Predictors Of Treatment Failure Research Articles

The Minimal Residual Disease Using Liquid Biopsies in Hematological Malignancies.

Simple SummaryMonitoring the response to treatment in hematologic malignancies is essential in defining the best way to optimize patient management. In general, achieving a deeper response has been shown to lead to a better prognosis, and the techniques used to study the minimal residual disease (MRD) are becoming more precise. The use of liquid biopsies, that is, analyzing the presence of alterations in nucleic acids, usually in peripheral blood or other biological fluids, is being studied and optimized with increasingly innovative molecular techniques, such as next-generation sequencing (NGS) in the monitoring of the MRD, avoiding, in many cases, more invasive tests in different hematological neoplasms. Currently, liquid biopsies are not standardized for the MRD monitoring, but there is increasing evidence of its correlation with other techniques to measure responses to treatments and patient outcomes.The study of cell-free DNA (cfDNA) and other peripheral blood components (known as “liquid biopsies”) is promising, and has been investigated especially in solid tumors. Nevertheless, it is increasingly showing a greater utility in the diagnosis, prognosis, and response to treatment of hematological malignancies; in the future, it could prevent invasive techniques, such as bone marrow (BM) biopsies. Most of the studies about this topic have focused on B-cell lymphoid malignancies; some of them have shown that cfDNA can be used as a novel way for the diagnosis and minimal residual monitoring of B-cell lymphomas, using techniques such as next-generation sequencing (NGS). In myelodysplastic syndromes, multiple myeloma, or chronic lymphocytic leukemia, liquid biopsies may allow for an interesting genomic representation of the tumor clones affecting different lesions (spatial heterogeneity). In acute leukemias, it can be helpful in the monitoring of the early treatment response and the prediction of treatment failure. In chronic lymphocytic leukemia, the evaluation of cfDNA permits the definition of clonal evolution and drug resistance in real time. However, there are limitations, such as the difficulty in obtaining sufficient circulating tumor DNA for achieving a high sensitivity to assess the minimal residual disease, or the lack of standardization of the method, and clinical studies, to confirm its prognostic impact. This review focuses on the clinical applications of cfDNA on the minimal residual disease in hematological malignancies.

Risk stratification for relapsed/refractory classical Hodgkin lymphoma integrating pretransplant Deauville score and residual metabolic tumor volume.

Pretransplant Deauville score (DS) is an imaging biomarker used for risk stratification in relapsed/refractory classical Hodgkin lymphoma (cHL). However, the prognostic value of residual metabolic tumor volume (rMTV) in patients with DS 4-5 has been less well characterized. We retrospectively assessed 106 patients with relapsed/refractory cHL who underwent autologous stem cell transplantation. Pretransplant DS was determined as 1-3 (59%) and 4-5 (41%), with a markedly inferior event-free survival (EFS) in patients with DS 4-5 (hazard ratio [HR], 3.14; p= .002). High rMTV41% (rMTVhigh , ≥4.4cm3 ) predicted significantly poorer EFS in patients with DS 4-5 (HR, 3.70; p= .014). In a multivariable analysis, we identified two independent factors predicting treatment failure: pretransplant DS combined with rMTV41% and disease status (primary refractory vs. relapsed). These two factors allow to stratify patients into three groups with divergent 2-year EFS: 89% for low-risk (51%; relapsed disease and either pretransplant DS 1-3 or DS 4-5/rMTVlow ; HR 1), 65% for intermediate-risk (28%; refractory disease and either DS 1-3 or DS 4-5/rMTVlow ; HR 3.26), and 45% for high-risk (21%; DS 4-5/rMTVhigh irrespective of disease status; HR 7.61) groups. Pretransplant DS/rMTV41% combination and disease status predict the risk of post-transplant treatment failure and will guide risk-stratified approaches in relapsed/refractory cHL.

Patient-specific genetic factors predict treatment failure in sofosbuvir-treated patients with chronic hepatitis C.

