Implications For Patient Selection Research Articles

A Web-Based Mental Health Platform for Individuals Seeking Specialized Mental Health Care Services: Multicenter Pragmatic Randomized Controlled Trial.

BackgroundWeb-based self-directed mental health applications are rapidly emerging to address health service gaps and unmet needs for information and support.ObjectiveThe aim of this study was to determine if a multicomponent, moderated Web-based mental health application could benefit individuals with mental health symptoms severe enough to warrant specialized mental health care.MethodsA multicenter, pragmatic randomized controlled trial was conducted across several outpatient mental health programs affiliated with 3 hospital programs in Ontario, Canada. Individuals referred to or receiving treatment, aged 16 years or older, with access to the internet and an email address, and having the ability to navigate a Web-based mental health application were eligible. A total of 812 participants were randomized 2:1 to receive immediate (immediate treatment group, ITG) or delayed (delayed treatment group, DTG) access for 3 months to the Big White Wall (BWW), a multicomponent Web-based mental health intervention based in the United Kingdom and New Zealand. The primary outcome was the total score on the Recovery Assessment Scale, revised (RAS-r) which measures mental health recovery. Secondary outcomes were total scores on the Patient Health Questionnaire-9 item (PHQ-9), the Generalized Anxiety Disorder Questionnaire-7 item (GAD-7), the EuroQOL 5-dimension quality of life questionnaire (EQ-5D-5L), and the Community Integration Questionnaire. An exploratory analysis examined the association between actual BWW use (categorized into quartiles) and outcomes among study completers.ResultsIntervention participants achieved small, statistically significant increases in adjusted RAS-r score (4.97 points, 95% CI 2.90 to 7.05), and decreases in PHQ-9 score (−1.83 points, 95% CI −2.85 to −0.82) and GAD-7 score (−1.55 points, 95% CI −2.42 to −0.70). Follow-up was achieved for 55% (446/812) at 3 months, 48% (260/542) of ITG participants and 69% (186/270) of DTG participants. Only 58% (312/542) of ITG participants logged on more than once. Some higher BWW user groups had significantly greater improvements in PHQ-9 and GAD-7 relative to the lowest use group.ConclusionsThe Web-based application may be beneficial; however, many participants did not engage in an ongoing way. This has implications for patient selection and engagement as well as delivery and funding structures for similar Web-based interventions.Trial RegistrationClinicalTrials.gov NCT02896894; https://clinicaltrials.gov/ct2/show/NCT02896894 (Archived by WebCite at http://www.webcitation.org/78LIpnuRO)

Predicting acute kidney injury after robot-assisted partial nephrectomy: Implications for patient selection and postoperative management

BackgroundAcute Kidney Injury (AKI) is a common occurrence after partial nephrectomy and is a significant risk factor for chronic kidney disease. We aimed to create a model that predicts postoperative AKI in patients undergoing robot-assisted partial nephrectomy (RAPN). MethodsWe identified 1,190 patients who underwent RAPN between 2008 and 2017 from a multicenter database. AKI was defined as a >25% reduction in eGFR from pre-RAPN to discharge. A nomogram was built based on a binary logistic regression that ultimately included age, sex, BMI, diabetes, baseline eGFR, and RENAL Nephrometry score. Internal validation was performed using the leave-one-out cross validation. Calibration was graphically investigated. The decision curve analysis was used to evaluate the net clinical benefit; a classification tree was used to identify risk categories. The same model was fit adding ischemia time during RAPN. ResultsMedian (IQR) age at surgery was 61 (50, 68) years; 505 (42%) patients were female, while 685 (58%) were male. Median (IQR) ischemia time during RAPN was 14 (10, 18) min. postoperative AKI occurred in 274 (23%) patients. All variables fitted in the model emerged as predictors of AKI (all P ≤ 0.005) and all were considered to build a nomogram. After internal validation, the area under the curve was 73%. The model demonstrated excellent calibration and improved clinical risk prediction at the decision curve analysis. In the low, intermediate, and high-risk groups the postoperative AKI rates were: 10%, 30%, and 48%, respectively. Adding ischemia time to the preoperative model fit the data better (likelihood ratio test: P < 0.001) and yielded an incremental area under the curve of 3% (95% confidence interval: 1, 5%) ConclusionWe developed a nomogram that accurately predicts AKI in patients undergoing RAPN. This model might serve (1) in the preoperative setting: for counsel patients according to their preoperative AKI risk (2) in the immediate postoperative: for identifying patients who would benefit from an early multidisciplinary evaluation, when considering also ischemia time.

