High Risk Of Treatment Failure Research Articles

SUCCESS RATE AFTER 2-STAGE SPACER-FREE TOTAL HIP ARTHROPLASTY EXCHANGE AND RISK FACTORS FOR REINFECTION: A PROSPECTIVE COHORT STUDY OF 187 PATIENTS

Two-stage prosthesis exchange is the treatment of choice for chronic periprosthetic joint infection (PJI) of a total hip arthroplasty (THA), especially when the bone and surrounding soft tissues are compromised or difficult-to-treat pathogens are implicated. (1) to determine the outcome of two-stage prosthesis exchange for the treatment of PJI after THA; and (2) to determine risk factors for reinfection leading to subsequent revision surgeries after reimplantation. We prospectively enrolled 187 consecutive patients who underwent a two-stage THA exchange with resection arthroplasty for PJI from 2013 to 2019. The mean (± SD [standard deviation]) duration of follow-up was 54.2 ± 24.9 months (range, 36 to 96), and the mean interval until reimplantation was 9.8 ± 8.9 weeks (range, 2 to 38). All patients remained in a spacer-free girdlestone situation between the two stages of treatment. Patients who remained infection-free after their two-stage treatment were considered to have achieved treatment success. The overall success rate was 85.6%. The cumulative probability of reinfection was 11.5% after one year and 14% after two years after reimplantation. High virulence or DTT (difficult-to-treat) pathogens were significant and independent risk factors for reinfection (HR [hazard ratio] = 3.71, 95% CI [confidence interval]: 1.47 to 9.36, P = 0.006 and HR = 3.85, 95% CI: 1.73 to 8.57, respectively, P = 0.001), as was previous two-stage hip prosthesis exchange (HR = 3.58, 95% CI: 1.33 to 9.62, P = 0.01). Overall reoperation and revision rates were 26.2 and 16.6%, respectively. Re-infected patients had an 80% higher probability of reoperation than non-infected ones (P < 0.001, log-rank = 102.6), and they were 55% more likely to undergo revision surgery during their follow-up (P < 0.001, log-rank = 55.4). Reinfection rates after two-stage spacer-free THA revision for PJI still remain high, but are comparable to those including cement spacers. Patients who have had prior failed two-stage implant exchanges or are infected by high-grade or difficult-to-treat pathogens are at high risk for treatment failure.

Daptomycin Exposure Prediction With a Limited Sampling Strategy.

Daptomycin is a cyclic lipopeptide antibiotic used to treat serious infectious endocarditis caused by Staphylococcus aureus. The pharmacodynamic parameter correlating best with efficacy is the ratio of the estimated area under the concentration (AUC0-24)-time curve to the minimum inhibitory concentration. The aim of the study is to develop a limited sampling strategy to estimate AUC0-24 using a reduced number of samples. Sixty-eight daptomycin AUC0-24 values were calculated for 50 White patients who underwent treatment for at least 5 consecutive days. Plasma concentrations were detected using a validated high-performance liquid chromatography-tandem mass spectrometry analytical method, with daptomycin-d5 as an internal standard. Multiple regression was used to evaluate the ability of 2 concentration-time points to predict the AUC0-24 calculated from the entire pharmacokinetic profile. Prediction bias was calculated as the mean prediction error, whereas prediction precision was estimated as the mean absolute prediction error. The development and validation datasets comprised 40 and 10 randomly selected patients, respectively. The AUC0-24 (mg*h/L) was best estimated using the daptomycin trough concentration and plasma concentrations detected 2 hours after dosing. We calculated a mean prediction error of 1.6 (95% confidence interval, -10.7 to 10.9) and a mean absolute prediction error of 11.8 (95% confidence interval, 5.3-18.3), with 73% of prediction errors within ±15%. An equation was developed to estimate daptomycin exposure (AUC0-24), offering clinical applicability and utility in generating personalized dosing regimens, especially for individuals at high risk of treatment failure or delayed response.

Predictive significance of pretreatment 18F-FDG PET volumetric parameters on survival outcomes in pediatric patients with locally advanced undifferentiated nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a rare pediatric cancer. Most children are first diagnosed with advanced locoregional disease. Identification of patients at higher risk of treatment failure is crucial as they may benefit from more aggressive initial treatment approaches. 18Fluorine-labeled fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) has shown promise as a prognostic tool for predicting outcomes. Retrospective study of pediatric patients with locally advanced undifferentiated NPC who underwent 18F-FDG PET/CT prior to intial treatment. Predictive significance of metabolic PET parameters on survival outcomes were estimated. Thirty-two children were included, age range was 7.1-18years at the time of diagnosis. The median follow-up duration was 46.1months. Three patients (9.4%) were classified as AJCC stage IIb, 13 patients (40.6%) as stage IIIa, eight patients (25%) as stage IIIb, and eight patients (25%) as stage IVa. Our findings revealed that high whole-body metabolic tumor volume at the threshold of hepatic reference SUVmean (WB-MTV-HR) (>135mL) was associated with significantly lower event-free survival (EFS) compared to the low WB-MTV-HR group (≤135mL) (3-year EFS: 50%±18% vs. 82%±8%; p=.015). Additionally, the 3-year overall survival (OS) rates differed significantly between the high whole-body metabolic tumor volume at the threshold of an SUV of 2.5 isocontour (WB-MTV-2.5) group (MTV >74mL) and the low WB-MTV-2.5 group (MTV ≤74mL) (63%±18% vs. 100%; p=.021). Our study suggests that WB-MTV parameters could serve as significant prognostic factors for disease progression in pediatric patients with locally advanced undifferentiated NPC. However, further prospective studies with larger sample sizes are needed to validate these findings.

