Aid Patient Selection Research Articles

Sa1466 EUS HAS THE POTENTIAL TO EVALUATE MEMBERS OF THE TUMOR NECROSIS FACTOR (TNF) SUPERFAMILY AND IDENTIFY DRUG TARGETS ON AN INDIVIDUAL PDAC PATIENT BASIS TO GUIDE PRECISION IMMUNE-ONCOLOGY ELIGIBILITY

The FDA has approved use of the programmed cell death-1 (PD-1) inhibitor, pembrolizumab, in MSI-High solid tumors. This is a rare event among pancreas ductal adenocarcinoma (PDAC) patients, occurring at a frequency of 0.8%. In order to decipher if other cancer immunotherapy targets are potential therapies for PDAC patients, the Tumor Necrosis Factor (TNF) Receptor Superfamily has gained prominence, due to its ability to activate antitumor T-cell immunity. Members include CD70, TNFSF4 (OX-40L) and TNFRSF9 (41BB). It is important to develop strategies to aid patient selection criteria to guide therapeutic decision-making for clinical trials. We sought to determine if EUS fine needle biopsy (FNB) treatment naïve PDAC specimens are suitable to evaluate the TNF Superfamily, and in turn identify potential targets on an individual patient basis. The cohort of 13 EUS FNB patient specimens, 7 of whom with ≥ stage III disease, a CA19-9 level of 227.5 (IQR 58-605) U/ml and overall mortality of 77% at 22.2 (IQR 13.4-36.1) months was evaluated by the Nanostring nCounter® PanCancer Immune Profiling Panel. This is a highly multiplexed mRNA gene expression panel designed to quantitate the expression of 770 genes. A ≥ 2-fold change in expression when compared to pancreas control tissue was deemed to be reflective of altered expression. The digital mRNA profiling panel revealed that 44.8% and 10% of evaluated genes had either increased or reduced expression, when compared to normal pancreas controls. Of the 30 TNF Superfamily gene members evaluated, 17 (56.7%) and 1 (3.3%) were up and downregulated in PDAC and 4 (13.3%) were each up and down regulated in surgical resection chronic pancreatitis specimens (n=3), respectively. (Figure 1) TNFRSF10C (alias TRAILR3) and TNFRSF11B (alias Osteoprotegerin) expressions were elevated in 12 (92.3%) PDAC specimens x12.2-fold (range x1.8 – x36.2 fold) and x6.5-fold (range x1.8 – x40.9 fold), respectively. CD70, an immune checkpoint, had a tumor-restricted expression pattern and was upregulated in 10 (77%) PDAC patients (x3.2-fold) but downregulated in chronic pancreatitis (x-4.23-fold). (Figure 2) EUS has a central role in guiding precision immune-oncology eligibility for clinical care and clinical trials. Using digital mRNA profiling, CD70 had a tumor-restricted expression pattern and was identified in 77% of PDAC patient specimens. Therefore, this suggests that such patients may be sensitive to monoclonal antibody therapy that targets and neutralizes CD70.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden

SummaryImmune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but prediction of their benefit is challenging. Neoantigens generated through impaired non-mismatch DNA repair may result in greater ICI activity. By analyzing 1,661 ICI-treated patients, we show that deletions and mutations in nucleotide excision repair (NER) and homologous repair (HR) pathways are predictors of ICI benefit independent of tumor mutation burden and tumor type. NER and HR mutations are also associated with objective response rates to ICIs in esophagogastric and non-small-cell lung cancers. In a cohort of 40,181 unique patients, NER and HR mutations are present in 3.4% and 13.9% of cancers, respectively. These results indicate that NER and HR gene mutations occur in a subpopulation of cancer patients and may aid patient selection for ICI therapy. Assessing NER and HR mutations in the context of other biomarkers may yield powerful predictors of ICI activity across different cancer types.

Rates and Predictors of Perioperative Complications in Cytoreductive Nephrectomy: Analysis of the Registry for Metastatic Renal Cell Carcinoma

