Early Course Of Treatment Research Articles

Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07–0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48–17.34]; Group 3: PD-L1− and thyroid irAE− : 30.49 [6.60–140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor–Node–Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

Comprehensive review of patients with hematologic malignancies in a cancer urgent care center: A single center experience.

144 Background: Patients with hematological malignancies are subjected to unique disease and therapy related complications that can lead to a substantial burden for them and their site of care. The emergency department has been the main gateway to acute care delivery for cancer patients, however, more recently cancer urgent care centers have been established to meet their specific care needs. This study describes the demographics and disease related characteristics of patients presenting to cancer urgent care centers and whether the visit prevented utilization of the emergency department. Methods: We performed a retrospective chart review of patients diagnosed with hematological malignancies seen in the cancer urgent care center at Henry Ford Cancer Institute between January 1, 2021, to December 31, 2022. We evaluated their demographics by race and gender, and then characterized them based on whether they were on active treatment during their visit, receiving standard of care or a clinical trial, and if they were early or late in their treatment course. Early treatment course was defined as within the first 2 cycles of therapy. We also evaluated the reason for their visit, and if an emergency department visit was prevented or not. Results: A total of 270 patients diagnosed with a hematological malignancy presented to the cancer urgent care center. 139 (51.5%) patients were male, and 141 (48.5%) were female. In terms of race, 145 (53.7%) were African American, followed by 72 (26.7%) Caucasian, with 53 (19.6%) of other races. The most common presenting reasons were gastrointestinal symptoms (63 patients [23.3%]), infectious symptoms (52 patients [19.3%]), and hematological symptoms (47 patients [17.4%]). 184 (68.1%) patients were on active treatment during their visit. Of these, 89 (33%) presented early in their treatment course. 227 patients (84%) were on standard of care treatment for their respective malignancy during the time of visit. 194 (71.9%) patient visits to the cancer urgent care prevented an emergency department visit. Conclusions: Our data demonstrates the major role of a cancer urgent care within a cancer care network. It showcases the large volume of patients with hematological malignancies that were seen in our cancer urgent care, and nearly 72% of these patients had an emergency department visit that was prevented. We will be further studying the seeming disparity in the racial proportion of such patients when compared to the race mix within the population as a whole.

Dynamic Stability of Volatile Organic Compounds in Respiratory Air in Schizophrenic Patients and Its Potential Predicting Efficacy of TAAR Agonists.

Volatile organic compounds (VOCs) in the breathing air were found to be altered in schizophrenia patients compared to healthy participants. The aim of this study was to confirm these findings and to examine for the first time whether these VOCs are stable or change in concentration during the early treatment course. Moreover, it was investigated whether there is a correlation of the VOCs with the existing psychopathology of schizophrenia patients, i.e., whether the concentration of masses detected in the breath gas changes when the psychopathology of the participants changes. The breath of a total of 22 patients with schizophrenia disorder was examined regarding the concentration of VOCs using proton transfer reaction mass spectrometry. The measurements were carried out at baseline and after two weeks at three different time points, the first time immediately after waking up in the morning, after 30 min, and then after 60 min. Furthermore, 22 healthy participants were investigated once as a control group. Using bootstrap mixed model analyses, significant concentration differences were found between schizophrenia patients and healthy control participants (m/z 19, 33, 42, 59, 60, 69, 74, 89, and 93). Moreover, concentration differences were detected between the sexes for masses m/z 42, 45, 57, 69, and 91. Mass m/z 67 and 95 showed significant temporal changes with decreasing concentration during awakening. Significant temporal change over two weeks of treatment could not be detected for any mass. Masses m/z 61, 71, 73, and 79 showed a significant relationship to the respective olanzapine equivalents. The length of hospital stay showed no significant relationship to the masses studied. Breath gas analysis is an easy-to-use method to detect differences in VOCs in the breath of schizophrenia patients with high temporal stability. m/z 60 corresponding to trimethylamine might be of potential interest because of its natural affinity to TAAR receptors, currently a novel therapeutic target under investigation. Overall, breath signatures seemed to stable over time in patients with schizophrenia. In the future, the development of a biomarker could potentially have an impact on the early detection of the disease, treatment, and, thus, patient outcome.