Comparative Effectiveness of Partial Gland Cryoablation Versus Robotic Radical Prostatectomy for Cancer Control

Background and objectiveThere is an absence of high-level evidence comparing oncologic endpoints for partial gland ablation, and most series used prostate-specific antigen (PSA) rather than biopsy endpoints. Our aim was to compare oncologic outcomes between partial gland cryoablation (PGC) and radical prostatectomy (RP) for prostate cancer. MethodsThis was a retrospective, single-center analysis of subjects treated with PGC (n = 98) or RP (n = 536) between January 2017 and December 2022 as primary treatment for intermediate-risk (Gleason grade group [GG] 2–3) prostate cancer. Oncologic endpoints included protocol surveillance biopsies after PGC in comparison to serial PSA testing after RP. The primary outcome was treatment failure, defined as a need for any salvage treatment or development of metastatic disease. Treatment failure and survival analyses were conducted using Cox proportional-hazard regression and Kaplan Meier survival curves. Key findings and limitationsAfter applying the inclusion/exclusion criteria, the PGC (n = 75) and RP (n = 298) groups were compared. PGC patients were significantly older (71 vs 64 yr; p < 0.001) but there were no differences in PSA, biopsy GG, or treatment year between the groups. The PGC group had higher rates of treatment failures at 24 mo (33% vs 11%; p < 0.001) and 48 mo (43% vs 14%; p < 0.001). One PGC patient (2.1%) and one RP patient (0.7%) had developed metastases by 48-mo follow-up (p = 0.4). On adjusted analysis, PGC was associated with a higher risk of treatment failure (hazard ratio 4.6, 95% confidence interval 2.7–7.9; p < 0.001). Limitations include observational biases associated with the retrospective study design. ConclusionsThis is the first comparative effectiveness study of cancer control outcomes for PGC versus RP. The results demonstrate an almost fivefold higher risk of treatment failure with PGC during short-term follow-up. Patient summaryWe compared cancer control outcomes for patients with intermediate-risk prostate cancer treated with partial prostate gland cryoablation versus radical prostatectomy. We found that partial gland cryoablation had an almost fivefold higher risk of treatment failure. Men with prostate cancer should be counseled regarding this difference in treatment failure.

Surgical Outcomes and Predictive Factors in Patients With Detrusor Underactivity Undergoing Bladder Outlet Obstruction Surgery.

This study was conducted to evaluate the efficacy of bladder outlet surgery in patients with detrusor underactivity (DU) and to identify factors associated with successful outcomes. We conducted a retrospective review of men diagnosed with DU in urodynamic studies who underwent bladder outlet surgery for lower urinary tract symptoms between May 2018 and April 2023. The International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry (UFM), and multichannel urodynamic studies were administered. Successful treatment outcomes were defined as either an IPSS improvement of at least 50% or the regaining of spontaneous voiding in patients urethral catheterization prior to surgery. The study included 93 male patients. Men diagnosed with significant or equivocal bladder outlet obstruction (BOO) experienced significant postoperative improvements in IPSS (from 20.6 to 6.0 and from 17.4 to 6.5, respectively), maximum urine flow rate (from 5.0 mL/sec to 14.4 mL/sec and from 8.8 mL/sec to 12.2 mL/sec, respectively) and voiding efficiency (from 48.8% to 86.0% and from 61.2% to 85.1%, respectively). However, in the group without obstruction, the improvements in IPSS and UFM results were not significant. The presence of detrusor overactivity (odds ratio [OR], 3.152; P=0.025) and preoperative urinary catheterization (OR, 2.756; P=0.040) were associated with favorable treatment outcomes. Conversely, an unobstructed bladder outlet was identified as a negative prognostic factor. In men with DU accompanied by equivocal or significant BOO, surgical intervention to alleviate the obstruction may enhance the IPSS, quality of life, and UFM results. However, those with DU and an unobstructed bladder outlet face a comparatively high risk of treatment failure. Preoperative detrusor overactivity and urinary catheterization are associated with more favorable surgical outcomes. Consequently, active deobstructive surgery should be considered for patients with DU who are experiencing urinary retention.

Explainable machine learning for early predicting treatment failure risk among patients with TB-diabetes comorbidity

The present study aims to assess the treatment outcome of patients with diabetes and tuberculosis (TB-DM) at an early stage using machine learning (ML) based on electronic medical records (EMRs). A total of 429 patients were included at Chongqing Public Health Medical Center. The random-forest-based Boruta algorithm was employed to select the essential variables, and four models with a fivefold cross-validation scheme were used for modeling and model evaluation. Furthermore, we adopted SHapley additive explanations to interpret results from the tree-based model. 9 features out of 69 candidate features were chosen as predictors. Among these predictors, the type of resistance was the most important feature, followed by activated partial throm-boplastic time (APTT), thrombin time (TT), platelet distribution width (PDW), and prothrombin time (PT). All the models we established performed above an AUC 0.7 with good predictive performance. XGBoost, the optimal performing model, predicts the risk of treatment failure in the test set with an AUC 0.9281. This study suggests that machine learning approach (XGBoost) presented in this study identifies patients with TB-DM at higher risk of treatment failure at an early stage based on EMRs. The application of a convenient and economy EMRs based on machine learning provides new insight into TB-DM treatment strategies in low and middle-income countries.

Two-stage total joint replacement for hip or knee septic arthritis: post-traumatic etiology and difficult-to-treat infections predict poor outcomes.

