Patients Experiencing Treatment Failure Research Articles

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

Medium term (> 12 months) outcomes after laparoscopic hiatal hernia repair without conventional fundoplication using PH4B-mesh implant (Phasix™) in 176 reflux patients: experience and technique.

Hiatal mesh repair remains a controversial topic among anti-reflux surgeons. Biosynthetic mesh cruroplasty may prevent early recurrence while avoiding late esophageal erosion and strictures associated with non-resorbable materials. So far, medium-term results on hiatal PH4B (Poly-4-Hydroxybutyrate) mesh repair from high-volume centers are lacking. We analyzed the medium-term efficacy and safety of PH4B mesh cruroplasty in 176 consecutive patients (≥ 18years) with symptomatic hiatal hernias. Treatment failure was defined as the clinical recurrence of reflux symptoms. Patients could choose between mesh augmented hiatal repair (combined with a modified anterior hemifundoplication and fundophrenicopexy), Nissen fundoplication, and magnetic sphincter augmentation at their discretion. We also describe the surgical approach to mesh augmented hiatal repair used at our center. On average, patients were 55 (± 14) years old and followed up for 22 (± 7; sum: 3931) months. Treatment failed in 6/176 (3%, 95% CI: 2-7%) patients. The 24-month Kaplan-Meier failure estimate was 2.8% (95% CI: 0.4-5%). Each centimeter in hernia size increased the risk of failure by 52% (p = 0.02). Heavier patients (BMI > 27) had an 11% higher probability of clinical symptom recurrence (p = 0.03). The dysphagia and bloating/gas rate were 13/176 (7%), each. 8 (5%) patients required endoscopy due to dysphagia but without intervention. No serious complications, including mesh infection and erosion, or fatalities, occurred. Augmented PH4B mesh cruroplasty without conventional fundoplication shows excellent intermediate-term results in patients with reflux disease due to hiatal hernia. Around one in thirty patients experience treatment failure within 2years of surgery. Hernia size and overweight are key determinants of treatment failure.

Immunosuppressive agents for frequently relapsing/steroid-dependent nephrotic syndrome in children: a systematic review and network meta-analysis.

This study aimed to systematically compare the efficacy of various immunosuppressive agents in treating pediatric frequently relapsing or steroid-dependent nephrotic syndrome (FRSDNS). We conducted systematic searches of PubMed, Embase, the Cochrane Library, and the Web of Science up to May 23, 2023. Outcome measures included relapses within 1 year, mean cumulative exposure to corticosteroids, patients with treatment failure at 1 year, relapse-free survival during 1 year, and adverse events. The quality of the included studies was evaluated using the modified Jadad scale, the Methodological Index for Non-Randomized Studies (MINORS), and the modified Newcastle-Ottawa Scale (NOS). Rituximab was found to be the most likely (92.44%) to be associated with the fewest relapses within 1 year and was also most likely (99.99%) to result in the lowest mean cumulative exposure to corticosteroids. Rituximab had the highest likelihood (45.98%) of being associated with the smallest number of patients experiencing treatment failure at 1 year. CsA was most likely (57.93%) to achieve the highest relapse-free survival during 1 year, followed by tacrolimus (26.47%) and rituximab (30.48%). Rituximab showed no association with serious side effects and had comparable adverse effects to ofatumumab and tacrolimus. Rituximab may be the most favorable immunosuppressive agent for treating pediatric FRSDNS. Nephrologists should consider this drug, along with their clinical experience, patient characteristics, and cost considerations, when choosing a treatment approach.

Cellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) represents a paradigm for targeted differentiation therapy, with a minority of patients experiencing treatment failure and even early death. We here report a comprehensive single-cell analysis of 16 APL patients, uncovering cellular compositions and their impact on all-trans retinoic acid (ATRA) response in vivo and early death. We unveil a cellular differentiation hierarchy within APL blasts, rooted in leukemic stem-like cells. The oncogenic PML/RARα fusion protein exerts branch-specific regulation in the APL trajectory, including stem-like cells. APL cohort analysis establishes an association of leukemic stemness with elevated white blood cell counts and FLT3-ITD mutations. Furthermore, we construct an APL-specific stemness score, which proves effective in assessing early death risk. Finally, we show that ATRA induces differentiation of primitive blasts and patients with early death exhibit distinct stemness-associated transcriptional programs. Our work provides a thorough survey of APL cellular hierarchies, offering insights into cellular dynamics during targeted therapy.

Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations.

The combination of anti-CD38 monoclonal antibodies to a proteasome inhibitor, an immunomodulatory agent and dexamethasone (quadruplet-QUAD) in sequence with autologous stem cell transplantation (ASCT) leads to deep and durable responses in newly diagnosed multiple myeloma (NDMM). Disease progression in the first year post-QUADs is uncommon. We analysed 274 consecutive NDMM patients treated with QUADs + ASCT. After a median follow-up of 21.3 months, 20 patients had disease progression <18 months and 21 had progression ≥18 months after the onset of a QUAD regimen. All patients received subsequent anti-MM therapy, and 38 were evaluated for response. Nine (22.0%) received T-cell redirecting therapy as the next treatment, and 21 (51.2%) at some point in the treatment course. Response to next therapy was 26.3% for patients with progression <18 months and 52.6% for those with progression ≥18 months after the onset of a QUAD regimen. Median PFS on the next therapy was 2.5 months (95% CI 1.5-3.4) for those with progression <18 months and 7.0 months (95% CI 3.6-10.5) for those with progression ≥18 months. Efforts should focus on the early deployment of therapies with new mechanism of action for patients experiencing treatment failure after QUADs.

Long-term efficacy and safety of nonablative monopolar radiofrequency in the treatment of moderate to severe acne vulgaris.

Acne vulgaris (AV) is a prevalent skin condition known for its potential to cause scarring and psychological distress, often leading to diminished self-esteem. While topical and oral treatments are commonly prescribed, some patients experience treatment failure, adverse effects, or contraindications to conventional therapies. In response to these challenges, laser and energy-based device therapies have emerged as promising alternatives for individuals who fall into these categories, showing considerable potential in the treatment of AV. This study aimed to evaluate the long-term efficacy and safety of a nonablative monopolar radiofrequency (NMRF) in treatment of moderate to severe AV. Twenty-four patients with moderate to severe AV underwent a series of two NMRF treatment sessions, spaced 4 weeks apart. To evaluate treatment outcomes, live in-person lesion counts and measurements of pore size and volume, and sebum production were quantified using Antera® 3D imaging system, and Sebumeter®, respectively. Patients' self-assessment data regarding degree of improvement and facial oiliness were gathered. Dermatology life quality index (DLQI) questionnaire was utilized to assess the impact of AV on their quality of life. All objective and subjective evaluations were conducted at the baseline, 1 month after the first treatment, and during follow-up visits 1, 3, and 6 months after the last treatment sessions. Adverse effects were also recorded during each visit. Twenty out of the 24 subjects completed the study protocol. The mean inflammatory lesion counts significantly reduced by 42.86% and 45.71% from the baseline at 3 (p = 0.027) and 6 months (p = 0.032) after the second treatment. Sebum excretion likewise significantly decreased from baseline by 11.62% (p = 0.012), 13.37% (p < 0.001), and 21.51% (p = 0.004), 1 month after the first treatment, 1 and 6 months after the second treatment, respectively. The pore volume continued to decrease by 35% (p = 0.003) and 41.5% (p < 0.001) at 1 and 6 months following the final treatment, respectively. The DLQI significantly decreased from 10.00 (interquartile range [IQR]: 6.50-15.00) to 2.00 (IQR: 1.00-4.75), corresponding to 80% improvement of the index, 1 month after the last treatment and was sustained up to the last follow-up visit. Patients' self-assessments on degree of improvement and facial oiliness also significantly improved following NMRF treatments. The treatments were well-tolerated without significant adverse effects. NMRF appears to be an effective and safe treatment for inflammatory AV, with therapeutic outcomes persisting up to 6 months after two treatment sessions.