Pre-LVAD Blood-Borne Infection is a Harbinger of Poor Prognosis after LVAD Implantation

Purpose Infections are common post-LVAD and are associated with increased mortality. Multiple risk factors have been identified including age and INTERMACS profile. However, the effect of pre-LVAD infections on post-LVAD outcomes is poorly studied. We aimed to determine the impact of pre-LVAD infections on post-LVAD infection risk and survival. Methods We retrospectively reviewed 106 pts implanted with LVAD at a large volume center. Infection data including type (bacterial, fungal, and viral) and source (blood-borne vs others) were collected pre- and post-LVAD. The cohort was divided into 4 groups based on source and type of pre-LVAD infection: Group 1: blood-borne bacterial or fungal, Group 2: other bacterial or fungal, Group 3: viral, Group 4: no infection. Survival free from any post-LVAD infection and survival were assessed using Cox proportional hazards. Multivariable analyses were performed adjusting for age and INTERMACS profile (≤ 2 vs > 2). Results Among 106 pts (age 58±1 yr, 82% male, 62% white), 47 pts (44%) had pre-LVAD infection: 40 pts (38%) bacterial or fungal, 7 (7%) viral; 13 (12%) had blood-borne infection. 58 pts (55%) had a post-LVAD infection. Median time to any infection was 21 days (IQR: 7-39) for the entire cohort and 11 days (IQR: 4-36) for pts with pre-LVAD blood-borne infection. Pts in Group 1 had significantly worse survival free from infection compared to other groups (Group 1 vs 4, HR CI: 3.3 (1.7-6.6)) and significantly worse survival compared to Group 4 (HR CI: 5.5 (1.4-22.1)) (Figure). Notably, survival at 1 yr was 59% for Group 1 compared to 93% for Group 4. After adjusting for age and INTERMACS profile, this relationship remained significant for the composite endpoint, but not survival alone. For pts in Group 1 with INTERMACS profile ≤ 2, 1 yr survival was 57%. Conclusion Occurrence of pre-LVAD blood-borne infection was associated with 72% increase in mortality or post-LVAD infection. This finding may carry important implications for patient selection.

Presence of Left Atrial or Left Ventricular Thrombus at the Time of CF-LVAD Implantation is Associated with Increased Post-Operative Risk of Stroke or Death

Purpose Patients with advanced HF are at increased risk for intra-cardiac thrombus formation. The impact of pre-existing left atrial (LA) or left ventricular (LV) thrombi on post-operative outcomes in LVAD patients is unknown. Methods We retrospectively reviewed 376 patients who underwent HeartMate II LVAD implantation from February 2009 through August 2018 at a single large volume center. Transthoracic echocardiography (TTE) within 1 month of implant, intra-operative transesophageal echocardiography (TEE), and operative reports were reviewed to identify patients with pre-existing LA (including appendage) or LV thrombus at the time of LVAD implantation. We assessed the composite endpoint of stroke and death at 6 months and 2 years. Results Of the 376 patients (age 57±13 years, 81% male, 47% ICM), 26 (6.9%) had a pre-existing thrombus (13 in LA and 15 in LV). Incidence of stroke at 6 months was 23% in patients with intracardiac thrombi and 9% in patients without intracardiac thrombi (p=0.02). Incidence of stroke at 2 years was 23% in patients with intracardiac thrombi and 14% in patients without intracardiac thrombi (p=0.22). Notably all strokes occurred in the first 6 months of device support in patients with intra-cardiac thrombi. Patients were significantly more likely to die or have a stroke in the first 6 months of device support if they had pre-existing intracardiac thrombi (HR (95%CI): 2.7 (1.4, 5.2), p Conclusion Pre-existing LA or LV thrombus is associated with decreased survival free of stroke following CF-LVAD implantation which may have important implications for patient selection and management.

Adjustment to amputation and interest in upper limb transplantation.

