Onset Of Treatment Research Articles

Transfusion needs after CD19 CAR T‐cells for large B‐cell lymphoma: predictive factors and impact on outcome. A DESCAR‐T study.

Introduction: Patients undergoing CAR T-cell therapy may experience severe cytopenias due to lymphodepleting chemotherapy and/or CAR T-cells. Transfusion needs represent a surrogate marker of severe anemia and thrombocytopenia. Transfusion needs may impact patients’ quality of life and CAR T-cells efficacy through transfusion-related immunomodulation. Here, we aimed to describe transfusion needs of patients receiving commercial CD19 CAR T-cells for relapse or refractory large B-cell lymphoma (LBCL), identify predictive factors associated with transfusions and search for correlations with CAR T-cells efficacy. Methods: Clinical data were collected form the DESCAR-T registry, the French national real-life registry for all patients treated with commercial CAR T-cells. Transfusion data were collected from the French national blood bank. We included all LBCL patients with at least 6-months follow-up from CAR T-cell infusion. Patients were censored for transfusions at relapse, new treatment onset, or death. Results: From August 2018 to September 2022, 671 patients in the DESCAR-T registry met the eligibility criteria. Overall, 382 patients (56.9%) received at least one transfusion after CAR T-cell infusion: 53.5% at the early phase (i.e. within the first month), and 37.8% at the late phase (i.e. beyond one month). Only 6% of the patients required transfusions beyond 3 months. The mean number of red blood cells (RBC) units and platelets transfusion per patient after CAR T-cell therapy were 3.5 (range, 0–90) and 5.1 (range, 0–127), respectively. Factors associated with transfusion needs after CAR T-cells therapy are presented in Table 1. Age, international prognostic index, primary refractory status, prior ASCT, bulk disease, and severe cytokine release syndrome (CRS) were associated with early but not late RBC transfusions. Early and late platelets transfusion shared the same risk factors except for severe CRS. No association was found between transfusions and response rate after CAR T-cell therapy. However, early transfusions (RBC and platelets) were associated with a shorter progression-free survival (median PFS = 3.2 vs. 6.0 months, p = 0.0168) and overall survival (median OS = 9.3 vs. 23.6 months, p < .0001). Late platelets transfusions were associated with decreased PFS (median = 5.6 vs. 12.0 months, p = 0.0072) and OS (median = 13.8 vs. NR, p < .0001) whereas late RBC transfusions did not impact PFS nor OS. Conclusion: In our study, 56.9% of patients received transfusions after CAR T-cell therapy. We identified risk factors associated with early and late transfusion needs. Early transfusions (RBC and platelets) and late platelets transfusion were associated with worse survival. Our data shed light on the mechanisms of early and late anemia and thrombocytopenia, and on the potential impact of transfusions on CAR T-cells efficacy. Encore Abstract - previously submitted to EHA 2023 Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies Conflicts of interests pertinent to the abstract. E. Bachy Honoraria: Kite, a Gilead Company, Bristol Myers Squibb, Novartis, Pfizer, Incyte, ADC Therapeutics Research funding: Amgen, BMS Other remuneration: Kite, a Gilead Company, Bristol Myers Squibb, Novartis, Pfizer G. Cartron Consultant or advisory role: Roche, Celgene-BMS, Onwards Therapeutics, MedxCell, EmerCell, MabQi Honoraria: Sanofi, Abbvie, Takeda, Roche, Janssen, Roche, Celgene, Novartis, Incyte Other remuneration: Consulting fees from from Roche and Celgene-BMS T. Gastinne Consultant or advisory role: Takeda, Gilead Sciences Honoraria: Pfizer, Takeda, Gilead Sciences Educational grants: Roche, Pfizer F. Morschhauser Consultant or advisory role: Novartis and Gilead K. Bouabdallah Consultant or advisory role: Kite/Gilead, Takeda Honoraria: Kite/Gilead, Takeda Educational grants: Kite/Gilead O. Casasnovas Consultant or advisory role: ROCHE, TAKEDA, GLIEAD/KITE, MSD, BMS Honoraria: ROCHE, TAKEDA, GILEAD/KITE, MSD, BMS, AMGEN, ABBVIE, JANSSEN Educational grants: ROCHE, TAKEDA, GILEAD/KITE, MSD, BMS, AMGEN, ABBVIE, JANSSEN Other remuneration: ROCHE, TAKEDA, GILEAD/KITE (research funding to the institution) S. Choquet Other remuneration: Novartis, Kite Gilead C. Castilla-Llorente Honoraria: Gilead/Kite S. Guidez Honoraria: Gilead, Novartis, Incyte, Roche M. Loschi Honoraria: Alexion, BMS Celgene, Gilead, Iqone, MSD, Novartis, Pfizer, Sanofi and Sobi L. Drieu La Rochelle Consultant or advisory role: Gilead/kite Educational grants: TAKEDA, Gilead/kite R. Houot Consultant or advisory role: Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte, Miltenyi Honoraria: Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda and Roche

Evaluation of Two Pain Assessment Methods (Tactile and Air blast) for Comparison the Effectiveness of Nd:YAG Laser Therapy and Non-Laser Therapy on Dentin Hyper Sensitivity Treatment: A Systematic Review and Meta-analysis.