Estimating surgical probability: Development and validation of a prognostic model for patients with lumbar disc herniation treated with acupuncture.

Lumbar disc herniation (LDH) is a common cause of pain in the lumbar spine and legs. While acupuncture has become the primary conservative treatment for LDH, some patients experience treatment failure and require surgery, causing substantial concern for clinicians. We developed an effective personalized clinical prediction model to identify the independent risk factors associated with acupuncture failure in patients with LDH. Our model aimed to predict the probability of surgery within 6 months of acupuncture failure in patients with LDH. A total of 738 patients with LDH who underwent acupuncture at 4 Chinese hospitals between January 2019 and October 2021 were selected. The patients were divided into training (n = 496) and validation (n = 242) cohorts. Seven predictive variables, including smoking, Oswestry Disability Index (ODI) score, lower-limb herniation, disc herniation type, lumbar spinal stenosis, lumbar lateral recess stenosis, and acupuncture frequency, were selected as risk factors using least absolute shrinkage and selection operato (LASSO) regression. A prediction model was developed using multivariate logistic regression analysis and a nomogram was constructed. The model exhibited good discrimination, with an area under the ROC curve (AUC) of 0.903 for the development cohort and 0.899 for the validation cohort. The Hosmer-Lemeshow goodness-of-fit test was a good fit for both cohorts (P = .956 for the development cohort; P = .513 for the validation cohort). Decision curve analysis (DCA) demonstrated that the threshold probabilities for the 2 cohorts ranged from > 4% and 5-95%, respectively. Therefore, the prediction model had a good net benefit. The nomogram established in this study, incorporating 7 risk factors, demonstrated a good predictive ability. It could predict acupuncture failure in LDH patients and the risk of surgery within 6 months, enabling physicians to conduct individualized treatment measures.

The Cellular and Protein Arms of Coagulation in Diabetes: Established and Potential Targets for the Reduction of Thrombotic Risk.

Diabetes is a metabolic condition with a rising global prevalence and is characterised by abnormally high blood glucose levels. Cardiovascular disease (CVD) accounts for the majority of deaths in diabetes and, despite improvements in therapy, mortality and hospitalisations in this cohort remain disproportionally higher compared to individuals with normal glucose metabolism. One mechanism for increased CVD risk is enhanced thrombosis potential, due to altered function of the cellular and acellular arms of coagulation. Different mechanisms have been identified that mediate disordered blood clot formation and breakdown in diabetes, including dysglycaemia, insulin resistance, and metabolic co-morbidities. Collectively, these induce platelet/endothelial dysfunction and impair the fibrinolytic process, thus creating a prothrombotic milieu. Despite these abnormalities, current antithrombotic therapies are largely similar in diabetes compared to those without this condition, which explains the high proportion of patients experiencing treatment failure while also displaying an increased risk of bleeding events. In this narrative review, we aimed to summarise the physiological functioning of haemostasis followed by the pathological effects of diabetes mellitus on platelets and the fibrin network. Moreover, we carefully reviewed the literature to describe the current and future therapeutic targets to lower the thrombosis risk and improve vascular outcomes in diabetes.

GTN Enhances Antitumor Effects of Doxorubicin in TNBC by Targeting the Immunosuppressive Activity of PMN-MDSC.

