Predictor Of Therapeutic Failure Research Articles

Monoclonal Anti-PCSK9 Antibodies: Real-World Data.

Background: Real-world data on the use of lipid-lowering therapy (LLT) in clinical practice show that about 80% of (very) high-cardiovascular (CV)-risk patients disregard the 2019 European Society of Cardiology (ESC) Guidelines' recommendations on dyslipidemias. The availability of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9mAb) should reduce this gap. Our aim was to provide data on PCSK9mAb use in clinical practice, investigating the achievement of the ESC Guidelines' recommendations in the real world. Methods: Between April 2018 and December 2022, patients who started on PCSK9mAb therapy (140 mg of evolocumab or 75 mg or 150 mg of alirocumab, subcutaneous injection every 2 weeks) were included in a prospective registry. Our cohort consisted of 256 patients: 95 (37.1%) were women (mean age: 65.43 ± 11.12 yrs), 53 (20.7%) were at high CV risk, and 203 (79.3%) were at very high CV risk. Results: After one year of PCSK9mAb treatment, nearly 60% of patients demonstrated full adherence to the ESC Guidelines' recommendations, defined as achieving at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C) levels along with reaching LDL-C target levels (≤55 and ≤70 mg/dL for very high and high risk, respectively). Concomitant high-dose statin therapy emerged as the primary predictor of LDL-C target attainment. Heterozygous familial hypercholesterolemia (HeFH), statin intolerance, and female gender were associated with a significant lower probability of achieving LDL-C target levels. Conclusions: Our analysis confirms that PCSK9mAb treatment is safe and effective, enabling 60% of our cohort to fully achieve the LDL-C guideline recommendations. The use of high-intensity statins emerged as a significant predictor of efficacy. Conversely, familial hypercholesterolemia and female gender were identified as predictors of therapeutic failure. Hence, it is crucial to address disparities in cardiovascular disease prevention between genders and to enhance strategies for managing elevated LDL-C in HeFH patients.

Diaphragmatic Ultrasound Predictors of High-Flow Nasal Cannula Therapeutic Failure in Critically Ill Patients With SARS-CoV-2 Pneumonia.

High flow nasal cannula (HFNC) is frequently used in patients with acute respiratory failure, but there is limited evidence regarding predictors of therapeutic failure. The objective of this study was to assess diaphragmatic ultrasound criteria as predictors of failure to HFNC, defined as the need for orotracheal intubation or death. Prospective cohort study including adult patients consecutively admitted to the critical care unit, from July 24 to October 20, 2020, with respiratory failure secondary to SARS-CoV-2 pneumonia who required HFNC. After 12hours of HFNC initiation we measured ROX index (ratio of SpO2 /FiO2 to respiratory rate), excursion and diaphragmatic contraction speed (diaphragmatic excursion/inspiratory time) by ultrasound, both in supine and prone position. In total, 41 patients were analyzed, 25 succeeded and 16 failed HFNC therapy. At 12hours, patients who succeeded HFNC therapy presented higher ROX index in supine position (9.8 [9.1-15.6] versus 5.4 [3.9-6.8], P < .01), and higher PaO2 /FiO2 ratio (186 [135-236] versus 117 [103-162] mmHg, P=.03). To predict therapeutic failure, the supine diaphragmatic contraction speed presented sensitivity of 89% and a specificity of 57%, while the ROX index presented a sensitivity of 92.8% and a specificity of 75%. Diaphragmatic contraction speed by ultrasound emerges as a diagnostic complement to clinical tools to predict HFNC success. Future studies should confirm these results.

(1,3)-β-D-glucan is able to predict therapeutic failure of patients with candidemia and not only mortality.

Candidemia is a major cause of bloodstream infection in tertiary hospitals worldwide and fungal biomarkers may provide early diagnosis. To evaluate the performance of (1-3)-β-D-glucan (BDG) in the diagnosis of candidemia and its ability to predict therapeutic failure. This was a prospective, multi-centre study conducted in 3 Brazilian hospitals. Clinical outcome was evaluated along 2weeks of treatment, and therapeutic failure was defined as the occurrence of persistent candidemia, Candida deep-seated infection or death. Baseline BDG detection was performed with the Fungitell® assay (Associates of Cape Cod, Falmouth-USA). We enrolled a total of 71 patients with candidemia and a control group with 110 healthy volunteers. The sensitivity and specificity of BDG for diagnosing candidemia were as follows: 71.8% (95% confidence interval [95% CI] 59.7% - 81.5%) and 98.2% (95% CI 92.9% - 99.7%), respectively. The only predictor of therapeutic failure was a higher BDG value at diagnosis of candidemia; a value>226pg/mL predicted failure with sensitivity and specificity of 75% and 78%, respectively. A high baseline serum BDG value was associated with therapeutic failure.

