Patient Selection For Future Trials Research Articles

SDPS-37 IDENTIFICATION OF TIME-COURSE RELATED, TREATMENT-RELATED, AND PATIENT-RELATED PROGNOSTIC FACTORS IN BRAF-MUTANT MELANOMA BRAIN METASTASES.

Abstract PURPOSE Patients with BRAF-mutant melanoma brain metastases (MBM) continue to have limited overall survival (OS), averaging 4 months, despite advancements in systemic therapies. Our study aims to identify patient-specific and treatment-related prognostic factors in BRAF-mutant MBM to inform treatment sequencing and patient selection in future studies and improve patient outcomes. METHODS The following data were manually curated from 100 patients with BRAF-mutant MBM diagnosed from 2009-2018, with primary cutaneous melanoma and who received initial MBM treatment at our institution: clinical and demographic, treatment, and OS outcomes. We compared OS with the log rank test using the Python package kaplanmeier between the various clinical, demographic and treatment (including treatment sequence) related variables. RESULTS Both elevated lactase dehydrogenase (LDH) was associated with shorter OS (p=0.023), as was leptomeningeal disease (p<0.001). Gender (male vs. female) and initial treatment modality (BRAFi vs. immunotherapy) did not significantly impact OS, (p=0.911 and 0.578, respectively). Breakthrough brain metastases were associated with shorter OS for patients who received initial systemic therapy for MBM (p<0.001), but breakthrough metastases did not significantly impact OS for the whole cohort (p=0.141). Additionally, patients who received BRAFi before MBM diagnosis had shorter OS (p=0.028). CONCLUSION In conclusion, we have identified some interesting relationships between OS and the sequencing of treatment modalities, as well as the timing of MBM presentation. These findings support further investigation of treatment sequencing to improve outcomes and the consideration of clinical variables, disease presentation, and treatment history to help refine patient selection for future trials for patients with BRAF-mutant MBM.

Stable cerebrospinal fluid neurogranin and β-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients.

Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer’s disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T−/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer’s disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T−/N−, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer’s disease continuum and controlled with normal markers (A−/T−/N−, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T−/N− and A+/T+/N+ as compared to A−/T−/N− healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A−/T−/N− to A+/T−/N− (n = 12), from A+/T−/N− to A+/T or N+ (n = 12), remained stable A+/T−/N− (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A−/T−/N− (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A−/T−/N− healthy controls, neurogranin was unaltered in A+/T−/N− (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T−/N− (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T−/N− (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = −0.29, P = 0.0006) than neurogranin (b = −0.20, P = 0.002) and BACE1 (b = −0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T−/N− to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer’s disease subgroups, putatively with different options for treatment.

Community-acquired pneumonia subgroups and differential response to corticosteroids: a secondary analysis of controlled studies.

BackgroundLatent class analysis (LCA) has identified subgroups with meaningful treatment implications in acute respiratory distress syndrome. We performed a secondary analysis of three studies to assess whether LCA can identify clinically distinct subgroups in community-acquired pneumonia (CAP) and whether the treatment effect of adjunctive corticosteroids differs between subgroups.MethodsLCA was performed on baseline clinical and biomarker data from the Ovidius trial (n=304) and the Steroids in Pneumonia (STEP) trial (n=727), both randomised controlled trials investigating adjunctive corticosteroid treatment in CAP, and the observational TripleP cohort (n=201). Analyses were conducted independently in two cohorts (Ovidius–TripleP combined and the STEP trial). In both cohorts, differences in clinical outcomes and response to adjunctive corticosteroid treatment were examined between subgroups identified through LCA.ResultsA two-class model fitted both cohorts best. Class 2 patients had more signs of systemic inflammation compared to class 1. In both cohorts, length of stay was longer and in-hospital mortality rate was higher in class 2. In the Ovidius trial, corticosteroids reduced the median length of stay in class 2 (6.5 versus 9.5 days) but not in class 1 (p-value for interaction=0.02). In the STEP trial, there was no significant interaction for length of stay. We found no significant interaction between class assignment and adjunctive corticosteroid treatment for secondary outcomes.ConclusionsIn two independent cohorts, LCA identified two classes of CAP patients with different clinical characteristics and outcomes. Given the different response to adjunctive corticosteroids in the Ovidius trial, LCA might provide a useful basis to improve patient selection for future trials.