BackgroundCytoreductive nephrectomy (CN) plays an important role in the treatment of a subgroup of metastatic renal cell carcinoma (mRCC) patients. ObjectiveWe aimed to evaluate morbidity associated with this procedure and identify potential predictors thereof to aid patient selection for this procedure and potentially improve patient outcomes. Design, setting, and participantsData from 736 mRCC patients undergoing CN at 14 institutions were retrospectively recorded in the Registry for Metastatic RCC (REMARCC). Outcome measurements and statistical analysisLogistic regression analysis was used to identify predictors for intraoperative, any-grade (AGCs), low-grade, and high-grade (HGCs) postoperative complications (according to the Clavien-Dindo classification) as well as 30-d readmission rates. Results and limitationsIntraoperative complications were observed in 69 patients (10.9%). Thrombectomy (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.08–1.75, p = 0.009) and adjacent organ removal (OR 2.7, 95% CI 1.38–5.30) were significant predictors of intraoperative complications at multivariable analysis. Two hundred seventeen patients (29.5%) encountered AGCs, while 45 (6.1%) encountered an HGC, of whom 10 (1.4%) died. Twenty-four (3.3%) patients had multiple postoperative complications. Estimated blood loss (EBL; OR 1.49, 95% CI 1.08–2.05, p = 0.01) was a significant predictor of AGCs at multivariable analysis. CN case load (OR 0.13, 95% CI 0.03–0.59, p = 0.009) and EBL (OR 2.93, 95% CI 1.20–7.15, p = 0.02) were significant predictors solely for HGCs at multivariable analysis. Forty-one patients (11.5%) were readmitted within 30 d of surgery. No significant predictors were identified. Results were confirmed in a subanalysis focusing solely on patients treated in the contemporary targeted therapy era. ConclusionsMorbidity associated with CN is not negligible. Predictors of high-grade postoperative morbidity are predominantly indicators of complex surgery. EBL is a strong predictor of postoperative complications. CN case load correlates with lower high-grade morbidity and highlights the benefit of centralization of complex surgery. However, risks and benefits should be balanced when considering CN in mRCC patients. Patient summaryWe studied patients with metastatic renal cancer to evaluate the outcomes associated with the surgical removal of the primary kidney tumor. We found that this procedure is often complex and adverse events are not uncommon. High intraoperative blood loss and a small number of cases performed at the treating center are associated with a higher rate of postoperative complications.

Developing a Process for Criteria-Led Discharge: Selection of Patients for Efficient and Effective Discharge (SPEED).

Criteria-led discharge (CLD) is an approach for maximizing bed capacity by expediting patient discharge. In acute medicine settings, patients commonly have multiple medical problems, which render single care pathway and clinical protocols of limited use. CLD offers potential, but little evidence exists about how to best implement it in these contexts. Retrospective case note analysis generated characteristics from patients' discharge plans to design a criterion-based framework to aid patient selection for CLD. These criteria were hypothetically tested on patient case notes (n = 50). CLD was identified as suitable (n = 27) and unsuitable (n = 23) from 50 case notes. Interrater agreement was 86% between 3 reviewers. This review has provided greater understanding of the complexity of discharge in acute medicine settings. Implementing CLD to optimize timeliness of patient discharge might offer a solution for selected patients.

Use of Deep Learning to Predict Final Ischemic Stroke Lesions From Initial Magnetic Resonance Imaging

Predicting infarct size and location is important for decision-making and prognosis in patients with acute stroke. To determine whether a deep learning model can predict final infarct lesions using magnetic resonance images (MRIs) acquired at initial presentation (baseline) and to compare the model with current clinical prediction methods. In this multicenter prognostic study, a specific type of neural network for image segmentation (U-net) was trained, validated, and tested using patients from the Imaging Collaterals in Acute Stroke (iCAS) study from April 14, 2014, to April 15, 2018, and the Diffusion Weighted Imaging Evaluation for Understanding Stroke Evolution Study-2 (DEFUSE-2) study from July 14, 2008, to September 17, 2011 (reported in October 2012). Patients underwent baseline perfusion-weighted and diffusion-weighted imaging and MRI at 3 to 7 days after baseline. Patients were grouped into unknown, minimal, partial, and major reperfusion status based on 24-hour imaging results. Baseline images acquired at presentation were inputs, and the final true infarct lesion at 3 to 7 days was considered the ground truth for the model. The model calculated the probability of infarction for every voxel, which can be thresholded to produce a prediction. Data were analyzed from July 1, 2018, to March 7, 2019. Area under the curve, Dice score coefficient (DSC) (a metric from 0-1 indicating the extent of overlap between the prediction and the ground truth; a DSC of ≥0.5 represents significant overlap), and volume error. Current clinical methods were compared with model performance in subgroups of patients with minimal or major reperfusion. Among the 182 patients included in the model (97 women [53.3%]; mean [SD] age, 65 [16] years), the deep learning model achieved a median area under the curve of 0.92 (interquartile range [IQR], 0.87-0.96), DSC of 0.53 (IQR, 0.31-0.68), and volume error of 9 (IQR, -14 to 29) mL. In subgroups with minimal (DSC, 0.58 [IQR, 0.31-0.67] vs 0.55 [IQR, 0.40-0.65]; P = .37) or major (DSC, 0.48 [IQR, 0.29-0.65] vs 0.45 [IQR, 0.15-0.54]; P = .002) reperfusion for which comparison with existing clinical methods was possible, the deep learning model had comparable or better performance. The deep learning model appears to have successfully predicted infarct lesions from baseline imaging without reperfusion information and achieved comparable performance to existing clinical methods. Predicting the subacute infarct lesion may help clinicians prepare for decompression treatment and aid in patient selection for neuroprotective clinical trials.

