Chance Of Response Research Articles

Transarterial Radioembolization Can Downstage Intermediate and Advanced Hepatocellular Carcinoma to Liver Transplantation.

Transarterial radioembolization (TARE) is an effective treatment to control tumor growth and improve survival in hepatocellular carcinoma (HCC). The role of TARE in downstaging patients to liver transplantation (LT) is unclear. The aim of this study was to investigate the downstaging efficacy of TARE for intermediate and advanced HCC. Intention-to-treat analysis with multistate modeling was performed. Patients moved through 5 health states: (1) from TARE to listing, (2) from TARE to death without listing, (3) from listing to LT, (4) from listing to death without LT, and (5) from transplant to death. Factors affecting the chance of death after TARE were considered to stratify outcomes. Two hundred fourteen patients underwent TARE. Of those, 43.9% had radiological response, 29.9% were listed, and 22.8% were transplanted. The probability of being alive without LT was 40.5% 1 y after TARE and 11.5% at 5 y. The chance of being listed was 9.4% at 1 y and 0.9% at 5 y. The probability of dying after TARE without LT was 38% at 1 y and 73% at 5 y. The overall survival of patients receiving LT was 61% at 5 y after transplant. Tumor beyond up-to-seven criteria, alfafetoprotein >400 ng/mL, and albumin-bilirubin ≥2 were associated with death. Three risk groups were associated with different response, chances of being listed, and receiving LT. Median survival was 3 y for low-risk, 1.9 y for intermediate-risk, and 9 mo for high-risk patients (P < 0.001). In intermediate and advanced HCC, TARE allows for a 44% chance of response, 30% downstaging, and 23% probability of permitting LT. Patient's and tumor's characteristics allow for risk stratification and predict survival from TARE.

Patient Preferences for Treatment in Relapsed/Refractory Acute Leukemia in the United Kingdom: A Discrete Choice Experiment.

Acute leukemia is a cancer of the white blood cells which progresses rapidly and aggressively. There are two types: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The latter has a rare subtype: acute promyelocytic leukemia (APL). For some patients, following first-line treatment, remission is not achieved ("refractory disease"), and for others the leukemia returns after achieving remission ("relapse"). For these individuals, outcomes are typically poor. It is, therefore, important to understand patients' treatment priorities in this context. Building upon formative qualitative research, an online survey containing a discrete choice experiment (DCE) was designed to explore patients' treatment preferences in the relapsed/refractory setting. The DCE attributes were mode of administration; quality of life during treatment; chance of response; duration of response; and quality of life during response. Each respondent completed twelve scenarios containing two hypothetical treatments. Participants were eligible if they lived in the United Kingdom and had a diagnosis of acute leukemia. The data were analysed using a latent class model. A total of 95 patients completed the survey. The latent class analysis identified two classes. For both, chance of response was the most important attribute. For class 1, every attribute was important, whereas for class 2, the only important attributes were quality of life (during treatment and response) and chance of response. A greater proportion of respondents would fall into class 1 overall, and those with ALL or APL and those more recently diagnosed were more likely to be in class 2. Our results indicate that patients are strongly concerned about the chance of response, as well as quality of life (to a lesser extent), when faced with different treatment options in the relapsed/refractory setting. However, there is significant preference heterogeneity within the patient population, and other treatment characteristics also matter to many.

Interventions for Enuresis in Children and Adolescents: An Overview of Systematic Reviews.

Enuresis is an involuntary and intermittent loss of urine during sleep, and its treatment can be done by pharmacological and non-pharmacological strategies. To conduct an overview to carry out a survey of the systematic reviews about treatment options for children/adolescents with enuresis. Databases used were Cochrane Library, PROSPERO, MEDLINE/PubMed, EMBASE, LILACS/BVS, PEDro, SciELO and Google Scholar. Any type of intervention for the treatment of enuresis in children/adolescents was selected by two independent researchers. Data extraction was done by two independent researchers. The risk of bias was assessed using Risk of Bias in Systematic Reviews (ROBIS) and A MeaSurement Tool to Assess Systematic Reviews (AMSTAR-2). Seven systematic reviews were included. According to ROBIS, three reviews had a low risk of bias, while the others had a high risk of bias. Based on AMSTAR-2, four systematic reviews were of moderate quality, two were low quality, and one was critically low quality. There is moderate confidence that the use of desmopressin plus an anticholinergic agent increases the chance of complete response compared to desmopressin alone. Neurostimulation may increase the risk of responses ≥50% and ≥90% compared to the control group. Likewise, it appears that electrical stimulation is superior to placebo about the chance of response ≥50%. In addition, there is clinical relevance in reducing enuresis episodes per week when neurostimulation is used compared to control groups.