Dentin hypersensitivity (DH) is a common irritating condition. A precise sensitive test for its assessment can greatly aid in appropriate treatment planning. This meta-analysis aims to compare the air blast and tactile tests for assessment of the efficacy Nd:YAG laser therapy versus non-laser treatments for DH in short-term and long-term follow-ups. For this review, an electronic search of the literature was carried out in three databases by two researchers for English articles published until March 10, 2021. Pooling of the data extracted from the selected articles was performed according to the PRISMA statement by the random-effect model. The mean difference (MD) and 95% confidence interval (CI) of pain score before the treatment onset and during the follow-up period according to the visual analog scale (VAS) were calculated. The level of heterogeneity was assessed by the I2 test, and a funnel plot was drawn to assess the publication bias of the reviewed studies. Of 152 articles primarily retrieved, 9 randomized clinical trials (RCTs) using the air blast test and 4 RCTs using the tactile test were subjected to quantitative synthesis. In the short-term follow-up and immediately after treatment, the air blast test showed superiority of laser therapy compared with non-laser treatments (SMD: 0.55, 95% CI: 0.05-1.04, p= 0.03). However, this difference was not significant according to the tactile test (SMD: 0.48. 95% CI: 0.01-0.96, p= 0.06). In the long-term follow-up, the difference between laser therapy and non-laser modalities was not significant according to both air blast (SMD= -0.38, 95% CI: -1.43-0.67, p= 0.48) and tactile (SMD=0.0, 95% CI: -0.38-0.38, p= 0.99) tests. Comparison of laser therapy and non-laser modalities in the short-term reveal-ed higher sensitivity of the air blast test due to its mechanism of action compared with the tactile test. Further studies are required to interpret the results in the long-term follow-up.

Low dose anti-PD(L)-1: A potentially effective alternative for greater accessibility in solid malignancies.

e21523 Background: Anti-PD(L)1 agents changed the treatment landscape of multiple tumor types yielding long-term responses in a significant proportion of patients. However, these drugs are costly and not accessible to patients from most countries. Mounting data suggest that lower doses of anti-PD(L)1 can be as efficacious as label-approved doses at lower costs. Herein we compare the outcomes of patients treated with low-dose anti-PD(L)1 agents (LD) and patients treated with conventional doses (CD) at a single tertiary hospital. Methods: This is an observational historical cohort study evaluating the outcomes of patients treated with anti-PD(L)-1 agents (either at LD or CD) at Hospital de Base, São José do Rio Preto - Brazil. We included patients older than 18yo, with solid malignancies and treated with any anti-PD(L)1 agent. Patients were classified as having received LD if the dose administered at the first cycle was below the label dose. Data were abstracted from electronic medical records. Efficacy outcomes, including overall survival (OS), progression-free survival (PFS), and overall response rate (ORR), were evaluated. Log-rank test and Chi-square or Fisher's exact test were used as appropriate. A p-value of 0.05 was considered statistically significant. Results: From January 2020 to October 2022, a total of 43 patients were included: 26 (60.4%) received LD and 17 (39.6%) received CD. The mean age of LD and CD was 66.9 (SD 14.5) and 64.8 (SD 9.7), respectively. Most patients presented with ECOG 0 or 1 (64% LD and 66% CD), had metastatic disease at treatment onset (92% LD and 94.1% CD), and were treated in the first line (50% LD and 64% CD). Most frequent tumor sites were melanoma (38.5% LD, 56.3% CD) and lung (29.9% LD, 18.8% CD). Only 23.1% and 17.6% of tumours in LD and CD were tested for PD-L1 expression, of which 83% and 33% had PD-L1 &gt; 1. Most patients from both groups were treated with pembrolizumab (92.3% LD and 82.4% CD). The mean dose of pembrolizumab was 89.6 mg (1.5 mg/kg) for LD and 171 mg (2.1 mg/kg) for CD. After a median follow-up of 23 months, there was no significant difference in median OS (mOS), mPFS, and ORR between LD and CD (Table). A sensitivity analysis with patients receiving pembrolizumab was performed and had similar results (Table). Conclusions: Our study suggests there is no difference between patients treated with LD and CD anti-PD(L)1 in terms of OS, PFS, and ORR. The numerically shorter OS and PFS in the CD group may be due to selection bias and should be interpreted cautiously. LD anti-PD(L)1 could be an alternative to expand access in places where CD is not affordable. [Table: see text]