Septic arthritis (SA) is a rare but significant clinical challenge in orthopedics that can impact patients' quality of life. This study aims to examine the clinical outcomes of patients undergoing two-stage total joint replacement (TJR) in hip and knee SA and analyze potential predictors of treatment failure. A retrospective analysis was conducted using data from a prospectively collected institutional arthroplasty registry from January 1st, 2012, to January 1st, 2019. Patients with hip or knee SA who underwent a two-stage TJR and had at least two years of follow-up were included. Demographic characteristics, surgical variables, and outcomes were collected and analyzed from clinical and surgical data. Statistical analysis was performed using IBM SPSS Statistics, with statistical significance at p < 0.05. One hundred and fourteen patients (61 with hip SA, 53 with knee SA) were included in the study. The mean follow-up was 72.8 months. Postoperatively, both clinical and functional outcomes significantly improved, as indicated by the Hip Society Score (HHS) and Knee Society Score (KSS). The overall success rate of the two-stage protocol was 89.5%. Complications that did not require revision occurred in 21% of cases. The most identified pathogen was methicillin-sensitive Staphylococcus aureus (MSSA). Difficult-to-treat (DTT) infections and post-traumatic etiology were identified as predictors of treatment failure in patients undergoing two-stage TJR for hip and knee SA. Two-stage TJR in hip and knee SA demonstrated favorable clinical outcomes at mid-term follow-up. The procedure significantly improved functional scores and achieved a high success rate, while DTT infections and post-traumatic etiology were associated with a higher risk of treatment failure.

Real-world practice and outcomes in pilonidal surgery: Pilonidal Sinus Treatment Studying The Options (PITSTOP) cohort.

Numerous surgical approaches exist for the treatment of pilonidal disease. Current literature on treatment is of poor quality, limiting the ability to define optimal intervention. The aim of this study was to provide real-world data on current surgical practice and report patient and risk-adjusted outcomes, informing future trial design. This UK-wide multicentre prospective cohort study, including patients (aged over 16 years) who had definitive treatment for symptomatic pilonidal disease, was conducted between May 2019 and March 2022. Patient and disease characteristics, and intervention details were analysed. Data on patient-reported outcomes, including pain, complications, treatment failure, wound issues, and quality of life, were gathered at various time points up to 6 months after surgery. Strategies were implemented to adjust for risk influencing different treatment choices and outcomes. Of the 667 participants consenting, 574 (86.1%) were followed up to the study end. Twelve interventions were observed. Broadly, 59.5% underwent major excisional surgery and 40.5% minimally invasive surgery. Complications occurred in 45.1% of the cohort. Those who had minimally invasive procedures had better quality of life and, after risk adjustment, less pain (score on day 1: mean difference 1.58, 95% c.i. 1.14 to 2.01), fewer complications (difference 17.5 (95% c.i. 9.1 to 25.9)%), more rapid return to normal activities (mean difference 25.9 (18.4 to 33.4) days) but a rate of higher treatment failure (difference 9.6 (95% c.i. 17.3 to 1.9)%). At study end, 25% reported an unhealed wound and 10% had not returned to normal activities. The burden after surgery for pilonidal disease is high and treatment failure is common. Minimally invasive techniques may improve outcomes at the expense of a 10% higher risk of treatment failure.

Demographic and clinical characteristics associated with failure of physical therapy in chronic low back pain: a secondary analysis from a randomized controlled trial.

The effect of physical therapy on pain and disability alleviation in patients with chronic low back pain (cLBP) has been demonstrated, but the risk factors for treatment failure remain unknown. To explore the associations of baseline demographic and clinical characteristics with treatment failure after physical therapy intervention for cLBP. A secondary analysis of a single-blind randomized clinical trial. A rehabilitation hospital. A total of 98 patients with cLBP completed the 12-month measurement. Patients were randomly grouped into 3-month therapeutic aquatic exercise or physical therapy modalities. The primary outcome was treatment failure, which was defined as a decrease in the numeric rating scale to less than 2.0 points at 12-month follow-up. Associations between baseline demographic and clinical characteristics with risk of treatment failure were assessed by logistic regressions. The pain intensity in the failure cases was alleviated after 3-month intervention but continuously increased at 6- and 12-month follow-up (P<0.05). Old age was significantly associated with an increased risk of treatment failure (adjusted OR 3.26, 95% CI 1.11-9.60). Compared with those receiving physical therapy modalities, the patients receiving therapeutic aquatic exercise had less risk of treatment failure (adjusted OR 0.19, 95% CI 0.08-0.47), and age (P=0.022) was a modifier for this association. Compared with younger ones, older patients with cLBP had a higher risk of treatment failure after physical therapy and gained a stronger benefit of long-term pain alleviation from therapeutic aquatic exercise. Therapeutic aquatic exercise is an effective therapy for cLBP and more helpful for preventing treatment failure than physical therapy modalities, especially for older patients.

Increased risk of periprosthetic joint infection after traumatic injury in joint revision patients

BackgroundPeriprosthetic joint infection (PJI) is a serious complication after total joint arthroplasty (TJA). Although some risk factors of PJI were well studied, the association between trauma and PJI remains unknown in revision patients.Materials and methodsBetween 2015 and 2018, a total of 71 patients with trauma history before revisions (trauma cohort) were propensity score matched (PSM) at a ratio of 1 to 5 with a control cohort of revision patients without a history of trauma. Then, the cumulative incidence rate of PJI within 3 years after operation between the two groups was compared. The secondary endpoints were aseptic revisions within 3 postoperative years, complications up to 30 postoperative days, and readmission up to 90 days. During a minimal 3-year follow-up, the survival was comparatively analyzed between the trauma cohort and the control cohort.ResultsThe cumulative incidence of PJI was 40.85% in patients with trauma history against 27.04% in the controls (P = 0.02). Correspondingly, the cumulative incidence of aseptic re-revisions was 12.68% in patients with trauma history compared with 5.07% in the control cohort (P = 0.028). Cox regression revealed that trauma history was a risk factor of PJI (HR, 1.533 [95%CI, (1.019,2.306)]; P = 0.04) and aseptic re-revisions (HR, 3.285 [95%CI, (1.790,6.028)]; P < 0.0001).ConclusionsOur study demonstrated that revision patients with trauma history carried a higher risk of PJI compared to those without trauma history. Moreover, after revisions, the trauma patients were still at higher risk for treatment failure due to PJI, periprosthetic joint fracture, and mechanical complications.