Understanding Relapsed/Refractory Acute Leukemia Patients' Treatment Preferences: Insights from Qualitative Research

Introduction Evidence on patient preferences is increasingly being used to inform regulatory and reimbursement decisions. In acute leukemia, the number of treatment options is expanding but there is limited quantitative evidence on patients' treatment preferences, especially in the event of relapse. The Acute Leukemia Advocates Network (ALAN) in collaboration with The Office of Health Economics are running a quantitative patient preference study using a discrete choice experiment (DCE) to 1/ Elicit adult acute leukemia patients' preferences for treatment outcomes and characteristics in the event of a future relapse 2/ Explore the tradeoffs that patients are willing to make between different hypothetical treatments 3/ Describe preference heterogeneity in the patient population and 4/ Provide useful insights that could demonstrate patient value for a range of upcoming health technology assessments of relapsed/refractory treatments and guide innovation and development throughout the medical product lifecycle. Here we report on two stages of qualitative research: 1/ Online bulletin boards (OBBs) to identify potential attributes for the DCE and 2/ Cognitive ‘think aloud’ pilot interviews to test participant understanding of the draft DCE survey. Methods Two structured OBBs were conducted - one each for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Each day, participants were asked up to four open questions on the following topics: “your diagnosis and expectation of treatment”, “your first experience of treatment”, “treatment following a relapse”, and “your treatment priorities”. Participants could see and respond to each other's answers. Three researchers acted as moderators and engaged in discussions where appropriate. Following the design of the DCE survey, a series of online one-on-one think-aloud interviews with AML and ALL participants was subsequently conducted to pilot the DCE survey. Interviewees were asked to verbally reflect on their responses, with occasional interviewer prompts. The pilots were conducted in two separate weeks, with a week in between to allow for changes to be made. All participants were recruited via ALAN and its members. Results A total of 12 AML and nine ALL patients took part in the OBBs, of which 15 were female. Age (range: 26-71; average: 51.1) and years of living with the disease (range: &amp;lt;3 to &amp;gt; 10 years) were varied. Both the AML and ALL groups agreed that the effectiveness of the treatment in achieving long-term stable remission would be most important. Severe long-term side effects would also be an important concern but many participants said they could put up with potentially severe short-term side effects for a good chance of long-term survival. Additional concerns were the length of hospital stays, availability of psychological/mental/emotional support, catheter-related pain and infections, and mode of administration (MoA). Several participants argued that an individualized approach to treatment is preferred. Thematic analysis of the OBB data led to the identification of five attributes for the DCE: chance of response (20-95%), duration of response (6-18 months), quality of life (QoL) during treatment (0-50%), QoL during response (25-75%), and MoA (tablets taken at home, injections requiring a hospital stay, injections as outpatient appointments). The DCE was designed using an efficient experimental design and coded as part of an online survey, and subsequently piloted (see Figure 1). In week 1 of the pilots (n=5 interviews), ‘duration of response’, was often misinterpreted as ‘duration of treatment’. Interviewees also interpreted treatment and response as potentially overlapping, and therefore struggled to separate the two QoL attributes. Therefore, we made several changes including explicitly structuring the choice tasks to distinguish treatment and response phases. The changes improved understanding in week 2 (n=5 interviews) and raised some additional minor issues for consideration. Conclusion People with acute leukemia have a range of concerns about treatments in the context of a relapse. However, the primary issues identified in the qualitative research relate to the chance and duration of treatment success, QoL during and after treatment, and the MoA. The pilot interviews were valuable in improving the wording and overall quality of the final survey, which has since been fully launched.

Treating depression in an outpatient setting: Predictors of patient response to bouldering psychotherapy, cognitive behavioural therapy or exercise alone.