According to pivotal clinical trials, cure rates for sofosbuvir-based antiviral therapy exceed 96%. Treatment failure is usually assumed to be because of virological resistance-associated substitutions or clinical risk factors, yet the role of patient-specific genetic factors has not been well explored. We determined if patient-specific genetic factors help predict patients likely to fail sofosbuvir treatment in real-world treatment situations. We recruited sofosbuvir-treated patients with chronic hepatitis C from five Canadian treatment sites, and performed a case-control pharmacogenomics study assessing both previously published and novel genetic polymorphisms. Specifically studied were variants predicted to impair CES1-dependent production of sofosbuvir's active metabolite, interferon-λ signalling variants expected to impact a patient's immune response to the virus and an HLA variant associated with increased spontaneous and treatment-induced viral clearance. Three hundred and fifty-nine sofosbuvir-treated patients were available for analyses after exclusions, with 34 (9.5%) failing treatment. We identified CES1 variants as novel predictors for treatment failure in European patients (rs115629050 or rs4513095; odds ratio (OR): 5.43; 95% confidence interval (CI): 1.64-18.01; P=.0057), replicated associations with IFNL4 variants predicted to increase interferon-λ signalling (eg rs12979860; OR: 2.25; 95% CI: 1.25-4.06; P=.0071) and discovered a novel association with a coding variant predicted to enhance the activity of IFNL4's receptor (rs2834167 in IL10RB; OR: 1.81; 95% CI: 1.01-3.24; P=.047). Ultimately, this work demonstrates that patient-specific genetic factors could be used as a tool to identify patients at higher risk of treatment failure and allow for these patients to receive effective therapy sooner.

Abstract P1-07-08: Endoxifen predicts early recurrence in breast cancer: A Brazilian prospective study

Abstract Tamoxifen is widely used in adjuvant therapy for breast cancer patients, but up to one-third of patients recur within 15 years after surgery even with its regular use. Low plasma levels of (Z)-endoxifen, the most active tamoxifen metabolite, have been studied as a possible predictor of treatment failure. Here, we evaluated plasma (Z)-endoxifen as a predictor of response to adjuvant treatment in breast cancer patients. Methods: One hundred forty nine patients were selected from a prospective cohort of consecutive newly diagnosed breast cancer patients recruited at a national referral center for treatment of cancer in Curitiba, Southern Brazil. Inclusion criteria were breast cancer women on stage I - III, positive hormone receptor tumors, operable, undergoing or not (neo)adjuvant chemotherapy, and signed for adjuvant tamoxifen for at least five years. At diagnosis, peripheral blood samples were collected for CYP2D6 genotyping for *1 *2, *3, *4, *5, *6, *7, *8, *9, *10, *17, *29 and *41 and subsequent metabolic activity scores according to phenotypes assigned for each allele (poor metabolizer PM; intermediate, IM; extensive, EM and ultrarapid metabolizer, UM). After the tamoxifen initiation, patients were evaluated at months 3, 6, and 12 for adherence and drug interactions, and plasma (Z)-endoxifen quantification. They were followed from April 2014 to April 2019. The study's primary objective was to evaluate whether (Z)-endoxifen plasma levels predict early recurrence in patients on adjuvant tamoxifen. The secondary aim was to evaluate an association between (Z)-endoxifen levels and clinical and phenotypic CYP2D6 metabolism variables. A Cox model estimated hazard ratios (HR) comparing recurrence free survival (RFS) according to (Z)-endoxifen plasma levels. The survival was compared using the Kaplan-Meier method and the log-rank test. Results: The median follow-up period was 52.3 months and at that point, there were 20 recurrences of 149 patients. At 3 months there were no cases of low adherence to tamoxifen. The (Z)-endoxifen levels were established by quartiles, with the first lower quartile being used as a cutoff (14.72nM). High (Z)-endoxifen levels at 3 months (>14.72nM) were detected in 75.8% (n = 113) of cases and low levels (≤14.72nM) in 24.2% (n = 36). There was no statistically significant difference between the groups with low or high (Z)-endoxifen levels regarding clinical and pathological variables, but there was a higher CYP2D6 PM/IM frequency in the low (Z)-endoxifen levels group (p<0.001). High (Z)-endoxifen levels were associated with lower RFS compared to low (Z)-endoxifen levels (HR 2.5, 95% CI 1.00-6.22, p=0.041). Low (Z)-endoxifen levels increased the recurrence risk even when adjusted for staging and molecular subtypes (HR 2.55, 95% CI 1.00-6.48, p<0.001) or staging and CYP2D6 phenotype (UM/EM vs IM/PM; HR 4.38, 95% CI 1.66-11.59, p=0.003), or prior chemotherapy exposure (HR 2.65, 95% CI 1.06-6.61, p=0.036). Conclusion: This is the first Brazilian prospective trial evaluating the association of plasma (Z)-endoxifen levels, with the clinical outcome in breast cancer women treated with adjuvant tamoxifen, controlled by predictable confounding factors of plasma (Z)-endoxifen levels, such as tamoxifen adherence, and drug interaction with CYP2D6 inhibitors. In our study, a low plasma level of (Z)-endoxifen (≤ 14.72nM) after 3 months of tamoxifen treatment was a predictor of early recurrence in patients under adjuvant tamoxifen (p=0.041). A longer follow-up and a larger cohort may be needed to confirm the (Z)-endoxifen cutoff value that is a predictor of long-term recurrence. Citation Format: Thais Almeida, Werner Schroth, Jeanine Marie Nardin, Thomas Mürdter, Solane Picolotto, Reiner Hoppe, Jenifer Primon Kogin, Elisa Daniele Gaio, Angela Dasenbrock, Raquel Cristina Skrsypcsak, Lucia Noronha, Hiltrud Brauch, José Claudio Casali-da-Rocha. Endoxifen predicts early recurrence in breast cancer: A Brazilian prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-08.