HYPERTENSION IN CANCER PATIENTS TREATED WITH ANTI-ANGIOGENIC BASED THERAPY: A POPULATION-BASED COHORT STUDY

Objective: Data from randomized clinical trials showed that new-onset hypertension is a common side effect of anti-angiogenic drugs. We compared the cumulative incidence of new-onset hypertension in cancer patients treated with either anti-angiogenic based therapy (AAG) or other chemotherapy only, and in patients who did not received antineoplastic agents (untreated). Design and method: Retrospective population-based cohort study based on the healthcare utilization databases of Lombardy Region (Italy). We identified the cohort of patients aged 40 years or older with a new diagnosis of cancer between 2009 and 2017. We excluded patients with antihypertensive treatment in the five years before cancer diagnosis. We 1:1:1 matched each patient who started a therapy with AAG (index case) with one patient treated with other chemotherapy only and with one untreated patient by date of cancer diagnosis, tumoral site and date of start of antineoplastic therapy. We followed-up each of the three matched patients from the date of start of AAG of the index case until the first date between onset of antihypertensive treatment with at least 3 prescriptions (the outcome of interest), death, migration or 2 years after the start of follow-up. We estimated the incidence cumulative function by considering death as competing event and we fitted a Fine and Grey regression model, adjusted for age, sex and Cancer Multimorbidity Score, in order to estimate the association between treatment and new-onset hypertension. Results: The final cohort included 3,333 1:1:1 matched patients (median age 62 years; 43.6% males). The cumulative incidence of new-onset hypertension was higher among patients treated with AAG, as compared to others. The cumulative incidence rapidly increased 1 year (26.3%) after starting therapy with AAG. The adjusted hazard ratios were 3.73 (95% CI 3.34 to 4.15) and 4.00 (3.56 to 4.48), when compared to patients treated with other chemotherapy and with those untreated, respectively. Moreover, patients treated with AAG also showed a significant increased risk of major cardiovascular events compared to others. Conclusions: Cancer patients treated with AAG showed a markedly higher risk of new-onset hypertension. The risk rapidly increased 1 year after the start of therapy.

Discriminant Analysis of the Prognostic Factors for Hearing Outcomes in Patients with Idiopathic Sudden Sensorineural Hearing Loss.

This study aims to determine and assess prognostic variables that might affect the hearing result in patients with idiopathic sudden sensorineural hearing loss following intratympanic steroid injection. In total, 190 patients with idiopathic sudden sensorineural hearing loss received intratympanic steroid injection. Two hearing indices (recovery and nonrecovery) will be analyzed as dependent variables; patient's age, time period between the onset of hearing loss and treatment, initial level of hearing (hearing loss pre), type of audiogram curve (upsloping, downsloping, and flat), presence of vertigo, presence of tinnitus, and diabetes) will be analyzed as prognostic factor variables. Recovery was seen in 72% of the patients. Different preinjection audiogram curves and hearing grades had a significant effect on recovery, absence of vestibular symptoms and no diabetic history were noted to have a good prognosis. Delay in treatment by more than 30 days from the onset of hearing loss was associated with a worse prognosis. Idiopathic sudden sensorineural hearing loss associated with late treatment plan more than 1 month, presence of vertigo, diabetes, and profound prehearing loss were negative prognostic factors. Whereas age, gender, and presence of tinnitus did not affect prognosis. More stable response was obtained when intratympanic steroids were added within 1 month after diagnosis, and the patient presented with mild or moderate hearing loss grade, flat or downsloping pure tone audiometery curve, and absence of vertigo and nondiabetic with significantly good results.

The NETFIT trial: Smart wearable medical devices to assess the quality of life of patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET).