Natural History of Functional Tricuspid Regurgitation Quantified by Cardiovascular Magnetic Resonance

BackgroundQuantitation of tricuspid regurgitant (TR) severity can be challenging with conventional echocardiographic imaging and may be better evaluated using cardiovascular magnetic resonance (CMR). ObjectivesIn patients with functional TR, this study sought to examine the relationship between TR volume (TRVol) and TR fraction (TRF) with all-cause mortality. MethodsWe examined 547 patients with functional TR using CMR to quantify TRVol and TRF. The primary outcome was all-cause mortality. Thresholds for mild, moderate, and severe TR were derived based on natural history outcome data. ResultsDuring a median follow-up of 2.6 years (interquartile range: 1.7 to 3.3 years), there were 93 deaths, with an estimated 5-year survival of 79% (95% confidence interval [CI]: 73% to 83%). After adjustment of clinical and imaging variables, including RV function, both TRF (adjusted hazard ratio [AHR] per 10% increment: 1.26; 95% CI: 1.10 to 1.45; p = 0.001) and TRVol (AHR per 10-ml increment: 1.15; 95% CI: 1.04 to 1.26; p = 0.004) were associated with mortality. Patients in the highest-risk strata of TRVol ≥45 ml or TRF ≥50% had the worst prognosis (AHR: 2.26; 95% CI: 1.36 to 3.76; p = 0.002 for TRVol and AHR: 2.60; 95% CI: 1.45 to 4.66; p = 0.001 for TRF). ConclusionsThis is the first study to use CMR to assess independent prognostic implications of functional TR. Both TRF and TRVol were associated with increased mortality after adjustment for clinical and imaging covariates, including right ventricular ejection fraction. A TRVol of ≥45 ml or TRF of ≥50% identified patients in the highest-risk strata for mortality. These CMR thresholds should be used for patient selection in future trials to determine if tricuspid valve intervention improves outcomes in this high-risk group.

The MAAPE score in intermediate and advanced hepatocellular carcinoma treated with Yttrium‐90 resin microsphere radioembolization

Yttrium-90 resin microsphere radioembolization (RE) is not recommended for routine use in intermediate or advanced hepatocellular carcinoma (HCC) by recent guidelines. This study aims to establish pre-treatment variables which predict survival in HCC patients treated with RE to identify those who will benefit most from it, and to inform patient selection for future trials. Single center, retrospective study of consecutive patients with HCC treated with RE from 2007 to 2018. Patients included if undergoing their first RE treatment for intermediate or advanced HCC; a Child-Pugh score of B7 or less; and a performance status of 1 or less. Multivariable Cox regression identified variables that were significantly associated with survival. A predictive score was developed based upon coefficients from the fitted Cox regression model, and cubic spline regression was used to identify prognostic groups. One hundred thirteen patients with intermediate (53.1%) and advanced HCC (45.1%) followed for a median of 13.2months were included. Variables associated with superior survival used to derive the MAAPE score were lower Model for End-Stage Liver Disease score (≤7), lower Alpha-fetoprotein (≤150IU/L), higher serum Albumin (>37g/L), absence of Portal vein tumor thrombus, and better performance status (Eastern Cooperative Oncology Group=0). Three survival prognostic groups were identified: good (median overall survival 25.0months), average (15.3months), and poor (6.3months) (overall log-rank test, P<0.001). The MAAPE score accurately identifies HCC patients in whom RE is safe and effective. This will allow for optimal patient selection for future trials of RE versus systemic therapy.

Neuroanatomical predictors of response to subcallosal cingulate deep brain stimulation for treatment-resistant depression

Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI. We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a >50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques. Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity. Normalization by intracranial volume nullified some between-group differences in volumetric measures. There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.

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.