Combined prognostic role of TARC and interim 18F-FDG PET/CT in patients with Hodgkin lymphoma-real world observational study.

Although the majority of patients with Hodgkin lymphoma (HL) has recently become long-term survivors, 20%-30% of HL patients have primary refractory disease or relapse. It is essential to identify patients at risk of treatment failure during first-line therapy. To objective of the present study was to investigate the combined prognostic role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging and thymus and activation-regulated chemokine (TARC) levels in Hodgkin lymphoma. Between 01/01/2013 and 01/03/2019 77 HL patients were enrolled in this study where serum TARC levels were measured by an immunoassay and 18F-FDG PET/CT scans were performed at baseline, after the second cycle of ABVD treatment (interim) and at the end of first-line therapy. Twenty-six patients (34%) had early-stage HL, while 51 patients presented with advanced-stage disease. Fifteen patients had primary refractory HL, while 1 patient relapsed after first-line therapy. Optimal TARC cut-off value for progression-free survival (PFS) was 700pg/mL based on receiver operating characteristic (ROC) curve analysis. With Cox regression analysis, 18F-FDG PET/CT with Deauville scores of 3, 4, or 5 and TARC levels above 700pg/mL predicted treatment failure at interim assessment. Inclusion of HL patients with a Deauville score of 3 to the high-risk population resulted in a 7-fold increase in the estimated risk of relapse compared to patients with Deauville score 4-5 with TARC levels above 700pg/mL. Patients with interim 18F-FDG PET/CT Deauville scores 3-5 had a significant survival benefit if their TARC levels were 700pg/mL. Positive predictive value (PPV) of interim 18F-FDG PET/CT scans with a Deauville score 3-5 was 47.8%, while combined PPV of a similar 18F-FDGPET/CT assessment and elevated TARC levels was 88.8%. Interim 18F-FDG PET/CT and TARC analyzed together accurately identify HL patients who do not respond sufficiently to treatment and who need an early change of therapy.

Prognostic stratification for patients with neuroendocrine tumours receiving 177Lu-Dotatate.

177Lu-Dotatate is increasingly used in patients with advanced neuroendocrine tumour (NET). However, few prognostic markers are available to stratify progression-free survival (PFS) of patients who received 177Lu-Dotatate. Clinicopathological data including baseline circulating biomarkers of patients with advanced NET who received 177Lu-Dotatate were routinely collected and were retrospectively analysed. Continuous variables were normalized by dividing them by their upper normal limits. The whole data set was randomly divided into a training set and a validation set. Univariate and multivariate logistic regression analyses were used to identify independent markers and to develop a scoring model to predict treatment failure at 1 year. In total, 195 patients were included. Elevated baseline chromogranin A (CgA), normal creatinine and previous chemotherapy were three risk factors independently associated with 1-year treatment failure. By combining these risk factors, a scoring model was developed which could accurately predict 1-year treatment failure both in the training set (area under curve, AUC, 0.813; 95% CI, 0.731-0.895; P< 0.001) and in the validation set (AUC, 0.816; 95% CI, 0.644-0.968; P< 0.001). After selecting a score of 29.7 as the cut-off value of the scoring model, patients could be stratified into two groups namely low-risk and high-risk with significantly different 1-year treatment failure rate, PFS and overall survival (OS; P< 0.001) both in the training set and validation set. In conclusion, baseline CgA, creatinine level and previous chemotherapy were independently associated with 1-year treatment failure of patients with advanced NET who received 177Lu-Dotatate and the scoring model and prognostic stratification based on these markers could accurately predict 1-year treatment failure, PFS and OS.

Blood count and fasting blood glucose level in the assessment of prognosis and survival in advanced cervical cancer.