NSCLC with uncommon EGFR mutations treated with atezolizumab plus bevacizumab and chemotherapy

ObjectivesFor refractory NSCLC patients with EGFR mutations, recent studies have demonstrated a favorable response to the combination of anti-angiogenic therapy and checkpoint inhibition but included only very few patients with uncommon EGFR mutations for which treatment options are still limited despite new targeted treatments. Materials and methodsSixteen stage IV NSCLC patients with uncommon EGFR mutations from 9 different German centers were treated in first or further line with Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel (ABCP). PFS was evaluated from start of ABCP and OS from time of initial diagnosis of stage IV. ResultsPatients with either an Exon 20 insertion (n = 9) or other uncommon EGFR mutations (n = 7) received ABCP in first, second or further line. Nine patients had received a TKI therapy in first line with an ORR of 66.7 % and a median time-to-next-treatment of 6.7 months. After a median number of 4 ABCP cycles, 4 patients (25.0 %) required a dose reduction of chemotherapy and 5 patients (31.3 %) suffered from grade 3 or 4 toxicity. Overall response rate was 81.3 % and disease control rate 87.5 %. 14 patients (87.5 %) received a maintenance with AB and the median follow-up after initial diagnosis was 24.3 months.Median PFS was 13.6 months for both the entire cohort and for Exon 20 insertions. Corresponding median OS was either not reached or 30.7 months. Landmark analysis at 12 months gave a PFS of 42.8 % and an OS of 93.3 %. Four patients were rechallenged with ABCP while progressing under maintenance and responded again. In further line therapy, clinical benefit was achieved in all of 3 patients receiving Amivantamab, but in only one of four patients receiving mobocertinib. ConclusionIn this retrospective analysis, ABCP achieves an encouraging outcome for patients with uncommon EGFR mutations and is a valuable option in the early treatment course.

NSCLC with uncommon EGFR mutations treated with atezolizumab plus bevacizumab and chemotherapy.

e21076 Background: Results of IMpower-150 and Orient-31 have demonstrated a favorable effect of combining anti-angiogenic therapy and checkpoint inhibition for refractory NSCLC patients with EGFR mutations. However, both studies included only very few patients with uncommon EGFR mutations, not allowing further analysis. For those patients, representing about 10% of EGFR mutant NSCLCs, treatment options are still limited. Methods: Analysis included 16 stage IV NSCLC patients with uncommon EGFR mutations from 9 different German centers which started treatment in first or further line with Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel (ABCP) between October 2018 and January 2022. EGFR mutations were detected by NGS (n = 15) or COBAS-PCR (n = 1). PFS was evaluated from start of ABCP and OS from time of initial diagnosis of stage IV. Results: 5 men and 11 women received ABCP therapy in first (n = 4), second (n = 9) or further line (n = 3). Mean age was 56 (36-77) years. Patients had either an Exon 20 insertion (n = 9) or point mutation (n = 2, S768I), an Exon 18 mutation (n = 3, G719X or E709A), an Exon 21 mutation (L861Q) or a compound mutation (G719C/S768I). 9 patients received a TKI therapy in first line (4x Afatinib; 5x Osimertinib) with an ORR of 66.7% (CR = 1; PR = 5; SD = 1; PD = 2) and a median time-to-next-treatment of 6.7 months (range: 2.1-39.1 months). Median number of full ABCP cycles were 4 (1-6), with 3 patients (23.1%) requiring a dose reduction of chemotherapy and 4 patients (30.8%) suffering from grade 3 or 4 toxicity (one immune related pneumonitis). 13 patients (84.6%) received a maintenance with AB and the median follow-up after initial diagnosis was 19.6 months (2.3-38.4). ORR was 81.3% with 2 CR, 11 PR, 1 SD and 1 PD (not available = 1). Median PFS by Kaplan-Meier analysis was 13.0 months for both the entire cohort (95%-CI: 8.4-17.6) and for Exon 20 insertions (95%-CI: 9.3-16.7). Corresponding median OS was either not reached or 30.7 months (95%-CI: 13.8-47.6). Landmark analysis at 12 months gave a PFS of 42.8% and an OS of 93.3%. Univariate Cox regression showed no association of PFS or OS with patient or treatment parameters, including PD-L1 expression, type of mutation or prior TKI treatment. 4 patients were rechallenged with ABCP while progressing under AB maintenance and responded again. 4 patients received mobocertinib as further treatment, but only one showed a clinical benefit. Conclusions: In this retrospective analysis, ABCP achieves an encouraging outcome for patients with uncommon EGFR mutations, comparable to results for common EGFR mutations in IMpower150 (ORR 71%, mPFS: 9.7 months, mOS 29.4 months). This in contrast to immunotherapy alone which shows poor ORR and PFS. Together with new targeted treatment options for Exon 20 insertions like amivantamab (ORR 40%, mPFS 8.3 months) or mobocertinib (ORR 28%, mPFS 7.3 months), ABCP is a valuable option in the early course of treatment for this patient cohort.