Highlights of This Issue

Using liquid chromatography/mass spectrometry (LC/MS)-based metabolomics and the MEK inhibitor RO4987655, 21 plasma metabolite markers of MEK inhibition in two sensitive BRAF mutant, human melanoma xenograft models were identified. Of these, it was found that on-treatment changes in the concentrations of 15 metabolites significantly predicted objective responses in patients with advanced melanoma treated with RO4987655. In patients with progressive disease, it was demonstrated that propionyl carnitine and amino acid levels increased; while in those patients that responded, phosphatidylcholines and sphingomyelin concentrations decreased. In addition, the pre-treatment levels of seven plasma metabolites (phosphatidylcholines and sphingomyelins) had significant prognostic value.Given the lack of meaningful clinical efficacy of pharmacological agents targeting the IGF pathway when applied in unselected cancer patients, the identification of selection biomarkers is of crucial importance. Sanderson and colleagues report that autocrine IGF2 overexpression hyperactivates the IGF pathway in colorectal cancer (CRC) and other cancers and predicts for sensitivity to the IGF1R/INSR inhibitor BI 885578, either as monotherapy or in combination with VEGF-pathway inhibition. Coupled with the identification of substantial subsets of IGF2-overexpressing patients in diverse tumor types, these findings support the assessment of IGF2 expression for patient selection in future trials of IGF pathway inhibitors.Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but most patients eventually develop acquired resistance. Here, Shien and colleagues have identified that the IL6 family cytokine oncostatin-M (OSM) induced a switch to the epithelial-to-mesenchymal phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner, and co-targeting inhibition of the oncogenic pathway and JAK1 revered resistance to targeted drugs. These results suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target.OPCML, a GPI anchored tumor-suppressor protein is a negative regulator of receptor tyrosine kinases (RTK), is inactivated by somatic methylation in many cancer types. Here, Zanini and colleagues report that restoration of OPCML in deficient cells leads to sensitization to anti-HER RTK inhibitors. OPCML interacts with HER2 and not EGFR, thereby disrupting formation of HER2-EGFR heterodimers leading to better response to both lapatinib and erlotinib in HER2-expressing cancer cell lines. High OPCML expression is associated with better clinical response to lapatinib therapy in breast cancer patients. These results suggest that OPCML/RTK inhibitor co-therapy could be a valuable sensitizing approach to RTK inhibitors.

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

CT angiography and CT perfusion improve prediction of infarct volume in patients with anterior circulation stroke.

IntroductionWe investigated whether baseline CT angiography (CTA) and CT perfusion (CTP) in acute ischemic stroke could improve prediction of infarct presence and infarct volume on follow-up imaging.MethodsWe analyzed 906 patients with suspected anterior circulation stroke from the prospective multicenter Dutch acute stroke study (DUST). All patients underwent baseline non-contrast CT, CTA, and CTP and follow-up non-contrast CT/MRI after 3 days. Multivariable regression models were developed including patient characteristics and non-contrast CT, and subsequently, CTA and CTP measures were added. The increase in area under the curve (AUC) and R2 was assessed to determine the additional value of CTA and CTP.ResultsAt follow-up, 612 patients (67.5 %) had a detectable infarct on CT/MRI; median infarct volume was 14.8 mL (interquartile range (IQR) 2.8–69.6). Regarding infarct presence, the AUC of 0.82 (95 % confidence interval (CI) 0.79–0.85) for patient characteristics and non-contrast CT was improved with addition of CTA measures (AUC 0.85 (95 % CI 0.82–0.87); p < 0.001) and was even higher after addition of CTP measures (AUC 0.89 (95 % CI 0.87–0.91); p < 0.001) and combined CTA/CTP measures (AUC 0.89 (95 % CI 0.87–0.91); p < 0.001). For infarct volume, adding combined CTA/CTP measures (R2 = 0.58) was superior to patient characteristics and non-contrast CT alone (R2 = 0.44) and to addition of CTA alone (R2 = 0.55) or CTP alone (R2 = 0.54; all p < 0.001).ConclusionIn the acute stage, CTA and CTP have additional value over patient characteristics and non-contrast CT for predicting infarct presence and infarct volume on follow-up imaging. These findings could be applied for patient selection in future trials on ischemic stroke treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00234-015-1636-z) contains supplementary material, which is available to authorized users.