Objective:Upper limb transplantation provides a new restorative option for individuals with amputations. As true for most operations, patient selection is critical to optimizing transplantation outcomes. To improve on the patient selection process, we used qualitative methods to better understand the issues regarding upper extremity loss as well as upper limb transplantation from the amputee point of view.Methods:Individuals with upper limb amputations (age range = 24–73 years) discussed their adjustment following amputation and their interest toward transplantation in either a focus group (n = 5) or semi-structured interview (n = 17). Transcripts were coded by theme and summarized.Results:Participants described a year-long process typified by adjustment to a new role as an amputee, both psychosocially and functionally. We found that the extent of adjustment was inversely related to an interest in transplantation.Conclusions:These findings could explain the difficulty in identifying “ideal” candidates for upper extremity transplantation and may have implications for patient selection and counseling.Level of Evidence:Prognostic Study, Level V

Safety and Efficacy of BIND-014, a Docetaxel Nanoparticle Targeting Prostate-Specific Membrane Antigen for Patients With Metastatic Castration-Resistant Prostate Cancer

Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)-targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring. To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration-resistant prostate cancer (mCRPC). A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016. Treatment with BIND-014 at a dosage of 60 mg/m2 was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred. The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (≥50% reduction from baseline) and changes in CTC number (from ≥5 to <5 cells per 7.5 mL of blood) (CellSearch). Changes in CTC number based on PSMA expression levels on CTCs were also evaluated (Epic Sciences). Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]). These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated. ClinicalTrials.gov Identifier: NCT01812746.

Outcomes of simultaneous liver-kidney transplantation: implications for patient selection.

Rates of simultaneous liver kidney (SLK) transplantation have continued to increase despite lack of clear allocation guidelines and outcomes data. The organ procurement and transplantation network (OPTN)/UNOS board approved a new SLK allocation policy to standardize medical eligibility and optimize organ utilization. This review highlights the rationale behind these new selection criteria and posttransplant outcomes in various patient populations. Uniform criteria for SLK transplantation were adopted in August 2017 and state SLK should be reserved for select patients with cirrhosis who have chronic kidney disease for longer than 3 months, sustained acute kidney injury, or particular metabolic diseases. Many patients who previously underwent SLK did not meet these criteria, reducing organ availability for patients awaiting kidney-alone transplantation. The new criteria includes a 'safety net' policy allowing for renal transplant priority for liver-alone recipients who do not meet criteria for SLK but fail to have renal recovery within the first year. The new SLK allocation policy was adopted to avoid kidney transplantation in those patients who have a significant chance of recovering renal function post-liver transplant and those with a poor chance of survival in whom SLK is futile.

Abstract PD4-11: Copy-number and targeted sequencing analyses to identify distinct prognostic groups: Implications for patient selection to targeted therapies amongst anti-endocrine therapy resistant early breast cancers

Abstract Hormone receptor positive breast cancer remains an ongoing therapeutic challenge. Despite optimal anti-endocrine therapies, most breast cancer deaths follow a diagnosis of early luminal cancer. Data describing molecular events in breast cancer has yet to be translated into actionable information to inform medical management and benefit patients. To understand the impact of multiple aberrations in the context of current therapy, we assessed the prognostic ability of genomic signatures as a putative stratification tool to targeted therapies. The analysis was performed based on an a priori hypothesis relating to molecular pathways which might predict response to targeted therapies currently under evaluation in late-stage clinical trials. In a case-control fashion, 420 patients from the Tamoxifen vs Exemstane Adjuvant Multinational Trial (TEAM) pathology cohort, were analysed to determine the prognostic, ability for these mutational and copy-number biomarkers representing the CCND/CDK, FGFR/FGF and AKT/PIK3CA to inform potential response to therapies targeting these pathways. Copy number analysis was performed using the Affymetrix Oncoscan™ Assay. Targeted sequencing was performed in a subset of samples for genes based on signaling cassettes mined from the ICGC. Pathways were identified as aberrant if there were copy number aberrations (CNAs) and/or mutations in any of the predetermined pathway genes: 1) CCND1/CCND2/CCND3/CDK4/CDK6 2) FGFR1/FGFR2/FGFR2/FGFR4 and 3) AKT1/AKT2/PIK3CA/PTEN. Kaplan Meier and log rank analyses were used for DRFS between groups. Hazard ratios were calculated using the Cox proportional hazard models adjusted for age, tumour size, grade, lymph node and HER2 status. 390/420 samples passed informatics QC filters. For the CCND/CDK pathway, patients with no CNA changes experienced a better DRFS (HR=1.94, 95% CI 1.45-2.61, p&amp;lt; 0.001). For the FGFR/FGF pathway, a similar outcome is seen among patients without CNAs (HR = 1.43, 95% CI 1.07-1.92 p=0.017). For AKT/PIK3CA, a decrease in DRFS was seen in those with aberrations (H=1.34, 95% CI 1.00-1.81, p=0.053). We demonstrated that CNAs of genes within CDK4/CCND, PIK3CA/AKT and FGFR pathways are independently linked to high risk of relapse following endocrine treatment. In this way, improving the clinical management of early breast cancers could be made, firstly by identifying those patients for whom current endocrine therapies are sufficient, thus reducing unnecessary treatment; and secondly, identifying those patients who are at high-risk for recurrence despite optimal endocrine therapy and the linking molecular features driving these cancers to treatment with targeted therapies. Citation Format: Bayani J, Kornaga EN, Crozier C, Jang GH, Kalatskaya I, Trinh QM, Yao CQ, Livingstone J, Hasenburg A, Kieback DG, Markopoulos C, Dirix L, Boutros PC, Spears M, Stein LD, Rea D, Bartlett JMS. Copy-number and targeted sequencing analyses to identify distinct prognostic groups: Implications for patient selection to targeted therapies amongst anti-endocrine therapy resistant early breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-11.