Predictors of Treatment Response to an Internet-Delivered Intervention Targeting Residual Cognitive Symptoms After Major Depressive Disorder

ObjectiveResidual cognitive symptoms after depression are common and associated with reduced daily life functioning and an increased risk of depression relapse. There is a lack of knowledge on treatments targeting residual cognitive symptoms after major depressive disorder (MDD), including the factors associated with treatment response. The aim of the current study is to explore factors of treatment response to a guided internet-delivered intervention for former depressed adults experiencing residual cognitive symptoms.MethodForty-three former depressed adults with residual cognitive symptoms were included. Linear mixed model analyses were used to investigate the impact of pre-treatment demographic-, illness, and symptom variables, and therapy process variables, such as credibility, expectancy, and user behavior, on reduction in residual cognitive symptoms from pre-treatment to 6-month follow-up.ResultsHaving had MDD for a year or less predicted more reductions in residual cognitive symptoms from pre- to 6-month follow-up. Higher levels of perceived treatment credibility and expectancy evaluated in the early course of treatment did also predict a positive treatment response. No demographic-, symptom-variables, previous number of episodes with MDD, and user behavior were associated with change in residual cognitive symptoms.ConclusionThis study suggests that individuals with shorter duration of previous depressions might have larger reductions in residual cognitive symptoms at 6-month follow-up compared to those with a longer duration of depression. Treatment credibility and expectancy also predicted treatment response and effort should also be made to ensure interventions credibility. Results should be interpreted with caution due to the study having a low sample size. Further investigation of predictors should be conducted in a full scale randomized controlled trial.

Response Prediction to Concurrent Chemoradiotherapy in Esophageal Squamous Cell Carcinoma Using Delta-Radiomics Based on Sequential Whole-Tumor ADC Map.

PurposeThe purpose of this study was to investigate the association between the radiomics features (RFs) extracted from a whole-tumor ADC map during the early treatment course and response to concurrent chemoradiotherapy (cCRT) in patients with esophageal squamous cell carcinoma (ESCC).MethodsPatients with ESCC who received concurrent chemoradiotherapy were enrolled in two hospitals. Whole-tumor ADC values and RFs were extracted from sequential ADC maps before treatment, after the 5th radiation, and after the 10th radiation, and the changes of ADC values and RFs were calculated as the relative difference between different time points. RFs were selected and further imported to a support vector machine classifier for building a radiomics signature. Radiomics signatures were obtained from both RFs extracted from pretreatment images and three sets of delta-RFs. Prediction models for different responders based on clinical characteristics and radiomics signatures were built up with logistic regression.ResultsPatients (n=76) from hospital 1 were randomly assigned to training (n=53) and internal testing set (n=23) in a ratio of 7 to 3. In addition, to further test the performance of the model, data from another institute (n=17) were assigned to the external testing set. Neither ADC values nor delta-ADC values were correlated with treatment response in the three sets. It showed a predictive effect to treatment response that the AUC values of the radiomics signature built from delta-RFs over the first 2 weeks were 0.824, 0.744, and 0.742 in the training, the internal testing, and the external testing set, respectively. Compared with the evaluated response, the performance of response prediction in the internal testing set was acceptable (p = 0.048).ConclusionsThe ADC map-based delta-RFs during the early course of treatment were effective to predict the response to cCRT in patients with ESCC.

Cost-utility analysis of inotuzumab ozogamicin for relapsed or refractory B cell acute lymphoblastic leukemia from the perspective of Taiwan's health care system.

