these findings indicate that inhibition of the Hedgehog signaling pathway may increase cellular radiation response in BCC and HNSCC cells.
Introduction
The rate of contralateral prophylactic mastectomy (CPM) has recently increased. The aim of this study is to assess perceptions of contralateral breast cancer (CBC) risk among breast ...cancer patients and to evaluate tumor and patient factors associated with risk perception.
Methods
We conducted a prospective survey study to evaluate perceptions of CBC risk in women newly diagnosed with ductal carcinoma in situ (DCIS) or stage I/II invasive breast cancer. Surveys were distributed in clinic prior to surgical consultation. Exclusion criteria included history of breast cancer, bilateral breast cancer, neoadjuvant chemotherapy or radiation for the current breast cancer, or
BRCA
mutation. Survey questions used open-ended responses or five-point Likert scale scoring (5 = very likely, 1 = not at all likely).
Results
Seventy-four women (mean age 54.5 years) completed the survey. Diagnoses included invasive ductal cancer (66.2%), invasive lobular cancer (9.5%), and DCIS (20.3%). Most women (54.1%) underwent breast-conserving surgery; the remaining had bilateral mastectomy including CPM (17.6%) or unilateral mastectomy (10.8%). Overall, women substantially overestimated their risk of developing CBC. The mean estimated 10-year risk of CBC was 31.4% 95% confidence interval (CI) 24.7–37.9% and 2.6 ± 0.15 on the rank scale. The perceived risk of CBC was not significantly associated with cancer stage, family history, age, or CPM.
Conclusions
At time of surgical evaluation, women with unilateral breast cancer substantially overestimated their risk of CBC; however, this elevated risk perception was not associated with choosing CPM. Early physician counseling is needed to provide women with accurate information regarding their true CBC risk.
Lung squamous cell carcinoma (LUSC) is associated with a worse prognosis than other histological subtypes of non-small cell lung cancer. Due to the vital role of CD8
T cells in anti-tumor immunity, ...the characterization of CD8
T cell infiltration-related (CTLIR) gene signature in LUSC is worthy of in-depth exploration. In our study, tumor tissues of LUSC patients from Renmin Hospital of Wuhan University were stained by multiplex immunohistochemistry to evaluate the density of infiltrated CD8
T cells and explore the correlation with immunotherapy response. We found that the proportion of LUSC patients who responded to immunotherapy was higher in the high density of CD8
T cell infiltration group than in the low density of CD8
T cell infiltration group. Subsequently, we collected bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) database. The abundance of infiltrating immune cells in LUSC patients was analyzed by using CIBERSORT algorithm, and weighted correlation network analysis was performed to identify the co-expressed gene modules related to CD8
T cells. We then developed a prognostic gene signature based on CD8
T cell co-expressed genes and calculated the CTLIR risk score, which stratified LUSC patients into high-risk and low-risk groups. With univariate and multivariate analyses, the gene signature was identified as an independent prognostic factor in LUSC patients. The overall survival of LUSC patients in the high-risk group was significantly shorter than that of the low-risk group in the TCGA cohort, which was validated in Gene Expression Omnibus datasets. We analyzed immune cell infiltration in the tumor microenviroment and found fewer CD8
T cells and more regulatory T cell infiltration in the high-risk group, which is characterized as an immunosuppressive phenotype. Furthermore, the LUSC patients in the high-risk group were predicted to have a better response to immunotherapy than those in the low-risk group when treated with PD-1 and CTLA4 inhibitors. In conclusion, we performed a comprehensive molecular analysis of the CTLIR gene signature in LUSC and constructed a risk model for LUSC patients to predict prognosis and immunotherapy response.
As the genomic region containing the Bcl‐2‐related ovarian killer (BOK) locus is frequently deleted in certain human cancers, BOK is hypothesized to have a tumor suppressor function. In the present ...study, we analyzed primary non‐small‐cell lung carcinoma (NSCLC) tumors and matched lung tissues from 102 surgically treated patients. We show that BOK protein levels are significantly downregulated in NSCLC tumors as compared to lung tissues (p < 0.001). In particular, we found BOK downregulation in NSCLC tumors of grades two (p = 0.004, n = 35) and three (p = 0.031, n = 39) as well as in tumors with metastases to hilar (pN1) (p = 0.047, n = 31) and mediastinal/subcarinal lymph nodes (pN2) (p = 0.021, n = 18) as opposed to grade one tumors (p = 0.688, n = 7) and tumors without lymph node metastases (p = 0.112, n = 51). Importantly, in lymph node‐positive patients, BOK expression greater than the median value was associated with longer survival (p = 0.002, Mantel test). Using in vitro approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGFβ‐induced migration and epithelial‐to‐mesenchymal transition (EMT) in lung adenocarcinoma‐derived A549 cells. We have identified epigenetic mechanisms, in particular BOK promoter methylation, as an important means to silence BOK expression in NSCLC cells. Taken together, our data point toward a novel mechanism by which BOK acts as a tumor suppressor in NSCLC by inhibiting EMT. Consequently, the restoration of BOK levels in low‐BOK‐expressing tumors might favor the overall survival of NSCLC patients.