Bouldering psychotherapy (BPT) for depression has proven effective, but nothing is known about its potential predictors of response. This study should identify predictors of response to BPT, cognitive behavioural therapy (CBT) and an active control (home-based exercise programme; EP) using a literature-based model. In a multicentre randomised controlled trial, 233 outpatients were assigned to BPT, CBT or EP. Response (reduction of at least 46% on the Montgomery-Åsberg Depression Rating Scale [MADRS]) and remission (≤7 MADRS points) were defined as suggested by the literature. Predictors of response were identified twofold: (1) univariate analyses followed by logistic regression analyses in each group with all predictors yielding a univariate p-value <.20 and (2) a backward regression analysis with all potential predictors. Only variables that emerged as predictors in both types of analyses were interpreted. There was a significantly greater proportion of responders (p = .035) in the BPT than in the EP. The chance of response in the BPT was higher for patients with a higher health-related quality of life. In the EP, response was higher for patients with lower interpersonal sensitivity, suffering from their first episode and living with a partner. Response rates in BPT are similar to or even higher than in other outpatient psychotherapy group therapies. BPT and CBT are suitable for a wide range of patients, but patients with higher functionality could start with psychoeducation and exercise.

Immune Checkpoint Inhibitors in pMMR/MSS Colorectal Cancer.

Immune checkpoint inhibitors have recently replaced over chemotherapy as the first-line treatment for microsatellite instability-high or mismatch repair deficient (dMMR/MSI-H) stage 4 colorectal cancers. Considering this success, many studies have tried to replicate the use of immune checkpoint inhibitors, either as a single agent or in combination with other therapeutic agents, in the treatment of proficient mismatch repair (pMMR/MSS) stage 4 colorectal cancers. This review summarizes the seminal clinical data about the immune checkpoint inhibitors used in pMMR/MSS colorectal cancers and some future directions. Studies concerning the use of immune checkpoint inhibitors as a single agent or in combination with other immune checkpoint inhibitors, targeted therapy, chemotherapy, or radiotherapy have proven inefficient in the treatment of pMMR/MSS colorectal cancer. However, a small subset of patients with pMMR/MSS colorectal cancer who has a mutation in POLE and POLD1 enzymes may respond to immunotherapy. Moreover, patients without liver metastasis appear to have a better chance of response. New immune checkpoint targets are being identified, such as VISTA, TIGIT, LAG3, STING signal pathway, and BTLA, and studies are ongoing to determine their efficiency in this disease type. Immune checkpoint inhibitor-based regimens have not yet shown any meaningful positive outcomes for most pMMR/MSS colorectal cancers. A beneficial effect among a minority of these patients has been observed, but concrete biomarkers of response are lacking. Understanding the underlying mechanisms of immune resistance should guide further research for overcoming these obstacles.

Intermittent inotropic support with levosimendan in advanced heart failure as destination therapy: The LEVO-D registry.

Patients with advanced heart failure (AHF) who are not candidates to advanced therapies have poor prognosis. Some trials have shown that intermittent levosimendan can reduce HF hospitalizations in AHF in the short term. In this real-life registry, we describe the patterns of use, safety and factors related to the response to intermittent levosimendan infusions in AHF patients not candidates to advanced therapies. Multicentre retrospective study of patients diagnosed with advanced heart failure, not HT or LVAD candidates. Patients needed to be on the optimal medical therapy according to their treating physician. Patients with de novo heart failure or who underwent any procedure that could improve prognosis were not included in the registry. Four hundred three patients were included; 77.9% needed at least one admission the year before levosimendan was first administered because of heart failure. Death rate at 1year was 26.8% and median survival was 24.7 [95% CI: 20.4-26.9] months, and 43.7% of patients fulfilled the criteria for being considered a responder lo levosimendan (no death, heart failure admission or unplanned HF visit at 1year after first levosimendan administration). Compared with the year before there was a significant reduction in HF admissions (38.7% vs. 77.9%; P<0.0001), unplanned HF visits (22.7% vs. 43.7%; P<0.0001) or the combined event including deaths (56.3% vs. 81.4%; P<0.0001) during the year after. We created a score that helps predicting the responder status at 1year after levosimendan, resulting in a score summatory of five variables: TEER (+2), treatment with beta-blockers (+1.5), Haemoglobin >12g/dL (+1.5), amiodarone use (-1.5) HF visit 1year before levosimendan (-1.5) and heart rate >70b.p.m. (-2). Patients with a score less than -1 had a very low probability of response (21.5% free of death or HF event at 1year) meanwhile those with a score over 1.5 had the better chance of response (68.4% free of death or HF event at 1year). LEVO-D score performed well in the ROC analysis. In this large real-life series of AHF patients treated with levosimendan as destination therapy, we show a significant decrease of heart failure events during the year after the first administration. The simple LEVO-D Score could be of help when deciding about futile therapy in this population.

VEGF-C serum level is associated with response to bevacizumab maintenance therapy in primary ovarian cancer patients.