Phenotypic subtypes and risk of local recurrence after radical resection for rectal cancer.

637 Background: Phenotypic subtypes for CRC are reported to stratify outcomes. The four subtypes are based on features within the consensus molecular subtypes (CMS): immune, canonical, latent and stromal. In 81 pts, we recently reported concordance between CMS and phenotypic subtypes. Of note, the stromal subtype matched the CMS4 subtype in 84%. Local recurrence (LR) after rectal cancer surgery remains a problem. Identifying those at risk determines who should receive neoadjuvant therapy (NT) and guides surgery. We evaluated whether phenotypic subtypes are associated with LR after radical treatment of rectal cancer. Methods: From a CRC database, pts with rectal cancer and phenotypic subtyping available were identified. Subtyping was performed based on immune cell infiltrate, stromal volume and tumor proliferation. LR was considered pelvic or peritoneal. Results: Between 1997-2007, 260 pts had surgery for rectal cancer. Most were &gt; 65yrs (63%), male (58%) and TNM stage II (39%) or III (37%). 32 (13%) received NT. For phenotypic subtypes, 88 (35%) were Immune, 47 (19%) Canonical, 48 (19%) Latent and 67 (27%) Stromal. Median FU was 138 months (min 88). 70 pts (27%) developed recurrence: LR in 23 (8.8%) and systemic in 44 (16.9%). LR was associated with higher T stage (pT1-3 7% vs pT4 17%, p = 0.024), presence of vascular invasion (15% vs 6%, p = 0.018), serosal involvement (21% vs 6%, p = 0.001), margin involvement (22% vs 7%, p = 0.010), &gt; 50% tumor stroma (18% vs 3%, p = 0.002) and phenotypic subtype (immune 5%, canonical 6%, latent 4% and stromal = 21%, p = 0.002). Similar LR rates were obtained after excluding pts who had NT: Immune (4%), canonical (4%), latent (5%) and stromal (23%). Of the 23 LRs, most were Stromal subtype (n = 14) vs Immune (n = 4), Canonical (n = 3) and Latent (n = 2). Apart from increased node positivity (50% vs 30-44% p &lt; 0.05), there were no differences in rates of pT4 disease, tumor grade, vascular invasion, serosal involvement and margin positivity between stromal subtype and other groups. Conclusions: LR after rectal cancer surgery was associated with the stromal subtype. Validation is needed but pre-treatment tumor subtyping may identify subsets at risk of LR and have implications for patient selection for neoadjuvant therapy.