e13627 Background: Patients diagnosed with an advanced NET are frequently deteriorating their quality of life due to tumor volume, hormone-release related symptoms and treatment toxicity. Changes on lifestyle of patients with solid tumors have shown an improvement in quality of life. However, NET patients are missed in those studies. Methods: We conducted a prospective, multicenter, observational study that included 40 patients with advanced NETs from 10 Spanish hospitals belonging to the Spanish Taskforce Group of Neuroendocrine and Endocrine Tumors (GETNE). The aim of the trial was to assess and monitor changes on different aspects in quality of life by a customized smartphone app linked to an activity wearable tracker. Data were analyzed at baseline and monthly for 16 weeks after physical activity, sleep and nutritional intervention. The primary objective was to evaluate improvement in the quality of life of patients with metastatic G1 and G2 GEP-NETs based on changes registered on the EORTC QOL-C30-GI.NET21 questionnaire during the first 16 weeks since the onset of an active systemic treatment with somatostatin analogs. Secondary endpoints included description of changes in physical exercise and sleep variables from baseline, as well as the evaluation of functional scales in patients with or without carcinoid syndrome. Results: A total of 40 patients were included in the study and all quality of life questionnaires were collected from week 0 to week 16 from 25 patients. In 15 patients there was a lack of compliance filling the questionnaires. All of the 25 patients analyzed experienced an improvement in at least one of the items of the QOL-C30 questionnaires of the primary endpoint after the first 16 weeks. As secondary outcomes it was shown a trend towards an improvement in vital signs, such as decrease in systolic blood pressure (median W0:130.7mmHg to W16:124.3mmHg p=0.3), diastolic (W0:88.7mmHg vs W16:83.3mmHg p=0.4) and heart rate (W0:93.3bpm vs W16:86bpm p=0.25). In addition, an improvement in sleep quality was observed, measured by the amount of deep REM sleep (W0:102.59 vs W16:115.3 median min/day p=0.31) or periods of light non-REM sleep (W0:301,43 vs W16:341,1 median min/day p=0.21). In the EORTC QLQ-C30 questionnaire, an improvement was observed in all functional scales (emotional function mean functional improvement (MFI) 5.3 (p=0.2), cognitive function MFI 4.0 (p=0.27), social function MFI 6.0 (p=0.3)), being deeply significant in role function (MFI 13.3 points; p=0.0156). There was an improvement in the symptomatology scales between W0 and W16, fatigue -3.7 p=0.3, nausea -1.3 p=0.5, pain -2.5 p=0.3, insomnia -9.7 p=0.05, anorexia -2.7 p= 0.3, diarrea -17.3 p=0.01. Conclusions: NETFIT trial showed that lifestyle intervention has a significant impact on the quality of life and symptomatic control of patients with metastatic G1/2 GEP-NETs.

Immunotherapy-related toxicities: A retrospective analysis of barriers to prompt detection and initiation of treatment in renal cell carcinoma.

e16547 Background: In 2021, there was an estimated 76,000 patients diagnosed with kidney cancer in the United States, and 90% of these patients were diagnosed with renal cell carcinoma (RCC). The current treatment for RCC is the use of immune checkpoint inhibitors (ICIs), which allow the body to naturally fight against cancer cells without impedance. A common side effect of this therapy, however, is immunotherapy-related adverse events (irAE), which are toxicities where the bodies overactive immune system attacks noncancerous organs. When irAEs arise, the patient’s immunotherapy is stopped, and a steroid regiment is begun to dampen the immune system before re-starting immunotherapy. Time is crucial when treating irAEs, and this study is aimed to identify barriers in the onset of steroid treatment and identify interventions that can help providers and patients identify toxicities and begin steroid treatment as soon as possible. Methods: We conducted a retrospective study analyzing adult patients (ages 18-75) being treated for RCC at UT Southwestern Medical Center and Moncrief Cancer Institute (MCI). We specifically looked at patients being treated with ipilimumab, nivolumab, and pembrolizumab. The first portion included a chart review to identify patients and identify barriers to prompt treatment, i.e. fear of worsening hyperglycemia in diabetics, access to healthcare, delay of re-initiating immunotherapy. The second portion of this study will be to identify and test a possible intervention for these patients to ensure timely recognition of toxicities and prompt initiation of steroids. Results: Upon review of 201 patients with RCC stage III/IV, the most common toxicity found was colitis (28.4%), followed by transaminitis (9.0%) and pneumonitis (9.0%). The most common method for identification of toxicities was routine lab work performed before immunotherapy administration (30.4%), check-ins at regularly scheduled appointments (21.7%), and after-hour physician telephone lines (19.6%). Additionally, the average time from irAE identification to steroid administration was 1.45 days. Excluding toxicities found either at office appointments or on routine lab work, the average time to steroids from identification was 3.55 days. Our data collection also demonstrated that routine labs were the most likely factor to identify immunotherapy toxicity in a timely manner. Conclusions: Continuation of current practices can lead to further decreases in time to steroid treatment. This study can be used as a blueprint and expanded to further investigate irAEs in other solid tumors as well as contribute to management of the ever-evolving immunotherapy landscape.

First in class TLR7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiation therapy in patients with advanced pancreatic adenocarcinoma: Results from the AGADIR study.