Mutational Dynamics Related to Antibiotic Resistance in M. tuberculosis Isolates from Serial Samples of Patients with Tuberculosis and Type 2 Diabetes Mellitus.

Genetic variation in tuberculosis is influenced by the host environment, patients with comorbidity, and tuberculosis-type 2 diabetes mellitus (TB-T2DM) and implies a higher risk of treatment failure and development of drug resistance. Considering the above, this study aimed to evaluate the influence of T2DM on the dynamic of polymorphisms related to antibiotic resistance in TB. Fifty individuals with TB-T2DM and TB were initially characterized, and serial isolates of 29 of these individuals were recovered on day 0 (diagnosis), 30, and 60. Genomes were sequenced, variants related to phylogeny and drug resistance analyzed, and mutation rates calculated and compared between groups. Lineage X was predominant. At day 0 (collection), almost all isolates from the TB group were sensitive, apart from four isolates from the TB-T2DM group showing the mutation katG S315T, from which one isolate had the mutations rpoB S450L, gyrA A90G, and gyrA D94G. This pattern was observed in a second isolate at day 30. The results provide a first overview of the dynamics of mutations in resistance genes from individuals with TB-T2DM, describing an early development of resistance to isoniazid and a rapid evolution of resistance to other drugs. Although preliminary, these results help to explain the increased risk of drug resistance in individuals with TB and T2DM.

OP37 Effect of the HLA-DQA1*05 allele on the efficacy of ustekinumab in patients with Crohn's Disease. Multicenter study based on the ENEIDA registry of GETECCU

Abstract Background HLA-DQA1*05 carriage is associated with the development of anti-drug antibodies and loss of response (LOR) to tumour necrosis factor antagonists (anti-TNF) in patients with inflammatory bowel diseases (IBD)1. Ustekinumab has shown very low rates of immunogenicity and presumably will not be affected by this risk. Identifying patients at high risk of treatment failure would be important when selecting therapy for IBD. The objective of this analysis was to investigate the relationship between the HLA- QA1*05 allele and ustekinumab on development of LOR and drug persistency. Methods This is a retrospective cohort study from a prospectively maintained ENEIDA registry. LOR was defined as recurrence or worsening of IBD related symptoms that required a change or intensification in treatment, hospitalization or surgery. Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. The HLA-DQA1*05 allele was determined from a saliva sample (kit OGD-600 de DNA Genotek Oragene) and DNA extraction with the Maxwell® RSC-Stabilized Saliva DNA kits. Results 204 patients with Crohn's disease were included. Previous exposure to biological drugs was 96% (61% ≥2 biological drugs). Basal faecal calprotectin levels were 907±970μg/g and PCR levels 16.2±25 mg/dL. The median follow-up was 417±154 days. During this period, 25%, 16% and 13% of the patients required drug intensification, hospitalization or surgery, respectively. 43% of the patients included were carriers of one or two copies of the HLA-DQA1*05 allele. The presence/absence of this allele was not associated with LOR to ustekinumab (20% vs 16%, p = ns) nor with drug withdrawal (11% vs 6%, p = ns). In the multivariate analysis (COX regression), only the number of previous biological drugs was associated with ustekinumab persistency. Conclusion The presence of the HLA-DQA1*05 allele is not related to LOR or persistency of ustekinumab treatment. First-line treatment with ustekinumab rather than anti-TNF agents may be considered in HLA-DQA1*05-positive patients, particularly when the use of a concomitant immunosuppressant is contraindicated. 1. Sazonovs A, Kennedy NA, Moutsianas L, Heap GA, Rice DL, Reppell M, Bewshea CM, et al. PANTS Consortium. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease. Gastroenterology. 2020 Jan;158(1):189-199.

P340 The association between colon pseudopolyps presence and clinical adverse events in UC patients treated with biologics

Abstract Background Colon pseudopolyps (aka post-inflammatory polyps) are potential marks of previous severe ulcerative colitis (UC) activity. The association between outcomes of patients treated for UC with biologics and presence (or lack of presence) of pseudopolyps, are unclear. Methods A single center, noninterventional retrospective cohort review study was performed on real-life data of adult patients with moderate-to-severe UC who were treated with biologics (infliximab, vedolizumab, ustekinumab) for a minimum of 6 months. The difference in first occurence of treatment failure defined as a negative composite outcome (need for steroid rescue therapy, biologic switch, IBD-related hospitalization and/or surgery) between two groups (with or without pseudopolyps) was investigated. Participants’ characteristics were assessed using descriptive statistics. Normal distribution was assessed using Kolmogorov-Smirnov and Shapiro-Wilk tests. Categorical variables were analyzed using Chi-square test and continuous variables using Mann-Whitney test. Kaplan-Meier analysis and log-rank test were used in order to assess difference in therapy duration between two groups. Results Total of 92 patients (51% females; smokers 17%; 24% with pseudopolyps) were included. There were no differences in key baseline characteristics such as age, sex, smoking status, extraintestinal manifestations, serum albumin and CRP as well as fecal calprotectin levels between groups of patients with or without pseudopolyps. Median duration of follow up was 18.5 months (IQR 8-37). Presence of pseudopolyps was not associated with a higher risk for treatment failure; there was no statisticaly significant difference in the occurrence (χ2(1, N =91)=1.38, p=0.31) of negative composite outcomes or time to develop negative composite factor (χ2(1, N =91)=1.57, p=0.21). Conclusion In our cohort we have failed to detect any association between presence of colon pseudopolyps and rates of first occurence of treatment failure in UC patients treated with biologics.