Endoscopic and histologic activity assessment considering disease extent and prediction of treatment failure in ulcerative colitis

Background and Aims DUBLIN score allows evaluation of disease activity and extent in ulcerative colitis (UC). This study aimed to evaluate DUBLIN score as a predictor of therapeutic failure as well as to associate endoscopic and histological activity scores to assess their joint performance. Methods Retrospective cohort study, with consecutive inclusion of patients undergoing total colonoscopy with serial biopsies between 2016 and 2019. DUBLIN score (0–9) was calculated as the product of Mayo endoscopic score (MSe 0–3) by disease extent (E1–E3). Histological activity was evaluated through Nancy score (0–4). Activity scores were correlated with biomarkers, treatment failure (therapeutic escalation, hospitalization and/or colectomy) and clinical remission at 6 months (Mayo partial score ≤ 1). Results One-hundred and seven patients were included. In 38.3% (n = 41) there was evidence of endoscopic activity (MSe ≥ 2) and in 50.5% (n = 54) histological activity (Nancy ≥ 2). MSe and DUBLIN scores showed good correlation (r = 0.943; p < .001) and both were significantly higher in patients with histological activity (p < .001). Therapeutic failure occurred in 25.2% (n = 27). MSe, DUBLIN, and Nancy scores were significantly associated with therapeutic failure (p < .001). The areas under the (AUC) ROC curve were 0.74 (MSe; p < .001), 0.78 (DUBLIN; p < .001) and 0.84 (Nancy; p < .001). Joint evaluation of endoscopic and histological activity by combining DUBLIN and Nancy scores was associated with therapeutic failure with a significantly higher AUC of 0.84 (p < .001) compared to the Dublin score alone (p = .003). Conclusion Mayo and DUBLIN endoscopic scores correlated with each other and with histological activity. The joint evaluation of endoscopic and histological activity allowed to predict with greater accuracy treatment failure.

P719 Effectiveness and safety of ustekinumab induction therapy in ulcerative colitis: A GETAID real-world cohort study

Abstract Background Phase III trials have demonstrated the efficacy and safety of ustekinumab in moderate-to-severe ulcerative colitis (UC), but no real-life data is currently available. Methods Between January and September 2019, all consecutive patients with UC treated with ustekinumab in 20 French GETAID centres were included. The primary outcome was steroid-free clinical remission (partial Mayo Clinic score ≤ 2) at weeks 12–16 without rectal bleeding subscore &amp;gt; 1. Results One hundred and three patients were included with a median age and disease duration of 39.3 [interquartile range (IQR), 29.1–52.3] and 7.6 [3.6–12.9] years, respectively. Most of the patients had left sided colitis (41.8%) or pancolitis (52.4%). History of immunomodulator, anti-TNF and vedolizumab therapies was noted in 84.5%, 99.0% and 85.4% of the cases, respectively. Steroid-free clinical remission and clinical remission rates were 35.0% and 39.8% at weeks 12–16, respectively. Normalisation of rectal bleeding and stool frequency (subscore 0 for both outcomes) was noted in 19.4% of patients whereas normalisation of rectal bleeding (subscore 0) with a stool frequency subscore of 0 or 1 was noted in 39.8%. Two patients discontinued ustekinumab before the weeks 12–16 visit and were referred to surgery. Predictors of therapeutic failure at weeks 12–16 were a partial Mayo Clinic score &amp;gt; 6 at week 0 (HR = 10.0, 95%CI [1.11––100.0], p = 0.04) and an history of previous use of anti-TNF and vedolizumab (HR = 33.3, 95%CI [2.4–100.0], p = 0.01). Improvement in endoscopic activity of UC at weeks 12–16 was observed according to Ulcerative Colitis Endoscopic Index of Severity (5.0 ± 1.2 vs. 3.8 ± 1.9, p &amp;lt; 0.001). Adverse events occurred in 7.8% and serious adverse events in 3.9%. Conclusion In this first real-life cohort study of refractory UC patients treated with ustekinumab, clinical remission without corticosteroids was observed in one-third of cases at weeks 12–16. Clinical severity and previous use of anti-TNF and vedolizumab were associated with therapeutic failure.

Predictors of therapeutic failure among patients with acute brucellosis treated by dual therapy with doxycycline‐rifampin

To determine the frequency of therapeutic failure among patients with acute and subacute brucellosis and to explore the predictors of failure. The study included 213 consecutive, naïve patients with acute and subacute brucellosis. All participants underwent clinical evaluation, chest radiography, stool microscopic examination and interferon-gamma release assay. Patients received the WHO-recommended therapy of doxycycline 200 mg/day and rifampin 900 mg/day, for 6 weeks. Mean age of the study population was 39.8 ± 12.2 years; 64.8% of them were males. The therapeutic failure rate was 16.4%. Adverse effects were reported by 13.1%. Multivariate analysis of factors associated with therapeutic failure revealed latent tuberculosis infection (LTBI) (OR 3.1, 95% CI, 1.9-24.6, P: 0.009), ascariasis (OR 2.6, 95% CI 1.5-17.9, P: 0.012), and the use of acid suppressive therapy (OR 2.1, 95% CI 1.2-19.5, P: 0.037) as the predictors of therapeutic failure. The prevalence of therapeutic failure among the Egyptian patients with acute/subacute brucellosis is increasing. Predictors of therapeutic failure are LTBI, ascariasis, and the use of acid suppressive therapy.