The objective of this study was to verify whether the parameters of the blood count and the fasting glucose level before treatment are related to prognosis and survival in cervical cancer (IIB-IVB staging). Patients with cervical cancer (stages IIB-IVB) were evaluated (n=80). Age, parity, staging, histological grade, histological type, hemoglobin, red blood cells, hematocrit, neutrophil, lymphocyte and platelet counts, red blood cell distribution width, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, fasting glucose levels, overall survival, and disease-free survival were evaluated. The results of laboratory parameters were compared using the Mann-Whitney U test. Receiver operating characteristic curve was used to obtain the area under the curve and determine the best cutoff values for each parameter. Survival was verified by using the Kaplan-Meier method, followed by the log-rank test. The level of significance was ≤0.05. Regarding staging, lower hemoglobin values (p=0.0013), red blood cells (p=0.009), hematocrit (p=0.0016), higher leukocytes (p=0.0432), neutrophils (p=0.0176), platelets (p=0.0140), red blood cell distribution width (RDW) (p=0.0073), neutrophil-lymphocyte ratio (p=0.0039), platelet-lymphocyte ratio (p=0.0006), and fasting glucose level (p=0.0278) were found in IIIA-IVB compared with IIB staging. Shorter disease-free survival was associated with hemoglobin ≤12.3 g/dl (p=0.0491), hematocrit ≤38.5% (p=0.05), neutrophil-lymphocyte ratio >2.9 (p=0.0478), and platelet-lymphocyte ratio >184.9 (p=0.0207). Shorter overall survival was associated with hemoglobin ≤12.3 g/dl (p=0.0131), hematocrit ≤38.5% (p=0.0376), neutrophil-lymphocyte ratio >2.9 (p=0.0258), and platelet-lymphocyte ratio >184.9 (p=0.0038). The analysis of these low-cost and easily accessible parameters could be a way to monitor patients in order to predict treatment failures and act as early as possible.

Lymphocyte-to-monocyte ratio is a short-term predictive marker of ulcerative colitis after induction of advanced therapy.

Advanced therapies for patients with mild-to-severe ulcerative colitis (UC) may result in treatment failure. We examined whether the lymphocyte-to-monocyte ratio (L/M ratio) could predict the failure of advanced therapies. This retrospective, observational, cohort study included 73 patients who were treated with advanced therapies at the Hamamatsu University School of Medicine (Shizuoka, Japan) between February 2011 and November 2020. The patients were divided into the non-failure and failure groups, and their leukocyte counts and ratios before induction were examined. Univariate and multivariate analyses were performed to identify the prognostic factors. Advanced therapies failed within 3 months in 15 (20.5%) patients. Only the L/M ratio was significantly lower in the failure group than in the non-failure group (P = 0.004). Receiver-operating characteristic (ROC) curve analysis revealed that an L/M ratio of ≤3.417 was predictive of treatment failure; the area under the curve (AUC) was 0.747 (95% CI, 0.620–0.874). Kaplan–Meier analysis revealed that the failure-free rate was significantly lower in the group with an L/M ratio of ≤3.417 than in the group with an L/M ratio of >3.417 (log-rank test P = 0.002). Cox proportional hazard regression analysis identified an L/M ratio of ≤3.417 as an independent risk factor for failure within 3 months after the induction of advanced therapies. Furthermore, ROC analysis of patients who did not receive immunomodulators also revealed that the cut-off L/M ratio was 3.417 and the AUC was 0.796 (95% CI, 0.666–0.925). In patients receiving advanced therapies for active UC, the L/M ratio can predict treatment failure within 3 months. L/M ratios could facilitate the transition from advanced therapies to subsequent treatments.

P526 Measurement of thiopurine metabolites concentrations after one week of treatment does not predict treatment failure in Inflammatory Bowel Disease patients

Abstract Background Conventional thiopurines such as azathioprine (AZA) and mercaptopurine (MP) remain drugs of choice in maintaining remission and corticosteroid sparing in inflammatory bowel disease (IBD). Early discontinuation of thiopurine therapy occurs frequently, due to slow onset of effect and a relatively high frequency of early adverse drug reactions (ADR). Some ADR such as hepatotoxicity and gastro-intestinal complaints are associated with the thiopurine metabolite concentrations 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine ribonucleotides (6-MMPR), in particular elevated 6-MMPR concentrations or unfavorable 6-MMPR/6-TGN ratios. Early measurement of thiopurine metabolites may help to optimize thiopurine therapy in IBD. The aim of this study was to assess the predictive value of thiopurine metabolite measurement one week after thiopurine therapy initiation on discontinuation during the first three months of therapy. Methods This was a multicenter prospective observational study in the Netherlands. Consecutive IBD patients who initiated thiopurine therapy were included and measurement of thiopurine metabolites was performed after 7 days (6 – 8) of treatment (T1). Patients were monitored for 12 weeks to document occurrence of ADR and early treatment discontinuation. Switching to an alternative thiopurine or adding allopurinol (as co-medication) was also considered as treatment discontinuation (to prevent ADR). 6-MMPR concentrations and 6-MMPR/6-TGN ratios were separately analyzed (Mann-Whitney U-tests) regarding therapy discontinuation within 12 weeks. P-values of ≤0.05 were considered statistically significant. Results In total, 255 patients were included, of which 83 were excluded due to either missing blood samples on T1 (n=54), dose adjustments within 12 weeks (n=25) or a delayed T1 measurement (n=4). Of the remaining 172 patients, 79 patients were male (46%), 102 patients had Crohn’s disease (59%) and 157 patients were treated with MP (91%). In total, 88 (51%) patients continued thiopurine therapy and 84 patients (49%) discontinued therapy within 12 weeks. Median 6-MMPR concentrations (1,295 versus 1,589 pmol x 108 red blood cells) and 6-TGN/6-MMPR ratios (8.8 versus 11.4) did not differ significantly between patients who continued versus discontinued therapy within 12 weeks (Figures 1 and 2). Conclusion In this study thiopurine metabolites at T1 did not relate to discontinuation of thiopurine therapy within 12 weeks. We will conduct additional pharmacodynamic studies to corroborate our hypothesis that early metabolite measurements may be of individual patients’ benefit.