(1) Background: Immunosuppression is a key barrier to effective anti-cancer therapies, particularly in triple-negative breast cancer (TNBC), an aggressive and difficult to treat form of breast cancer. We investigated here whether the combination of doxorubicin, a standard chemotherapy in TNBC with glyceryltrinitrate (GTN), a nitric oxide (NO) donor, could overcome chemotherapy resistance and highlight the mechanisms involved in a mouse model of TNBC. (2) Methods: Balb/C-bearing subcutaneous 4T1 (TNBC) tumors were treated with doxorubicin (8 mg/Kg) and GTN (5 mg/kg) and monitored for tumor growth and tumor-infiltrating immune cells. The effect of treatments on MDSCs reprogramming was investigated ex vivo and in vitro. (3) Results: GTN improved the anti-tumor efficacy of doxorubicin in TNBC tumors. This combination increases the intra-tumor recruitment and activation of CD8+ lymphocytes and dampens the immunosuppressive function of PMN-MDSCs PD-L1low. Mechanistically, in PMN-MDSC, the doxorubicin/GTN combination reduced STAT5 phosphorylation, while GTN +/- doxorubicin induced a ROS-dependent cleavage of STAT5 associated with a decrease in FATP2. (4) Conclusion: We have identified a new combination enhancing the immune-mediated anticancer therapy in a TNBC mouse model through the reprograming of PMN-MDSCs towards a less immunosuppressive phenotype. These findings prompt the testing of GTN combined with chemotherapies as an adjuvant in TNBC patients experiencing treatment failure.

Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia

To evaluate the clinical efficacy and safety of decitabine combined with modified CAG regimen (D-CAG regimen) in patients aged ≥70 years with newly diagnosed acute myeloid leukemia (AML). The clinical data of 59 AML patients (≥70 years old) who were newly diagnosed and treated in the Hematology Department of the First Affiliated Hospital of Nanjing Medical University from November 2010 to June 2021 were retrospectively analyzed. Among the 59 AML patients, 28 were males and 31 were females, with a median age of 74 (70-86) years. The complete remission (CR) rate was 69.4% (34/49), and the median duration of CR was 10.7 (0.6-125.4) months after 2 courses of D-CAG treatment. According to the British Medical Research Council (MRC) classification, there was only one patient in the favorable-risk group, and the CR rate was 71.8% (28/39) in the intermediate-risk group, and 55.6% (5/9) in the adverse-risk group, respectively. There was no statistical difference in the CR rate between the intermediate-risk and adverse-risk group. Referring to ELN 2017 genetic risk classification, CR rate was 88.2% (15/17) in the favorable-risk group, 45.5% (5/11) in the intermediate-risk group, and 66.7% (14/21) in the adverse-risk group. There was no significant difference in CR rate between the favorable-risk and adverse-risk categories, but both were significantly higher than that in the intermediate-risk group (P <0.05). Next-generation sequencing (NGS) analysis showed that 11 gene mutations with a frequency of more than 10%, including TET2 mutation (35.6%), ASXL1 mutation (30.5%), NPM1 mutation (28.8%), FLT3-ITD mutation (27.1%), DNMT3A mutation (22.0%), IDH1 mutation (15.3%), CEBPA single mutation (13.6%), TP53 mutation (13.6%), IDH2 mutation (11.9%), RUNX1 mutation (11.9%), and NRAS mutation (10.2%). There were no statistical differences in mutation frequency of these 11 genes between CR group and non-CR group. Compared with normal karyotypes, patients with complex karyotypes were more likely to develop TP53 mutations (P <0.001), while FLT3-ITD and DNMT3A mutations were more likely to occur in patients with normal karyotypes (P =0.04, P =0.047). The median follow-up, overall survival (OS), and event-free survival (EFS) of all the patients was 11.7 (1.5-128.2) months, 12.3 (1.5-128.2) months, and 8.5 (1.5-128.2) months, respectively. The median OS and EFS of CR patients were 19.8 and 13.3 months, respectively, which were significantly longer than 6.4 and 5.7 months in patients experiencing treatment failure (P < 0.001, P =0.009). In regard to genes with mutation frequency >10%, there were no statistical differences in CR rate, median OS, and median EFS between mutated and wild-type patients by Chi-square test and survival analysis. Univariate analysis showed that age, hemoglobin, lactate dehydrogenase, cytogenetics and CR were factors affecting prognosis, while multivariate analysis showed that only CR failure was an independent adverse prognostic factor for OS. The major adverse reactions to D-CAG regimen were grade 3-4 myelosuppression, pulmonary infection, and fever (infection focus was not identified). D-CAG regimen is safe and effective in the treatment of AML patients ≥70 years old, and can partially improve the prognosis of elderly and high-risk patients.