Abstract TP46: The Probability of an Endovascular Intervention Target Independent of Time From Last Known Well

Introduction: Selection of patients based on treatment-related targets has been especially important for endovascular therapy. Recently presented trial evidence has demonstrated that cases with an eligible arterial occlusion and a target PWI-DWI mismatch were able to successfully receive treatment beyond the 6 hour window. Method: The LESION Study is a prospective cohort study of the baseline MR imaging (&lt;24 hrs from onset and prior to treatment) of 1,092 consecutive ischemic stroke presentations with admission NIHSS ≥4. Multiple therapeutic targets were assessed. Endovascular intervention target was defined as the presence of ischemia on MRA in the ICA or MCA-M1 arterial branches. Presence of PWI-DWI mismatch was qualitatively determined by vascular neurologists. Multivariate logistic regression was used to test for association of time from onset with presence of an endovascular target, while examining the roles of presentation and imaging characteristics. Results: Probability of an endovascular target decreases over the first 24 hours (OR=0.96; p=0.004). However, stratification or adjustment for a PWI-DWI mismatch signal and/or admission NIHSS confounds the effect of occlusion target over time. Stratification by mismatch demonstrates a consistently higher proportion of endovascular target presence in those with a concurrent target mismatch. For cases with a target mismatch, presentation within the 6 hour window is associated with just a 17% greater likelihood of endovascular target relative to those beyond 6 hours (OR=1.17; p &gt; 0.05). In multivariate modeling: NIHSS, mismatch, and sex were all identified as independent risk factors for presence of an endovascular target (all p &lt; 0.01), while time was not significantly associated with target presence. Discussion: While the presence of an arterial occlusion in territories relevant to endovascular intervention appear to be related to time from onset, stratified and adjusted analyses show that this relationship is not maintained when limited to cases with and without a target mismatch identified. This finding has clinical and methodological implications for selection of patients for intervention at varying time intervals.

Predicting device failure after percutaneous repair of functional mitral regurgitation in advanced heart failure: Implications for patient selection

BackgroundPatients with heart failure (HF) and severe symptomatic functional mitral regurgitation (FMR) may benefit from MitraClip implantation. With increasing numbers of patients being treated the success of procedure becomes a key issue. We sought to investigate the pre-procedural predictors of device failure in patients with advanced HF treated with MitraClip. MethodsFrom April 2012 to November 2016, 76 patients with poor functional class (NYHA class III–IV) and severe left ventricular (LV) remodeling underwent MitraClip implantation at University Hospitals of Trieste and Bologna (Italy). Device failure was assessed according to MVARC criteria. Patients were subsequently followed to additionally assess the patient success after 12months. ResultsMean age was 67±12years, the mean Log-EuroSCORE was 23.4±16.5%, and the mean LV end-diastolic volume index and ejection fraction (EF) were 112±33ml/m2 and 30.6±8.9%, respectively. At short-term evaluation, device failure was observed in 22 (29%) patients. Univariate predictors of device failure were LVEF, LV and left atrial volumes and anteroposterior mitral annulus diameter. Annulus dimension (OR 1.153, 95% CI 1.002–1.327, p=0.043) and LV end-diastolic volume (OR 1.024, 95% CI 1.000–1.049, p=0.049) were the only variables independently associated with the risk of device failure at the multivariate model. ConclusionsPre-procedural anteroposterior mitral annulus diameter accurately predicted the risk of device failure after MitraClip in the setting of advanced HF. Its assessment might aid the selection of the best candidates to percutaneous correction of FMR.

The In-Hospital Cost of Ventricular Assist Device Therapy: Implications for Patient Selection.

Ventricular assist device (VAD) therapy is increasingly utilized to support patients in end-stage heart failure. However, VAD programs are resource intensive and demand active monitoring to ensure long-term sustainability. The purpose of this study was to analyze total cost trends of the VAD program at our academic medical center. Retrospective analysis of University of California - Los Angeles's VAD program between 2013 and 2014 was performed. Total in-hospital costs from the date of VAD surgery admission were queried and normalized to a z score. Multivariable linear regression analysis with step-wise elimination was used to model total costs. Overall, 42 patients received a VAD during the study period, with 19 (45%) receiving biventricular support. On univariate analysis, high body mass index, biventricular support, time between VAD implantation and discharge, and total length of hospital stay were correlated with higher costs (all p < 0.02). On multivariable analysis, time between VAD implantation and discharge and biventricular support remained significantly related to total costs (overall R = 0.831, p < 0.001). The time between VAD implantation and discharge and the use of biventricular support were the most predictive factors of total cost in our VAD population. Reducing hospital stay post-VAD implantation is important in minimizing the cost of VAD care.