4153 Background: Pancreatic adenocarcinoma is refractory to immune checkpoint inhibitors such as PD1/PDL1 antagonists. Investigating alternative immunotherapeutic approaches is a crucial need for this devastating disease. The potent immunostimulatory effects of Toll-like receptor (TLRs) have spurred efforts aimed at the development of TLR agonists as new immune-oncology agents. Radiation therapy combined with TLRs agonists has been shown to enhance antitumor immunity in the preclinical setting. Methods: AGADIR is a multi-cohort, phase 2, multicenter, open-label study investigating the novel TLR 7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiotherapy (SBRT) in patients with advanced cancers. Cohort A enrolled patients with advanced pancreatic adenocarcinoma. BDB001 was administered IV at the dose of 0.75 mg/m² on days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 on day 1 every 3 weeks. Atezolizumab was given at the dose of 1200 mg every 3 weeks. SBRT of at least one metastatic lesion was started at least one week after the first administration of atezolizumab and at the latest before the Cycle 2 Day 1. The primary endpoint is disease control rate defined as the proportion of participants with complete response, partial response or stable disease, as per adapted RECIST v1.1, observed within 24 weeks of treatment onset. Secondary endpoints include objective response, progression-free survival, overall survival and safety. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 32 pts were enrolled in 3 centers (14 male, 18 female). Median age was 64 years (range 38 – 78). Median number of previous treatment lines was 1 (range 1 – 5). The most common treatment related adverse events were grade 1/2 asthenia, chills and fever. No death was related to the treatment. Among the 21 patients for whom central review was performed at the time of this writing, best tumor response was confirmed partial response, stable disease and progressive disease in 2 (9.5%), 6 (28.5%) and 13 (62.0%) patients respectively. The disease control rate was 38.0% (95%CI 18.1-61.5). Conclusions: The AGADIR study met its first endpoint for disease control rate in patients with advanced pancreatic cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03915678 .

Targeting EZH2 to overcome the resistance to immunotherapy in microsatellite stable colorectal cancer: Results from the CAIRE study.

3599 Background: Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. Targeting EZH2 can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). The CAIRE study is first study investigating the impact of EZH2 inhibition in combination with immune checkpoint inhibitor in solid tumors. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of tazemetostat (800 mg BID) combined with durvalumab (1120 mg every 3 weeks) in patients with advanced microsatellite stable colorectal cancer. The primary endpoint was the disease control rate within 24 weeks after treatment onset defined as the proportion of patients with at least a tumor assessment showing connfirmed or unconfirmed complete response, confirmed or unconfirmed partial response or stable disease based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 47 pts were enrolled at Institut Bergonié (Bordeaux, Centre). Median age was 67.7 (range 39.6 – 84.0). Median number of previous treatment lines was 4: (range 1 – 6). The most common treatment related adverse events were grade 1/2 asthenia, nausea. No death was related to the treatment. Among the 34 pts for whom blinded central review of imaging was available for at least one imaging tumor assessment, best tumor response was confirmed partial response, stable disease and progressive disease in 1 (2.9%), 11 (32.3%) and 22 (64.7%) patients respectively. The disease control rate was 35.3% (95%CI 19.7 – 53.5). Conclusions: The CAIRE study met its first endpoint for disease control rate in patients with advanced colorectal cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT04705818 .

A nomogram model to predict the risk of drug-induced liver injury in patients receiving anti-tuberculosis treatment.

Objectives: To establish an individualized nomogram to predict the probability of drug-induced liver injury (DILI) in tuberculosis patients receiving anti-tuberculosis treatment. Methods: The clinical information of patients admitted to a tertiary hospital between January 2010 and December 2022 was retrospectively reviewed from the clinical records. Patients with baseline liver diseases (hepatis B or C infection and fatty liver) or taking liver protective drugs were excluded. The maximum values in liver function test within 180days after anti-tuberculosis treatment were collected to determine the occurrence of DILI. The candidate variables used for establishing prediction model in this study were the last results within the 30days before the treatment onset. The final variables were included after univariate and multivariate logistic regression analyses and applied to establish the nomogram model. The discrimination power and prediction accuracy of the prediction model were assessed using the area under the receiver operating characteristic (AUC) curve and a calibration chart. The clinical effectiveness was assessed via decision curve analysis (DCA). The established model was validated in two validation groups. Results: A total of 1979 patients with 25 variables were enrolled in this study, and the incidence of DILI was 4.2% (n = 83). The patients with complete variables were divided into training group (n = 1,121), validation group I (n = 492) and validation group II (n = 264). Five variables were independent factors for DILI and included in the final prediction model presented as nomogram: age (odds ratio [OR] 1.022, p = 0.023), total bilirubin ≥17.1μmol/L (OR 11.714, p < 0.001), uric acid (OR 0.977, p = 0.047), neutrophil count (OR 2.145, 0.013) and alcohol consumption (OR 3.209, p = 0.002). The AUCs of the prediction model in the training group, validation group I and validation group II were 0.833, 0.668, and 0.753, respectively. The p-values of calibration charts in the three groups were 0.800, 0.996, and 0.853. The DCA curves of the prediction model were above the two extreme curves. Conclusion: The nomogram model in this study could effectively predict the DILI risk among patients under anti-tuberculosis drug treatment.