Abstract B23: Targeted exome sequencing for effectors involving the MAPK and PI3K pathways of cutaneous melanoma in the minority population: Identifying unique molecular signatures

Abstract Background: Melanoma is a global problem, as its incidence is rising faster than any other malignancy for both men and women. Since Caucasians are primarily affected by melanoma, most of the clinical effort and patient education is focused on this cohort. In minorities, melanoma is usually detected at a more advanced stage, distributed on sun-protected areas and associated with a worse survival. Previous studies have depicted the relevance of alterations in the MAPK and PI3K pathways; however, inclusion of a multi-ethnic population comprising of unique groups such as Native Hawaiians, Pacific Islanders, Filipinos, and other Asians has been limited. Methods: IRB approval was obtained for this retrospective analysis. From 2008 to 2013, 10 Asian/Pacific Islander patients histologically confirmed to have invasive conventional (non-acral) cutaneous melanoma were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, ulceration, and mitoses per mm squared were compiled. Using a cloud based in silica primer design software target genes was chosen. Multiplex primers were generated. Coverage was assessed using the University of California, Santa Cruz (UCSC) and National Center for Biotechnology Information (NCBI) genome browsers to ensure that known pathogenic single nucleotide polymorphisms were captured from the latest dbSNP genome build. Targets included AKT, BRAF, C-KIT, MEK, MTOR, NRAS, and PI3K. This pre-designed multiplexed panel contains genes across families representing driver mutations in signaling pathways. Next generation sequencing was performed using the Ion Torrent Personal Genome Machine™. Results: Our findings demonstrated a unique molecular distribution. Interestingly in our non-Caucasian cohort of conventional melanoma, PI3K mutations were found in 30% (normally 2-6% in Caucasians) of the biospecimens, which supports our hypothesis that ethnic minorities may have a distinct biological profile. Furthermore, 40% of this minority cohort had a c-KIT mutation which is atypical for non-acral melanoma; in addition 2 of these c-KIT mutations were novel and not classically associated with melanoma in Caucasians. What is also compelling is that 50% had simultaneous mutations, including 30% that had a concomitant PI3K mutation. Demographics of the multi-ethnic cohort included mean age of 57.5 years (range 19-80) and male gender (4/10; 40 %). Tumor location primarily involved the extremity (8/10; 80%); median Breslow thickness was 1.97 mm (range 0.77-16.0), and mean mitoses per mm squared was 5.2 (range 0-16). Conclusion: This is compelling data that may be applied to patient selection in future trials utilizing targeted agents and assist with gleaning insight into the mechanism of melanoma genesis. Molecular profiling diverse cohorts may improve the identification of novel molecular signatures germane to melanoma biology and therapy. Note: This abstract was not presented at the conference. Citation Format: Shane Y. Morita. Targeted exome sequencing for effectors involving the MAPK and PI3K pathways of cutaneous melanoma in the minority population: Identifying unique molecular signatures. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B23.

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD).

ObjectiveThe CHIMES Study compared MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. We aimed to verify if patient selection based on two prognostic factors (ie, stroke severity and time to treatment) improves detection of a treatment effect with MLC601.MethodsAnalyses were performed using data from the CHIMES Study, an international, randomized, placebo‐controlled, double‐blind trial comparing MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. Three subgroups, that is, onset to treatment time (OTT) ≥48 hours; baseline National Institute of Health Stroke Scale (NIHSS) ≥10; both OTT ≥48 hours and baseline NIHSS ≥10, were analyzed using modified Rankin Scale (mRS) ≤1 and a composite endpoint of mRS ≤1, Barthel Index ≥95, and NIHSS ≤1 at month 3.ResultsPlacebo response rates were lower (ie, worse natural outcome) among subgroups with prognostic factors. Conversely, MLC601 treatment effects were significantly higher in the subgroups with prognostic factors than for the entire cohort, being highest among patients with both OTT ≥48 hours and baseline NIHSS of 10 to 14: odds ratios of 2.18 (95% CI 1.02 to 4.65) for month 3 mRS ≤1 and 3.88 (95% CI 1.03 to 14.71) for the composite endpoint.Conclusions: Patients who have moderately severe strokes and longer OTT demonstrate better treatment effects with MLC601. These factors can guide patient selection in future trials.