ObjectiveAt present, maintenance therapy with the antiangiogenic agent bevacizumab or with PARP-inhibitors represent two options for BRCA-wildtype ovarian cancer patients, after platinum-based first line chemotherapy. The identification of molecular markers to predict patient response to different maintenance therapies remains a major challenge. In the present study we analyzed the predictive potential of vascular endothelial growth factor C (VEGF-C) to identify ovarian cancer patients that might benefit from an antiangiogenic therapy.Methods101 patients with primary epithelial ovarian cancer were analyzed for serum levels of VEGF-A,–C and CA-125 by ELISA. Serum levels were compared between patients with low pT-stage (pT1a-pT2c n = 11), healthy individuals (n = 27) and patients with higher pT-stage (> = pT3 n = 90). Adjusted ROC curves and an adjusted logistic regression model were carried out to evaluate the potential impact of VEGF-A and -C, as well as CA-125 serum level concentration on bevacizumab-therapy response, under consideration of covariates such as FIGO, pM, pN and residual tumor after surgery.ResultsA patient which has in comparison twice the VEGF-C concentration in serum, has a significant increased chance of response to bevacizumab by a factor of 2.79. Further, only VEGF-C serum levels were significantly higher in the group of patients with lower pT-stage compared to healthy individuals, whereas VEGF-A or CA-125 serum levels could not discriminate between healthy individuals and patients with ovarian cancer at low pT-stages.ConclusionVEGF-C serum level might serve as as a biomarker to evaluate treatment response under bevacizumab.

Pit organ-based infrared discrimination sensitivity and signal transduction in the Burmese python (Python molurus bivitattus)

Burmese pythons (Python molurus bivitattus) use a unique infrared (IR) targeting system to acquire prey, avoid predators and seek thermoregulatory sites through detection of IR energy in the environment. Previous studies of sensitivity of the python IR system that relied on analysis of complex, natural behaviors lacked robust, reliable responses in animals habituated to experiments, and in vitro electrophysiological study failed to test behavioral function of the implicated protein thermoreceptor, TRPA1. The present study used conditioned discrimination procedures to analyze behavioral sensitivity and signal transduction in the python IR system. Pythons trained to behaviorally discriminate thermal stimuli averaged 70% correct choices, but failed to make correct choices when pit organs were physically occluded with IR-blocking material. The pythons exhibited greater sensitivity to thermal stimuli than previously reported, evident by correct choices that exceeded chance in response to a 14 × 10−6 W cm−2 irradiance contrast, or 0.5 °C thermal differential. Finally, in a test of the behavioral role of the putative thermoreceptor protein TRPA1, despite pit organ treatment with a TRPA1 inhibitor, python performance exceeded chance and was similar to baseline discrimination and control trials. Collectively, the results suggest that the IR system is a high sensitivity, broad-spectrum thermosensor that may operate through different and/or multiple thermoreceptive proteins with overlapping spectral response profiles. The findings reported here provide a better understanding of the relationship between the brain, behavior and environment in driving survival and ecological success of the Burmese python, especially as an invasive megapredator in the southern United States.

Effects of drying and orientation to perennial refuges on aquatic biodiversity across two basins differing in aridity

AbstractIntermittent streams are globally distributed, comprise over half the length of the global river network, and are expected to become more prevalent. However, most studies of intermittent streams are conducted at extremes of scale, are limited in taxonomic and temporal scope, and focus exclusively on drying patterns. Here, we assessed how both flow intermittency and orientation to perennial refuges affect aquatic invertebrates and aquatic and semiaquatic vertebrates across 2 years within two intermittent river basins differing in their aridity. We used loggers to characterize flow intermittency and wet–dry mapping to determine orientation to perennial refuges of reaches. In winter and summer 2015 and 2016, we collected and identified invertebrates and visually surveyed vertebrates. Using permutational multivariate analyses of variance with distance matrices, we found distinct invertebrate communities by basin, flow class (perennial or intermittent), and season, and distinct vertebrate communities by basin, and between flow classes and seasons in the more arid basin. Invertebrate communities had higher beta diversity in the more arid than mesic basin, whereas the opposite was true for vertebrates. We identified indicator species for all combinations of basin and flow class, perennial reaches combined from both basins, each basin, and some combinations of flow class and season within basins. Flow intermittency and orientation to perennial refuge predictors correlated well with both invertebrate and vertebrate communities. However, we did not find nestedness of communities that differed significantly from that expected by chance in response to increasing flow intermittency or distance to refuges. Lastly, basin, flow intermittency, and orientation to perennial refuge predictors were generally important for modeling taxon richness and densities, and richness and densities decreased with increasing flow intermittency and distance to perennial refuges. Collectively, our data suggest that intermittent streams harbor unique biodiversity, but also that some taxa have context‐dependent responses to intermittency and orientation to perennial refuges. These findings also suggest that future increases in stream drying are likely to lead to changes to stream communities with high potential for the loss of aquatic biodiversity.

