Early Treatment Failure Research Articles

Autologous transplant vs. CAR-T therapy in patients with DLBCL treated while in complete remission

In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015–2021) vs. CAR-T (2018–2021) using the Center for International Blood & Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT (n = 281) or commercial CAR-T (n = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p < 0.001), a lower 2-year cumulative incidence of relapse (27.8% vs. 48% ; p < 0.001), and a superior 2-year OS (78.9% vs. 65.6%; p = 0.037). In patients with early (within 12 months) treatment failure, auto-HCT was associated with a superior 2-year PFS (70.9% vs. 48.3% ; p < 0.001), lower 2-year cumulative incidence of relapse (22.8% vs. 45.9% ; p < 0.001) and trend for higher 2-year OS (82.4% vs. 66.1% ; p = 0.076). In the multivariable analysis, treatment with auto-HCT was associated with a superior PFS (hazard ratio 1.83; p = 0.0011) and lower incidence of relapse (hazard ratio 2.18; p < 0.0001) compared to CAR-T. In patients with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with improved clinical outcomes compared to CAR-T. These data support the consideration of auto-HCT in select patients with LBCL achieving a CR in the relapsed setting.

On the Role of Early Case Detection and Treatment Failure in Controlling Tuberculosis Transmission: A Mathematical Modeling Study

Tuberculosis (TB) remains a pressing global health concern, demanding urgent attention to mitigate its spread and impact. In this study, we present a rigorous mathematical model of TB transmission that incorporates early case detection and addresses the critical issue of treatment failure. Through the development of a system of nonlinear ordinary differential equations, we conduct comprehensive analyses to assess the dynamics of TB transmission and the efficacy of intervention strategies. Our findings underscore the urgent need for effective TB control measures. Mathematical analyses reveal that the model exhibits a TB-free equilibrium, which is globally asymptotically stable only if the control reproduction number falls below one. However, we identify a concerning phenomenon: the model demonstrates a forward bifurcation when the control reproduction number equals one, suggesting that the disease-free equilibrium loses its stability, while simultaneously, the stable unique endemic equilibrium begins to emerge. Moreover, sensitivity analysis highlights the complex interplay between case detection rates, treatment failure probabilities, and TB transmission dynamics. Contrary to expectations, increasing case detection rates and minimizing treatment failure probabilities may not consistently reduce the basic reproduction number or the size of the infected population. Instead, there exists a critical threshold for intervention effectiveness, beyond which TB transmission can be significantly curtailed. Biologically, this phenomenon may occur if there is no balance between case detection and treatment efforts. If treatment quality does not improve, then case detection will not have a significant impact, and in the worst case scenario, it can exacerbate the intervention’s negative effects. These findings underscore the urgency of implementing targeted intervention strategies to combat TB transmission effectively. Failure to meet the critical intervention threshold risks undermining TB elimination efforts and exacerbating the global TB burden. Through numerical simulations, we elucidate potential intervention scenarios necessary for achieving TB elimination goals in human populations. In conclusion, our study highlights the urgent imperative for coordinated action to control TB transmission effectively. By elucidating the dynamics of TB spread and intervention efficacy, we provide valuable insights to inform evidence-based policy decisions and accelerate progress towards TB elimination on a global scale.

Time-domain diffuse optical imaging technique for monitoring rheumatoid arthritis disease activity: experimental validation in tissue-mimicking finger phantoms

Objective. Effective treatment within 3–5 months of disease onset significantly improves rheumatoid arthritis (RA) prognosis. Nevertheless, 30% of RA patients fail their first treatment, and it takes 3–6 months to identify failure with current monitoring techniques. Time-domain diffuse optical imaging (TD-DOI) may be more sensitive to RA disease activity and could be used to detect treatment failure. In this report, we present the development of a TD-DOI hand imaging system and validate its ability to measure simulated changes in RA disease activity using tissue-mimicking finger phantoms. Approach. A TD-DOI system was built, based on a single-pixel camera architecture, and used to image solid phantoms which mimicked a proximal interphalangeal finger joint. For reference, in silico images of virtual models of the solid phantoms were also generated using Monte Carlo simulations. Spatiotemporal Fourier components were extracted from both simulated and experimental images, and their ability to distinguish between phantoms representing different RA disease activity was quantified. Main results. Many spatiotemporal Fourier components extracted from TD-DOI images could clearly distinguish between phantoms representing different states of RA disease activity. Significance. A TD-DOI system was built and validated using finger-mimicking solid phantoms. The findings suggest that the system could be used to monitor RA disease activity. This single-pixel TD-DOI system could be used to acquire longitudinal measures of RA disease activity to detect early treatment failure.