The impact of perioperative CA19-9 change on the survival and recurrence patterns after adjuvant chemoradiotherapy in resectable extrahepatic cholangiocarcinoma.

Perioperative CA19-9 value in pancreato-biliary cancers has been recognized as a prognostic factor. Herein, we investigated survival differences and recurrence patterns after adjuvant chemoradiotherapy by perioperative CA19-9 change in surgically resected extrahepatic cholangiocarcinoma. Patients were divided into those with preoperative normal CA19-9 (Group 1, n = 52), those with high preoperative and normalized postoperative CA19-9 (Group 2, n = 80), and those with both high pre- and postoperative CA19-9 (Group 3, n = 21). Depending on the group defined above, the 5-year overall survival (OS) (59.6%, 38.7%, and 9.5%, P < 0.001) and disease-free survival (55.8%, 31.2%, and 9.5%, P < 0.001) between the three groups differed. On multivariable analysis in patients other than group 1, poor prognosticators for OS were high postoperative CA19-9 (HR 2.26, P = 0.008) and N1 disease (HR 2.33, P = 0.001). Group 3, compared with group 2, showed higher distant metastasis rate, shorter disease-free interval, and higher CA19-9 at the time of recurrence. Survival and recurrence patterns after adjuvant chemoradiotherapy are significantly affected by perioperative CA19-9 change. This may have important implications in patient selection for adjuvant chemoradiotherapy and clinical trial design.

Relationship of lymphocyte and eosinophil counts and immune-related adverse events in recipients of programmed death-1 (PD-1) inhibitor therapy: A single-center retrospective analysis.

e14586 Background: Inhibition of the PD-1 checkpoint can cause immune activation in non-target tissues, resulting in immune-related adverse events (irAE) in up to 50% of patients. Biomarkers that are associated with irAEs in patients treated with PD-1 inhibitors may have implications for patient selection and clinical management. Methods: We performed an IRB-approved retrospective chart review of adult solid tumor patients treated with nivolumab or pembrolizumab at a single institution from January 2015 until November 2016. Patients were excluded if concurrently receiving investigational therapies, or on unreported clinical trials. Data were collected on treatment history, leukocyte counts, and irAE, defined as adverse events with a potential immunologic basis with grading performed using CTCAE v.4.0. Results: 172 patients were included (lung n = 54; melanoma n = 61; kidney n = 25; esophageal n = 12; bladder n = 8; other tumors n = 12) with median age 67. 18% were treated with concurrent ipilimumab. 31% experienced an adverse event of any grade with a mean time to develop an irAE of 3.5 months. Of those with an irAE, 85% required treatment, 68% were grade ≥ 2, 32% were grade 3 or 4 and 35% required therapy discontinuation due to the irAE. In univariate analysis, a higher ALC at both the start of therapy and at 1 month was associated with increased risk of an irAE of grade ≥ 2 (p &lt; 0.05). A higher absolute lymphocyte count (ALC) or higher absolute eosinophil count (AEC) at 1 month into therapy was associated with increased risk of all irAE (p &lt; 0.05) as well as irAE requiring treatment (p &lt; 0.05). In addition, in a multivariate regression analysis including age, race, tumor type, prior chemotherapy, prior radiation, and concurrent ipilimumab therapy, an ALC &gt; 2000 at the start of therapy was a significant predictor of irAE of grade ≥ 2 (p &lt; 0.05 and OR 2.0), as was an ALC &gt; 2000 at 1 month into therapy (p &lt; 0.05 and OR 1.86). Conclusions: These results suggest that high lymphocyte and eosinophil counts early in the course of anti-PD1 therapy may be associated with a higher risk for clinically significant irAE.

Copy-number and targeted sequencing analyses to identify distinct prognostic groups: Implications for patient selection to targeted therapies amongst anti-endocrine therapy resistant early breast cancers.