Predicting Endovascular Treatment Outcomes in Acute Vertebrobasilar Artery Occlusion: A Model to Aid Patient Selection from the ASIAN KR Registry.

Background The decision to perform endovascular treatment (EVT) for stroke related to vertebrobasilar occlusion (VBO) remains controversial. Purpose To identify preprocedural predictors of good outcomes and to develop a model to aid patient selection for VBO. Materials and Methods For this retrospective study using a Korean multicenter registry, a predictive model for good outcomes (modified Rankin scale score, 0-2) was generated based on a derivation sample of patients with VBO (January 2011-February 2016). Preprocedural parameters, including onset-to-puncture time, infarct volume, occlusion type as a surrogate marker of intracranial atherosclerotic stenosis-related occlusion or embolic occlusion (truncal-type occlusion vs branching site occlusion), and collateral status, were analyzed. Continuous variables were dichotomized based on receiver operating characteristic analysis. Multiple logistic regression analysis was performed to generate a predictive model. The model was internally validated with the bootstrap method and was externally validated with a single-center sample (April 2016-December 2018). Results A predictive model was generated from 71 patients (mean age, 67 years ± 11 [standard deviation]; 41 [58%] men) and was externally validated in 32 patients (mean age, 72 years ± 13; 19 [59%] men). The composite of initial DW imaging volume of less than 10 mL (odds ratio [OR], 19.3; 95% confidence interval [CI]: 3.0, 126.4; P = .002), onset-to-puncture time of less than 8 hours (OR, 8.7; 95% CI: 1.8, 42.0; P = .007), and branching-site occlusion (OR, 6.1; 95% CI: 1.5, 26.0; P = .01) could be used to predict good outcomes, with a median area under the receiver operating characteristic curve of 0.86 (interquartile range [IQR], 0.77-0.95; bootstrap optimism-corrected C statistic, 0.837) in the derivation sample and 0.78 (IQR, 0.62-0.95) in the validation sample. Results failed to show an association between collateral status and outcome (P = .67). Conclusion When selecting patients with vertebrobasilar occlusion for endovascular treatment, the combination of onset-to-puncture time of less than 8 hours, initial infarct volume of less than 10 mL, and presence of branching-site occlusions is indicative of a good outcome. © RSNA, 2020 Online supplemental material is available for this article.

Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations?

The DNA damage response (DDR) machinery is responsible for detecting DNA damage, pausing the cell cycle and initiating DNA repair. Ataxia telangiectasia and Rad3-related (ATR) protein is a key kinase at the heart of the DDR, responsible for sensing replication stress (RS) and signalling it to S and G2/M checkpoints to facilitate repair. In cancer, loss of G1 checkpoint control and activation of oncogenes that drive replication, result in cancer cells more likely to enter S phase with increased RS. These cancer cells become more reliant on their S and G2/M checkpoints, making this an attractive anti-cancer target. Targeting ATR is the focus of many oncology drug pipelines with a number of potent, selective ATR inhibitors developed, four (M6620, M4344, AZD6738 and BAY1895344) are currently in clinical development. Here we summarise the pre-clinical data supporting the use of ATR inhibitors as monotherapy and in combination with chemotherapy, radiotherapy and novel targeted agents such as PARP inhibitors. We discuss the current clinical trial data and the challenges of taking ATR inhibitors into the clinic and of identifying biomarkers to aid patient selection.