Abstract A80: Acral melanoma in the Hawaiian Islands: Exploring immunologic PDL-1 signature in the minority population

Abstract Background: While acral melanoma (AM) is the least common subtype amongst the principal histologic variants of cutaneous melanoma (CM), darker-skinned individuals such as Asians, Pacific Islanders, and African Americans are more frequently affected. Asian/Pacific Islanders with AM in particular, exhibit the worst survival amongst all ethnic groups. Recent studies have profiled the importance of programmed cell death ligand 1 (PDL-1) in the therapeutic armamentarium for melanoma. However, the pathologic features and immunologic characteristics of AM evaluating PDL-1 in the minority population have not been thoroughly analyzed. Methods: IRB approval was obtained for this retrospective analysis. From 2004 to 2011, 17 Asian/Pacific Islander patients histologically confirmed to have invasive AM were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, ulceration, tumor infiltration lymphocyte (TIL) status, and mitoses per mm squared were compiled. Immunohistochemistry was performed targeting the PDL-1 (CD274) antigen on primary tumor cells in formalin-fixed paraffin-embedded archived biospecimens. PDL-1 expression was graded on a scale from 0 (absent) to 2 (high). Results: Our findings demonstrated that PDL-1 expression was low in this series (3/17; 17.6%). All AM patients had a non-brisk TIL response. A significant proportion of our entire cohort (8/17; 47.1%) exhibited thick primary lesions (&amp;gt;4.0 mm) with a high propensity for ulceration (8/17; 47.1%). Demographics of the Asian/Pacific Islander cohort included mean age of 63.8 years (range 40-86) and male gender (9/17; 53 %). Tumor location primarily involved the foot (11/17; 64.7%); median Breslow thickness was 3.98 mm (range 0.96-11.0), and mean mitoses per mm squared was 3.9 (range 0-10). Conclusion: Asian/Pacific Islanders with AM were found to have a low frequency of PDL-1 expression. The lack of a brisk lymphocytic host response in AM may provide insight into its mechanism of tumorigenesis. This is the first study to our knowledge that has examined the immunologic signature of TIL and PDL-1 status in a multi-ethnic population of AM patients. This is compelling data that may be applied to patient selection in future trials utilizing immunotherapy. Citation Format: Shane Y. Morita. Acral melanoma in the Hawaiian Islands: Exploring immunologic PDL-1 signature in the minority population. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A80. doi:10.1158/1538-7755.DISP13-A80

PTK2 expression and immunochemotherapy outcome in chronic lymphocytic leukemia

AbstractAddition of rituximab (R) to fludarabine and cyclophosphamide (FC) has significantly improved patient outcomes in chronic lymphocytic leukemia (CLL). Whether baseline gene expression can identify patients who will benefit from immunochemotherapy over chemotherapy alone has not been determined. We assessed genome-wide expression of 300 pretreatment specimens from a subset of 552 patients in REACH, a study of FC or R-FC in relapsed CLL. An independent test set was derived from 282 pretreatment specimens from CLL8, a study of FC or R-FC in treatment-naïve patients. Genes specific for benefit from R-FC were determined by assessing treatment-gene interactions in Cox proportional hazards models. REACH patients with higher pretreatment protein tyrosine kinase 2 (PTK2) messenger RNA levels derived greater benefit from R-FC, with significant improvements in progression-free survival, independent of known prognostic factors in a multivariate model. Examination of PTK2 gene expression in CLL8 patients yielded similar results. Furthermore, PTK2 inhibition blunted R-dependent cell death in vitro. This retrospective analysis from 2 independent trials revealed that increased PTK2 expression is associated with improved outcomes for CLL patients treated with R-FC vs FC. PTK2 expression may be a useful biomarker for patient selection in future trials. These trials were registered at www.clinicaltrials.gov as #NCT00090051 (REACH) and #NCT00281918 (CLL8).