Abstract 1757: Characterizing novel immunomodulating interactions for potentiating HDAC3 inhibition in non-Hodgkin lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and represents a highly heterogeneous and aggressive disease. Up to 40% of all DLBCL patients experience treatment failure after the standard immunochemotherapy R-CHOP. Defining novel therapeutic strategies is therefore a pressing need. Reduced acetylation at histone 3 lysine 27 (H3K27ac) represents a pathogenetic hallmark of DLBCL and selective histone deacetylase 3 inhibition (HDAC3i) has recently emerged as a viable strategy to reverse abnormal epigenetic signatures and induce strong anti-tumor effects by increasing H3K27ac. Despite this compelling rationale, the overall response remains suboptimal, suggesting unrecognized mechanisms of resistance. To unbiasedly uncover sensitizers, we performed a genome-wide CRISPR screen and identified knockout (KO) of the top candidate GNAS (encoding G-protein α subunit, Gαs) for sensitizing resistant DLBCL cells to HDAC3i. The sensitizing effects on reduced viable cell number were only observed in GNAS KO cells treated with HDAC3i, but not in the control cells (“synthetic lethality”). We have validated this sensitizing phenotype in multiple resistant cell lines including three human DLBCL cell lines and one mouse B-cell lymphoma cell line. Interestingly, we showed that the sensitization was not related to the canonical G-protein functions but to novel regulatory mechanisms in viral mimicry activation and chromatin modification. Compared with the control conditions, the interaction between GNAS KO and HDAC3i has been linked with differential chromatin accessibility and endogenous retrovirus expression, upregulated double-stranded RNA expression, and increased phosphorylation of TBK1 whose activation plays a vital role in antiviral immune responses. Strikingly, a selective TBK1 degrader completely and specifically rescued the sensitizing phenotype in GNAS KO cells treated with HDAC3i, confirming the critical role of TBK1 in inducing sensitization. Furthermore, we identified potential immune interactions by exploring the clinical data from tumor samples of 309 DLBCL patients that low GNAS expression was correlated with cytokine and inflammatory signaling as well as stromal cell interactions in the tumor microenvironment, altogether associated with longer overall survival. These observations were aligned with our results in the mouse xenograft and allograft tumor experiments that GNAS KO with/without HDAC3i led to differential phenotypes. Overall, our research uncovers novel immunomodulating activities for potentiating the efficacy of epigenetic agents in non-Hodgkin lymphoma. This expands our understanding of novel interactions between immune and epigenetic regulation in lymphoma biology and provides new therapeutic opportunities for patients with resistant lymphoma who have poor prognoses and limited treatment options. Citation Format: Michael Y. He, Kit I. Tong, Mehran Bakhtiari, Ryder Whittaker Hawkins, Ting Liu, Yong Zeng, Noorhan Ghanem, Housheng Hansen He, Robert Kridel. Characterizing novel immunomodulating interactions for potentiating HDAC3 inhibition in non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1757.