Tolerability and efficacy of BrECADD versus BEACOPP in advanced stage classical Hodgkin lymphoma: GHSG HD21, a randomized study.

LBA7000 Background: We hypothesized that therapy with the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) guided by positron emission tomography after two cycles (PET2) could improve the treatment of advanced-stage classical Hodgkin lymphoma (AS-cHL). The HD21 trial aimed at demonstrating superiority over the intensified BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in terms of treatment-related morbidity (TRMB) and non-inferiority (NI) in terms of progression-free survival (PFS). This is the first report of the final confirmative analysis of the HD21 trial. Methods: HD21 is an international, open-label, randomized phase III trial including AS-cHL patients 18-60 years at diagnosis. Patients were randomized to receive individualized 4 or 6 cycles of either BEACOPP or BrECADD guided by PET2 results. The co-primary endpoints included TRMB and PFS, which had been successfully established recently. Testing for superiority was planned with mature follow-up of four years. An adjusted alpha level of 0.047 was required to cross the efficacy boundary for superiority. The trial was conducted in accordance with ICH-GCP (NCT02661503) and supported by a research grant from Takeda Oncology. Results: The ITT (intention-to-treat) cohort for the efficacy analysis consisted of 1482 patients, of which 742 were randomized to receive BrECADD and 740 to BEACOPP. Median age was 31.1 years (range 18 to 60), 44% were female. PET2 was negative in 424 (57.5%) and 426 (58.2%) patients for BrECADD or eBEACOPP, respectively, and these were scheduled for 4 treatment cycles. With median follow-up of 48 months, 4y-PFS was 94.3% for BrECADD (95%-CI 92.6-96.1), and 90.9% for BEACOPP (95%-CI 88.7-93.1). The hazard ratio was 0.66 [95% CI 0.45-0.97], p=0.035). PFS benefit of BrECADD was driven by a reduction in early treatment failures, i.e., primary progression within 3 months (5 vs. 15) or early relapse between months 3 and 12 (11 vs. 23) and observed across all investigated subgroups. PET2-negative patients in the BrECADD group showed a 4-year PFS of 96.5%. 4-year OS was 98.5% for BrECADD and 98.2% for BEACOPP. Analyses of gonadal function demonstrated significantly higher follicle stimulating hormone recovery rates after one year in both men (67% vs. 24%) and women (89% vs. 68%) with higher birth-rates in the BrECADD group (n=60 vs. n=43). Conclusions: BrECADD is significantly more effective than BEACOPP and is associated with an unprecedentedly high 4-year PFS, reducing the risk of progression, relapse or death by a third. Together with an abbreviated treatment duration of only 3 months for the majority of patients and a favorable tolerability, treatment with PET2-individualized BrECADD sets a new benchmark for the treatment of adult patients with AS-cHL. Clinical trial information: NCT02661503 .

Diffusion weighted MRI and apparent diffusion coefficient as a prognostic biomarker in evaluating chemotherapy-antiangiogenic treated stage IV non-small cell lung cancer: A prospective, single-arm, open-label, clinical trial (BevMar)

PurposeWhen treating Lung Cancer, it is necessary to identify early treatment failure to enable timely therapeutic adjustments. The Aim of this study was to investigate whether changes in tumor diffusion during treatment with chemotherapy and bevacizumab could serve as a predictor of treatment failure. Material and MethodsA prospective single-arm, open-label, clinical trial was conducted between September 2014 and December 2020, enrolling patients with stage IV non-small cell lung cancer (NSCLC). The patients were treated with chemotherapy-antiangiogenic combination. Diffusion weighted magnetic resonance imaging (DW-MRI) was performed at baseline, two, four, and sixteen weeks after initiating treatment. The differences in apparent diffusion coefficient (ADC) values between pre- and post-treatment MRIs were recorded as Delta values (ΔADC). We assessed whether ΔADC could serve as a prognostic biomarker for overall survival (OS), with a five year follow up. Results18 patients were included in the final analysis. Patients with a ΔADC value ≥ -3 demonstrated a significantly longer OS with an HR of 0.12 (95 % CI; 0.03– 0.61; p = 0.003) The median OS in patients with a ΔADC value ≥ -3 was 18 months, (95 % C.I; 7–46) compared to 7 months (95 % C.I; 5–9) in those with a ΔADC value < -3. ConclusionOur findings suggest that early changes in tumor ADC values, may be indicative of a longer OS. Therefore, DW-MRI could serve as an early biomarker for assessing treatment response in patients receiving chemotherapy combined with antiangiogenic therapy.

Neuropilin2 in Mesenchymal Stromal Cells as a Potential Novel Therapeutic Target in Myelofibrosis.