Abstract B178: A functional mutational profile of a compendium of 350 patient-derived tumor xenografts (PDXs).

Abstract Introduction: PDXs are an increasingly popular tool for drug discovery. One reason is that well-characterized tumor models enable streamlining of testing procedures, as molecular markers and drug efficacy can be assessed simultaneously. At Oncotest we have &amp;gt;350 well-characterized PDXs representing many tumor types including niche tumors. The aim of this study was to define PDXs by functionally distinct mutational profiles. Methods: Mutational analyses were conducted for well-studied oncogenes and tumor suppressor genes by Sequenom (OncoCarta panels 1, 2 and 3), the results of which were validated and extended by Sanger sequencing (targeted sequencing of exons containing hotspots of mutations). Results: We categorized mutational profiles of tumor types well-represented in the PDX collection by identifying common driver mutations and then dividing the mutation carrying tumors into sub-groups based on additional mutations. For example, we identified melanoma PDXs (MEXFs) with activating BRAF mutations and MEXFs with activating NRAS mutations. We then analyzed whether BRAF or NRAS mutant MEXFs also carried a PTEN mutation. We found that of 13 BRAF-mutant MEXFs, 8 had a PTEN mutation. Of the 7 NRAS mutant MEXFs, 2 carried a PTEN mutation. When testing a drug in melanoma, it will be of interest to include representative models from each of the sub-groups with distinct mutational profiles, as they can be expected to respond differently to treatment. We were also interested in screening all tumor types for mutations primarily present in distinct histologies and identifying mutations in new histologies. This could lead to a new histology being of interest for therapeutic intervention with a targeted agent, or the definition of tumors by a specific mutation or mutational profile, rather than by histology, as a potential concept for patient selection for future trials. For example, we analyzed IDH1 and IDH2 mutations, which are mostly studied in glioma and myeloproliferative disease in PDXs from &amp;gt;25 histologies. We found five PDXs with mutations in IDH1 and IDH2 known to produce the oncometabolite R(-)-2-hydroxyglutarate: Two melanoma PDXs, one liver PDX, two colon cell-line derived xenografts (CDXs) and one NSCLC PDX. The mutations are rare events in each of the histologies, but, if broad mutational screening is done, patients carrying druggable mutations regardless of the tumor histology may benefit from treatment targeting these mutations. Conclusions: Compiling mutation data of several genes leads to the identification of genetic sub-groups of a tumor histology, which is a useful basis for the efficacy testing of novel drugs, as potential biomarker information is simultaneously collected. Screening different histologies for well-characterized mutations can potentially identify additional histologies or individual tumors for the further use of drugs targeting such mutations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B178. Citation Format: Rebekka Krumbach, Jagatheswari Virajah, Thomas Metcalfe, Heiner Fiebig, Vincent Vuaroqueaux. A functional mutational profile of a compendium of 350 patient-derived tumor xenografts (PDXs). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B178.

The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma.

Background:Recent preclinical studies identified Axl, a tyrosine kinase receptor implicated in tumour progression and epithelial-to-mesenchymal transition, as a putative therapeutic target in malignant pleural mesothelioma (MPM), an invariably fatal malignancy with limited treatment options. Here, we studied the expression of Axl and its ligand Gas-6 (growth arrest signal-6) in primary specimens of MPM, correlating their expression levels with tumour phenotype and clinical outcomes.Methods:Two independent cohorts of consecutive patients diagnosed with MPM were studied: a derivation cohort composed of 63 cases and a validation set of 35 cases. Clinical variables including patients' demographics, tumour stage, histotype, performance status (PS), Axl and Gas-6 staining were tested for predicting overall survival (OS) using univariate and multivariate analyses.Results:In the derivation cohort, Axl (P=0.001) but not Gas-6 overexpression (P=0.35) emerged as a univariate prognostic factor for OS, together with stage (P=0.05), PS (P<0.001) hypoalbuminaemia (P<0.001) and anaemia (P<0.001). Multivariate analyses confirmed Axl overexpression (P=0.01), PS (P=0.01), hypoalbuminaemia (P<0.001) and anaemia (P=0.04) as independent predictors of OS. The prognostic role of Axl overexpression was externally validated in an independent cohort (P=0.03).Conclusion:Overexpression of Axl is found in the majority of MPM specimens and influences patient's survival independently from other established prognostic factors. Such information may support patient selection for future trials.