Combination of nivolumab with standard induction chemotherapy in children and adults with EBV-positive nasopharyngeal carcinoma : Protocol of aprospective multicenter phase2trial.

Treatment of Epstein-Barr virus(EBV)-positive nasopharyngeal carcinoma (NPC) with cisplatin/5-fluorouracil (5-FU) induction chemotherapy, followed by radiochemotherapy and subsequent interferon‑β, has yielded high survival rates in children, adolescents, and young adults. Aprevious study has shown that reduction of radiation dose from 59.4 to 54.0 Gy appears to be safe in patients with complete response (CR) to induction chemotherapy. As immune checkpoint-inhibitors have shown activity in NPC, we hypothesize that the addition of nivolumab to standard induction chemotherapy would increase the rate of complete tumor responses, thus allowing for areduced radiation dose in agreater proportion of patients. This is aprospective multicenter phase2 clinical trial including pediatric and adult patients with their first diagnosis of EBV-positive NPC, scheduled to receive nivolumab in addition to standard induction chemotherapy. In cases of non-response to induction therapy (stable or progressive disease), and in patients with initial distant metastasis, treatment with nivolumab will be continued during radiochemotherapy. Primary endpoint is tumor response on magnetic resonance imaging (MRI) and positron emission tomography (PET) after three cycles of induction chemotherapy. Secondary endpoints are event-free (EFS) and overall survival (OS), safety, and correlation of tumor response with programmed cell death ligand 1 (PD-L1) expression. As cure rates in localized EBV-positive NPC today are high with standard multimodal treatment, the focus increasingly shifts toward prevention of late effects, the burden of which is exceptionally high, mainly due to intense radiotherapy. Furthermore, survival in patients with metastatic disease and resistant to conventional chemotherapy remains poor. Primary objective of this study is to investigate whether the addition of nivolumab to standard induction chemotherapy in children and adults with EBV-positive NPC is able to increase the rate of complete responses, thus enabling a reduction in radiation dose in more patients, but also offer patients with high risk of treatment failure the chance to benefit from the addition of nivolumab. EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) No. 2021-006477-32.

Predictors of Death in Rifampicin Resistant Tuberculosis Patients Treated with the Short Course in Conakry, Guinea.

The emergence of rifampicin-resistant tuberculosis (RR-TB) is a major issue for TB control programs due to high risk of treatment failure and death. The objective of this study was to describe survival and to determine predictors of death in RR-TB patients treated with the short regimen (9-11 months) in the Conakry TB treatment centers. Sociodemographic, clinical, and survival data were collected prospectively between 2016 and 2021 on RR-TB patients in the Department of Pneumo-Phtisiology, the Carrière and the Tombolia TB centers. The Kaplan-Meier method was used to estimate the cumulative incidence of death of patients. The Cox regression model was used to identify the predictors independently associated with death. Of 869 patients, 164 (18.9%) patients died during treatment, 126 of them within 120 days of treatment initiation. The factors associated with death during treatment were as follows: patients treated in the Carrière TB center (adjusted hazard ratio [aHR] = 1.65; 95% CI: 1.06-2.59) and in the Department of Pneumo-Phtisiology (aHR = 3.26; 95% CI: 2.10-5.07), patients ≥ 55 years old (aHR = 4.80; 95% CI: 2.81-8.19), patients with no history of first-line TB treatment (aHR = 1.51; 95% CI: 1.05-2.16), and patients living with HIV (aHR = 2.81; 95% CI: 1.94-4.07). The results of this study can help the national TB control program to reconsider its therapeutic strategy to improve patient care in case of RR-TB. Large prospective clinical studies should be conducted to provide evidence of the impact of such factors like previous history of TB treatment and HIV infection on survival of RR-TB patients.

Update and Application of a Deep Learning Model for the Prediction of Interactions between Drugs Used by Patients with Multiple Sclerosis.

Patients with multiple sclerosis (MS) often take multiple drugs at the same time to modify the course of disease, alleviate neurological symptoms and manage co-existing conditions. A major consequence for a patient taking different medications is a higher risk of treatment failure and side effects. This is because a drug may alter the pharmacokinetic and/or pharmacodynamic properties of another drug, which is referred to as drug-drug interaction (DDI). We aimed to predict interactions of drugs that are used by patients with MS based on a deep neural network (DNN) using structural information as input. We further aimed to identify potential drug-food interactions (DFIs), which can affect drug efficacy and patient safety as well. We used DeepDDI, a multi-label classification model of specific DDI types, to predict changes in pharmacological effects and/or the risk of adverse drug events when two or more drugs are taken together. The original model with ~34 million trainable parameters was updated using >1 million DDIs recorded in the DrugBank database. Structure data of food components were obtained from the FooDB database. The medication plans of patients with MS (n = 627) were then searched for pairwise interactions between drug and food compounds. The updated DeepDDI model achieved accuracies of 92.2% and 92.1% on the validation and testing sets, respectively. The patients with MS used 312 different small molecule drugs as prescription or over-the-counter medications. In the medication plans, we identified 3748 DDIs in DrugBank and 13,365 DDIs using DeepDDI. At least one DDI was found for most patients (n = 509 or 81.2% based on the DNN model). The predictions revealed that many patients would be at increased risk of bleeding and bradycardic complications due to a potential DDI if they were to start a disease-modifying therapy with cladribine (n = 242 or 38.6%) and fingolimod (n = 279 or 44.5%), respectively. We also obtained numerous potential interactions for Bruton's tyrosine kinase inhibitors that are in clinical development for MS, such as evobrutinib (n = 434 DDIs). Food sources most often related to DFIs were corn (n = 5456 DFIs) and cow's milk (n = 4243 DFIs). We demonstrate that deep learning techniques can exploit chemical structure similarity to accurately predict DDIs and DFIs in patients with MS. Our study specifies drug pairs that potentially interact, suggests mechanisms causing adverse drug effects, informs about whether interacting drugs can be replaced with alternative drugs to avoid critical DDIs and provides dietary recommendations for MS patients who are taking certain drugs.