Efficacy of Αtezolizumab-Βevacizumab in BCLC-C cirrhotic patients with hepatocellular carcinoma according to the type of disease progression, the type of BCLC-C and liver disease severity.

The aim of our study was to evaluate, under real-life conditions, survival of patients with advanced HCC (BCLC-C), either initially presenting in that stage or migrating from BCLC-A to BCLC-C within 2years after curative LR/RFA, treated either with Atezolizumab-Bevacizumab or TKIs. Sixty-four cirrhotic patients with advanced HCC, who either initially presented as BCLC-C and were treated with Atezo-Bev (group A, N = 23) or TKIs (group B, N = 15) or who migrated from BCLC-A to BCLC-C stage within 2years after LR/RFA and were either treated with Atezo-Bev (group C, N = 12) or TKIs (group D, N = 14), were retrospectively evaluated. The four groups were comparable for all baseline parameters (demographics/platelets/liver disease etiology/diabetes/varices/Child-Pugh stage/ALBI grade) except for CPT score and MELD-Na. Using Cox-regression analysis, we observed that survival of group C after systemic treatment onset was significantly higher compared to group A (HR 3.71, 1.20-11.46, p = 0.02) and presented a trend to statistical significance when compared to group D (HR 3.14, 0.95-10.35, p = 0.06), adjusted for liver disease severity scores. When all BCLC-C patients classified as such due to PS only were excluded from the study, a trend for the same survival benefit in group C was shown, even in the most difficult-to-treat population with extrahepatic disease or macrovascular invasion. Cirrhotic patients with advanced HCC initially diagnosed in BCLC-C, exhibit the worst survival irrespective of treatment schedule, whereas patients progressing to BCLC-C following disease recurrence after LR/RFA, seem to mostly benefit from Atezo-Bev, even patients with extrahepatic disease and/or macrovascular invasion. Liver disease severity seems to drive survival of these patients.

Analyzing the network of parent-rated ADHD symptoms before and 2 weeks after the onset of pharmaceutical treatment.

Via a network analysis approach, following 2 weeks of the medication Ritalin, the present study investigated the quality of symptom interactions and the pattern of behavior changes to identify locations of functional weaknesses in the network interactions of symptomology. Ritalin® prescribed for 112 children (aged 4-14) with attention deficit hyperactivity disorder (ADHD) as diagnosed by five child and adolescent psychiatrists. Their parents completed Swanson, Nolan, and Pelham-IV questionnaire (SNAP-IV) before and after Ritalin® onset as the pre and post-test, respectively. Then, the network analysis approach was used to discover the pattern of changes in symptom interactions. The results indicated that in 2 weeks following its initiation, Ritalin significantly reduced restlessness and interactions between symptoms of impulsivity. "Inability to follow instructions" and "difficulty waiting their turn" symptoms were the most central symptoms of strength. Three symptoms, "Often has difficulty waiting their turn," "runs and climbs in situations where it is inappropriate" and "does not follow through on instructions," had the most expected influence. In the 14-day period of investigation, Ritalin® was effective in breaking some interactions and components of ADHD, but no significant mitigation of other components of the detected symptomatology network. Follow-up investigations using network analysis can clarify the dynamics of the network changes after initiation of medications.

Outcomes of an exercise program in patients with dorsal or volar midcarpal laxity: a cohort study of 213 patients

Purpose Describing the outcomes of an exercise program on wrist and hand function for patients with midcarpal instability (MCI). Materials and methods This study has a prospective cohort design. Two hundred and thirteen patients with MCI were included. The intervention was a 3-month exercise program consisting of hand therapy and home exercises. The primary outcome was perceived wrist and hand function evaluated with the Patient-Rated Wrist/Hand Evaluation (PRWHE) three months after treatment onset. Secondary outcomes were conversion to surgery, pain, and satisfaction with treatment results. Results PRWHE total scores improved from 51 ± 19 (mean ± SD) to 33 ± 24 at 3 months (95% CI: 36–30, p < 0.001). All visual analog scales for pain demonstrated clinically relevant improvements at 6 weeks and 3 months (p < 0.001). At 3 months, 81% of the participants would undergo the treatment again. After a median follow-up of 2.8 years, 46 patients (22%) converted to surgery. Conclusions We found clinically relevant improvements in hand and wrist function and pain. Most participants would undergo treatment again and 78% of the participants did not convert to surgery. Hence, non-invasive treatment should be the primary treatment choice for patients with MCI.