A Clinical Validation Study of Anatomical Risk Scoring for Procedural Stroke in Patients Treated by Carotid Artery Stenting in the International Carotid Stenting Study

Vascular anatomy of the aortic arch and supra-aortic arteries has been suggested as influencing the risk of carotid artery stenting (CAS). The expert opinion based Delphi anatomical risk (DAR) score was developed to predict difficulty of CAS in relation to procedural stroke risk, and thereby aid patient selection. The aim was to validate the DAR score in the context of a randomised clinical trial. In this post hoc analysis of the International Carotid Stenting Study (ICSS), only patients treated by CAS with available pre-procedural CT angiography (CTA) were included. Patients with tortuous anatomy unsuitable for stenting were excluded from ICSS. CTA based vascular anatomy was rated by two independent observers. Every possible combination of anatomy resulted in a risk score, divided in four categories of expected risk (low, < 5.0; low-intermediate, 5.0-5.9; high-intermediate, 6.0-6.9; high, ≥ 7.0). Binomial logistic regression was used to assess the relationship between anatomical risk score and procedural risk of any stroke. Differences between predefined age groups were also assessed. A total of 275 patients were included. Interobserver reliability for all anatomical risk factors was high (κ=0.76-0.84). In total, 16 strokes (6%) occurred in the procedural period. No significant relationship was observed between the DAR score and risk of procedural stroke, with the risk of stroke being 9% in the high risk vs. 4% in the low risk categories (p=.49). A higher mean DAR score was observed in patients ≥70 years compared with younger patients (4.6±1.5 vs. 3.9±1.4, p<.001), which was mainly explained by higher rates of arch atheroma (44% vs. 20%, p<.001). Prolonged intervention duration was significantly associated with increased stroke risk (11% vs. 4%, p<.04), but not with the DAR score. No statistically significant association was found between anatomical difficulty, as defined in the DAR score, and procedural stroke risk. However, the small sample size potentially rendered the study underpowered to detect group differences, and confirmation with a larger sample is essential.

Neurocognitive mechanisms of prefrontal stimulation

The difficulty in treating mood and anxiety disorders has sparked clinical interest in novel treatments, such as transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). However, underlying mechanisms of action are unclear. It is established that people with mood and anxiety disorders have negative cognitive biases, such as increased vigilance to threat. Psychiatric treatments have acute effects on these cognitive biases, which predict later therapeutic action. Such effects are proposed as cognitive biomarkers of response. A healthy volunteer investigation revealed an anxiolytic-like effect (reduced threat vigilance) of single-session tDCS on a behavioural test of proven clinical relevance (Ironside et al., 2016, Biological Psychiatry). Complementing this, we used functional imaging to reveal that, in a sample of trait anxious females, tDCS of the DLPFC increased activation in an attentional control network and reduced amygdala response to fearful face distractors (Ironside et al., under revision, JAMA Psychiatry). This provides causal evidence that modulating activity in the DLPFC inhibits amygdala response to threat, providing a potential neural mechanism for the previous reduction in vigilance to threat. Collectively, these results propose an emerging neurocognitive model of the mechanisms of action of tDCS. We also examined pairing tDCS with attentional bias modification training and found no effect of stimulation. However, DLPFC tDCS has been successfully paired with other paradigms such as cognitive control training. As highlighted in the next talks, we suggest that computationally specified learning tasks may be more sensitive. Together, findings point to an anxiolytic-like effect of DLPFC tDCS on cognitive and neural biomarkers relevant to mood and anxiety disorders, indicating potential neurocognitive mechanisms that may mediate the reported clinical efficacy of DLPFC tDCS. This has implications as the identification of treatment response markers that could aid patient selection for future trials and ultimately guide treatment selection for patients.

Abstract P3-06-13: Whole exome sequencing of HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary durable complete responses (ExdCR) to trastuzumab (T)

Abstract Background: Trastuzumab (T) has shown clinical efficacy in early-stage and MBC. However, within 1-year 40-50% develop resistance to T. The exact mechanism of the development of T resistance is not completely understood. Anecdotal observations suggest that a small fraction of patients with HER2+ MBC may be "extraordinary durable complete responders (ExdCR)". Indeed, we previously reported that 9% of MBC achieve dCR following T and chemotherapy. Understanding the genomic mechanisms underlying exceptional dCR to T may improve patient selection and treatment rationale to identify HER2+ MBC pts who are more likely to achieve dCR following T treatment. Methods: Genomic DNA was extracted from paraffin embedded formalin fixed (FFPE) tissue. Whole exome sequencing (WES) on primary tumours from 9 MBC ExdCR &amp;gt; 60 mo (5 matched T:N) and 6 non-responders (NR) or PR &amp;lt; 6 mo (3 matched T:N). Tumours were analysed for single nucleotide variants (SNVs) point mutations, insertions/deletions (indels), copy number alterations (CNA), and tumour mutational burden. Detailed clinicopathologic data was collected for each patient and linked to the genomic information. Results: WES of matched tumour:normal samples revealed differences in SNVs and indels between the ExdCR pts compared to NR. Mutations in TP53 were found in 2/5 ExdCR pts and in 0/3 NR. Initial analysis of CNA revealed that HER2 is significantly more amplified in ExdCR pts compared to NR, and this was also shown by IHC and FISH. Conclusions: We present a genomic landscape of extraordinary durable complete responders compared to non-responders using WES. High variability exists in mutation profile of ExdCR pts with few overlapping genes. Further analysis into clinically relevant genomic and molecular alterations will be performed to potential aid in patient selection and choice of therapy, and novel drug targets. Citation Format: Walsh N, Gullo G, Quinn C, Furney SJ, Crown J. Whole exome sequencing of HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary durable complete responses (ExdCR) to trastuzumab (T) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-13.