Bone marrow fibrosis in myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML) is associated with poor prognosis and early treatment failure. Myelofibrosis (MF) is accompanied by reprogramming of multipotent bone marrow mesenchymal stromal cells (MSC) into osteoid and fiber-producing stromal cells. We demonstrate NRP2 and osteolineage marker NCAM1 (neural cell adhesion molecule 1) expression within the endosteal niche in normal bone marrow and aberrantly in MPN, MDS MPN/MDS overlap syndromes and AML (n = 99), as assessed by immunohistochemistry. Increased and diffuse expression in mesenchymal stromal cells and osteoblasts correlates with high MF grade in MPN (p < 0.05 for NRP2 and NCAM1). Single cell RNA sequencing (scRNAseq) re-analysis demonstrated NRP2 expression in endothelial cells and partial co-expression of NRP2 and NCAM1 in normal MSC and osteoblasts. Potential ligands included transforming growth factor β1 (TGFB1) from osteoblasts and megakaryocytes. Murine ThPO and JAK2V617F myelofibrosis models showed co-expression of Nrp2 and Ncam1 in osteolineage cells, while fibrosis-promoting MSC only express Nrp2. In vitro experiments with MC3T3-E1 pre-osteoblasts and analysis of Nrp2-/- mouse femurs suggest that Nrp2 is functionally involved in osteogenesis. In summary, NRP2 represents a potential novel druggable target in patients with myelofibrosis.

Detection of novel Plasmodium falciparum coronin gene mutations in a recrudescent ACT-treated patient in South-Western Nigeria.

Routine surveillance for antimalarial drug resistance is critical to sustaining the efficacy of artemisinin-based Combination Therapies (ACTs). Plasmodium falciparum kelch-13 (Pfkelch-13) and non-Pfkelch-13 artemisinin (ART) resistance-associated mutations are uncommon in Africa. We investigated polymorphisms in Plasmodium falciparum actin-binding protein (Pfcoronin) associated with in vivo reduced sensitivity to ART in Nigeria. Fifty-two P. falciparum malaria subjects who met the inclusion criteria were followed up in a 28-day therapeutic efficacy study of artemether-lumefantrine in Lagos, Nigeria. Parasite detection was done by microscopy and molecular diagnostic approaches involving PCR amplification of genes for Pf18S rRNA, varATS, telomere-associated repetitive elements-2 (TARE-2). Pfcoronin and Pfkelch-13 genes were sequenced bi-directionally while clonality of infections was determined using 12 neutral P. falciparum microsatellite loci and msp2 analyses. Antimalarial drugs (sulfadoxine-pyrimethamine, amodiaquine, chloroquine and some quinolones) resistance variants (DHFR_51, DHFR_59, DHFR_108, DHFR_164, MDR1_86, MDR1_184, DHPS_581 and DHPS_613) were genotyped by high-resolution melting (HRM) analysis. A total of 7 (26.92%) cases were identified either as early treatment failure, late parasitological failure or late clinical failure. Of the four post-treatment infections identified as recrudescence by msp2 genotypes, only one was classified as recrudescence by multilocus microsatellites genotyping. Microsatellite analysis revealed no significant difference in the mean allelic diversity, He, (P = 0.19, Mann-Whitney test). Allele sizes and frequency per locus implicated one isolate. Genetic analysis of this isolate identified two new Pfcoronin SNVs (I68G and L173F) in addition to the P76S earlier reported. Linkage-Disequilibrium as a standardized association index, IAS, between multiple P. falciparum loci revealed significant LD (IAS = 0.2865, P=0.02, Monte-Carlo simulation) around the neutral microsatellite loci. The pfdhfr/pfdhps/pfmdr1 drug resistance-associated haplotypes combinations, (108T/N/51I/164L/59R/581G/86Y/184F), were observed in two samples. Pfcoronin mutations identified in this study, with potential to impact parasite clearance, may guide investigations on emerging ART tolerance in Nigeria, and West African endemic countries.

Real-World Data on Therapies for Relapsed or Refractory Multiple Myeloma: Key Data from ASH 2023-A Podcast.

Immunotherapies have significantly improved outcomes in patients with multiple myeloma yet maintaining a durable response in heavily pretreated patients remains challenging. Therapies that target Bcell maturation antigen (BCMA) provide additional treatment options in patients whose disease becomes refractory to several drug classes in early lines of therapy. Clinical trial data from selected patient populations and controlled settings are complemented by real-world data (RWD) from actual clinical practice. In this podcast, the authors reviewed and discussed seven abstracts presented at the 65th Annual Meeting of the American Society of Hematology, focusing on BCMA-directed therapies, emphasizing the value of RWD in treatment decision-making, and suggesting how RWD can help advance multiple myeloma research. These abstracts include real-world outcome studies in patients with relapsed or refractory multiple myeloma with triple-class exposed or refractory disease (abstracts 542, 3358, and 6727); an analysis on disease burden associated with delayed diagnosis (abstract 3771); comparability of real-world outcomes vs clinical trial data (abstracts 91 and 545); and outcomes in patients with multiple myeloma who experienced early treatment failure after upfront quadruplet therapy (abstract 1989).Podcast available for this article.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019

BackgroundArtemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania.MethodsThis was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy.ResultsA total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported.ConclusionThis study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018

BackgroundThe use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania.MethodsA single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature ≥ 37.5 °C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety.ResultsA total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan–Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported.ConclusionThis study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.