We conduct a cost-utility analysis of inotuzumab ozogamicin (INO) versus chemotherapy as the standard of care (SOC) for adults with relapsed or refractory B cell acute lymphoblastic leukemia. A Markov model incorporating transition probabilities between health states was applied to simulate disease progression. The model inputs, including overall survival, progression-free survival, and utility parameters, were obtained from the INO-VATE ALL trial and literatures. The Taiwan Cancer Registry Database and the Health and Welfare Database were utilized to identify the patient cohort and medical costs from the perspective of National Health Insurance Administration. The lifetime medical costs (in 2017 US dollars), quality-adjusted life years (QALYs) gained, and associated incremental cost-effectiveness ratio (ICER) were the main study outcomes. The lifetime medical costs for INO and SOC were $176,795 and $69,496, and the QALYs gained were 2.25 and 0.84, respectively. The ICER for INO versus SOC was $76,044 per QALY gained, which is slightly more than three times Taiwan's gross domestic product per capita (i.e., $73,224). Favorable economic results for INO versus SOC were found with an increased time horizon for model simulation, less discounting for the future benefit, and higher stem cell transplantation (SCT) rate after INO treatment; and among patients aged less than 55years, with no SCT history, or in the first salvage treatment. INO versus SOC has higher costs but is more effective. The use of INO is favorable for patients in the early treatment course and when more future benefit associated with INO is considered.

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study

BackgroundWhile the number of therapeutic options for treating inflammatory bowel diseases (IBD) is increasing, evidence for rational treatment decisions is scarce in many cases. In particular, appropriate biomarkers to predict the response to the anti-α4β7 integrin antibody vedolizumab are currently lacking.MethodsWe performed a cohort study with 21 patients suffering from ulcerative colitis (UC), in which first-time treatment with vedolizumab was initiated. CD4+ T cells were isolated from the peripheral blood and dynamic adhesion to recombinant mucosal vascular addressin cell adhesion molecule (MAdCAM-)1 in vitro as well as the effect of vedolizumab on such adhesion in vitro was determined. The expression of α4β1 integrin on peripheral blood CD4+ T cells was quantified by flow cytometry. Electronic patient records were reviewed to determine clinical response to vedolizumab.ResultsDynamic adhesion of peripheral blood CD4+ T cells to MAdCAM-1 and the reduction of adhesion following vedolizumab treatment in vitro were higher and the change in α4β1 expression on CD4+ T cells was different in vedolizumab responders and non-responders. Responders could be identified with high specificity and positive-predictive value.ConclusionsDetermining dynamic adhesion of CD4+ T cells to MAdCAM-1 and the in vitro response to vedolizumab before treatment initiation or dynamic integrin regulation in the early course of treatment seem to be promising tools to predict the clinical response to vedolizumab therapy. Larger prospective studies are warranted.

COMPARISON OF THE SPEED OF REMISSION BETWEEN BILATERAL AND RIGHT UNILATERAL ECT IN A COHORT OF GERIATRIC PSYCHIATRY PATIENTS

Introduction • Electroconvulsive therapy (ECT) has been clinically proven to be an effective form of treatment for severe depression. It is also a safe treatment option when a quick response is needed. ECT is especially useful in the geriatric population where the complications of severe depression like not eating or drinking, self-neglect, deteriorating medical co morbidities lead to increased morbidity and mortality. •Several studies have compared efficacy of the different electrode placements as well as any resulting cognitive side effects from ECT. • A randomized trial comparing bifrontal, bitemporal and right unilateral electrode placement in ECT (commonly referred to as CORE) showed clinical and statistically significant antidepressant outcomes with all three electrode placements. Bitemporal electrode placement in this study however resulted in a more rapid decline in symptoms over the early course of treatment leading to the recommendation that bitemporal leads be considered the preferred placement for urgent clinical situations. Of note the mean age characteristics of these patients was 53.1 and all carrying a diagnosis of Unipolar/bipolar depression with/without psychosis, receiving acute ECT treatment. • In Phase I of the PRIDE study, a sample of geriatric patients with severe depression were given RUL ECT 3?times a week. One of the secondary outcomes they looked at was the speed of remission which was determined by the number of RUL ECT treatments required to achieve remission. In this study, the mean number of RUL ECT treatments to achieve remission was 7.3. • In this retrospective chart review we hypothesized that using bitemporal electrode placement would lead to remission of symptoms with fewer ECT treatments than right unilateral placement among a strictly geriatric population. • Potentially fewer treatments could lead to lower treatment costs, reduce the risk of cognitive impairment and illness burden by achieving quicker response. Methods •Retrospective chart review of 20 inpatient psychiatry patients all over age 65. Diagnoses included Major depressive disorder with psychosis (6), without psychosis (11), Bipolar disorder, depressed (2) and schizoaffective disorder (1). •All 20 patients received and responded positively to acute ECT treatment at Mount Sinai Hospital administered 3 times a week. •10 patients received bitemporal treatment and 10 received right unilateral treatment. •Treatment outcome was measured by the Quick Inventory of Depressive Symptomatology (QIDS) before each ECT treatment. The QIDS-SR is a self-report inventory that measures depressive symptom severity in the following domains: sleep, psychomotor activity, appetite/weight, sad mood, concentration, energy, interest, guilt and suicidal ideations/intent. • We looked at QIDS scores at baseline and over the course determined how many ECT treatments each group received before their QIDS scores were reduced by 50%. Results Of the 20 patient ECT records reviewed, 11 were male and 9 females. 6 patients were between ages 66-70 and the remaining 14 patients were all above age 70. . At the start of ECT the average QIDS score for patients receiving bitemporal ECT was 19.8 and for RUL was 17. This indicates a moderate to severe depression from the QIDS inventory. . The average number of ECT treatments to achieve 50% QIDS score reduction in bitemporal ECT was 4.5 and that for RUL ECT was 4.1. Conclusions The average number of bitemporal ECT treatments to achieve a QIDS score reduction of 50% was 4.5 whilst that for right unilateral ECT was 4.1. • Patients that received bilateral ECT had higher average QIDS scores of 19.8 suggesting that sicker patients are treated with BL ECT. This could potentially have been because of a perceived need for a quicker response compared to RUL ECT which was not consistent with our findings. •We observed that there was little difference in the number of treatments needed to achieve fifty percent reduction in symptoms. From our findings it appears that in the geriatric population both bitemporal and right unilateral electrode placements have rapid onset of action with only a marginal difference. •Our study was limited by it being a retrospective medical chart review with only 20 patients. This research was funded by: Not Applicable