PD25-08 THE BLADDER TUMOR MICROBIOME MAY AUGMENT RESPONSE TO BCG IN NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023PD25-08 THE BLADDER TUMOR MICROBIOME MAY AUGMENT RESPONSE TO BCG IN NON-MUSCLE INVASIVE BLADDER CANCER Zaeem Lone, Jacob Knorr, Glenn Werneburg, Ava Adler, Jose Agudelo, Rebecca Campbell, Petar Bajic, Nima Almassi, Christopher Weight, Georges Pascal-Haber, Aaron Miller, and Byron Lee Zaeem LoneZaeem Lone More articles by this author , Jacob KnorrJacob Knorr More articles by this author , Glenn WerneburgGlenn Werneburg More articles by this author , Ava AdlerAva Adler More articles by this author , Jose AgudeloJose Agudelo More articles by this author , Rebecca CampbellRebecca Campbell More articles by this author , Petar BajicPetar Bajic More articles by this author , Nima AlmassiNima Almassi More articles by this author , Christopher WeightChristopher Weight More articles by this author , Georges Pascal-HaberGeorges Pascal-Haber More articles by this author , Aaron MillerAaron Miller More articles by this author , and Byron LeeByron Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003303.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intravesical installation of BCG has been the gold standard for the management of non-muscle invasive bladder cancer (NMIBC). However, approximately 30-40% of patients experience treatment failure and it remains unclear who will benefit from this therapy. One potential modifiable factor in treatment response may be the urinary microbiome. Therefore, we sought to investigate how the urinary microbiome may differ between BCG responders and non-responders and identify any commensal bacteria that might increase the efficacy of this therapy. METHODS: 16S next-generation sequencing (NGS) and shotgun metagenomics were performed on formalin-fixed bladder tumors from patients prior to intravesical BCG therapy for NMIBC. BCG responders was defined as no recurrence two years after induction. Differences in the alpha and beta diversity of the two populations were compared. Subsequently, to validate the NGS data, GFP-tagged BCG was co-cultured with a urothelial carcinoma (UC) cell line (SW780) and candidate bacteria based on the NGS data. A Pearson-Chi Square test was utilized to compare percent internalization. Additionally, fresh tumor samples were collected at the time of transurethral resection of bladder tumor (TURBT) and were cultured in five different media conditions to confirm the viability of the tumor microbiome and quantify the bacterial mass per sample. RESULTS: Forty-seven patients (23 responders, 24 non-responders) were included in the analysis. Overall microbiome composition differed significantly as determined by both NGS (p=0.042) and shotgun metagenomics (p=0.047). Lactobacillus spp were significantly enriched in the BCG responders. Co-culture with increasing concentrations of Lactobacillus crispatus resulted in increased BCG-GFP internalization in UCC (179/1133, 16%) when compared to controls (75/1166, 6%) (p<0.001). Additionally, from ten fresh tumor samples, four samples produced viable bacteria through culture-based approaches and we calculated tumor bacterial density at 1.25×106 colony forming units/gram of tissue. CONCLUSIONS: A compositional difference exists in the tumor microbiome of BCG responders and non-responders. Lactobacillus crispatus was associated with a significant increase in the internalization of BCG. Our findings suggest that an association exists between the tumor microbiome and response to BCG, which may offer new strategies to improve intravesical therapy for NMIBC patients. Source of Funding: Case Comprehensive Cancer Center Summer Medical Student Award © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e732 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zaeem Lone More articles by this author Jacob Knorr More articles by this author Glenn Werneburg More articles by this author Ava Adler More articles by this author Jose Agudelo More articles by this author Rebecca Campbell More articles by this author Petar Bajic More articles by this author Nima Almassi More articles by this author Christopher Weight More articles by this author Georges Pascal-Haber More articles by this author Aaron Miller More articles by this author Byron Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

Correlation between assessment of cytochrome P450 1A2 activity and enzyme activity scores, and their relation to clozapine exposure.

Cytochrome P450 1A2 (CYP1A2) is involved in the metabolism of antipsychotic drugs such as clozapine and olanzapine. Personalization of these treatments requires an accurate estimation of CYP1A2 activity. In this study, we aimed (1) to evaluate the correlation between activity score (AS), covariate-corrected activity score (CCS) and the phenotype of CYP1A2 using a caffeine test probe and (2) to investigate their relationship with dose-adjusted clozapine concentrations in a subgroup of the cohort. A multicentric, retrospective and observational study was carried out in the French university hospitals of Marseille and Tours. CYP1A2 activity was calculated by the paraxanthine/caffeine (17X/137X) ratio determined 4h after an oral intake of 100 mg caffeine. AS was calculated according to the CYP1A2*1F alleles. CCS was calculated according to the CYP1A2*1F alleles, smoking status and the presence of concomitant inhibitors. As expected, among the 89 patients included, the 17X/137X ratio was significantly higher in patients who smoked. We found a significant but modest correlation between the 17X/137X ratio and CCS (R2 = 0.3, P = 1.74 × 10-8 ) but none between the 17X/137X ratio and AS (R2 = -0.007, P = 0.52). AS was not correlated with dose-adjusted clozapine levels, contrary to CCS (R2 = 0.19, P = 0.016) and especially the 17X/137X ratio (R2 = 0.42, P = 1.7 × 10-5 ). Correlation with clozapine concentrations showed the advantage of the 17X/137X ratio over the CCS in clozapine dose optimization. CYP1A2 activity, especially when determined by the caffeine probe, may be used to personalize clozapine dosing for patients experiencing treatment failure.