Abstract PL1: Genomic Profiling in Early Stage ER Positive Breast Cancers/Precision Medicine

Abstract Genomic profiling has become mainstream for the management of early ER+ breast cancer and has become a favoured approach for research into pathways that govern prognosis and response and resistance to medical therapies.Management: Several commercial tests are available for the assessment of residual risk of recurrence of patients receiving hormonal therapies. We have compared several of these in postmenopausal patients treated with anastrozole or tamoxifen in the ATAC trial, including OncotypeDX (ODX), Prosigna (PAM50) and EndoPredict (EP). While PAM50 and EP provide estimates of risk that by design integrate tumour size and nodal status, estimates from ODX are also improved substantially by integration with clinicopathologic factors. The 3 tests include genes related to proliferation and to dependence on estrogen signalling with the ODX being dominated by the latter and PAM50 by the former. This may explain the better performance of the PAM50 than ODX at cessation of endocrine treatment after 5 years when the outcome for patients with high ER appears to worsen. While the tests have largely been validated in postmenopausal cases they are used in premenopausal cases as well. We found that while individual gene modules varied in expression across the menstrual cycle there was little systemic variability in the overall estimates of risk. Our recent work has indicated that mutations in TP53 add significant prognostic information to that from the commercial profiling tests.Research: We have conducted genomic analyses during presurgical therapy of ER+ breast cancer to determine the key pathways of endocrine resistance using change in Ki67 as the end-point of response. Very few tumours with low levels of ER by IHC (&amp;lt;10% positive cells) or rtPCR showed a Ki67 response. A group of the most widely studied genes in breast cancer including FOS and JUN show very marked increases in expression during surgical procedures and can lead to erroneous interpretation in the absence of controls. Considering intrinsic subtypes, tumours categorised as basal-like or HER2-enriched have little chance of Ki67 response; luminal B tumours showed a slightly lower chance of response. GSEA revealed that several hallmarks reflecting immune signalling were those most strongly associated poor Ki67 response with the interferon gamma and alpha and IL6-JAK-STAT3 signalling hallmarks being particularly involved. TME deconvolution indicated a broad involvement of many immune cell types. Other hallmarks of resistance included E2F target genes and hypoxia. Mutation of TP53 was strongly associated with Ki67 poor response. RNAseq profiling of patients treated with palbociclb as well as letrozole revealed high CCNE1 expression as associated with endocrine resistance. Citation Format: M Dowsett. Genomic Profiling in Early Stage ER Positive Breast Cancers/Precision Medicine [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PL1.

Biosimulation Using the Cellworks Computational Omics Biology Model (CBM) Predicted Novel Biomarkers for Hyper-CVAD (CVAD) Treatment Response and Combination of Rituximab and Cladribine (RC) in CVAD Resistant Cases of Mantle Cell Lymphoma (MCL)

Biosimulation Using the Cellworks Computational Omics Biology Model (CBM) Predicted Novel Biomarkers for Hyper-CVAD (CVAD) Treatment Response and Combination of Rituximab and Cladribine (RC) in CVAD Resistant Cases of Mantle Cell Lymphoma (MCL)

763P Treatment response to non-platinum therapies in ovarian cancer patients according to BRCA status: A retrospective analysis of a large multicentric cohort

Ovarian Cancer (OC) patients (pts) who are not eligible for platinum rechallenge, are candidates for single-agent non-platinum treatments though chances of response are low. The predictive role of BRCA mutations (mut), which has been studied thoroughly for platinum compounds, is not well defined in this setting. We aimed to describe the single-agent activity of non-platinum compounds in a large multicentric cohort of OC pts with a known BRCA status.