Prospects of diagnostic and prognostic biomarkers of pyometra in canine

Pyometra is one of the most common uterine pathologies of intact bitch at middle to advanced age. In the early stages, the disease shows subtle changes, making diagnosis a challenge. In contrast, at later stages, it manifests as potentially life-threatening systemic inflammatory response syndrome. Ultrasonographic examination of the uterus aids in the diagnosis, although it has limitation in ascertaining the clinical severity of pyometra. Moreover, differentiation of cystic endometrial hyperplasia from pyometra could not be discerned with greater accuracy. Therefore, false negative diagnosis of pyometra patients leads to development of systemic inflammatory response, which delays administration of therapies and results in deaths during early course of treatment. Further, indiscriminate use of broad-spectrum antimicrobials at higher dose in false positive cases considerably contributes to the rising pool of drug resistant pathogens, thereby increasing the risk of case fatality due to sepsis in a long-term. Monitoring the circulating pro-inflammatory cytokines, acute phase proteins, endotoxin, growth factors and inflammatory mediators is the current trend in pyometra research, especially for developing diagnostic and prognostic biomarkers. The present review deals with the prospects of developing diagnostic and prognostic biomarkers in the canine pyometra.

Reduced connectivity in anterior cingulate cortex as an early predictor for treatment response in drug-naive, first-episode schizophrenia: A global-brain functional connectivity analysis

BackgroundAntipsychotic medications may have acute effect on brain functional connectivity (FC) after only a few days of treatment. It is unclear if early changes in FC can predict treatment response in patients with schizophrenia. MethodsThe study included 32 patients with drug-naive, first-episode schizophrenia and 32 healthy controls. Resting-state functional magnetic resonance imaging was obtained from the patients at two time-points (pre-treatment baseline and 1 week after treatment) and healthy controls at baseline. Patients were treated with olanzapine for 8 weeks, and clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at three time points (baseline, 1 week and 8 weeks after treatment). Imaging data were analyzed using global-brain FC (GFC) and support vector regression (SVR). ResultsAt baseline, an increased GFC was observed in bilateral anterior cingulate cortex (ACC) in patients compared with healthy controls. After 1 week of olanzapine treatment, patients showed decreased GFC in bilateral ACC compared to the baseline values. SVR analysis suggested a positive relationship between GFC changes in bilateral ACC at week 1 and improvement in negative symptoms at week 8 (r = 0.957, p < 0.001). ConclusionAn early decrease in GFC in bilateral ACC may serve as a predictor for treatment response in patients with schizophrenia. If further confirmed, our finding may be able to help clinicians decide, during the early treatment course, whether the patient should stay on the chosen antipsychotic medication or switch to a different one.