Durability of single tablet regimen for patients with HIV infection in Southern Taiwan: data from a real-world setting

BackgroundA single-tablet regimen (STR) has been associated with better drug adherence. However, the durability of different STRs was unknown in the real-world settings. Our aim was to investigate the durability of different initial STR regimens in antiretroviral-naive patients starting STR in southern Taiwan.MethodThis was a retrospective study of antiretroviral-naive patients that initiated first-line antiretroviral regimens with STRs between May 2016 and December 2017. The primary endpoint was time to virological failure. Secondary endpoints were STR discontinuation due to toxicity/intolerance. Durability was defined as time from the initiation until discontinuation/modification. Kaplan- Meier curves were plotted assessing time to virological suppression, treatment failure and discontinuation for the three STRs and Cox proportional hazards model was used to analyze the factors associated with time to viral suppression, treatment failure or discontinuation.ResultsTwo hundred and twenty-three patients were included: The median follow-up duration (IQR) was 73.9 (48–101.6) weeks, 25 patients (11%) experienced virological failure; the 48 weeks probability of treatment failure was 22.9% (16/70) for Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF), 24.1% (13/54) for Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) and 24.2% (24/99) for Abacavir/Dolutegravir/Lamivudine (ABC/DTG/3TC) (p=0.16). Fifty-six patients (25%) discontinued their STRs owing to toxicity/intolerance. When compared to EFV/FTC/TDF, treatment with FTC/RPV/TDF (aHR 8.39, CI 1.98–35.58, p = 0.004) and ABC/DTG/3TC (aHR 8.40, CI 2.39–29.54, p=0.001) were more likely to have treatment failure. The predictors for treatment failure included age ≦ 30 years old (aHR 3.73, CI 1.25–11.17, p = 0.018), switch between different STR (aHR 2.3, CI 1.18–4.50, p = 0.001) and free of active syphilis infection (aHR 0.24, CI 0.08–0.73, p = 0.012). The risk factor for treatment discontinuation included younger age ≦ 30 years old (aHR 3.82, CI 1.21–12.37, p = 0.023), treatment with EFV/FTC/TDF (aHR 8.65, CI 2.64–28.39, p < 0.001) and free of active syphilis infection (aHR 0.16, CI 0.04–0.62, p = 0.006).ConclusionYounger age was associated with treatment failure and drug discontinuation. Active syphilis infection s/p treatment was associated with free from treatment failure and discontinuation. This probably driven by the more frequently sexual health education and counseling when patients had syphilis infection. Treatment with ABC/DTG/3TC was associated with higher risk of treatment failure. The STR durability was dependent on the drug toxicity/intolerance, age and syphilis infection.

Antireflux mucosal intervention (ARMI) procedures for refractory gastroesophageal reflux disease: a systematic review and meta-analysis.