Efficacy of artesunate-amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria in mainland Tanzania

BackgroundDiversification of artemisinin-based combination therapy (ACT) is suggested as one of the strategies that can be used to contain artemisinin resistance. Artesunate-amodiaquine (ASAQ) is one of the artemisinin-based combinations that can be used in the diversification strategy as an alternative first-line treatment for uncomplicated malaria in mainland Tanzania. There is however limited data on the efficacy of ASAQ in mainland Tanzania. This study assessed the efficacy of ASAQ for treatment of uncomplicated Plasmodium falciparum malaria in selected sentinel sites for therapeutic efficacy studies in mainland Tanzania.MethodsBetween December 2018 and March 2020, children aged between 6 months and 10 years, attending at Nagaga, Mkuzi, and Mlimba primary health facilities, and with suspected uncomplicated malaria infection were screened for eligibility to participate in the study. Malaria infection was screened using microscopy. Children with uncomplicated P. falciparum monoinfection and who fulfilled all other inclusion criteria, and had none of the exclusion criteria, according to the World Health Organization (WHO) guidelines, were treated with ASAQ. Follow-up visits were scheduled on days 0, 1, 2, 3, 7, 14, 21, and 28 or on any day of recurrent infection for clinical and laboratory assessment. Polymerase chain reaction (PCR)-corrected cure rate on day 28 was the primary outcome.ResultsA total of 264 children, 88 in each of the three study sites (Mlimba, Mkuzi and Nagaga health facilities) were enrolled and treated with ASAQ. The ASAQ PCR-corrected cure rate was 100% at all the three study sites. None of the participants had early treatment failure or late clinical failure. Furthermore, none of the participants had a serious adverse event.ConclusionASAQ was highly efficacious for the treatment of uncomplicated P. falciparum malaria in mainland Tanzania, therefore, it can be deployed as an alternative first-line treatment for uncomplicated malaria as part of diversification strategy to contain the spread of partial artemisinin resistance in the country.

The Role of Serum IL-23 and Volatile Organic Compound Levels to RECIST 1.1 in The Evaluation of Therapeutic Response in Lung Cancer

The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) is the gold standard for the assessment of lung cancer progression. However, the assessment and diagnosis of early treatment failure is challenging due to the limitations of current tools, as well as the long intervals and unavoidable side effects.This study aims to correlate volatile organic compound (VOC) patterns, serum level of interleukin-23 (IL-23), and RECIST 1.1 to assess chemotherapy response in lung cancer patients at Saiful Anwar Hospital. A prospective observational study was performed to 47 lung cancer patients who received three cycles of platinum-based chemotherapy. Using the Breath Analyzer to measure certain volatile organic compounds (VOCs), the study observed that three of the seven VOCs examined, formaldehyde (CH2O), toluene (C7H8), and hexane (C6H14), showed lower levels after three cycles of chemotherapy. Furthermore, there was a negative correlation between RECIST1.1 and acetone (C3H6O) (p=0.023), while RECIST1.1 and methane (CH4) had a positive correlation (p=0.011). Moreover, a significant positive correlation was observed between IL-23 after-chemotherapy and RECIST 1.1 (p=0.000). According to this study, a correlation exists between methane, IL-23, and RECIST 1.1 after three cycles of chemotherapy. The increase in methane and IL-23 aligns with the disease progression determined by RECIST 1.1. Furthermore, The decrease in acetone after chemotherapy showed a negative correlation with RECIST1.1, consistent with disease progression.Keywords: Volatile Organic Compound, Interleukin-23, RECIST 1.1.