Abstract 135: A Clinical Validation Study of Anatomical Risk Scoring for Procedural Stroke in Carotid Artery Stenting

Introduction: Vascular anatomy of aortic arch and supra-aortic arteries is often suggested to influence risk of carotid artery stenting (CAS). The expert opinion-based Macdonald anatomical risk score (MARS) was developed to predict difficulty of CAS in relation to 30-day stroke risk, and hereby aid in patient selection. We aimed to validate the MARS for procedural stroke after CAS. Methods: In this post-hoc analysis of the International Carotid Stenting Study (ICSS), 275 CAS patients with available pre-procedural CT angiography were included. CTA-based vascular anatomy was rated by two independent observers. Every possible combination of anatomy resulted in a risk score, which is divided in four categories of expected risk (low: &lt;5.0; low-intermediate: 5.0–5.9; high-intermediate: 6.0–6.9; high: ≥7.0). Binomial logistic regression was used to assess the relation between anatomical risk scoring, as defined in the MARS, and procedural (&lt;30 days) risk of any stroke. Differences between predefined age groups were also assessed. Results: Interobserver reliability for all anatomical risk factors was high (κ 0.76-0.84). In total, 16 strokes (5.8%) occurred in the procedural period. We observed no significant relationship between the MARS and risk of any procedural stroke, with the risk of stroke in the high-risk versus the low-risk MARS group being 9.1% vs 4.4%, respectively ( P =0.49). A higher mean MARS was observed in patients ≥70 years compared to younger patients (4.6±1.5 vs 3.9±1.4, P &lt;0.001), which was mainly explained by higher rates of arch atheroma (44% vs 20%, P &lt;0.001). Conclusion: No clear association between anatomical difficulty, as defined in the MARS, and procedural any stroke risk could be found. Nevertheless, MARS is feasible and reliable based on CTA imaging. Currently running and future clinical trials and registries are recommended to include baseline CTA imaging of the carotid arteries in order to adequately determine the value of the MARS in selection of high-risk patients for CAS.

What features on intra-operative cholangiogram predict ERCP outcome in patients post-cholecystectomy

Introduction: Intraoperative cholangiography is often performed at time of laparoscopic cholecystectomy to exclude choledocholithiasis. An ERCP is typically performed if there is evidence of choledocholithiasis on IOC. Unfortunately, ERCP is associated with high rates of complications such as pancreatitis, bleeding, perforation and cholangitis. Identifying IOC features predictive of ERCP outcome may aid patient selection and reduce the number of ERCPs necessary for this indication. Method: A retrospective study was performed on 152 patients across 3 tertiary hospitals. All patients between January 2012 to December 2017 who underwent a laparoscopic cholecystectomy, had an IOC with filling defect, and a subsequent ERCP were identified. Size and number of these filling defects were measured. Absence or presence of intraductal stones at subsequent ERCP were recorded. A survival analysis using a Cox model studying the relationship between stone size, ERCP status, and the number of days between IOC and ERCP was performed. Result: Most patients with multiple filling defects or single filling defect larger than 4.5mm progress to have a positive ERCP. In our cohort, the positive predictive value was 82.0% (95%CI: 64.5% - 93.2%). In our cohort, 80% of single stones smaller than 4.5mm were found to have passed into the intestine by day 10, resulting in a negative ERCP (95% CI: 52.9% - 84.1%). Conclusion: Patients with multiple filling defects or single filling defects greater than 4.5mm on IOC should undergo an ERCP as 82% of these patients will have a positive ERCP. Patients with single filling defects smaller than 4.5mm should undergo an alternative diagnostic modality, such as endoscopic ultrasound or MRCP at least 10 days post-cholecystectomy. This is because 80% of these small stones pass into the intestine at this time point and have a negative ERCP.

Implications of Image-Defined Risk Factors and Primary-Site Response on Local Control and Radiation Treatment Delivery in the Management of High-Risk Neuroblastoma: Is There a Role for De-escalation of Adjuvant Primary-Site Radiation Therapy?