Predictors of therapeutic failure among naïve patients with pulmonary tuberculosis: contribution of diabetes mellitus and metformin therapy

Predictors of therapeutic failure among naïve patients with pulmonary tuberculosis: contribution of diabetes mellitus and metformin therapy

P572 Medical therapies for stricturing Crohn's disease: efficacy and cross-sectional imaging predictors of therapeutic failure

P572 Medical therapies for stricturing Crohn's disease: efficacy and cross-sectional imaging predictors of therapeutic failure

The -174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis.

Objective. To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results. Patients with MTX or LEF had significant decrement in DAS-28 (p < 0.001); nevertheless, only 14% and 12.5% achieved DAS-28 < 3.2 at 3 and 6 months. After 6 months with any of these drugs the -174G/G genotype carriers (56%) had higher risk of therapeutic failure compared with GC (RR: 1.19, 95% CI: 1.07–1.56). By analyzing each drug separately, after 6 months with LEF, GG genotype confers higher risk of therapeutic failure than GC (RR = 1.56; 95% CI = 1.05–2.3; p = 0.003), or CC (RR = 1.83; 95% CI = 1.07–3.14; p = 0.001). This risk was also observed in the dominant model (RR = 1.33; 95% CI = 1.03–1.72; p = 0.02). Instead, in patients receiving MTX no genotype was predictor of therapeutic failure. We concluded that IL-6 -174G/G genotype confers higher risk of failure in therapeutic response to LEF in Mexicans and if confirmed in other populations this can be used as promissory genetic marker to differentiate risk of therapeutic failure to LEF.

Predictors of nonresponse to intravenous immunoglobulin therapy in Kawasaki disease

PurposeIt has been reported that 10% to 20% of children with Kawasaki disease (KD) will not respond to intravenous immunoglobulin (IVIG) treatment. In this study, we aimed to identify useful predictors of therapeutic failure in children with KD.MethodsWe examined 309 children diagnosed with KD at the Kyungpook National University Hospital and the Inje University Busan Paik Hospital between January 2005 and June 2011. We retrospectively reviewed their medical records and analyzed multiple parameters in responders and nonresponders to IVIG.ResultsAmong the 309 children, 30 (9.7%) did not respond to IVIG. They had significantly higher proportion of neutrophils, and higher levels of aspartate aminotransferase, alanine aminotransferase (ALT), total bilirubin, and N-terminal fragment of B-type natriuretic peptide than did responders. IVIG-nonresponders had a significantly longer duration of hospitalization, and more frequently experienced coronary artery lesion, and sterile pyuria. No differences in the duration of fever at initial treatment or, clinical features were noted.ConclusionTwo independent predictors (ALT≥84 IU/L, total bilirubin≥0.9 mg/dL) for nonresponse were confirmed through multivariate logistic regression analysis. Thus elevated ALT and total bilirubin levels might be useful in predicting nonresponse to IVIG therapy in children with KD.

Esophageal Stasis on a Timed Barium Esophagogram Predicts Recurrent Symptoms in Patients With Long-Standing Achalasia

In achalasia, early recognition of the need for retreatment is of crucial importance to reduce morbidity and long-term complications such as esophageal decompensation. In clinical practice, symptoms and parameters of esophageal function including lower esophageal sphincter (LES) pressure and esophageal emptying are used to decide whether additional treatment is required. However, which of these tests performs best remains unclear. A cohort of 41 patients with long-standing achalasia (median 17 years), underwent esophageal manometry, timed barium esophagogram and symptom evaluation. Patients were followed up for 10 years, and were regarded as a therapeutic failure if Eckardt score was >3 or when retreatment was needed. Predictors of therapeutic failure were evaluated. Of the 41 included patients, 7 patients had an elevated LES pressure (>10 mm Hg) and 26 had esophageal stasis >5 cm on timed barium esophagogram. During follow-up, 25 patients had recurrence of symptoms and were considered therapeutic failures. Of the 25 patients, 5 had an elevated LES pressure, whereas 22 had esophageal stasis on barium esophagogram. Hence, the sensitivity to predict the need of retreatment is higher for esophageal stasis (88%) compared with LES pressure (20%). A total of 16 patients (39%) were in long-term remission, of which 12 patients (75%) did not have stasis at their initial visit. In contrast to LES pressure, esophageal stasis is a good predictor of treatment failure in patients with long-standing achalasia. Based on these findings, we propose to use timed barium esophagogram rather than esophageal manometry as test to decide on retreatment.