Predicting early endodontic treatment failure following primary root canal treatment

BackgroundUnderstanding when and why endodontic treatments fail could help clinicians make prognoses and thus improve treatment outcomes. This study was aimed to assess potential predictors of early endodontic treatment failure. We explored factors contributing to the failure of initial root canal treatment were explored, with a specific emphasis on evaluating the influence of the time elapsed since the initial treatment.MethodsThis retrospective cohort study enrolled 1262 patients who sought endodontic treatment at our department and 175 patients were included for analysis. Potential causes of endodontic treatment failure were investigated, such as inadequate obturation quality, inadequate coronal status, the presence of additional untreated canals, anatomical complexity, instrument separation, iatrogenic perforation, cracks, and endodontic-periodontal lesions. The patients were divided into “short-term” and “long-term” groups depending on the time that had passed since the initial treatment (i.e., < 5 and > 10 years, respectively). The causes of failure in the short-term and long-term group were analyzed and compared using logistic regression analyses. Subgroup analysis was performed according to the number of years since the initial treatment in the short-term group to further investigate the association between the time and cause of failure (i.e., < 1, 2, 3, and 4 years, respectively).ResultsUntreated additional canals were present in 21.7% of all cases, and in 36.9 and 6.4% of cases in the short-term and long-term groups, respectively. Multivariable analysis showed that the presence of untreated additional canals was significantly associated with short-term compared to long-term failure. Untreated additional canals were also associated with endodontic failure within 1, 2, 3, and 4 years.ConclusionsThe presence of untreated additional canals was a predictor of endodontic failure within 5 years following initial root canal treatment. To optimize long-term prognosis, it is important to detect and treat all root canals during the initial treatment.

Genetic Evaluation of Interlukin-22 Single Nucleotide Polymorphism (rs1179251) with Plasmodium falciparum Clearance among Children Less Than 10 Years in the North Region of Cameroon

IL-22 is a pro and anti-inflammatory cytokine which induces the regeneration of hepatocytes cells during the immune response. Evidence has shown that genetic polymorphisms on IL-22 gene could affect the immune response and consequently the parasite clearance and the treatment outcome of malaria. This study aimed at determining the prevalence of the SNP rs1179251 of the Interleukin-22 gene and a possible association with P. falciparum clearance among children less than 10 years old in the North region of Cameroon. A case-control study was performed on 184 conveniently collected blood samples, spotted on Whartman No 3 filter paper from the SPAQ (Sulfadoxine-Pyrimethamine + Amodiaquine) clinical trial carried out in Garoua and Yagoua in 2015, from which DNA was extracted using Chelex-100 method. Genotyping of the IL-22 gene SNPs was performed using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP). Parasite clearance was defined as the disappearance of pre-treatment parasites without subsequent recurrence, irrespective of whether recurrence is a reinfection or a recrudescing parasite. Treatment outcomes were classified according to the WHO guidelines; patients that experienced early treatment failure (ETF), and late parasitological failure (LPF) were classified as failures (56 cases), while patients that experienced adequate clinical parasitological response (ACPR) were classified as successes (128 controls). The chi square test was used to establish the association between the SNP rs1179251 and parasite clearance. A P-value less than 0.05 was considered as statistically significant. The findings revealed that the mutant allele C was the most predominant with a frequency of 74.46%, with the ancestral allele G having a frequency of 25.54%. These results showed that carriers of the mutant allele C could be 3.7 times more likely not to clear the parasites during treatment but this was not statistically significant (P=0.07, OR= 3.72). In conclusion, no association was found between the SNP rs1179251 of IL-22 gene and Plasmodium falciparum clearance. So, in spite of the importance of IL-22 gene in immune responses, the studied polymorphism does not serve a decisive role in Plasmodium falciparum clearance.

Predicting disease recurrence in limited disease small cell lung cancer using cell-free DNA-based mutation and fragmentome analyses.

Limited disease (LD) small cell lung cancer (SCLC) treated with definitive concurrent chemoradiotherapy (CCRT) potentially experience disease recurrence. We investigated the feasibility of circulating-tumor DNA (ctDNA)-based genomic and fragmentome analyses to assess the risk of recurrence. Targeted sequencing was conducted using pre-treatment and on-treatment blood samples from definitive CCRT-treated patients with LD-SCLC (n=50). Based on 12-month recurrence-free survival (RFS), patients were categorized into persistent-response (PeR, n=29) and non-PeR (n=21) groups. Fragmentome analysis was conducted using ctDNA fragments of different lengths: P1 (100-155 bp) and P2 (160-180 bp). Patients with TP53 (n=15) and RB1 (n=11) mutation in on-treatment samples demonstrated significantly shorter RFS than patients with wild-type (WT) (P=0.05, P=0.0014, respectively). Fragmentome analysis of all available on-treatment samples (n=26) revealed that the non-PeR group (n=10) had a significantly higher P1 range (P=0.003) and lower P2 range (P=0.002). The areas under the curves for P1, P2, and the fragmentation ratio (P1/P2) in distinguishing the PeR and non-PeR were 0.850, 0.725, and 0.900, respectively. Using optimal cut-off, longer RFSs were found with the low-fragmentation-ratio group than with the high-fragmentation-ratio group (not reached vs. 7.6 months, P=0.002). Patients with both WT RB1 and a low-fragmentation-ratio (n=10) showed better outcomes than patients with both mutated RB1 and a high-fragmentation-ratio (n=10; hazard ratio, 7.55; 95% confidence interval: 2.14-26.6; P=0.002). RB1 mutations and high fragmentation ratios correlated with early disease recurrence. Analyzing ctDNA could help in predicting early treatment failure and making clinical decisions for high-risk patients.