Comment on: Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: A randomized, double‐blind placebo‐controlled crossover 4g study and an open‐label 8g extension study

To the Editor: We read with interest the results of this clinical study by Golombick et al. [1]. This and two previous articles from the same authors show that in some, but not all patients with monoclonal gammopathies, the paraprotein load, urinary bone turnover, and the free light chain ratio (FLCr), prognostic factors for progression of disease, did moderately improve. Although the results are hopeful and the medico-scientific world looked forward to the recent follow-up of the previous studies, they also indicate that it is still unclear which criteria would allow to preselect responsive patients so that trials could become more meaningful. Curcumin had been chosen by the authors because of its capacity to down-regulate interleukin-6 (IL-6), an inflammatory cytokine, known to be associated to indicators of systemic inflammation such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR). Curcumin has been known for centuries in India as an anti-inflammatory compound and long-term curcumin intake significantly reduces CRP levels [2]. There is consequently reason to speculate that the observed response to curcumin might be associated to the presence of inflammation. This is especially true as inflammation-related microenvironmental factors may locally sustain ongoing lymphoproliferation and B cell transformation [3]. Regrettably, however, neither IL-6 nor CRP or ESR levels, associated to an unfavorable prognosis, have been reported. In case the authors are in the possession of data on IL-6, CRP, or ESR, it would be very easy to verify whether or not their results gain in statistical significance when the presence of inflammation at baseline is used as a patient selection criterion. Even if for none of these indicators data would be available, it might still be tempted to gain insight on the basis of existing results. Absolute levels of FLCs rather than their ratio have recently been suggested as potential biomarkers of immune stimulation and inflammation. CRP appears to be a most relevant indicator in acute illnesses. However, in cases where the CRP response is limited it appears associated to FLC levels [4]. Stratification of the available data according to the absolute levels of uninvolved FLCs (uFLCs) might, therefore, be used in an attempt to verify whether there is an association between the response of the three prognostic factors used to curcumin and the baseline level of uFLCs. If such an association is found and if the response of the three markers is coherent, uFLCs levels might serve as a criterion for patient selection in future trials on curcumin for monoclonal gammopathy of undetermined significance (MGUS) and thereby improve their statistical significance. Curcumin has given some hope to doctors and patients because it is relatively nontoxic in healthy people. Nevertheless, there are reasons for concern about safety in patients with monoclonal gammopathies [5]. As stated by the authors, curcumin may benefit some but not all patients with high risk MGUS. A rapid identification of the subgroup of patients who could benefit from curcumin treatment would be appreciated by all concerned. We, therefore, eagerly look forward to the above suggested further elaboration by the authors on the interesting results of their study [1]. Alphons J. M. Vermorken*, Jingjing Zhu*, Willem J. M. Van de Ven*, Emmanuel Andrès , * Department of Human Genetics, Laboratory for Molecular Oncology, KU Leuven, Belgium, Department of Internal Medicine, Diabetes and Metabolic Disorders, University Hospital of Strasbourg, Strasbourg, France.

Risk stratification of local-regional failure in bladder cancer after radical cystectomy.