Safety and Effectiveness of Miltefosine in Post-Kala-Azar Dermal Leishmaniasis: An Observational Study.

Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis. Oral miltefosine (MF) is the first-line treatment for PKDL patients in South Asia. This study assessed the safety and effectiveness of MF therapy after 12 months of follow-up to explore more precise data. In this observational study, 300 confirmed PKDL patients were enrolled. MF with the usual dose was administered to all patients for 12 weeks and followed up for 1 year. Clinical evolution was recorded systematically by photographs at screening and at 12 weeks, 6 months, and 12 months after treatment onset. Definitive cure consisted of disappearance of skin lesions with a negative PCR at 12 weeks or with >70% of lesions, disappearing or fading at 12-month follow-up. Patients with reappearing clinical features and any positive diagnostics of PKDL during the follow-up were considered as nonresponsive. Among 300 patients, 286 (95.3%) completed 12 weeks of treatment. The per-protocol cure rate at 12 months was 97%, but 7 patients relapsed and 51 (17%) were lost to 12-month follow-up, resulting in a final cure rate of only 76%. Eye-related adverse events were noted in 11 (3.7%) patients and resolved in most (72.7%) within 12 months. Unfortunately, 3 patients had persistent partial vision loss. Mild to moderate gastrointestinal side effects were seen in 28% patients. Moderate effectiveness of MF was observed in the present study. A significant number of patients developed ocular complications, and thus MF for treatment for PKDL should be suspended and replaced with a safer alternative regimen.

Bidirectional effects of parental and adolescent symptom change in trauma-focused cognitive behavioral therapy.

The current study examines dynamic, bidirectional associations between parent and adolescent symptom improvement in response to children's therapy for posttraumatic stress disorder (PTSD). Data were collected from a racially and ethnically heterogeneous sample of 1,807 adolescents (age 13-18 years old; 69% female) and a parent participating in Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) at a community outpatient behavioral health clinic. Parents self-reported their depressive symptoms and youth self-reported their PTSD and depressive symptoms at the onset of treatment and every three months for up to nine months. Using a bivariate dual change score model (BDCSM) we examine: (a) individual dyad members' change in symptoms and (b) the bidirectional associations between changes in the parent's and youth's symptoms across treatment. Parents' and adolescents' symptoms at the start of treatment were correlated and both parents' and adolescents' symptoms decreased over the course of treatment. Parents' elevated depressive symptoms at each time point contributed to smaller decreases in their children's PTSD and depressive symptoms at the subsequent time point. Adolescents' elevated symptoms at each time point contributed to greater decreases in their parents' symptoms at the subsequent time point. These findings highlight the impact that parents and children have on each other's response to children's trauma-focused psychotherapy. Notably, parents' depressive symptoms appeared to slow their children's progress in treatment, suggesting that attending to parents' symptoms and providing them with supportive services may be an important adjunct to children's interventions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effectiveness of a transdisciplinary approach on hyperphagia management among patients with Prader Willi syndrome

BackgroundOne of the main characteristics of Prader Willi syndrome (PWS) is hyperphagia and obesity. This study sought to evaluate behaviours related to hyperphagia in individuals with PWS under a non-pharmacological transdisciplinary approach. MethodsThis observational study included PWS patients under a traditional non-pharmacological nutritional approach immersed within a regular transdisciplinary treatment (RTT) and a control group of PWS individuals without RTT. All individuals were evaluated using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). ResultsForty-three individuals were evaluated. The mean age at baseline (treatment onset) was 18.4±8.3 years in the RTT group and 19.1±6.9 years in the control group (p=0.74). Hyperphagia-related behaviours were significantly lower among those under RTT (RTT 5.7±3.7 vs control 13.1±7.5, p<0.0001). This was also identified within the three categories: arguing or manipulating to obtain food (2.71±2.1 vs 5.41±3.2, p=0.003), sneaking food (1.33±1.5 vs 3.55±3.3, p=0.007), and anger or tantrums related to food (1.67±1.8 vs 4.09±2.7, p=0.001). After a mean treatment duration of 41.0 months, the RTT group had a reduction in body mass index (baseline 38.7±17.1kg/m2 vs follow-up 29.2±9.2kg/m2; p<0.0001). A significant association between RTT duration and BMI reduction (p=0.037) was identified. ConclusionWe observed a positive impact on behaviours related to hyperphagia and a BMI reduction in PWS individuals in a context of a non-pharmacological nutritional approach as part of an RTT.