Treatment completion, asparaginase completion, and oncologic outcomes among children, adolescents and young adults with acute lymphoblastic leukemia treated with DFCI Consortium Protocols.

Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) face worse outcomes than children. While pediatric-inspired protocols have improved outcomes, the ability of patients to complete these intensive regimens and the reasons for discontinuation are unknown. We analyzed a cohort of 332 AYA patients (aged 15-49 years) and 1159 children (aged 1-14 years) with Ph-negative ALL treated on DFCI consortium protocols. We found that AYA patients completed treatment at lower rates than children (60.8% vs. 89.7%, p < 0.001), primarily due to higher rates of early treatment failure (14.5% vs. 2.4%, p < 0.001). Withdrawal from treatment for toxicity, social/personal, or unknown reasons was uncommon, but higher among AYA patients (9.3% vs 4.7%, p = 0.001). Patients who remained on assigned therapy for one year had favorable overall survival (AYA 5-year OS 88.9%; children 5-year OS 96.4%; p < 0.001). Among patients who continued treatment for 1 year, AYA patients completed asparaginase (defined as receiving 26+ weeks) at lower rates than children (79.1% vs. 89.6%, p < 0.001). Patients who received more weeks of consolidation asparaginase had higher overall and event-free survival. Efforts should focus on identifying patients at risk for early treatment failure and optimizing asparaginase delivery.

P. falciparum genetic markers associated with drug resistance from patients with treatment failure in the Southern part of Senegal in 2017.

Artemisinin Combination Therapies (ACT) stand as the most potent antimalarial treatments. In response to the emergence of ACT-resistant malaria parasites in Southeast Asia, the World Health Organization (WHO) has recommended continuous monitoring of the effectiveness of ACT and other antimalarials. To address this need, we collected dried blood spots from malaria patients during a 42-days drug efficacy trial evaluating the efficacy of Artesunate plus Amodiaquine (ASAQ), Artemether Plus Lumefantrine (AL) and Dihydroarthemisinine plus Piperaquine (DHAPQ) on simple P. falciparum malaria in 2017. Blood samples were collected on Day 0, prior to the patients' initial ACT dose, and on any days of recurrent parasitemia. Genetic markers such as Merozoite Surface Protein 1 (MSP1) and Merozoite Surface Protein 2 (MSP2) were genotyped to differentiate between recrudescence and re-infestation cases. Furthermore, PCR Single Specific Oligonucleotide Probes combined with-ELISA platform (PCR-SSOP-ELISA) and PCR-RFLP techniques were used to identify Pfcrt 72-76 mutant haplotype and Pfmdr1_86Y allele associated with chloroquine and amodiaquine resistance, respectively. Out of the 320 patients enrolled in the study, only 43 (13.43%) experienced relapses. Upon PCR correction, our analysis revealed that recrudescent infections affected 13 patients, with 8 in the ASAQ group, 5 in the AL group, and none in the DHAPQ group. Notably, no early treatment failures (within the first 3 days of treatment) were observed, and all recurrences occurred between Day 21 and Day 42. The prevalence of the Pfcrt wild-type haplotype CVMNK and Pfmdr N86 allele was 67.03% and 97.70%, respectively. In contrast, the mutant types CVIET and 86Y were found at 32.97% and 2.3%, respectively. The high prevalence of the CVMNK wild haplotype suggests that the parasites remain sensitive to chloroquine, while the low prevalence of the 86Y mutants indicates continued effectiveness of amodiaquine. Furthermore, the low prevalence of strains exhibiting the combination of CVIET and 86Y suggests that the use of multiple antimalarials is valuable for resistance control. Notably, none of the relapse cases carried the 86Y mutation or the combination of 86Y and CVIET.

Biomarkers of minimal residual disease and treatment.