Early assessment of circulating tumor cell results in a community-based practice

621 Background: Circulating tumor cells (CTC) have been shown to aid in the therapeutic management of patients with metastatic breast cancer. We chose to validate this finding, compare performance to other commonly used biological markers and determine how best to utilize this diagnostic test in community-based practice. Methods: 50 women with met breast cancer (9% first, 26% second, and 53% third or later) (27% hormonal, 64% chemo) were followed for 8 months. 72% of the patients were ER/PR positive, 71% were Her-2 negative. Pt assessment was in Fairfax, VA. and blood shipped to Veridex for analysis using CellSearch. CellSearch is an automated system with anti-EPCAM coated iron particles to capture and enrich CTC. Captured events are imaged using an automated fluorescence microscope. True epithelial cells are DAPI positive (nuclear stain), cytokeratin 8,18 or 19 positive, and CD45 negative. Results: Results were analyzed in 2 ways: for concordance of CTC and CA 27.29 to the clinical decision, and for prediction of the pt’s response to therapy at the next assessment. 26 progressions were recorded by clinical exam. 50% of the samples analyzed had 0 cells, while 23% exceeded the cutoff of 5 CTC. Of the 18 positive CellSearch tests recorded during this study, 15 (83%) were true positives (sensitivity of 58%). 21 of 44 positive CA27.29 results were true positives (48%) for a sensitivity of 88%. The low number of false positive CTC results (3) compared to the relatively high number of false positive CA 27.29 results (23), resulted in a much higher positive predictive value (PPV) of CellSearch (83%) compared to CA 27.29 (48%). In comparing results to next patient visit, the resulting sensitivity, specificity, and PPV for CellSearch increased (72%, 100%, and 100% respectively) compared to the performance of CA 27.29, which remained unchanged (86%, 36%, and 40%). Conclusions: We conclude that the overall accuracy of the CellSearch CTC test compared to the CA 27.29 test (80% v 54%, p<0.01) makes CTC counts a more reliable indicator and predictor of therapeutic failure. Our results indicate that a CellSearch result greater than 5 CTC indicates therapeutic failure with high accuracy, whereas the high false positive rate of tumor markers makes them less reliable. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Veridex Veridex

Correlation of intrinsic chemoresistance of non-small-cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations.

At diagnosis, most small-cell lung cancers (SCLCs) are chemosensitive, whereas non-small-cell lung cancers (NSCLCs) are usually chemoresistant. Activation of ras genes and HER-2/neu genes (also known as ERBB2) is encountered in subpopulations of NSCLC but not in SCLC and has been linked to shortened survival. Therefore, activation of these genes may be associated with intrinsic chemoresistance in NSCLC. Studies have also suggested that the multidrug-resistant phenotype expressed by the MDR1 gene (also known as PGY1) does not correlate with the in vitro chemosensitivity of NSCLC cells or with clinical response to therapy and does not explain the spectrum of cross-resistance to drugs. The purpose of this study was to investigate the relationships between chemoresistance and the presence of ras gene point mutations and overexpression of the HER-2/neu gene in NSCLC cell lines, which indicates gene activation. Using a panel of 20 NSCLC cell lines established from untreated patients, we assessed the differences in HER-2/neu messenger RNA (mRNA) expression in the cell lines with or without ras mutations. We performed in vitro drug sensitivity testing by the tetrazolium-based MTT [i.e., 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H- tetrazolium bromide] assay with doxorubicin, carmustine, cisplatin, melphalan, mitomycin, and etoposide, and we determined the differences in IC50 values (i.e., the drug concentrations required to inhibit cell growth by 50%) for the cell lines. We found a statistically significant correlation between the IC50 values for all six drugs and the degree of HER-2/neu gene expression in all 20 cell lines (r = .67-.86; P < .005) as well as in the subpopulation of eight cell lines with ras mutations (r = .83-.98; P < .05). The IC50 values for doxorubicin, carmustine, cisplatin, and melphalan were not significantly different in the cell lines with or without ras mutations, but the values for mitomycin and etoposide in lines with ras mutations were slightly lower than in those without ras mutations (borderline significance, P = .031). Levels of HER-2/neu expression in cell lines with ras mutations were lower than those without ras mutations, but the difference was not statistically significant. Our findings indicate that overexpression of HER-2/neu is a marker for intrinsic multidrug resistance in NSCLC cell lines. If the clinical relevance of our findings is confirmed, HER-2/neu gene expression can be used as a predictor of therapeutic failure in NSCLCs. The relationships between HER-2/neu gene expression, cell proliferation, and chemoresistance in NSCLC require further investigation.