Association between prior somatic disease and 5-year relapse risk among 11,856 incident patients with schizophrenia

BackgroundSomatic diseases have been associated with an increased risk for subsequent schizophrenia; however, it is unknown whether prior somatic diseases negatively affect early treatment outcomes after a first-time schizophrenia diagnosis. MethodsWe included all individuals born in Denmark after January 1st, 1977 and first-time diagnosed with schizophrenia between January 1st, 1996 and December 31st, 2015. We identified all life-time somatic hospital contacts and all prescriptions within the year before the first-time schizophrenia diagnosis and followed patients for up to five years regarding risk for schizophrenia (re)-hospitalization (relapse). We performed Cox regression analyses calculating hazard rate ratios (HRR) including 95%-confidence intervals (CI) and adjusted for relevant confounders. ResultsWe followed a total of 11,856 patients with a first-time schizophrenia diagnosis (58.7% male, mean age 23.1 (SD = 4.7) years) for 39,033 person-years, whereof 5506 (46.4%) had relapse with schizophrenia re-hospitalization during 5-year of follow-up. Somatic hospital contacts ever before (95.4%; HRR = 1.30; 95%-CI = 1.07–1.59), and specifically during the year before schizophrenia diagnosis (42.5%; HRR = 1.36; 95%-CI = 1.11–1.66) were associated with an increased risk of schizophrenia relapse as were a greater number of prior somatic hospital contacts (p < 0.001). Individuals with up to four different prescriptions for somatic medications showed a trend towards a slightly lower risk of relapse. ConclusionSomatic diseases and health seeking patterns might have an impact on the course of schizophrenia, where severe somatic comorbidity, specifically during the year before first-time schizophrenia diagnosis, seem to negatively affect early treatment course, whereas previous somatic medication use may indicate a better compliance and help-seeking behavior.

Caregiver-reported antiretroviral therapy non-adherence during the first week and after a month of treatment initiation among children diagnosed with HIV in Ethiopia

ABSTRACTTo achieve optimal virologic suppression for children undergoing antiretroviral therapy (ART), adherence must be excellent. This is defined as taking more than 95% of their prescribed doses. To our knowledge, no study in Ethiopia has evaluated the level of treatment adherence at the beginning of the child’s treatment. Our aim was therefore to evaluate caregiver-reported ART non-adherence among children and any predictors for this during the early course of treatment. We conducted a prospective cohort study of 306 children with HIV in eight health facilities in Ethiopia who were registered at ART clinics between 20 December 2014 and 20 April 2015. The adherence rate reported by caregivers during the first week and after a month of treatment initiation was 92.8% and 93.8%, respectively. Our findings highlight important predictors of non-adherence. Children whose caregivers were not undergoing HIV treatment and care themselves were less likely to be non-adherent during the first week of treatment (aOR = 0.17, 95% CI: 0.04, 0.71) and the children whose caregivers did not use a medication reminder after one month of treatment initiation (aOR = 5.21, 95% CI: 2.23, 12.16) were more likely to miss the prescribed dose. Moreover, after one month of the treatment initiation, those receiving protease inhibitor (LPV/r) or ABC-based treatment regimens were more likely to be non-adherent (aOR = 12.32, 95% CI: 3.25, 46.67). To promote treatment adherence during ART initiation in children, particular emphasis needs to be placed on a baseline treatment regimen and ways to issue reminders about the child’s medication to both the health care system and caregivers. Further, large scale studies using a combination of adherence measuring methods upon treatment initiation are needed to better define the magnitude and predictors of ART non-adherence in resource-limited settings.