Minimal residual disease (MRD) has been defined as a very small numbers of cancer cells that remain in the body after curative treatment. Its presence or absence will ultimately determine prognosis. With the introduction of new technologies the presence of MRD in patients with solid tumours can be detected and characterized. As MRD predicts future relapse, be it early or late treatment failure, in an otherwise asymptomatic patient its treatment and when to start treatment remains to be determined. Thus the concepts of personalized medicine using different biomarkers to classify the biological properties of MRD maybe come possible. Based on this determinations it may be possible to use targeted therapies rather than all patients with the same type of cancer receiving a standard treatment. However, it is important to understand the limitations of the different technologies, what these techniques are detecting and how they may help in the treatment of patients with cancer. The majority of published studies are in patients with metastatic cancer and there are few reports in patients with MRD. In this chapter the concept of MRD, the methods used to detect it and what treatments may be effective based on the biological characteristics of the tumour cells as determined by different biomarkers is reviewed. MRD depends on the phenotypic properties of the tumour cells to survive in their new environment and the anti-tumour immune response. This is a dynamic process and changes with time in the wake of immunosuppression caused by the tumour cells and/or the effects of treatment to select resistant tumour cells. With the use of biomarkers to typify the characteristics of MRD and the development of new drugs a personalized treatment can be designed rather than all patients given the same treatment. Patients who are initially negative for MRD may not require further treatment with liquid biopsies used to monitor the patients during follow-up in order to detect those patients who may become MRD positive. The liquid biopsy used during the follow up of MRD positive patients can be used to detect changes in the biological properties of the tumour cells and thus may need treatment changes to overcome tumour cell resistance.

Novel Chemotherapy-Free Initial Treatment of Rituximab Biosimilar Plus Pegylated Interferon α-2b in Pts with Untreated Advanced Indolent B-Cell Non-Hodgkin's Lymphoma: Results of the Ripple 3-Year Follow-up Study

Background: Indolent B-cell lymphoma (iBCL) are clinically heterogeneous and accounts for 10-15% of all kinds of subtypes in NHL in China. Although iBCL have a relatively good survival, majority of these lymphomas is considered incurable. The favorable activity and safety profile of rituximab monotherapy in the initial treatment of iBCL has been proven. Interferon alpha (IFN-α) was effective in modulating immune responses and may enhance the clinical efficacy of rituximab in vitro and in vivo studies. Clinical combination of rituximab and conventional IFN-α was associated with fewer early treatment failures compared to single agent rituximab. Peginterferon-α-2(peg-IFN-α2) has a longer half-life with less toxicity. It is also recommended as one of the therapeutic options for chronic hepatitis B virus (CHB) infection. The RIPPLE study (ClinicalTrials. gov identifier: NCT04246359) was initiated to evaluate the efficacy and safety of rituximab plus pegylated interferon α-2b for treatment-naive patients with iBCL. This publication provides long-term follow-up data. Methods: This trial enrolled pts aged 18-80 years with newly diagnosed iBCL including follicular lymphoma (FL, grade 1-2,3a), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), small lymphocytic lymphoma (SLL). Pts were eligible if they had ECOG ≤ 2, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. Further eligibility criteria were HBsAg positivity with HBV DNA load &amp;lt;3000 IU/mL prior to study; serum ALT level of &amp;lt;5 times the upper limit of normal. During induction phase, pts received rituximab biosimilar (Henliritux ® Shanghai Henlius Biotech) 375 mg/m 2 intravenous infusion on d1. Peg-IFN-α2b (Pegberon ®, Xiamen Amoytop Biotech) was given at a dose of 135ug, subcutaneously, on d1,8. The combination repeated every 21 days for 6 cycles. Responded pts receive rituximab (every 2 months) plus peg-IFN-α2b (every month) maintenance at the dose described above, for up to 2 years until disease progression and intolerance. Simultaneously, CHB pts orally treated with entecavir continuously. The primary endpoint is ORR assessed by investigators per Lugano 2014 criteria. Key secondary endpoints included TTR, DOR, PFS, OS, HBV DNA load clearance, and safety. Adverse events (AEs) were summarized according to NCI CTCAE v5.0. Results: From September 2018 to July 2021, 57 eligible pts with median age of 54 (range, 29-75) years were enrolled from 6 institutions in China. Thirty (56.1%) are female, 21(36.8%) pts were symptomatic and 22(38.6%) pts with FLIPI score≥3, 6(10.5%) pts suffer from hepatitis B with HBV DNA load &amp;lt;3000 IU/mL at study entry. At cutoff date, there were 26(45.6%) FL (grade 1-2), 21(36.8%) MALT, 7(12.3%) FL (grade 3a) , 2(3.5%) SLL, 1(1.8) LPL pts enrolled. Of 57 response evaluable pts, 38(66.7%) pts achieved an objective response including 29(50.9%) pts with CR based on investigators. ORR were 69.2% (18/26), 71.4% (5/7), 61.9% (13/21), 0, 100% (2/2) and the CR rates were 46.2% (12/26), 71.4% (5/7), 52.4% (11/21), 0, 50% (1/2) for FL (grade 1-2), FL (grade3a), MALT, LPL, SLL, respectively (Figure 1-2). Median HBV DNA load clearance time was 1.8 months (1.3-2.1months), no hepatitis B virus reactivation reported. With median follow-up time was 34.2 months (IQR:26.5-42.3 months), median OS, PFS and DoR was not reached; 3-years OS and PFS rate of whole cohort was 92.5%, 70.4%, respectively (Figure 3 C-D). Median TTR was 3.0months (1.5-5.2months). The most common treatment-emergent adverse events (TEAEs) were hematological relevance toxicities. The most common hematological TEAEs (&amp;gt;30%) were neutropenia 63.2% (36/57), anemia 36.5% (19/57), thrombocytopenia 29.8% (17/57). Non-hematological TEAEs (&amp;gt;10%) were fever (28.1%, 16/57), transaminase elevated (26.3%, 15/57), fatigue (26.3%, 15/57), infusion reaction (21.7%, 10/46). No treatment-related death occurred. Conclusion: Rituximab biosimilar plus pegylated interferon α-2b provided favorable response in newly diagnosed advanced iBCL with mild toxicity. No hepatitis B virus reactivation was observed.