The Minnesota Refined Acute GVHD Score Predicts Response to Initial Therapy, Survival and Non-Relapse Mortality after Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Background: Despite prophylactic treatments with immunosuppressive agents, approximately 50% of transplant recipients develop acute GVHD (aGVHD) with an overall response rate (ORR) to steroid front-line therapy of approximately 64% and a 6-month overall survival (OS) of 66% (Martin PJ, BBMT 2012;18:1150-63). Recently, the University of Minnesota (MN) identified a new clinical refined risk score that was more powerful than the IMBTR score to predict response and survival of patients with aGVHD (MacMillan ML et al, BBMT 2015;21:761-7). In particular, at aGVHD onset patients at standard (SR) and high-risk were characterized by opposite outcomes in terms of ORR (69% vs 43%), non-relapse mortality (NRM; 22% vs 44%) and OS (71% vs 52%). This score was mainly based on patients receiving a transplant either from a matched-related-donor or a matched or mismatched unrelated donor. Because haploidentical transplant (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is becoming a widespread option for patients lacking a HLA identical donor, we set to identify whether the refined MN aGVHD risk score is useful in the setting of Haplo-SCT in order to early identify which patients are at higher risk of death for aGVHD and may benefit from upfront, intensified treatments.Methods: Between 2011 and 2016, 318 patients received a Haplo-SCT with PT-Cy. 87 patients (27%) developed aGVHD of grade 2-4. Median age was 56 year old (20-72), 56 were male and 18 (21%) of them received a transplant from a female donor. Graft source comprised peripheral blood stem cells (PBSC) in 64 (73%) and bone marrow (BM) in 23 (37%), 56% of the patients received a reduced intensity (RIC) and 38% a non-myeloablative (NMA) conditioning, 53% had a HCT-CI>3 and 14% an unfavorable (D/R: Neg/Pos) CMV serostatus. Acute GVHD characteristics were as follows: 61 (70%) had grade 2 and 26 (30%) grade 3-4 according to Glucksberg staging, 25 (29%) had a grade A-B and 62 (71%) a grade C-D according to IMBTR index, 63 (72%) had only skin and 24 (28%) also visceral involvement, 65 (75%) were classified as standard risk (SR) and 22 (28%) as high-risk according to the MN risk score2. Front line therapy consisted of steroid in 59% of the subjects and steroid combined with extracorporeal photochemotherapy in 41%.Results: Day 28 cumulative incidence (CI) of non-responder (NR) was 21% (95% CI: 12-29) and CI of aGVHD relapse within 6 months was 8% (95% CI: 1-14). CI of cGVHD was 16% (95% CI: 9-25). 3y-OS was 55% (95% CI: 43-66) and 1y-NRM 23% (95% CI: 15-32). CI of CMV reactivation after aGVHD onset was 40% (95% CI: 29-50). Patients' outcome according to the main variables is summarized in Table I. Day 28 CI of of NR differed between MN SR and high-risk patients: 15% vs 36%, p=0.09. Glucksberg, IMBTR and visceral/non visceral grading had a similar capacity to identify patients with different chance of response. On multivariate analysis no variable was independently associated with day 28 probability of NR: of note, the MN high-risk group had a hazard ratio (HR) of 1.7 (95% CI: 0,2-12,6). Relative to 1y-NRM and 3y-OS rates, patients with high risk MN score were at higher risk od death: relative to SR, 1y-NRM was 50% vs 14% (p=0.0002) and a 3y-OS was 42% vs 60% (p=0.04). The IMBTR score was not capable to distinguish different groups in terms of NRM and OS, while stage 3-4 aGVHD according to Glucksberg grading was associated with a worse NRM, but not OS. Only the distinction between visceral and no-visceral aGVHD yielded results similar to the MN risk score (Table I). On multivariate analysis no variable was an independent predictor of NRM or OS due to the small patients number. Of note, in terms of NRM, high-risk MN group had a HR of 2.7 (95% CI: 0,2-26,8) and visceral GVHD had a HR of 1.5 (95% CI: 0.2-10.2). Relative to OS, high-risk MN group had a HR of 2.0 (95% CI: 0,3-11,3), while visceral GVHD had a HR of 1.7 (95% CI: 0.3-8.7).Conclusion: The refined MN aGVHD risk score is useful to identify at aGVHD onset patients at higher risk of non-response and mortality also in the contest of Haplo-SCT with PT-Cy. This score appears more powerful than the IBMTR, but similar to Glucksberg grading, to identify patients at higher risk. These preliminary observations need to be validated on a larger number of patients in order to identify whether the MN risk score may be useful to orient treatment decisions for aGVHD occurring after Haplo-SCT with PT-Cy. [Display omitted] DisclosuresCarlo-Stella:Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim: Consultancy, Honoraria; ADC Therapeutics: Research Funding. Santoro:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Phase I trials and therapeutic intent in the age of precision oncology: What is a patient's chance of response?