The predictive value of Image-Defined Risk Factors (IDRFs) developed by the International Neuroblastoma Risk Group Task Force as it relates to primary-site management is undefined and may aid patient selection for de-escalation of adjuvant radiation therapy to the primary site in high-risk neuroblastoma. Patients (N=76) with high-risk neuroblastoma treated on prospective trials at our institution from 1997 to 2014 were eligible for inclusion. IDRFs were defined based on pretherapy imaging. Overall survival, progression-free survival, and locoregional failure-free survival (LRFFS) were described using the Kaplan-Meier estimator and tested across strata by using the log-rank test. Twenty of 76 patients (26%) experienced local (n=6), regional (n=6), or combined locoregional failure (n=8) with or without distant failure. Ten (50%) of the locoregional failures had concurrent distant relapse. Of patients who completed all therapy, both those with no IDRFs and those with >90% resection had a 3-year LRFFS of 100%, with or without radiation therapy. Patients with either ≥1 IDRF or<Gross Total Resection (GTR) or the inability to complete all therapy had inferior 3-year LRFFS of 77.8% and 14.4% with or without radiation therapy, respectively (P<.04). Patients treated with a dose ≥30.6Gy as part of therapy for residual disease had an 83.3% locoregional control rate. Patients with >90% tumor resection and no primary site IDRFs at diagnosis may be candidates for de-escalation of adjuvant primary-site radiation therapy, although validation of these findings in future studies is required.

Outcomes after transaortic transcatheter aortic valve implantation: long-term findings from the European ROUTE†.

There is lack of data regarding the longer-term outcomes of patients undergoing transaortic (TAo) transcatheter aortic valve implantation (TAVI). We aimed to provide a contemporary snapshot of the types and frequencies of events in the year following TAo-TAVI. The Registry of the Utilization of the TAo-TAVI approach using the Edwards SAPIEN Valve (ROUTE) is a multicentre, European, prospective, observational registry of aortic stenosis patients undergoing TAo-TAVI. Patients were grouped according to the composite end point death, myocardial infarction, stroke/transient ischaemic attack, major vascular complications, life-threatening bleeding, acute kidney injury (AKI) and/or cardiovascular rehospitalization. Two hundred and fifty-three patients with a mean age of 81.5 ± 5.8 years were included, of whom 89 (35.2%) patients met the composite end point (the event group) and 164 (64.8%) patients did not (the event-free group). New York Heart Association (NYHA) class III/IV (85.2% vs 71.8%, P = 0.017), Canadian Cardiovascular Society angina class III/IV (22.6% vs 11.4%; P = 0.021), pulmonary disease (32.6% vs 18.9%; P = 0.015) and renal insufficiency (15.7% vs 3.0%; P < 0.001) were more common in the event group. At 1 year, the most common event was death (19.1%), followed by AKI stage II or III (14.7%). The baseline renal insufficiency was the strongest independent predictor of composite end point achievement [odds ratio (OR) 7.55, 95% confidence interval (CI) 2.33-24.56], followed by NYHA class III/IV (OR 2.316, 95% CI 1.06-5.06) and pulmonary disease (OR 2.91, 95% CI 1.45-5.85). Pulmonary disease was also an independent predictor of 1-year mortality (OR 3.01, 95% CI 1.34-6.75). Long-term outcomes after TAo-TAVI appear to be similar to those for TAVI via other non-transfemoral access routes. Awareness of characteristics associated with poorer outcomes may aid patient selection and identification of those requiring closer post-procedural monitoring. ClinicalTrials.gov identifier: NCT01991431.

Development and validation of a penumbra-based predictive model for thrombolysis outcome in acute ischemic stroke patients.

The use of thrombolysis in acute ischemic stroke is restricted to a small proportion of patients because of the rigid 4·5-h window. With advanced imaging-based patient selection strategy, rescuing penumbra is critical to improving clinical outcomes. In this study, we included 155 acute ischemic stroke patients (84 patients in training dataset, age from 43 to 80, 59 males; 71 patients in validation dataset, age from 36 to 80, 45 males) who underwent MR scan within the first 9-h after onset, from 7 independent centers. Based on the mismatch concept, penumbra and core area were identified and quantitatively analyzed. Moreover, predictive models were developed and validated to provide an approach for identifying patients who may benefit from thrombolytic therapy. Predictive models were constructed, and corresponding areas under the curve (AUC) were calculated to explore their performances in predicting clinical outcomes. Additionally, the models were validated using an independent dataset both on Day-7 and Day-90. Significant correlations were detected between the mismatch ratio and clinical assessments in both the training and validation datasets. Treatment option, baseline systolic blood pressure, National Institutes of Health Stroke Scale score, mismatch ratio, and three regional radiological parameters were selected as biomarkers in the combined model to predict clinical outcomes of acute ischemic stroke patients. With the external validation, this predictive model reached AUCs of 0·863 as short-term validation and 0·778 as long-term validation. This model has the potential to provide quantitative biomarkers that aid patient selection for thrombolysis either within or beyond the current time window.