Background:Endoscopic treatments are increasingly being offered for refractory gastroesophageal reflux disease (GERD). Three procedures have similar concepts and techniques: antireflux mucosectomy (ARMS), antireflux mucosal ablation (ARMA), and antireflux band ligation (ARBL); we have collectively termed them antireflux mucosal intervention (ARMI). Here, we systematically reviewed the clinical outcomes and technical aspects.Methods:The PubMed, Embase, and Cochrane Library databases were searched from inception to October 2021. The primary outcome was the clinical success rate. The secondary outcomes were acid exposure time, DeMeester score, need for proton pump inhibitors (PPIs), endoscopic findings, and adverse events.Results:Fifteen studies were included. The pooled clinical success rate was 73.8% (95% confidence interval (CI) = 69%–78%) overall, 68.6% (95% CI = 62.2%–74.4%) with ARMS, 86.7% (95% CI = 78.7%–91.9%) with ARMA, and 76.5% (95% CI = 65%–85.1%) with ARBL. ARMI resulted in significantly improved acid exposure time, DeMeester score, and degree of hiatal hernia. Furthermore, 10% of patients had dysphagia requiring endoscopic dilatation after ARMS or ARMA, and ARMS was associated with a 2.2% perforation rate. By contrast, no bleeding, perforation, or severe dysphagia was noted with ARBL. Severe hiatal hernia (Hill grade III) may predict treatment failure with ARMA.Conclusions:The three ARMI procedures were efficacious and safe for PPI-refractory GERD. ARMA and ARBL may be preferred over ARMS because of fewer adverse events and similar efficacy. Further studies are necessary to determine the optimal technique and patient selection.

Seroprevalence of hepatitis C virus antigen in patients with chronic liver disease and hepatocellular carcinoma at 12th week of treatment: a cross-sectional study.

epidemiological data suggests that more than 50% of hepatitis C virus (HCV) patients fail treatment. The objective of the study was to highlight the seroprevalence of hepatitis C virus antigen (HCV Ag) at the 12th week of treatment. during a cross-sectional study, participants with chronic liver disease and hepatocellular carcinoma (HCC) were recruited between December 2020 and March 2022 at the Yaoundé General Hospital (HGY) and the University Teaching Hospital of Yaounde (UTHY). Five millilitres of blood samples were taken from each consenting participant and then a qualitative search for HCV Ag by Enzyme-Linked Immuno Assay (ELISA) was performed. Analysis of the results was performed using SPSS Version 25.0 software. out of the 192 participants selected for the study, only 92 (47,9%) participants were at 12 weeks of treatment, including 69 (75%) participants positive for the hepatitis C virus antibody (HCV Ab) by RDT. Of these participants, 44 (47.8%) participants were positive for HCV Ag by ELISA, respectively 19/37 (51.3%), 14/19 (73.6%), 11/13 (84.6%) with chronic hepatitis (HC), Cirrhosis, and HCC (P<0.0001). our results showed a high prevalence of HCV Ag in patients at their 12th week of treatment which predicts treatment failure and calls for public policy to develop new management strategies to prevent HCV treatment failure in our context.

Cancer stem cell-mediated therapeutic resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy. In the clinic, therapeutic resistance is largely attributed to tumor heterogeneity. Growing evidence indicates that cancer stem cells (CSCs) are the major source of tumor heterogeneity. Hence, uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics. CSCs resemble embryonic stem cells. Embryonic development-related genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC. Multiple strategies have been applied to identify oncofetal drivers. The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure. Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance. This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance.

A Model to Predict Treatment Failure in Patients Undergoing Upfront Surgery for Resectable Colorectal Liver Metastases

Introduction: Patients who recur in the first year after resection of CRLM do poorly. Aim of our study was to predict treatment failure in patients undergoing upfront resection with a nomogram. Methods: Data from patients resected between 1991 and 2019 was randomly split (70:30) into two cohorts. Treatment failure was defined as any recurrence or death within 12 months. Nomogram was constructed using multivariable logistic regression on the training cohort and validated using the testing cohort. Results: 783 patients were included. Primary tumor characteristics included 50% left sided; 75.2% T3/4 and 56.5% node positive. Median disease-free interval was 10 months, median number of metastases was 1 (1-50) with a median size of 3.6 cm (0.2-22). 222 (28.3%) patients recurred within 1 year. Recurrence mostly involved distant organs with or without liver involvement (67.6%). Curative-intent treatment was possible in 37.8% of these patients. Primary location, T-stage and node status, disease-free interval, number, and size of metastases were associated with treatment failure. The AUC from the validation of the model was 0.6 (95%CI 0.52-0.68). Patients with a high-risk of treatment failure (≥40%) had a worse survival from the landmark time of 12 months from surgery compared to those with low-risk (2-years 82% vs. 70%; p=0.0002) Conclusions: Primary location, T stage, nodes status, disease-free interval, number, and size of metastases are associated with treatment failure. The survival of patients with a probability of treatment failure ≥40% is unfavorable. Future trials investigating the role of neoadjuvant therapy in these high-risk patients are warranted.

Immunogenicity of botulinum toxin.