SU‐F‐J‐59: Assessment of Dose Response Distribution in Individual Human Tumor

Purpose:To fulfill precision radiotherapy via adaptive dose painting by number, voxel‐by‐voxel dose response or radio‐sensitivity in individual human tumor needs to be determined in early treatment to guide treatment adaptation. In this study, multiple FDG PET images obtained pre‐ and weekly during the treatment course were utilized to determine the distribution/spectrum of dose response parameters in individual human tumors.Methods:FDG PET/CT images of 18 HN cancer patients were used in the study. Spatial parametric image of tumor metabolic ratio (dSUV) was created following voxel by voxel deformable image registration. Each voxel value in dSUV was a function of pre‐treatment baseline SUV and treatment delivered dose, and used as a surrogate of tumor survival fraction (SF). Regression fitting with break points was performed using the LQ‐model with tumor proliferation for the control and failure group of tumors separately. The distribution and spectrum of radiation sensitivity and growth in individual tumors were determined and evaluated.Results:Spectrum of tumor dose‐sensitivity and proliferation in the controlled group was broad with α in tumor survival LQ‐model from 0.17 to 0.8. It was proportional to the baseline SUV. Tlag was about 21∼25 days, and Tpot about 0.56∼1.67 days respectively. Commonly tumor voxels with high radio‐sensitivity or larger α had small Tlag and Tpot. For the failure group, the radio‐sensitivity α was low within 0.05 to 0.3, but did not show clear Tlag. In addition, tumor voxel radio‐sensitivity could be estimated during the early treatment weeks.Conclusion:Dose response distribution with respect to radio‐sensitivity and growth in individual human tumor can be determined using FDG PET imaging based tumor metabolic ratio measured in early treatment course. The discover is critical and provides a potential quantitative objective to implement tumor specific precision radiotherapy via adaptive dose painting by number.

Attention and executive functions in the early course of pediatric epilepsy.

Our prospective study aimed at exploring attention and executive functions in children with new-onset epilepsy prior to and during the early course of antiepileptic treatment. Sociodemographic and epilepsy-related factors were analyzed as potential predictors both of impaired cognitive functions as well as for changes in cognitive functioning in the early course of illness. From a total group of 115 children aged six to 17years without major disabilities, 76 children were assessed longitudinally with a screening tool for attention and executive functions (EpiTrack Junior®). Sociodemographic variables (gender, age at epilepsy onset, need of special education) and epilepsy-related variables (etiology of epilepsy, semiology of seizures, number of seizures) were considered as potential predictors for impaired functions prior to treatment and for deterioration/amelioration in cognitive functions in the early course. Attention and executive functions of children with new-onset epilepsy were significantly more often impaired when compared with a healthy population, but less often when compared with children with chronic epilepsy. The majority of children showed stable cognitive functioning in the early course of treatment. The risk of impaired cognitive functions was significantly heightened when etiology of epilepsy was unknown or not classifiable. The chance for improvement of functioning was lowered by having a genetic epilepsy, or an unknown semiology of seizures. Children with new-onset epilepsy are at high risk for impaired attention and executive functions even prior to antiepileptic treatment, especially when etiology of their epilepsy remains unclear. The high stability of cognitive functioning in the early course can be used in counseling of families who worry about negative side effects of drug treatment. Finally, a systematic assessment of cognitive functions in children with new-onset epilepsy is necessary to detect subtle deficits in the early course and adjust treatment accordingly.

Adipose-derived mesenchymal stromal cells modulate experimental autoimmune arthritis by inducing an early regulatory innate cell signature.

Modulation of innate immune responses in rheumatoid arthritis and other immune‐mediated disorders is of critical importance in the clinic since a growing body of information has shown the key contribution of dysregulated innate responses in the progression of the disease. Mesenchymal stromal cells (MSCs) are the focus of intensive efforts worldwide due to their key role in tissue regeneration and modulation of inflammation. In this study, we define innate immune responses occurring during the early course of treatment with a single dose of expanded adipose‐derived MSCs (eASCs) in established collagen‐induced arthritis. eASCs delay the progression of the disease during the early phase of the disease. This is accompanied by a transient induction of Ly6C+ monocytes that differentiate into IL10+F4/80+ cells in arthritic mice. Strikingly, the induced IL10+F4/80+ myeloid cells preferentially accumulated in the draining lymph nodes. This effect was accompanied with a concomitant declining of their frequencies in the spleens. Our results show that eASCs attenuate the arthritic process by inducing an early innate cell signature that involves a transient induction of Ly6C+ monocytes in periphery that differentiate into IL10+F4/80+ macrophages. Our findings demonstrate that early regulatory innate cell responses, involving the monocyte compartment, are targeted by the eASCs during the onset of collagen‐induced inflammation.