Approximately One Half of Patients Greater Than 40 Years Old Achieve Patient Acceptable Symptomatic State 6 Months After Arthroscopic Partial Meniscectomy

The purposes of this study were to 1) calculate the minimal clinically important difference (MCID) in a population of patients undergoing arthroscopic partial meniscectomy (APM) based on Knee Injury and Osteoarthritis Outcomes Scores (KOOS), 2) quantify the difference between the proportion of patients reaching MCID based on KOOS versus the proportion who considered surgery to be successful based on a "yes" answer to a patient acceptable symptom state (PASS) question, and 3) calculate the percentage of patients experiencing treatment failure (TF). A large, single-institution clinical database was queried for patients undergoing isolated APM (>40 years of age). Data were collected at regular time intervals, including KOOS and PASS outcome measures. Calculation of MCID using a distribution-based model was performed using preoperative KOOS scores as baseline. Comparison of the proportion of patients surpassing MCID was made to the proportion of patients answering "yes" to a tiered PASS question at 6 months after APM. Proportion of patients experiencing TF was calculated using patients who responded "no" to a PASS question and "yes" to a TF question. Three-hundred and fourteen of 969 patients met inclusion criteria. At 6 months following APM, the percentage of patients meeting or exceeding the MCID for each respective KOOS subscore ranged from 64 to 72% compared to 48% who achieved a PASS (P < .0001 for each subscore). Fourteen percent of patients experienced TF. Six months after APM, approximately one half of the patients achieved a PASS and 15% experienced TF. The difference between achieving MCID based on each of the KOOS subscores and achieving success via PASS ranged from 16% to 24%. Thirty-eight percent of patients undergoing APM did not fit neatly into overt success or failure categorization. Level III, retrospective cohort study.

Early and Deep Molecular Responses Achieved with Frontline Asciminib in Chronic Phase CML - Interim Results from ALLG CML13 Ascend-CML