ARIA treatment benefits are related to severity of dichotic listening deficits in children

This study investigated the relationship between dichotic listening (DL) benefits from treatment with Auditory Rehabilitation for Interaural Asymmetry (ARIA) and the severity of DL deficits quantified prior to the onset of treatment. We hypothesized that children with more severe DL deficits would demonstrate greater benefits following ARIA. A scale that quantifies deficit severity was applied to dichotic listening scores obtained before and after training with ARIA at multiple clinical sites (n=92). Using multiple regression analyses, we evaluated the predictive effects of deficit severity on DL outcomes. Results demonstrated that deficit severity can predict benefits from ARIA, as measured by improvements in DL scores in both ears. ARIA is an adaptive training paradigm for improving binaural integration abilities in children with DL deficits. The results from this study suggest that children with more severe DL deficits achieve greater benefits from ARIA and that a severity scale may provide important clinical information for recommending intervention.

Age-Dependent Normalization Functions for T Lymphocytes in Healthy Individuals.

Lymphocyte numbers naturally change through age. Normalization functions to account for this are sparse and mostly disregard measurements from children in which these changes are most prominent. In this study, we analyze cross-sectional numbers of mainly T lymphocytes (CD3+, CD3+CD4+, and CD3+CD8+) and their subpopulations (naive and memory) from 673 healthy Dutch individuals ranging from infancy to adulthood (0-62 y). We fitted the data by a delayed exponential function and estimated parameters for each lymphocyte subset. Our modeling approach follows general laboratory measurement procedures in which absolute cell counts of T lymphocyte subsets are calculated from observed percentages within a reference population that is truly counted (typically the total lymphocyte count). Consequently, we obtain one set of parameter estimates per T cell subset representing both the trajectories of their counts and percentages. We allow for an initial time delay of half a year before the total lymphocyte counts per microliter of blood start to change exponentially, and we find that T lymphocyte trajectories tend to increase during the first half a year of life. Thus, our study provides functions describing the general trajectories of T lymphocyte counts and percentages of the Dutch population. These functions provide important references to study T lymphocyte dynamics in disease, and they allow one to quantify losses and gains in longitudinal data, such as the CD4+ T cell decline in HIV-infected children and/or the rate of T cell recovery after the onset of treatment.

Quality analysis of prescriptions of polymyxin B in a high-complexity public hospital

Objectives: The study proposed to evaluate the quality of polymyxin B prescription in a Brazilian high-complexity public teaching and reference hospital. Methods: This study of drug use describes the medical prescription habits, with the retrospective collection carried out with critically ill patients using polymyxin B. The dose by weight for each patient's first prescription was calculated from the Infectious Diseases Society of America (IDSA) guideline to assess the loading dose adequacy. The glomerular filtration rate (GFR) was estimated to evaluate the adequacy of the dose prescribed at the onset of treatment, based on the Kidney Disease – Improving Global Outcomes (KDIGO). Results: 346 prescriptions were analyzed, representing 259 patients. Only 61 (17.6%) included a loading dose of polymyxin B. On the other hand, no adjusted doses were identified in 147 (73.1%) prescriptions for patients whose GFR range requires renal adjustment. A total of 438 cultures were analyzed, and 97 carbapenem-resistant GNB were selected for the study (22.2%). A loading dose was identified in only 13 (13.4%) of these prescriptions, and 80 (82.5%) prescriptions had no dose adjustment by renal function. The prevalent microorganism was Klebsiella pneumoniae (70 [16.0%]). Conclusion: The study identified high rates of non-compliance with the protocol for using polymyxin B concerning the loading dose and a high percentage of cases in compliance with the protocol regarding the nonindication of renal adjustment. The development of institutional clinical protocols and the performance of the ASP team are critical to rationalizing the use and avoiding unsatisfactory clinical and microbiological results.

Mediators of Placebo Response to Cannabinoid Treatment in Children with Autism Spectrum Disorder.

The placebo response has a substantial impact on treatment outcome. However, data regarding mediators of the placebo response in children with autism spectrum disorder (ASD) are sparse. This retrospective study investigated possible mediators of the placebo response among participants of a placebo-controlled trial of cannabinoid treatment for behavioral problems in children with ASD (CBA trial, age 5-21 years). We used a specifically designed questionnaire to explore possible mediators of the placebo response in 88 participants of the CBA trial who received a placebo and had valid outcome scores. The parents of 67 participants completed the questionnaire. The placebo response was positively associated with the child's comprehension of the treatment purpose (p = 0.037). There was also a trend for participants who had a relative aggravation of symptoms before treatment onset to improve following placebo treatment (p = 0.053). No other domains, including parental expectations, previous positive experience with similar treatments (behavioral conditioning), parental locus of control, quality of the patient-physician relationships, and adherence to study medications were associated with placebo-response. This finding suggests that efforts to explain the treatment purpose to children with disabilities may enhance treatment efficacy in clinical practice and decrease differences in the placebo response between study arms. Contrary to our hypothesis, parental expectations regarding cannabinoid treatment were not associated with the placebo response.