Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.     

Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

Stereotactic Body Radiotherapy for Centrally Located Primary Non–Small-Cell Lung Cancer: A Meta-Analysis

BackgroundThe purpose of the study was to evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) for centrally located, primary non–small-cell lung cancer (NSCLC).Materials and MethodsSystematic search of 4 databases (PubMed, MEDLINE, EMBASE, and Cochrane Library) was performed for literature published until May 9, 2018. Primary (overall survival [OS] and local control [LC] rates) and secondary (Grade ≥3 toxicity) endpoints were reported.ResultsThirteen studies encompassing 599 patients with central NSCLCs were included. Median values of T1 tumor proportion, tumor size, and median survival were 55.3% (range, 0%-75%), 3.3 (range, 2.1-4.1) cm, and 26 (range, 14-68.9) months, respectively. Pooled rates of 1-, 2-, and 3-year OS rates were 84.3% (95% confidence interval [CI], 75.7-90.3), 64.0% (95% CI, 52.9-72.2), and 50.5% (95% CI, 39.4-61.5), respectively. Pooled rates of 1-, 2-, and 3-year LC rates were 89.4% (95% CI, 80.8-94.4), 82.2% (95% CI, 71.7-89.4), and 72.2% (95% CI, 55.0-84.7), respectively. Pooled rate of Grade ≥3 complication was 12.0% (95% CI, 7.3-19.0). Meta-regression analyses showed significant positive relationships between biologically equivalent dose using an α/β of 10 Gy in the linear quadratic model (BED_10Gy) and 1- and 2-year LC rates (P < .001 and P < .001), and 1- and 2-year OS rates (P = .0178 and P = .032), and Grade ≥3 complication rate (P = .0029). In subgroup comparisons between BED_10Gy <100 Gy versus ≥100 Gy, 1- and 2-year LC rates were significantly different but not for OS and Grade ≥3 complication rates.ConclusionOur results suggests that SBRT is potent for tumor control in central NSCLC, although complications should be further minimized through optimization of dose-fractionation scheme and accurate planning. Using BED_10Gy ≥100 Gy yielded higher LC rates, and dose escalation was related to OS, LC, and complications.     

Assessment of a Radiomic Signature Developed in a General NSCLC Cohort for Predicting Overall Survival of ALK-Positive Patients With Different Treatment Types

BackgroundThe purpose of the study was to investigate the potential of a radiomic signature developed in a general non–small-cell lung cancer (NSCLC) cohort for predicting the overall survival of anaplastic lymphoma kinase (ALK)-positive (ALK⁺) patients with different treatment types.Materials and MethodsAfter test-retest in the Reference Image Database to Evaluate Therapy Response data set, 132 features (intraclass correlation coefficient > 0.9) were selected in the least absolute shrinkage and selection operator Cox regression model with a leave-one-out cross-validation. The NSCLC radiomics collection from The Cancer Imaging Archive was randomly divided into a training set (n = 254) and a validation set (n = 63) to develop a general radiomic signature for NSCLC. In our ALK⁺ set, 35 patients received targeted therapy and 19 patients received nontargeted therapy. The developed signature was tested later in this ALK⁺ set. Performance of the signature was evaluated with the concordance index (C-index) and stratification analysis.ResultsThe general signature had good performance (C-index > 0.6; log rank P < .05) in the NSCLC radiomics collection. It includes 5 features: Geom_va_ratio, W_GLCM_Std, W_GLCM_DV, W_GLCM_IM2, and W_his_mean. Its accuracy of predicting overall survival in the ALK⁺ set achieved 0.649 (95% confidence interval [CI], 0.640-0.658). Nonetheless, impaired performance was observed in the targeted therapy group (C-index = 0.573; 95% CI, 0.556-0.589) whereas significantly improved performance was observed in the nontargeted therapy group (C-index = 0.832; 95% CI, 0.832-0.852). Stratification analysis also showed that the general signature could only identify high- and low-risk patients in the nontargeted therapy group (log rank P = .00028).ConclusionThis preliminary study suggests that the applicability of a general signature to ALK⁺ patients is limited. The general radiomic signature seems to be only applicable to ALK⁺ patients who had received nontargeted therapy, which indicates that developing special radiomics signatures for patients treated with tyrosine kinase inhibitors might be necessary.     

Applying Human-Centered Design to the Development of an Asthma Essentials Kit for School-Aged Children and Their Parents

This study aimed to design and test an asthma essentials kit to support parent–child shared asthma management. Fourteen children (age range?=?7–11 years) with asthma and their parents participated in this study. Development of the asthma essentials kit involved a generative phase, focused on understanding and designing to meet user needs, and an evaluative phase, which entailed narrowing, evaluating, and refining the asthma essentials kit. As is typical in human-centered design, analysis was iterative throughout the design process such that findings informed each subsequent phase. The final asthma essentials kit concepts collectively addressed the three user-identified priorities: roles and responsibilities, desire for normalcy, and shared asthma management. Concept prototypes included a to-go bag, cue card, wearable device, and mobile health application. Usability and acceptability testing showed that the asthma essentials kit prototypes were highly useful, acceptable, and easy to navigate. Human-centered design holds promise in developing interventions to meet user needs.