e15045 Background: Patients with stage ≥T2 transitional cell carcinoma (TCC) of the bladder are typically treated with radical cystectomy (RC) + pelvic node dissection (PND) +/- chemotherapy. Adjuvant radiation therapy (RT) has no clearly defined role, although local-regional failure (LF) following RC remains a significant problem. Adjuvant RT could potentially reduce LF, but the morbidity reported in the past for such RT discouraged its use. Modern RT techniques with improved normal tissue sparing have rekindled interest in adjuvant RT. Identifying subgroups with differing LF risk could facilitate patient selection for adjuvant RT protocols. Methods: From 1990 - 2008, 442 patients with TCC of the bladder were followed after RC + PND +/- chemotherapy at the Hospital of the University of Pennsylvania. 132 (30%) received neoadjuvant or adjuvant chemotherapy. LF was scored as any failure within the pelvis before or within 3 months of distant failure. Univariate, multivariate Cox regression, and recursive partitioning analyses (RPA) were performed to identify subgroups with differing LF risk. Results: On univariate analysis, stage ≥pT3, nodes removed (<10 vs. ≥10), positive margins, positive nodes (pN+), node density, hydronephrosis, lymphovascular invasion, mixed histology disease and type of surgical diversion were significant predictors of LF, while chemotherapy, gender, race and BMI were not. Age at surgery was a marginal predictor of LF. On multivariate analysis, stage ≥pT3, nodes removed (<10 vs. ≥10), positive margins, pN+ and age were significant independent predictors of LF with hazard ratios of 3.36, 2.98, 2.08, 1.84, 1.04(per yr), respectively (p <0.05 for all variables). Different cut points and definitions were explored for pT stage, pN status, number of nodes removed and chemotherapy status, but none improved the regression models. RPA identified 3 patient subgroups with significantly different LF risk (logrank/p<0.01): low (<pT3), intermediate (≥pT3 + >10 nodes), and high (≥pT3 + <10 nodes) with 5 yr LF rates of 11%, 31% and 73%. Conclusions: The risk of LF after RC varies significantly among different subgroups of TCC patients. This risk stratification model could facilitate patient selection in future trials.

Influence of underlying disease on the outcome of critically ill patients with acute renal failure

Background and objective: The development of acute renal failure (ARF) in critically ill patients is associated with an increase in hospital mortality. Recently, it was shown that starting renal replacement therapy early and using high-filtrate flow rates can improve the outcome, but this could not be confirmed in later investigations. Studying selected patient subgroups could provide a useful basis for patient selection in future trials evaluating the outcome of renal replacement therapies. We, therefore, investigated the impact of the underlying disease on the outcome of patients with ARF. Methods: We retrospectively analysed 306 patients with ARF who were treated with renal replacement therapy. Patients were classified according to six initial diagnosis groups: haemorrhagic shock, post-cardiac surgery, post-liver transplantation, trauma, severe sepsis and miscellaneous. Univariate and multivariate multiple logistic regression analysis was used to determine which factors influenced the outcome. Results: Underlying disease proved to be the only independent risk factor for mortality that was present at intensive care unit (ICU) admission (P = 0.047). Patients with severe sepsis had a significantly higher mortality rate (68%) than ARF patients as a whole (51%) (P = 0.02). Length of stay in the ICU, the use of catecholamines, the delay before ARF onset, and the correlation between APACHE II score and ICU length of stay proved to be additional independent predictors of outcome. Conclusions: Patient selection and subgroup definition according to the underlying disease could augment the usefulness of future trials evaluating the outcome of ARF.

Influence of underlying disease on the outcome of critically ill patients with acute renal failure

The development of acute renal failure (ARF) in critically ill patients is associated with an increase in hospital mortality. Recently, it was shown that starting renal replacement therapy early and using high-filtrate flow rates can improve the outcome, but this could not be confirmed in later investigations. Studying selected patient subgroups could provide a useful basis for patient selection in future trials evaluating the outcome of renal replacement therapies. We, therefore, investigated the impact of the underlying disease on the outcome of patients with ARF. We retrospectively analysed 306 patients with ARF who were treated with renal replacement therapy. Patients were classified according to six initial diagnosis groups: haemorrhagic shock, post-cardiac surgery, post-liver transplantation, trauma, severe sepsis and miscellaneous. Univariate and multivariate multiple logistic regression analysis was used to determine which factors influenced the outcome. Underlying disease proved to be the only independent risk factor for mortality that was present at intensive care unit (ICU) admission (P = 0.047). Patients with severe sepsis had a significantly higher mortality rate (68%) than ARF patients as a whole (51%) (P = 0.02). Length of stay in the ICU, the use of catecholamines, the delay before ARF onset, and the correlation between APACHE II score and ICU length of stay proved to be additional independent predictors of outcome. Patient selection and subgroup definition according to the underlying disease could augment the usefulness of future trials evaluating the outcome of ARF.