What's new?
Bcl‐2‐related ovarian killer (BOK) is one of the most frequently deleted Bcl‐2 family members in human cancer. Here the authors identify a possible cell death‐independent tumor suppressor function of BOK. They find that BOK is epigenetically silenced and that its overexpression decreases anchorage‐independent growth in non‐small‐cell lung carcinoma (NSCLC). In vivo, BOK levels were predictive of survival in lymph node‐positive patients, pointing to BOK expression as a new prognostic marker in later stage NSCLC.
To investigate the impact of PDZ-binding kinase (PBK) on the clinical outcome of patients with oral squamous cell carcinoma (OSCC) who received radiotherapy.
PBK immunoreactivity of cancer specimens ...obtained from 179 patients with primary OSCC was analyzed by immunohistochemistry.
High PBK expression in tumor cells tended to be associated with advanced N-stage. The 5-year survival rate was greater for patients with high total PBK expression than in those with low PBK expression. After adjustment, high PBK remained associated with a favorable outcome. In subgroups according to tumor stage, the prognostic role was significant in patients with stage III/IV rather than those with stage I/II disease.
We suggest that PBK expression should be used as an independent prognostic marker for patients with OSCC treated with radiotherapy, especially for those with advanced-stage disease.
: Head and neck squamous cell carcinoma (HNSCC) are head and neck cancers. On the other hand, ferroptosis is a novel iron-dependent and ROS reliant type of cell death observed various disease ...conditions.
: We constructed a prognostic multilncRNA signature based on ferroptosis-related differentially expressed lncRNAs in HNSCC.
: We identified 25 differently expressed lncRNAs associated with prognosis of HNSCC. Kaplan-Meier analyses revealed the high-risk lncRNAs signature associated with poor prognosis of HNSCC. Moreover, the AUC of the lncRNAs signature was 0.782, underscoring their utility in prediction HNSCC prognosis. Indeed, our risk assessment model was superior to traditional clinicopathological features in predicting HNSCC prognosis. GSEA revealed the immune and tumor-related pathways in the low risk group individuals. Moreover, TCGA revealed T cell functions including cytolytic activity, HLA, regulation of inflammationp, co-stimulation, co-inhibition and coordination of type II INF response were significantly different between the low-risk and high-risk groups. Immune checkpoints such as PDCD-1 (PD-1), CTLA4 and LAG3, were also expressed differently between the two risk groups.
A novel ferroptosis-related lncRNAs signature impacts on the prognosis of HNSCC.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, which ranks as the sixth of cancer-related death. Despite the emergence of targeted therapy, advanced-stage HCC remains ...largely incurable due to low response rate and therapeutic resistance. In this review, we mainly focused on the current progression of multi-kinase inhibitors and immunotherapies in the treatment of HCC. We highlight the mechanism underlying the ineffectiveness of these targeted therapies, including oncogenic alterations in driver genes and downstream pathways, high heterogeneity of HCC, and the mutual interaction of tumor microenvironment that promotes therapeutic resistance. We also discussed how these previous studies suggested for future therapeutic strategies. Besides, the complexity of HCC heterogeneity and cancer revolution need to be recognized in personalized therapy. Establishment of a drug screening system and identification of biomarkers of response is also in urgent need to overcome drug resistance. Meanwhile, a combination of targeted therapies could also be explored as a promising strategy in the future.
•Despite the emergence of targeted therapy, advanced-stage HCC remains largely incurable due to therapeutic resistance.•Multiple factors contribute to drug resistance of HCC patients against MKIs.•Further studies are expected to identify biomarkers for response and promote efficacy of immunotherapy.•Insight into heterogeneity of HCC and combined therapy could be the next step forward the future of precision medicine.
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