Botulinum toxin treatment is the most common non-surgical cosmetic treatment. Although there are many available treatments using botulinum toxin, their effects are temporary and repeated injections are required. These frequent injections can trigger an immunological response. In addition, botulinum toxin acts as an antigen in the body; thus, its effect disappears progressively due to this immunological reaction, which may cause treatment failure. Active botulinum toxin consists of a core neurotoxin and complexing proteins, the exact effects of which remain unclear. However, the complexing proteins are closely related to the immune response and the formation of neutralizing antibodies. Since neutralizing antibodies can lead to treatment failure, their formation should be prevented. Furthermore, various methods of detecting neutralizing antibodies have been used to predict treatment failure.

An observational longitudinal study of the use of ROX index to predict treatment failure in patients receiving continuous positive airway pressure for COVID-19.

An observational longitudinal study of the use of ROX index to predict treatment failure in patients receiving continuous positive airway pressure for COVID-19.

What patient characteristics predict treatment success or failure in short- and long-term psychotherapies?

Background Patient factors make a strong contribution to psychotherapy outcome. Pre-treatment patient characteristics – demographic, pathology and personal – may either facilitate achievement of recovery and lasting benefits or constitute a risk for different kinds of treatment failure. Methods A narrative review focused on evaluating the role of pre-treatment patient characteristics on the success or failure of short- and long-term psychotherapy for mood and anxiety disorders. Success was conceptualized as significant improvement or recovery and failure as non-improvement, deterioration, or non-attendance/dropout. Results There is no consistent evidence of demographic variables as predictors of treatment failure, except for lower socioeconomic status, being male and ethnic minority status for therapy non-attendance. Patients’ pathology, i.e. severity of psychiatric symptoms, greater functional impairment, personality disorder and other comorbidities, have been shown to be mostly associated with lesser recovery across different types of disorders, especially in short-term therapies, but it does not consistently predict treatment failure. Some pre-treatment personal characteristics (e.g. secure attachment style) and capacities (e.g. motivation, self-observing capacity and good overall psychological suitability) mostly increase the likelihood of therapy success whereas some vulnerabilities and poor psychological suitability, or overall complexity (i.e. combination of demographic, clinical and personality factors), increase the risk of poor outcome mostly in short-term but not in long-term therapy, or moderate dropout. Likewise, the subsequent match between therapy type and patient’s pre-treatment expectations and preferences may account for different aspects of treatment failure. Conclusions The relative importance of pre-treatment patient characteristics on treatment failure is not known. Meta-analyses on this issue are needed.

Evaluation of Adverse Effects of Topical Glaucoma Medications on Trabeculectomy Outcomes Using the Glaucoma Medications Intensity Index.

IntroductionTrabeculectomy is commonly performed for glaucoma when medications are unable to control disease progression or have intolerable adverse effects. Previous studies have suggested that a higher number of and/or longer treatment duration with preoperative topical glaucoma medications are associated with a higher risk of trabeculectomy failure, but most of these studies lack quantification of exposure. The aim of this study was to investigate the relationship between preoperative exposure to topical glaucoma medications and trabeculectomy outcome, using a new method for quantifying accumulated exposure.MethodsConsecutive patients with primary open-angle glaucoma (POAG) or normal-tension glaucoma (NTG) who underwent primary trabeculectomy between 2013 and 2017 were retrospectively reviewed. The Glaucoma Medications Intensity Index (GMII) was calculated for each eye by multiplying the number of drops per week by duration of use (in years). The relationship between the GMII and postoperative outcome in terms of 1- and 2-year success rates and survival time was analyzed.ResultsA total of 55 eyes from 40 subjects were analyzed, all with follow-up > 6 months (mean 2.72 ± 1.46 years). The GMII for eyes with successful (n = 41) and failed (n = 14) outcome at last visit was 111.71 ± 78.59 and 167.41 ± 85.04, respectively, and significantly higher in failed eyes (P = 0.03). Univariate regression analysis of age, gender, cup–disc ratio, previous phacoemulsification, diabetes, hypertension, dyslipidemia, preoperative number of glaucoma medications/treatment duration/intraocular pressure (IOP), and GMII showed age and GMII to be possible predictors of treatment failure. On subsequent multivariate analysis, only GMII was correlated with failure (odds ratio 1.021, 95% confidence interval 1.00–1.05; P = 0.05). When GMII ≥ 80, the postoperative survival time was shorter (P = 0.02), the 1-year IOP, number of glaucoma medications, and number of needlings performed were higher (P = 0.03, P < 0.01, P < 0.03, respectively), and reduction in glaucoma medication was less (P = 0.02).ConclusionThe GMII can be used to predict eyes at higher risk for trabeculectomy that may benefit from additional perioperative intervention or treatment. It can also help the surgeon time the surgery before the GMII becomes too high, thereby optimizing the patient’s postoperative outcome.