524 Background: Hormone receptor positive breast cancer is a therapeutic challenge. Despite optimal anti-endocrine therapies, most breast cancer deaths follow a diagnosis of early luminal cancer. To understand the impact of multiple aberrations in the context of current therapy, we assessed the prognostic ability of genomic signatures as a putative stratification tool to targeted therapies. Methods: This a priori study is based on molecular pathways which might predict response to targeted therapies. DNA from 420 patients from the phase III TEAM pathology cohort were used. Patients with a distant recurrence within 5 years were matched by clinical variables to those disease-free at follow up. Copy number analysis was performed using the Affymetrix Oncoscan Assay. Targeted sequencing was performed in a subset of samples for genes based on signaling cassettes mined from the ICGC. Pathways were identified as aberrant if there were copy number variations (CNVs) and/or mutations in any of the pre-determined pathway genes: 1) CCND1/CCND2/CCND3/CDK4/CDK6; 2) FGFR1/FGFR2/FGFR2/FGFR4; and 3) AKT1/AKT2/PIK3CA/PTEN. Kaplan-Meier and log-rank analyses were used for DFS between groups. Hazard ratios were calculated using the Cox proportional hazard models adjusted for age, tumour size, grade, lymph node and HER2 status. Results: 390/420 samples passed informatics QC filters. For the CCND/CDK pathway, patients with no CNV changes experienced a better DFS (HR = 1.7, 95% CI 1.3-2.3, p &lt; 0.001). For the FGFR/FGF pathway, a similar outcome is seen among patients without CNVs (HR = 1.5, 95% CI 1.1-2.0; p = 0.005). For AKT/PIK3CA, a decrease in DFS was seen in those with aberrations (HR = 1.4, 95% CI 1.0-1.8, p = 0.03). Conclusions: We demonstrated that CNVs of genes within CDK4/CCND, PIK3CA/AKT and FGFR pathways are independently linked to high risk of relapse following endocrine treatment, with implications for identifying those patients who are at high-risk for recurrence despite optimal anti-endocrine therapy and linking molecular features driving these cancers to targeted therapies.

FAK expression as a prognostic marker in colorectal cancer: A single institution study of 298 patients.

623 Background: Focal adhesion kinase (FAK) is an attractive therapeutic target in solid cancers, but there is no method for patient selection based on FAK expression nor biomarker for therapeutic response. Previous FAK expression studies were not standardized and showed varying correlations. This single-institution study aims to define FAK expression patterns in colorectal cancer (CRC) and correlate with patient outcomes and expression in other solid cancers. Methods: We analyzed 635 samples from 298 patients (pt) with CRC using tissue microarrays (TMAs) stained for FAK and scored 0-3 by a single pathologist. The TMAs contained samples of 298 primary tumors with 290 matching normal tissue and 47 matching metastases. As an internal control, we examined FAK and outcomes in 135 breast cancer pt and 145 melanoma pt. FAK expression and pt outcomes were evaluated using Kruskal-Wallis exact and Wilcoxon signed-rank tests. Results: FAK expression correlated with aggressive phenotype in CRC primaries. Matching normal colon had lower FAK than primaries (Mean FAK 0.61 vs 1.87, p &lt; 0.001). Higher primary tumor FAK was associated with higher tumor stage; the 88 T1-2 primaries had a mean FAK 1.54, compared to FAK 2.06 in the 99 T3-4 tumors (p &lt; 0.001). There was no difference in FAK among Stage II-IV pt, nor between mean FAK in the primaries (1.87) versus metastases (1.73). When FAK was dichotomized as high vs low (high = FAK &gt; 2), high primary tumor FAK was associated with shorter overall survival (OS). Median OS was 91 months (95% CI 73-130) in high FAK (n = 122 pt) vs 155 months (95% CI 124-196) in low FAK (n = 176 pt), p = 0.007. The OS rates at 5 and 10 years in high FAK were 65% and 43%, vs 79% and 61% in low FAK. FAK in CRC metastases did not correlate with OS (p = 0.945). In contrast, when CRC was compared to breast cancer and melanoma, FAK did not show the same correlations in outcome. Conclusions: For the first time, by standardizing FAK quantification, we have identified that FAK expression in the primary correlates with outcome in CRC. These data may have implications in selection of patients for adjuvant therapy. Normal colon and earlier stage CRC had lower FAK expression compared to more advanced stages, suggesting a therapeutic window for FAK as a target.

Scaffold-free cartilage tissue engineering with a small population of human nasoseptal chondrocytes.