The advancement of therapeutic strategies in oncology such as precision oncology has generated significant interest in better estimating the response of modern phase I cancer clinical trials. These estimates have varied widely. In this commentary, we provide an umbrella review of phase I response rates and discuss methodological reasons for variation in prior estimates which include limited use of unpublished data, the inclusion of expansion cohorts that artificially raise response rates of cumulative response rates, varying enrolment of haematologic malignancies, and increased next in class drugs.

MURINE AVATARS FOR PRECISION MEDICINE IN ENDOMETRIOSIS

Endometriosis is a chronic, gynecologic disease afflicting 1-in-10 reproductive-aged women. Response to medical therapy is highly variable as endometriotic lesions do not consistently respond to first-line, progestin-based therapy. We have previously demonstrated in a retrospective study that progesterone receptor (PR) status in lesions can predict response to progestins. Low PR status was associated with a <10% chance of response, suggesting that some women may benefit from alternative hormonal therapy as first-line.

Outcome analyses in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with 177Lu-DOTATATE – Impact of treatment order and combination on mortality.

4606 Background: Neuroendocrine tumors of the gastroenteropancreatic tract present heterogeneous with several systemic treatment options in the advanced setting. PRRT with 177Lu-DOTATATE targeting the SSTR-2 receptor of these tumors showed effective responses in the NETTER-1 trial in the short as well as long term follow-up of patients. The aim of our study was to determine the HRQoL and outcome of GEP-NET patients. Methods: 41 GEP-NET patients who received 177Lu-DOTATATE (mean: 3 cycles) between 2012 and 2017 at University Hospital Zurich (USZ) were included in this retrospective analysis. HRQoL parameters (fatigue, insomnia, loss of appetite, abdominal pain, nausea, emesis, diarrhea, weight loss) were assessed before and after treatment. At least 3 weeks after the last PRRT cycle, data on blood parameters, HRQoL, and overall survival data were extracted from patient records. To determine factors influencing the success of PRRT therapy and survival, we recorded pre- and post-PRRT treatments (e.g. selective internal radiation therapy/SIRT, somatostatin analogue therapy/SSA, TKI or chemotherapy) and the time-point of PRRT in the therapeutic sequence was analyzed. Results: Baseline rates of HRQoL and ECOG performance status were assessed (baseline mean: ECOG 0). PRRT was well tolerated, with most patients reporting no significant deterioration in HRQoL after treatment. Blood parameters (hemoglobin, leucocyte and platelet counts, creatinine) and glomerular filtration rate were not significantly affected by PRRT therapy. The number of previous treatments did not influence survival after PRRT; neither did the length of the time period between first diagnosis and PRRT. Patients with a SIRT treatment prior to PRRT had an elevated mortality odds ratio of 4.083. If SIRT was applied to patients with a pancreatic tumor, the mortality odds ratio was 1.33 compared to patients without a pancreatic tumor. Post-PRRT SSA increased the odds for survival, with a mortality odds ratio of 2.33 for patients without SSA after PRRT. Conclusions: Patients with advanced GEP-NETs may benefit from PRRT with 177Lu-DOTATATE, as this treatment appears to be well tolerated and does not significantly impair the HRQoL or symptom load. SIRT before PRRT seems to lower the chances of response and reduces survival instead using this sequence vice versa. This trend was also seen if SSA was not used after PRRT. But these trends have to be proven in prospective trials.

Inferential reasoning in the visual and auditory modalities by cotton-top tamarins (Saguinus oedipus).

Nonhuman primate species appear to vary markedly in inferential reasoning abilities as measured by a classic inference-by-exclusion cup task. Even within species, individuals who can solve the cup task in the visual domain often struggle to use analogous auditory cues. Here we tested five cotton-top tamarins (Saguinus oedipus), cooperatively breeding New World monkeys that use both visual and auditory information when foraging, to investigate whether they might be able to solve the inference-by-exclusion task in both domains. Four subjects completed the testing series in both domains. Although three subjects performed well in the visual task, only one subject chose food location significantly above chance in response to positive auditory cues. These results demonstrate the first evidence of inferential reasoning abilities in a callitrichid species, while also revealing the performance asymmetry between the visual and auditory modalities observed in many other primates. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Association of noninvasive, radiographic measurement of prostate-specific membrane antigen (PSMA) expression with response to PSMA-targeted radionuclide therapy (TRT).