Default Time from Tuberculosis Treatment in the Southern Republic of Benin Using Mixture Cure Model for Survival Analysis

Background: To date, this is the first statistical analysis of default time from tuberculosis (TB) treatment conducted in the republic of Benin. This cohort study assessed the cured fraction, the conditional probability of default (CPD) from treatment course and identified the risk factors predicting its timing. Methods: TB case was a patient with positive culture for the Mycobacterium tuberculosis complex or with two sputum smears positive for acid-fast bacilli. The 2008’s cohort of TB patients was extracted from Benin national TB registry. Active TB Patients who were diagnosed between November 2007 and December 2008 were included and followed up to December, 23 rd 2009 relative to their specific initiation date. Default was defined using the WHO guidelines. Primary endpoint was the time to default from the anti-TB treatment course. Risk factors were assessed with univariate and multivariate Cox regression integrating the mixture cure models. Results: More than 5% (n=64) of defaulters were identified with a cured fraction of 94.1%. About 3% of patients defaulted within the first 2 months (CPD = 0.025 ± 0.004). HIV/AIDS co-infection and TB history were independently associated with default time (log-rank = 35.21; P < 0.0001 and log-rank = 10.11; P = 0.0015 respectively). With Cox proportional hazards (PH) analysis, predictors of default time were HIV/AIDS, TB history and Age (hazard ratio [HR] = 3.82 [2.28; 6.41], P < 0.0001 for HIV-positive, HR = 0.13 [0.03; 0.53], P = 0.0045 for previous-TB infection and Age (HR = 3.49 [1.25; 9.74], P = 0.0170 for 65 years old or more, respectively). With logistic Cox PH mixture cure model HIV/AIDS and Age significantly increased the probability of default (Odds Ratios [OR] = 4.04 [2.64; 7.08], P < 0.0001 for HIV-positive, and OR = 4.23 [1.58; 12.10], P = 0.006 for 65 years old or more, respectively) whereas TB history significantly reduced default probability (OR = 0.04 [0.004; 0.54], P = 0.0148 for previous-TB infection. Conclusion: Whatever the alternative model considered, this study provides the first evidence that HIV/AID, TB history and Age were the major predictive factors of default time from anti-TB treatment in Benin. Therefore, additional efforts to improve the compliance of patients with anti-TB treatment through a better management of the co-infection with HIV/AIDS in accordance with patient’s specific age group may be an important feature of a prospective TB control strategy in the future. This should be emphasized in the early treatment course for these subgroups of TB patients.

Miliary Tuberculosis Induced Acute Liver Failure.

Hepatobiliary tuberculosis is uncommon even in endemic countries. It is associated with a high mortality and is even diagnosed early in the disease course. Acute liver failure (ALF) caused by tuberculosis bacilli has been reported in only a few reports. All previous cases have been diagnosed by postmortem examination. Time to antituberculosis treatment is very critical. In case of suggestive findings on clinical and radiologic examination, antituberculosis treatment should be initiated immediately. Drug use can be a challenge in patients with ALF. However, as long as the other possible causes of ALF can be excluded and hepatotoxic drugs were avoided during the early course of treatment, such a highly fatal presentation of tuberculosis can be treated safely. Here, we report a case of acute liver failure as a presentation of miliary tuberculosis. He was treated successfully with antituberculosis treatment.

Hamilton depression rating subscales to predict antidepressant treatment outcome in the early course of treatment

BackgroundHamilton depression rating scale (HAMD) subscales provide an economic alternative for the full scale; however, their ability to detect onset of improvement in the early course of treatment (EI) has not yet been researched. The present study investigated in patients with major depression (MD) whether the subscales are a comparable option to predict treatment remission in the early course of treatment. MethodsBased on data from 210 MD patients of a 6-week randomised, placebo-controlled trial comparing mirtazapine (MIR) and paroxetine (PAR), the discriminative and predictive validity of EI for (stable) remission at treatment end was evaluated for seven subscales and the HAMD17 in the total and in treatment subgroups (MIR vs. PAR). Receiver operating characteristics (ROC) curves (at week 2) and the Clinical Global Impression scales (CGI) (at study endpoint) were used to validate the 20% EI criterion for the subscales. ResultsOnly the Evans6 and Toronto7 subscale had almost the same predictive value as the HAMD17 (e.g., sensitivities stable remission Evans6/Toronto7: 96/95% vs. 96% HAMD17). The optimal cut-off for EI to predict remission was just below 20% for most subscales and slightly over 20% for stable remission. LimitationsStudy sample representativeness, non-independence of subscales, missing external validation criterion, lack of control group. ConclusionsThe Evans6 and Toronto7 subscales are valuable alternatives in situations, where economic aspects play a larger role. A sum score reduction of ≥20% as definition for EI seems also appropriate for the HAMD subscales, in the total as well as in the antidepressant subgroups.