1423. Overview of Paediatric Urinary Tract Infections in the Gulf Co-operation Council (GCC) Countries, A Literature Review

Abstract Background Urinary tract infections (UTIs) are among the most frequent infections in the pediatric population, occasionally associated with concealed renal anomalies. Hence, early treatment is pertinent to reduce morbidities for better patient outcomes. The study aimed to review published literature from the gulf region in the last decade on UTIs etiology, common risk factors, current antimicrobial management, outcomes, and common resistance patterns. Methods This narrative literature review was conducted by evaluating articles published for a 10-years period from 2011 to 2021 using “Google Scholar” and “PubMed” databases. The search included regional clinical practice guidelines, systematic review and meta-analysis conducted across Gulf Cooperation Council countries (GCC). The search was limited to English literature and patients below 18 years old. Results The prevalence of UTIs among pediatrics in the age group of 0 to18 years ranged from 9.9% to 50.8% across the region. Data obtained from 11,092 children revealed that Escherichia coli was the primary cause of UTI (26% to 93.5%), followed by Klebsiella pneumoniae (3.8% to 76.4%). Furthermore, Extended-spectrum beta-lactamases (ESBLs) producing pathogens were observed in 7% to 35.2%. Higher ESBL rates were observed in patients with recurrent UTIs. Ampicillin and Co-trimoxazole, and 3rd generation cephalosporins were mainly prescribed as first-line antibiotics. Increased resistance to Ampicillin, Co-trimoxazole, and 3rd generation cephalosporins while low resistance to Nitrofurantoin, Amikacin, and Meropenem was documented. Vesicoureteral reflux was the most common risk factor for UTIs. Renal abnormalities were also observed to provide a nidus for bacterial growth. There is an evident lack of data in the region on antimicrobial treatment duration, possible predictors of treatment failure, and epidemiological data on multidrug resistance. Conclusion Urinary tract infections (UTIs) in pediatrics are a common therapeutic challenge in the region. Larger scale multicenter national and regional epidemiology studies are a prerequisite in the region. There is a need to monitor antimicrobial resistance in pediatrics &amp; enhance surveillance for the advancement of management. Disclosures Nervana Habashy, B. Pharm, Pfizer (Employee) Ashraf Hassanien, MD, Pfizer (Employee) Ayman Kurdi, MD, Pfizer (Employee)

Trends and predictive factors for treatment failure following artemisinin-based combination therapy among children with uncomplicated malaria in Ghana: 2005\u20132018

BackgroundSince the introduction of artemisinin-based combination therapy (ACT) in Ghana in 2005 there has been a surveillance system by the National Malaria Control Programme (NMCP) and the University of Ghana Noguchi Memorial Institute for Medical Research (UG-NMIMR) to monitor the therapeutic efficacy of ACTs for the treatment of uncomplicated malaria in the country. We report trends and determinants of failure following treatment of Ghanaian children with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) combinations.MethodsPer protocol analyses as well as cumulative incidence of day 28 treatment failure from Kaplan Meier survival analyses were used to describe trends of failure over the surveillance period of 2005–2018. Univariable and multivariable cox regression analyses were used to assess the determinants of treatment failure over the period.ResultsDay 28 PCR-corrected failure, following treatment with ASAQ, significantly increased from 0.0% in 2005 to 2.0% (95% CI: 1.1–3.6) in 2015 (p = 0.013) but significantly decreased to 0.4% (95% CI: 0.1–1.6) in 2018 (p = 0.039). Failure, following treatment with AL, decreased from 4.5% (95% CI: 2.0–9.4) in 2010 to 2.7% (95% CI: 1.4–5.1) in 2018, though not statistically significant (p = 0.426). Risk of treatment failure, from multivariable cox regression analyses, was significantly lower among children receiving ASAQ compared with those receiving AL (HR = 0.24; 95% CI: 0.11–0.53; p < 0.001); lower among children with no parasitaemia on day 3 compared with those with parasitaemia on day 3 (HR = 0.02; 95% CI: 0.01–0.13; p < 0.001); and higher among children who received ASAQ and had axillary temperature ≥ 37.5 °C on day 1 compared with those with axillary temperature < 37.5 °C (HR = 3.96; 95% CI: 1.61–9.75; p = 0.003).ConclusionsTreatment failures for both ASAQ and AL have remained less than 5% (below WHO’s threshold of 10%) in Ghana since 2005. Predictors of treatment failure that need to be considered in the management of uncomplicated malaria in the country should include type of ACT, day 3 parasitaemia, and day 1 axillary temperature of patients being treated.