5013 Background: Prostate surface membrane antigen (PSMA) is usually overexpressed in PC and is enriched in castration-resistant tumors. PSMA-TRT is of increasing interest to the field. Many in the field of theranostics have assumed that PSMA uptake on imaging is a pre-requisite for response. We have conducted a number of trials which have incorporated PSMA imaging, but have not selected patients for treatment based upon imaging results and performed an analysis examining the relationship between imaging and response. Methods: Men with mCRPC had either planar radiolabeled J591 imaging (111In-J591 and/or 177Lu-J591) or 68Ga-PSMA11 PET/CT. Visual scores were assigned based upon PSMA uptake in tumors compared to liver uptake and scored on a 0-4 scale. Imaging scores were associated with PSA decline (≥30%, ≥50%) using Cox regression analysis. As several studies were dose-escalation in nature with prior demonstration of dose-response, we controlled for dose administered. Results: 216 men with metastatic CRPC, median PSA 72.45ng/dl, were treated with PSMA-TRT as follows: 177Lu-J591 (n=136), 177Lu-PSMA-617 (n=38), Lu-J591 + Lu-PSMA-617 combination (n=6), 225Ac-J591 (n=7), 90Y-J591 (n=29). 116 (53.7%) pts received low dose and 100 (46.3%) high dose as previously defined in the individual studies. 55 (25.5%) pts had low PSMA expression by imaging (VS 0-1) whereas 161 (74.5%) had high PSMA (VS 2-4). High PSMA expression was associated with more frequent PSA decline (≥30%: 39.2 vs 17.9% p=0.003; ≥50%: 27.5 vs 8.9% p=0.004). When controlling for dose level, this association remained significant for low (≥30%: 25 vs 8.6% p=0.04) and high doses of radionuclide therapy (≥50%: 34.9 vs 9.5% p=0.02). 13 (6%) pts with no PSMA uptake (VS=0) had PSA declines. Conclusions: This is the first study to formally analyze response to PSMA-TRT by PSMA imaging expression in an unselected patient population. The level of PSMA expression measured by imaging is associated with the chance of response. However, a subset of patients without any significant PSMA uptake on imaging did demonstrate response to PSMA-TRT, indicating that imaging cannot exclude all patients that might benefit. Clinical trial information: NCT03545165, NCT03276572, NCT03042468, NCT02552394.

Pembrolizumab in men with heavily treated metastatic castration-resistant prostate cancer (mCRPC).

172 Background: Pembrolizumab is approved for patients with metastatic, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors who have progressed on prior therapy and have no satisfactory treatment options. However, very few men with PC were included in these initial studies. We evaluated the clinical activity of pembro in a cohort of men with mCRPC and their responses based on molecular genotype. Methods: We performed a retrospective, IRB-approved review of all men with mCRPC in the Duke Cancer Center who were treated with pembro in order to define the duration of therapy, time to PSA-progression, and imaging responses according to prior/concurrent therapy and by molecular subtypes. Results: We identified 51 men who received ≥1 cycle of pembro for mCRPC. Of these, 86% (44/51) had ≥3 prior lines of therapy after ADT, including abiraterone (88%), docetaxel (86%), enzalutamide (enza, 80%), and sipuleucel-T (74%). Somatic tumor sequencing was available in 18/51 men (35%). We found that 16% (8/51) had a ≥50% confirmed PSA decline with pembro, with 8% (4/51) having ≥90% PSA decline. Two of 4 had mutations in LRP1b, one of whom also had MSH2loss and was MSI-H and TMB-high; of the other 2 patients, one had no actionable mutations and the other had no genetic testing available. Fifty-nine percent (30/51) of men were treated with concurrent therapy with pembro (most commonly enza); however, all patients with PSA responses who were concurrently treated with enza had prior documented PSA progression on enza. Overall, the median time to discontinuation of treatment was 5.8 months (mo), median PSA-PFS, defined as a 25% increase in PSA from baseline, was 1.4 mo, and median OS was 6.7 mo. Among patients with ≥50% PSA decline, duration of response ranged from 3.7 to 16.3 mo with 5 patients with ongoing responses. Conclusions: In a heavily pre-treated population of men with mCRPC, pembrolizumab was associated with a ≥50% PSA decline in 16% (8/51) of men, including a dramatic ≥90% PSA response in 8% (4/51), two of whom harbored LRP1b mutations, one also with MSH2loss and a MSI-H tumor. Large prospective studies with genomic testing are needed to identify men with the greatest chance for response to immunotherapy.