Autologous Transplant (auto-HCT) Is Associated with Improved Clinical Outcomes Compared to CAR-T Therapy in Patients (pts) with Large B-Cell Lymphoma (LBCL) Achieving a Complete Remission

Introduction: CAR-T therapy is the standard of care for pts with relapsed LBCL as early as in the second line in those with early relapse or with primary refractory disease. In practice, pts who are intended to receive CAR-T, commonly require interim therapy before leukapheresis, wherein a small fraction may achieve a complete remission (CR). Having chemosensitive disease, these pts can be considered for auto-HCT. Also, there are reports indicating the efficacy of CAR-T therapy in CR pts (Strati et al., Haematologica, 2023; Wudhikarn et al., Blood Adv, 2022). We compared the outcome of pts with LBCL who received CAR-T vs. auto-HCT while in a CR. Methods: Pts aged 18-75 years with DLBCL or primary mediastinal lymphoma who received CAR-T (between 2018-2021) or auto-HCT (between 2015-2021) while in a CR by PET or CT were included in this analysis using the data from the Center for International Blood &amp; Marrow Transplant Research (CIBMTR) registry. Primary endpoints included progression-free survival (PFS) and overall survival (OS). Treatment-related mortality (TRM) and relapse rate were among the secondary endpoints. Results: We identified 360 pts with LBCL who were in a CR before receiving CAR-T (n=79, tisa-cel 53%, axi-cel 46%, and liso-cel 1%) or auto-HCT (n=281). Median follow-up was 24.7 months (range 3.3-49.4) for the CAR-T cohort and 49.7 months (range 3.0-95.4) for the auto-HCT cohort. Selected baseline characteristics are shown in Table 1. CRs were confirmed by PET scan in 90% of CAR-T pts and 99.6% of auto-CAR-T pts (p &amp;lt; 0.01). The most common lymphodepletion regimen for CAR-T was Cy/Flu (82.3%) and the most common conditioning regimen for auto-HCT was BEAM (77.6%). Thirty-seven (13.2%) of auto-HCT pts had a later CAR-T but no pts from the CAR-T cohort had subsequent auto-HCT. In univariate analysis, treatment with CAR-T was associated with a higher rate of relapse at 2 years (48% vs. 27.8%; p &amp;lt; 0.001), a lower rate of 2-year PFS (47.8% vs. 66.2%; p &amp;lt; 0.001) and lower 2-year OS (65.6% vs. 78.9%; p=0.037). There was no difference in rates of 2-year TRM (4.1% vs. 5.9%; p=0.673). Similarly, focusing on patients with early (12 months) treatment failure (CAR-T =57 and auto-HCT=163), treatment with CAR-T was associated with a higher 2-year relapse rate (45.9% vs. 22.8%; p &amp;lt;0.001) and an inferior 2-year PFS (48.3% vs.70.9%.; p &amp;lt;0.001) compared to auto-HCT (figure-2) while there was no difference in 2-year OS or TRM. In the multivariable analysis of outcomes, treatment with CAR-T was associated with higher risk of relapse (HR 2.18; p &amp;lt; 0.0001) and an inferior PFS (HR 1.83; p=0.0011) compared to auto-HCT. There was no difference in the risk of TRM (HR 0.59; p=0.36) or OS (HR 1.44; p=0.12). Conclusions: In pts with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with a lower relapse rate and an improved PFS compared to CAR-T, including in pts with early treatment failure (within 12 months). These results are in line with previously reported improved clinical outcomes with auto-HCT compared to CAR-T in pts in partial remission (Shadman et al. Blood, 2022). The data support utilization of auto-HCT in pts with relapsed LBCL achieving a CR.