Cartilage tissue engineering is a promising approach to provide suitable materials for nasal reconstruction; however, it typically requires large numbers of cells. We have previously shown that a small number of chondrocytes cultivated within a continuous flow bioreactor can elicit substantial tissue growth, but translation to human chondrocytes is not trivial. Here, we aimed to demonstrate the application of the bioreactor to generate large-sized tissues from a small population of primary human nasoseptal chondrocytes. Experimental study. Chondrocytes were cultured in the bioreactor using different medium compositions, with varying amounts of serum and with or without growth factors. Resulting engineered tissues were analyzed for physical properties, biochemical composition, tissue microstructure, and protein localization. Bioreactor-cultivated constructs grown with serum and growth factors (basic fibroblast growth factor and transforming growth factor beta 2) had greater thickness, as well as DNA and glycosaminoglycan (GAG) contents, compared to low serum and no growth factor controls. These constructs also showed the most intense proteoglycan and collagen II staining. The combination of bioreactor conditions, serum, and growth factors allowed the generation of large, thick scaffold-free human cartilaginous tissues that resembled the native nasoseptal cartilage. There also may be implications for patient selection in future clinical applications of these engineered tissues because their GAG content decreased with donor age. NA. Laryngoscope, 127:E91-E99, 2017.

The Role of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography in the Management of Patients With Prostate Cancer: Implications for Selection of Patients for Radiation Therapy

The Role of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography in the Management of Patients With Prostate Cancer: Implications for Selection of Patients for Radiation Therapy

The effect of oral positioning on the hypopharyngeal airway.

It is generally assumed that mouth opening decreases the hypopharyngeal cross-sectional area (HA) and that tongue protrusion (TP) increases the HA. We hypothesize that a substantial number of patients do not exhibit this expected pattern. Prospective cohort conducted at a tertiary academic center. With a flexible fiberoptic scope in position, the hypopharyngeal airway was visualized and assessed in 189 patients with the mouth closed. Patients were then asked to open the mouth with the tongue in neutral position (MOTN) to determine the effect on the airway. The same methodology was used to compare the airway with the MOTN versus TP. Basic demographics, including age, gender, body mass index, and presence and severity of obstructive sleep apnea (OSA), were collected. Student t test, Mantel-Haenszel chi-square, and Cochran-Armitage analyses were assessed for significant relationships and trends with oral positions. Although mean HA decreased with MOTN (P < 0.0001), 33% of patients exhibited an increase in HA. Similarly, mean HA increased with TP (P = 0.0018); however, 38% of patients demonstrated a decrease in HA. There was no significant relationship in HA between OSA and non-OSA patients. For those with OSA, increasing severity trended toward a higher incidence of smaller HA with TP (P = 0.038). The airway is typically most obstructed with mouth opening (MOTN) and most patent with tongue protrusion (TP). Nevertheless, hypopharyngeal changes with MOTN and TP followed a paradoxical pattern in one-third of our population. This may have implications in patient selection for targeted OSA treatment. 4. Laryngoscope, 127:1471-1475, 2017.

Patient knowledge of anticoagulant treatment does not correlate with treatment quality

ObjectivesThe objectives of this study were to investigate whether patient knowledge is a predictor of treatment stability in anticoagulant clinic patients and to evaluate the correlation between the patients' subjective assessment of own knowledge and their score on a validated knowledge assessment instrument. Study designThis is a prospective study where international normalized ratio (INR) stability was followed up 6 months after knowledge assessment. MethodsWe analyzed data of 42 consecutive patients new to vitamin-K antagonist (VKA) treatment and 64 experienced patients from an anticoagulant clinic offering patient education. The patients filled out a VKA knowledge assessment questionnaire with 24 items under standardized conditions, and simultaneously, they were asked about their subjective knowledge. Subsequently, time in range of INR (TIR) was collected for each patient. ResultsOut of the 106 patients, 52 had 18 or more correct answers (>75%), defined as a ‘satisfactory level’ of objective knowledge. The average TIR was 73%, and treatment stability was significantly higher in experienced patients than new patients. We found no correlation between objective knowledge and TIR (Spearman rho = −0.03, P = 0.78). Most patients (77%) reported a high subjective knowledge of VKA, but no correlation was found between objective and subjective knowledge (Spearman rho = 0.129, P = 0.19). ConclusionWe observed that many patients had a low level of knowledge of VKA, despite high treatment stability and patient education. The patient's own assessment of knowledge was not found to predict objective knowledge, which could have implications for selection of patients for self-test or self-management of treatment.