High IL1-RA Plasma Levels at Baseline Allow to Identify Hodgkin Lymphoma Patients with High Risk of Treatment Failure

Introduction: About 10% of localized stages and 20-30% of advanced stages patients (pts) with classical Hodgkin lymphoma (cHL) progress or relapse after the first line of treatment. Therapeutic failures prediction at diagnosis is a major challenge to modulate treatments to minimize acute and long-term toxicities, while having optimal efficacy. The development of prognostic tools is crucial to help therapeutic decision. In 2007, Casasnovas et al. JCO 2007, demonstrated that a plasma cytokine signature composed of IL1-RA, IL-6 and sCD30 could predict pts outcomes and identify pts with high risk of treatment failure. However, it was unusable in routine practice as the ELISA technique used had extensive delay. Since interim PET during induction chemotherapy became the standard approach to guide the therapeutic strategy, and therefore the use of new pre-therapeutic biomarkers deserves to be investigated in the context of PET-guided treatment. As PD-L1, and thymus and activation-related chemokine (TARC) have an important role in cHL physiopathology we analyzed the prognostic impact on progression-free, and overall survival (PFS and OS) of pretherapeutic plasma levels of PD-L1 and TARC in addition to IL1-RA, IL-6, sCD30, in pts treated with a PET-guided strategy. Method: The dosage of IL1-RA, IL-6, PD-L1 and TARC was performed using the ELLA automated immunoassay system (Biotechne) while sCD30 was performed in triplicate using ELISA assay. Samples were prospectively collected (period 2016-2020) within the biocollection BIO-LYMPH (NCT04417803) in the pts treated in the department of Hematology at Dijon Hospital. X tile analysis was used to define the optimal cutoff for survival prediction for each cytokine. Survival functions of pts' subgroups defined by the cytokine circulating levels were estimated using the Kaplan-Meier product limit method and compared using the log rank test. The Cox proportional hazard regression model was used to estimate HRs and associated 95% CI in univariate and multivariate analyses. Results: Among the 105 pts enrolled in this study (Median age: 36 years, range: 17 - 85), 60% were under 45 years, 61% had advanced stage disease, 58% B symptoms, and 39% an IPS &amp;gt;2. 63% of pts had nodular sclerosis HL subtype and 22% had EBV associated HL. Response was assessed at the end of treatment: 89 pts (84 %) achieved a complete response, 4 pts (4%) a partial response, and 9 pts (9%) had progressive disease. With a median follow-up time of 40 months (1-78 months), 13 pts (12 %) relapsed with a median time to relapse of 16 months (range, 4 to 65 months), 14 pts (13 %) died (11 due to cHL progression; 1 due to septic shock; 1 from SARS covid infection; and 1 after a traumatism). While pretherapeutic plasmatic levels of IL-6, sCD30, TARC and PD-L1 did not impact pts survival, IL1-RA was an independent predictor of both PFS and OS. Indeed, 31% of pts harbored high IL1-RA plasma level (≥ 740 pg/ml) and had an unfavorable PFS (5y-PFS: 50.2% vs 86.7%; HR=4.2, CI=2.1-10.3, p=0.0001, figure 1A) and OS (5y-OS 71.4% vs 95%, HR=4.49, CI=1.3-14.2, p=0.006). PET2 positivity (17% of pts) had an unfavorable prognosis value on PFS (5y-PFS 58% vs 86.6%, HR 4.3, CI= 1.4-12.8, p=0.014) but not on OS (5y-OS 91.8% vs 74.1%; HR=3.2 CI=0.7-14.4, p=0.15) independent from pretherapeutic IL1-RA plasma level (PFS multivariate analysis: PET2 positivity HR=2.43, CI=1-6, p= 0.05; High level IL1-RA HR= 3.4, CI=1.5-8.3, p= 0.005). The combination of both PET2 results and pretherapeutic IL1-RA plasma levels allow to stratify pts' outcome into 3 groups (figure 1B): - Pts (57%) with low levels of IL1-RA and negative PET2 had a 5y-PFS of 89.3% and 5y-OS of 95.8%, - Pts with high levels of IL1-RA or positive PET2 (35%) had a 5y-PFS of 57% and 5y-OS of 74.8% whereas - Pts with both (8%) had a 5y-PFS of 42.9% and 5y-OS of 71.4%. The groups with one or 2 prognostic factors (PET2+ or high IL1RA and PET2+ &amp; high IL1RA) had a significantly different PFS compared to the double negative group (1 factor: HR=4.7, CI=1.8-12.2, p=0.0011 and 2 factors: HR= 8.57, CI=2.5-28.3, p=0.0004 respectively). The group with 1 prognosis factor had a significantly different OS (HR=4.1, CI=1.1-15.3, p=0.03) compared to double negative group but not the 2 factors group (HR= 4.9, CI=0.8-30, p=0.08). Conclusion: Pretherapeutic IL1-RA plasma levels allow to stratify the prognosis of pts with cHL treated with first line PET-guided strategies and add prognosis information to PET2 response.

