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A thorough Single-Center Evaluation of Postoperative Vomiting and nausea Subsequent Orthognathic Surgery.
RESULTS We found that Kdm6a deficiency activated cytokine and chemokine pathways, promoted M2 macrophage polarization, increased cancer stem cells and caused bladder cancer in cooperation with p53 haploinsufficiency. We also found that BBN treatment significantly enhanced the expression of proinflammatory molecules and accelerated disease development. Human bladder cancer samples with decreased KDM6A expression also showed activated proinflammatory pathways. Notably, dual inhibition of IL6 and chemokine (C-C motif) ligand 2, upregulated in response to Kdm6a deficiency, efficiently suppressed Kdm6a-deficient bladder cancer cell growth. CONCLUSIONS Our findings provide insights into multistep carcinogenic processes of bladder cancer and suggest molecular targeted therapeutic approaches for patients with bladder cancer with KDM6A dysfunction. ©2020 American Association for Cancer Research.PURPOSE The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E-mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with CRC. EXPERIMENTAL DESIGN Paired fresh tumour biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM CRC enrolled in a Phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS). RESULTS Confirmed response rates, median PFS, and overall survival (OS) were higher in BM1 subtype patients compared to BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, while cell cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell cycle signatures revealed that BM subtype encompasses the majority of the effect. CONCLUSIONS BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context. Copyright ©2020, American Association for Cancer Research.In the era of cancer immunotherapy, there is a high interest in combining conventional cancer therapies such as radiotherapy with drugs that stimulate the immune system. The observation that ionizing radiation applied to mouse tumors could delay the growth of distant lesions ("abscopal effect") and this was potentiated by immunostimulatory drugs, led to clinical trials in which often only one lesion was irradiated. The results of these first clinical trials combining radio and immunotherapy are now becoming available. These results show that, while immunotherapy potentiates the local effects of radiotherapy, the abscopal effect is still infrequent. Transcriptomic analysis of resected colorectal cancer (CRC) metastases allows to distinguish three molecular subtypes with distinct potential to benefit from localized therapies and/or immunotherapy; the subtype with characteristics consistent with the existence of preexisting immunity is the most likely to respond to radiation. Recent preclinical data suggests these preexistent T cells can survive radiation and contribute to its therapeutic effect. In this review, we discuss possible reasons for the preclinical/clinical discrepancies regarding the abscopal effect, and we propose irradiation of multiple or all tumors combined with systemic immunotherapy, patient selection based on tumor subtype, and rational therapeutic combinations that take into account preexisting immunity, as possible avenues to increase the efficacy of radio-immunotherapy. Copyright ©2020, American Association for Cancer Research.PURPOSE Treatment with PD-(L)1 blockade can produce remarkably durable responses in non-small cell lung cancer (NSCLC) patients. However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. EXPERIMENTAL DESIGN In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (PFS≥12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n=18) or by targeted sequencing (n=6). RESULTS 31 NSCLC patients with long-term benefit to PD-(L)1 blockade were identified and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; by contrast, all four patients with detectable ctDNA eventually progressed (Fisher's p less then 0.0001; PPV 1 [95% CI 0.51-1]; NPV 0.93 [95% CI 0.80-0.99]). CONCLUSIONS ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression. Copyright ©2020, American Association for Cancer Research.PURPOSE While various studies have highlighted the prognostic significance of pathological complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known. EXPERIMENTAL DESIGN PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. FPH1 ic50 Hazard ratios (HRs), with 95% probability intervals (PIs), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piecewise-exponential proportional hazards hierarchical models including pCR as predictor. RESULTS Overall, 52 of 3209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR 0.31, 95% PI 0.24-0.39), particularly for triple negative (HR 0.18, 95% PI 0.10-0.31) and HER2+ (HR 0.32, 95% PI 0.21-0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR 0.22, 95% PI 0.15-0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR 0.36, 95% PI 0.19-0.67) and those without adjuvant chemotherapy (HR 0.36, 95% PI 0.27-0.54), with no significant difference between the two groups (p = 0.60). INTERPRETATION Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple negative and HER2+ breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/de-escalation strategies in the adjuvant setting based on neoadjuvant response. Copyright ©2020, American Association for Cancer Research.HER2+ early breast cancer is a heterogeneous disease, comprising all the intrinsic breast cancer subtypes. The only biomarker available nowadays for anti-HER2 treatment selection is HER2 status itself, but estrogen receptor (ER) status is emerging as a robust predictive marker within HER2+ disease. In this Perspective, we discuss the biological and clinical differences between patients with HER2+/ER positive (ER+) disease versus those with HER2+/ER negative (ER-neg) tumors, namely short- and long-term (>5 years after diagnosis) prognosis, response to neoadjuvant treatment and benefit from adjuvant anti-HER2 targeted therapies. We also address other possible biomarkers to be used for patient selection in future clinical trials, like gene signatures, PAM50 subtypes, tumor-infiltrating lymphocytes, PIK3CA mutations, and changes in Ki67 score during treatment and discuss their limitations. Finally, we suggest new clinical trial designs that can have an impact on clinical practice, aiming to test treatment de-escalation separately for patients with HER2+/ER+ and HER2+/ER-neg tumors. We also propose an integrated classification of HER2+ disease, comprising DNA, RNA, protein expression and microenvironment characteristics, in order to identify those tumors that are truly "HER2-addicted" and may benefit the most from anti-HER2 treatment. Copyright ©2020, American Association for Cancer Research.BACKGROUND A new dual resolution imaging x-ray detector system (Canon Medical Systems Corporation, Tochigi, Japan) has a standard resolution 194 µm pixel conventional flat-panel detector (FPD) mode and a high-resolution 76 µm high-definition (Hi-Def) mode in a single unit. The Hi-Def mode enhances the visualization of the intravascular devices. OBJECTIVE We report the clinical experience and physician evaluation of this new detector system with Hi-Def mode for the treatment of intracranial aneurysms using a Pipeline embolization device (PED). METHODS During intervention at our institute, under large field of view (FOV) regular resolution FPD mode imaging, the catheter systems and devices were first guided to the proximity of the treatment area. Final placement and deployment of the PED was performed under Hi-Def mode guidance. A post-procedure 9-question physician survey was conducted to qualitatively assess the impact of Hi-Def mode visualization on physicians' intraoperative decision-making. One-sample t-test was performed on the responses from the survey. Dose values reported by the x-ray unit were also recorded. RESULTS Twenty-five cases were included in our study. The survey results indicated that, for each of the nine questions, the physicians in all cases indicated that the Hi-Def mode improved visualization compared with the FPD mode. For the 25 cases, the mean cumulative entrance air kerma was 2.35 Gy, the mean dose area product (DAP) was 173.71 Gy.cm2, and the mean x-ray exposure time was 39.30 min. CONCLUSIONS The Hi-Def mode improves visualization of flow diverters and may help in achieving more accurate placement and deployment of devices. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Over the last decade dramatic advances have been made in both the technology and data available to better understand the multifactorial influences on child and adolescent health and development. This paper seeks to clarify methods that can be used to link information from health, education, social care and research datasets. Linking these different types of data can facilitate epidemiological research that investigates mental health from the population to the patient; enabling advanced analytics to better identify, conceptualise and address child and adolescent needs. The majority of adolescent mental health research is not able to maximise the full potential of data linkage, primarily due to four key challenges confidentiality, sampling, matching and scalability. By presenting five existing and proposed models for linking adolescent data in relation to these challenges, this paper aims to facilitate the clinical benefits that will be derived from effective integration of available data in understanding, preventing and treating mental disorders.
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