Factors Predicting a Good Symptomatic Outcome After Prostate Artery Embolisation (PAE).

As prostate artery embolisation (PAE) becomes an established treatment for benign prostatic obstruction, factors predicting good symptomatic outcome remain unclear. Pre-embolisation prostate size as a predictor is controversial with a handful of papers coming to conflicting conclusions. We aimed to investigate if an association existed in our patient cohort between prostate size and clinical benefit, in addition to evaluating percentage volume reduction as a predictor of symptomatic outcome following PAE. Prospective follow-up of 86 PAE patients at a single institution between June 2012 and January 2016 was conducted (mean age 64.9years, range 54-80years). Multiple linear regression analysis was performed to assess strength of association between clinical improvement (change in IPSS) and other variables, of any statistical correlation, through Pearson's bivariate analysis. No major procedural complications were identified and clinical success was achieved in 72.1% (n=62) at 12months. Initial prostate size and percentage reduction were found to have a significant association with clinical improvement. Multiple linear regression analysis (r2=0.48) demonstrated that percentage volume reduction at 3months (r=0.68, p<0.001) had the strongest correlation with good symptomatic improvement at 12months after adjusting for confounding factors. Both the initial prostate size and percentage volume reduction at 3months predict good symptomatic outcome at 12months. These findings therefore aid patient selection and counselling to achieve optimal outcomes for men undergoing prostate artery embolisation.

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

Background:We sought to develop a prognostic scoring system to aid in patient selection for immune checkpoint inhibitor (ICI) phase 1 clinical trials.Methods:Clinical data from patients treated in phase 1 ICI clinical trials at MD Anderson (MDA) Center were analysed. Seventeen clinical factors were studied. Recursive partitioning analysis, a tree-based model, was used to develop a regression tree and identify optimal cut-points based on differences in survival for each clinical factor. A Cox proportional hazards regression model was then used to identify factors independently affecting overall survival. A prognostic scoring system was subsequently developed.Results:A total of 172 patients (105 CTLA4- and 67 PD1-based) were analysed. Seven factors were independently associated with worse overall survival (OS): age>52 years (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.1–2.4), Eastern Cooperative Oncology Group performance status>1 (HR 2.81, 95%CI 1.3–6.3), lactate dehydrogenase >466 (which is 0.75 × the upper limit of normal at our institution) (HR 2.1, 95% CI 1.4–3.2), platelet count >300 × 103μL−1 (HR 1.8, 95% CI 1.2–2.8), absolute neutrophil count >4.9 × 103μL−1 (HR 2.3, 95% CI 1.5–3.5), absolute lymphocyte count <1.8 × 103μL−1 (HR 3.3, 95% CI 1.9–5.7), and liver metastases (HR 1.8, 95% CI 1.2–2.6). An index was created by dividing the cohort into risk groups based on the number of factors present: 0–2, 3, 4, or 5–6. Median OS was 24.2 months, 11.6 months, 8.0 months, and 3.8 months for patients with 0–2, 3, 4, or 5–6 risk factors, respectively; log-rank test, P<0.0001. The Harrell c-index of this scoring system was 0.72, indicating better predictability than the Royal Marsden Hospital score (c-index 0.67) and MDA score (c-index 0.61).Conclusions:We have developed a novel ‘MDA-ICI’ prognostic scoring system for patients treated in phase 1 ICI clinical trials. Prospective evaluation and external validation is warranted and may help aid patient selection for future clinical trials.

Transcranial Direct Current Stimulation for the Treatment of Depression: a Review of the Candidate Mechanisms of Action

Numerous studies published in the last 10 years indicate that repeated administration of prefrontal transcranial direct current stimulation (tDCS) is a potential effective treatment for major depressive disorder (MDD). However, the mechanisms of action are unclear and methods of patient selection for clinical trials are limited. This review seeks to examine the potential neural and cognitive mechanisms of action of tDCS in the treatment of MDD, to aid patient selection for future clinical trials. Cognitive measures of tDCS efficacy in the treatment of MDD have begun to be examined over the past 5 years. Baseline measures of working memory and letter fluency have been shown to predict treatment response. In addition, tDCS reduced cognitive deficits induced by stress, suggesting a protective mechanism. Baseline measures of working memory and letter fluency may aid patient selection in future clinical trials of tDCS. In addition, reduction of stress responsivity may be a key mechanism of action for tDCS in clinical groups and merits further investigation, acutely and post-treatment.