Association of Age with Acuity and Severity of Illness at Initial Presentation in Children, Adolescents, and Young Adults with Leukemia

Background: Adolescent and Young Adult (AYA) patients, historically defined by the National Cancer Institute as patients between 15-39 years, diagnosed with cancer are at risk for increased mortality compared with younger patients. Age 10 has been an alternate threshold for higher risk of treatment failure in leukemia. Acuity of illness - as defined by intensive care unit (ICU) level resource use at admission - in children with acute myeloid leukemia (AML) was shown in prior data from the Pediatric Health Information System to mediate excess mortality in Black patients (Winestone et al, Am J Hematol., 2017). This study aims to evaluate the acuity and severity of illness in patients presenting with new diagnoses of leukemia and evaluate whether AYAs have a higher acuity and severity of illness compared to younger patients. Methods: We performed a retrospective analysis of 771 patients aged 1-21 years with initial presentation of newly diagnosed leukemia at Children's Healthcare of Atlanta (CHOA) between 2010-2018. Exclusion criteria included those who received any treatment at another facility or those for whom information about the first 72 hours following presentation to the hospital was not available. High acuity of illness was defined (yes/no) as any ICU admission or ICU-level resource use - regardless of physical location in the hospital - by organ system (cardiovascular, respiratory, renal, hematologic, and neurologic) on manual chart review. High severity of illness was defined as initial white blood cell (WBC) count ≥ 50,000 cells/microliter or central nervous system (CNS) disease. Both acuity and severity were assessed during the first 72 hours following the point of diagnosis. Multivariable logistic regression was used to examine the association of age at diagnosis with acuity or severity of illness, controlling for sex, race/ethnicity, insurance status, and type of leukemia. Results: Among 536 patients with complete data to date, the median age was 6 years (interquartile range 3-12 years, 65.5% aged 1-9 years, 34.5% aged 10-21 years), 53.4% were male, 45.7% were Non-Hispanic White, and 65.7% had private insurance. Diagnoses included B-cell acute lymphoblastic leukemia (ALL) (70.5%), AML (16.4%), T-cell ALL (9.3%), and other leukemias (3.7%) (juvenile myelomonocytic, chronic myeloid, and Burkitt's). High acuity of illness was seen in 24.2% of patients and was more likely in older patients (10-21 years, 33.5% versus 1-9 years, 19.4%, p &amp;lt;0.01). Figure 1 illustrates involved organ systems by age group. High severity of illness was seen in 31.3% of cases, and although not significant, was also more likely in older patients (10-21 years, 32.5% versus 1-9 years, 27.9%, p=0.06). In multivariable analysis, compared to patients aged 1-9 years, patients aged 10-21 years had an increased odds of high acuity of illness [odds ratio (OR) 1.69, 95% confidence interval (CI 1.09-2.63)]. Patients with T-ALL also had an increased odds of high acuity of illness [OR 3.40 (CI 1.76-6.54); referent B-ALL]. The odds of high severity of illness did not differ by age [10-21 years OR 1.23 (CI 0.81-1.86)], but was significantly higher by Non-Hispanic Black race [OR 1.83 (CI 1.14-2.94); referent Non-Hispanic White] and type of leukemia [T-ALL OR 3.90 (CI 2.03-7.48); other leukemia OR 3.26 (CI 1.28-8.32); referent B-ALL] (Table 1). Discussion and Conclusions: AYA patients had an increased likelihood of high acuity of illness requiring ICU-level care at presentation, indicating a risk for disparities of outcomes from the point of initial presentation. Future directions will examine the association of acuity of illness with mortality in this cohort, as well as the role of race/ethnicity on severity of illness and mortality. This research will ultimately help inform strategies toward narrowing age disparities in outcomes of AYA leukemia.

Early Identification of Refractory/Relapsed Diffuse Large B Cell Lymphoma with Serial Ctdna Sampling

Background: Diffuse Large B Cell Lymphoma (DLBCL) is an aggressive lymphoma that is curable in 60% of patients with chemoimmunotherapy. Outcomes are poor for those experiencing relapsed or refractory disease (rrDLBCL), particularly for patients with primary refractory disease (REFR, &amp;lt; 9 months from diagnosis) and early relapse (ER, 9 months to 2 years from diagnosis). Some of these patients would be candidates for chimeric antigen receptor T cell therapy (CART) in second line, where outcomes are superior when the disease burden is low. Therefore, exploring strategies to identify these high-risk patients early is important. Plasma circulating tumor DNA has been shown to be prognostic in various DLBCL cohorts. Method: We developed a custom panel of 170 genes to identify early treatment failure in a cohort of 171 patients that had profiling performed on 323 plasma samples. Plasma samples were taken serially starting at diagnosis and as patients progressed through frontline treatment. All plasma samples underwent DNA extraction, library preparation and subsequent sequencing using a panel of DLBCL related genes at high read depth (~1000x). Single nucleotide variant (SNV) calling was carried out using a custom pipeline including paired normal DNA for improved somatic variant detection. ctDNA fraction was estimated based on the highest variant allele fraction detected, using a loss of heterozygosity somatic model. Our ctDNA analysis focused on samples at diagnosis, cycle 2 of therapy, and end of treatment in order to identify early determinants of refractory disease. Changes in ctDNA levels between time points were represented as log2 ratio of ctDNA fraction. Results: rrDLBCL cases were separated into 3 categories based on the time between diagnosis and progressive disease (PD): 47 REFR, 34 ER, and 31 late relapse (LR, &amp;gt;24 months). The remaining patients were disease free after frontline therapy for over 24 months (CR, n=59), resulting in a cohort enriched for rrDLBCL (65% of cases). The average international prognostic index (IPI) of each group at diagnosis was REFR=3.38, ER=2.87, LR=2.81, and CR=2.41. Cell of Origin, as determined by Hans algorithm, showed a higher number of non-GCB samples in ER and LR groups (53% and 60%, respectively) while REFR and CR displayed increased GCB cases (63% and 66%, respectively). The REFR patients were significantly more likely to be of a 4/5 IPI score at diagnosis than other groups (p=0.0203). Progression-free survival (PFS2) at relapse therapy for REFR (median=0.29 years) was shorter when compared to both ER (p=0.0104, median=0.44 years) and LR (p=0.0012, median=0.80 years). Using the diagnostic plasma sample, there was no significant difference in ctDNA fraction in any of the three groups. When the sample with the highest ctDNA fraction was compared between patients, REFR had significantly higher levels than LR and CR, consistent with a higher overall tumor burden (p=0.001 and 0.026, respectively). There was a trend towards higher ctDNA fraction at the end of treatment in both REFR and ER groups. As ctDNA dynamics are known to be informative of molecular response, we compared patients using the change in ctDNA fraction at cycle 2 of therapy (log2 ratio). This value was significantly different in REFR patients (p=0.0073 vs ER), consistent with a lower rate of molecular response to treatment. Conclusions: While refractory and later relapsed DLBCL have similar ctDNA features at diagnosis, we find they have distinct ctDNA dynamics during treatment. REFR had higher maximal ctDNA levels across time points and both REFR and ER patients exhibited higher levels of ctDNA at end of treatment. Moreover, patients with minimal change in ctDNA levels at cycle 2 of therapy are at a high risk of treatment failure and refractory disease. Further exploration of the specific mutational patterns is ongoing. These results could enable the earlier identification of rrDLBCL and facilitate the prioritization of approaches for therapeutic intervention in rrDLBCL.

CD49d Expression Is Included in a Revised 4-Factor Model Predicting Outcome in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib: A Multi-Center Real-World Experience

Introduction. Expression of the CD49d integrin chain has prognostic impact on ibrutinib (IB)-treated CLL patients (Tissino et al, J Exp Med, 2018; Tissino et al, Blood 2020). In addition, a 4-factor (4-f) score, based on TP53 aberration, β2-microglobulin (β2M), lactate dehydrogenase (LDH) and previous therapy lines was proposed to identify patients at a higher risk of treatment failure or death during IB therapy (Ahn et al, J Clin Oncol, 2020; Morabito et al, Am J Hematol, 2021). The clinical impact of TP53 disruption was recently refined by demonstrating that only the co-presence of TP53 deletion and mutations, and not the single aberrations, has prognostic value in the IB setting (Bomben et al, Leukemia 2022). The aim here is to integrate these observations in a comprehensive scoring for the management of IB-treated patients. Methods. This study is a retrospective/multicenter analysis of 410 CLL patients treated with IB in the current clinical practice (December/2013-March/2021). Outcome data were updated as of March/2023. Median follow-up from IB treatment was 29.5 months (95% CI 26.7-33.1 months); 57 patients were treatment naïve (0 previous lines), while 353 had ≥1 previous lines. CLL patients were characterized for CD49d expression and for the 4-f variables, TP53 disruption was evaluated by FISH and TP53 mutational status by NGS (low-VAF mutations included). OS or PFS were measured from the date of IB treatment to the date of death (OS), or progression/death (PFS) or last follow-up. Results. 1) The canonical 4-f was applied as previously described, identifying 111 low-, 163 intermediate (int)-, and 136 high-risk patients. Patients in the low-risk group had a longer OS than patients in the int-, and high-risk groups ( P=0.0115 and P=0.0011), while no difference was found comparing patients in the int- vs. high-risk groups (P=0.3036). 2) We generated a modified version of the 4-f score by considering: i) as TP53 disrupted only patients presenting a concomitant TP53 deletion and mutation (n=93); ii) since no difference in terms of OS was found comparing previously untreated patients (n=57) and patients treated with 1 previous line (n=157; P=0.78), these two groups were combined (n=214) and kept separated from patients who had received &amp;gt;1 previous lines of therapy (n=196). Accordingly, the 4-f-modified identified 218 low-, 109 int-, and 83 high-risk patients, the 3 groups presented different OS, the latter model outperforming the canonical 4-f score (C-indices 0.616 vs 0.639; P&amp;lt;0.0001). 3) CD49d-high CLL cases (i.e. CLL with CD49d expression ≥30% and/or with CD49d-bimodal expression; n=268) had shorter OS and PFS intervals ( P=0.0005 and 0.0194, respectively) than CD49d-low cases (n=142). By combining these observations, CD49d remained an independent prognostic factor for OS ( P=0.004) in a multivariable model, which included the 4-f-modified int-risk ( P=0.0585) and high-risk ( P=0.0011) groups. Driven by these findings, we re-analyzed the single parameters of the 4-f score along with CD49d expression. According to a new multivariable analysis (Fig. A), LDH was not included in the final model, which in turn included CD49d expression as independent OS predictor ( P=0.0011). 4) We then redesigned a novel 4-f model excluding LDH data in favor of CD49d expression data (4-factor-CD49d). Each of the four factors contributed one point and stratified patients (n=407/410) into three groups with a significantly different risk for OS probability, merged on a one-to-one risk group comparison basis: score 0-1, low-risk (n=185); score 2-3, int-risk (n=211); score 4, high-risk (n=11; Fig. B). The inclusion of CD49d into this novel 4-f model improved its prediction capability (C-index=0.663; P&amp;lt;0.0001 versus both the original 4-f and the 4-f-modified). Similar results were obtained when considering PFS as clinical readout. Conclusions. Evidence is provided that in the context of CLL patients treated with IB in a real-world setting, variables like B2M, the number of previous lines of therapy and assessment of TP53 disruption remain important tools for identifying patients at a higher risk of relapse/death. Here we emphasize the need of a comprehensive assessment of TP53 aberrations considering TP53 deletions and mutations simultaneously, and propose to add the assessment CD49d expression, integrating these four variables into a novel 4-f-CD49d scoring system. Further validation in independent cohorts is needed.