Immunoclassification characterized by CD8 and PD-L1 expression is associated with the clinical outcome of gastric cancer patients.

BackgroundGastric cancer (GC) is a major cause of cancer deaths, especially in Eastern Asia. Current classification systems, including the WHO, Lauren, and TCGA, have clarified the pathological and molecular profiles of GC. However, these classifications lack an association with clinical outcome and guidance for medication selection.ObjectiveWe aimed to identify a new immunoclassification for GC to better predict patient prognosis and aid in patient selection for immunotherapy.ResultsFor all samples, 35 were EBV positive (+) and 112 were EBV negative (-). EBV infection was associated with the number of CD3+ T cells (OR = 2.91 95% CI 1.27-6.68, p = 0.012) and PD-L1 expression in TME (OR = 2.57, 95% CI 1.13–5.82, p = 0.024). EBV+ patients showed a poor overall survival (OS) compared with EBV- patients (HR = 2.37; 95% CI, 1.03–5.41; p = 0.011). Importantly, WIR patients lived significantly shorter than SIR patients with high CD8+ T cells and low PD-L1 expression (HR = 3.37; 95% CI, 1.63–6.97; p = 0.015).Materials and Methods147 formalin-fixed and paraffin-embedded (FFPE) samples of GC were obtained. Epstein-Barr virus (EBV) infection was measured. Immune markers including CD3, CD8 and PD-L1 were detected by immunohistochemistry (IHC) at tumor infiltration area (TI) and invasive margin area (IM) in tumor microenvironment (TME). PD-L1 expression was assessed by immunoreactive score (IRS) system. For immunoclassification, patients were classified into two subgroups: strong immunoreaction (SIR) and weak immunoreaction (WIR) defined by the number of CD8+ T cells and PD-L1 expression in TI.ConclusionsIn this study, we suggest a new immunoclassification for gastric cancer which is associated with patient outcome and may provide a way to guide immunotherapy in the future.

Molecular imaging of T cell co-regulator factor B7-H3 with 89Zr-DS-5573a.

B7-H3 is a transmembrane protein widely expressed in a variety of cancers and has been shown to play a role in anti-tumor immunity. This study aims to develop a molecular imaging probe to identify B7-H3 expression in tumors and to develop 89Zr-DS-5573a as a theranostic that could aid patient selection in clinical Phase I studies.Methods: The anti-B7-H3 humanised monoclonal antibody DS-5573a was labeled with zirconium-89 (89Zr-), and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution and imaging studies were performed with positron emission tomography and magnetic resonance imaging (PET/MRI) studies to identify and quantitate 89Zr-DS-5573a tumor uptake in a B7-H3-positive breast cancer model (MDA-MB-231) and a B7-H3-negative murine colon cancer model (CT26). Imaging and biodistribution studies were also performed in MDA-MB-231 tumor-bearing SCID mice in the absence and presence of therapeutic DS-5573a antibody dose (3 mg/kg DS-5573a).Results: 89Zr-DS-5573a showed high and specific binding to B7-H3-expressing MDA-MB-231 cells (immunoreactivity on day 0, 75.0 ± 2.9%), and low binding to B7-H3-negative CT26 cells (immunoreactivity on day 0, 10.85 ± 0.11%) in vitro. 89Zr-DS-5573a demonstrated good serum stability in vitro with 57.2 ± 2.0% of immunoreactivity remaining on day 7. In vivo biodistribution studies showed high uptake of 89Zr-DS-5573a in B7-H3-expressing MDA-MB-231 tumor-bearing mice, achieving 32.32 ± 6.55 %ID/g on day 7 post injection in BALB/c nu/nu mice and 25.76 ± 1.79 %ID/g in SCID mice, with minimal evidence of non-specific uptake in normal tissues, and excellent tumor localization on PET/MRI. In a combined imaging/therapy study, receptor saturation was demonstrated in tumors responding to therapy.Conclusion: 89Zr-DS-5573a demonstrates specific and prolonged targeting of B7-H3-expressing tumors in vivo. Saturation of binding sites was demonstrated in tumors responding to DS-5573a therapy. These results indicate that 89Zr-DS-5573a has potential to target B7-H3-expressing tumors in cancer patients. Furthermore 89Zr-DS-5573a has the potential to provide important insights into T cell biology through its specific binding to B7-H3.