ATP-competitive BCR::ABL1 inhibitors are effective as frontline treatment for many Chronic Phase (CP) CML patients. However, a significant minority of patients experience treatment failure with currently available drugs, due to resistance or toxicities. Asciminib, a first-in-class drug that inhibits BCR::ABL1 by binding to its myristoyl site, is efficacious in patients who have failed 2 or more lines of treatment (Rea et al, Blood 2021). The Australasian Leukaemia Lymphoma Group (ALLG) CML13 ASCEND-CML trial aims to assess its tolerability and efficacy in the frontline setting. ALLG CML13 is a prospective open-label phase II study, enrolling 100 patients over 15 Australian and New Zealand sites. Patients commence treatment with asciminib 40mg twice a day (BID), and are assessed thereafter according to optimal 2020 ELN targets (BCR::ABL1 ≤10%, ≤1% & ≤0.1% at 3, 6, 12 months respectively); and ≤0.01% at 18 months. Patients with treatment failure (BCR::ABL1 >10% at 3 or 6 months; BCR::ABL1 >1% at 12 or 18 months) continue asciminib and add either imatinib, dasatinib or nilotinib, according to physician preference. Patients who have not failed, but have not achieved optimal response at 6, 12, or 18 months, have their asciminib dose doubled to 80mg BID. Co-primary end points are achievement of early molecular response (EMR, BCR::ABL1 ≤10% at 3 months) and major molecular response (BCR::ABL1 ≤0.1%) by 12 months. We report a protocol-specified interim analysis of EMR that allows for reporting of repeated confidence intervals. This trial received funding support from Novartis. By data cut-off at July 15, 2022, the trial remains open to recruitment with 79/100 patients registered, with a median follow-up of 10 (0-19) months. The most commonly reported grade 3/4 adverse events thus far were neutropenia, and thrombocytopenia (n=5 and 4, 5.5% and 5.2%, respectively); as well as increased lipase and amylase without clinical pancreatitis (n=6 & 2; 7.8% & 2.6%, respectively). Grade 3 increased AST/ALT, anaemia, back pain, abdominal pain and infection were each reported once. Nine patients have discontinued asciminib: 1 with persistent grade 4 cytopenia requiring HSCT, 4 with recurrent asymptomatic lipase elevations (including 1 patient who registered but had not started therapy), 1 withdrawn consent and 1 lost to follow-up. Two patients had resistance: 1 had confirmed loss of MMR at 9 months after reaching a nadir of 0.067% at 6 months, without evidence of a kinase domain or myristoyl site mutation; 1 transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T (40%), A337V (10%) and P465S (10%), having previously achieved BCR::ABL1 of 0.37% at 3 months. The molecular analysis for EMR includes all registered patients with at least 3 months of follow-up (n=63); 1 patient missed this assessment, and 3/63 patients had withdrawn by this timepoint (all 4 scored as non-responders). EMR was achieved by 59/63 (93.7%; 99.1% CI 81.1-98.9%). By 3 months, 11 patients have already achieved MR4 or better; 29/63 patients achieved MMR (Fig 1 & 2). Three patients had asciminib dose escalation on protocol: 1 patient with BCR::ABL1 of 1.1% at 6 months, and 2 with BCR::ABL1 of 0.34% and 0.43% at 12 months; subsequent molecular results are pending. Trial interim analysis suggest asciminib to have favorable tolerability and efficacy as frontline treatment for CP-CML. The EMR rate is particularly encouraging, and is likely to translate to improved long term outcomes, with higher achievement of deep molecular responses and potentially treatment-free survival. Equally encouraging is the safety profile and early discontinuation rate. Cytopenia and lipase elevations were the most common adverse events, and appear to be ABL1 inhibitor class effects, though clinically relevant pancreatitis has not occurred. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pre-Radiation CT-Based Radiomic Features Predict Locoregional and Distant Failure in Locally Advanced Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Locally advanced head and neck cancer treatment often involves aggressive multimodal therapy. While outcomes have improved in certain groups (HPV-positive disease), locoregional (LRF) and distant failure (DF) remain persistent problems. Accurate prediction of these risks would provide vital clinical insight; for instance, a patient with low LRF risk could be de-escalated, while a patient at high-risk for DF could be offered systemic options in lieu of aggressive local therapy. In this study we explore the use of CT-based radiomic features (quantitative sub-visual cues) for this purpose. <h3>Materials/Methods</h3> We identified patients with primary or recurrent locally advanced head/neck cancer treated between 2014-2020 who received a definitive or adjuvant RT course (naïve to RT prior). Histologies included squamous cell carcinoma (SCC), poorly differentiated carcinoma (nasopharyngeal or salivary origin), high-risk parotid malignancies, and skin SCC metastatic to the parotid/neck. Patients had at least 12 months of follow-up and charts were assessed for LRF and DF. CT simulation images were extracted from our treatment planning system, and specific contoured regions of interest (ROIs) were selected including the peritumoral region or post-surgical tumor bed (high-risk clinical tumor volume, CTV HR) and involved/elective neck levels (CTV Necks). CT scans were resampled to be isotropic and 3D radiomic features (Gabor wavelet, Hara lick, and CoLlAGe) were extracted from within CTV HR and CTV Necks ROIs. Using a Wilcoxon rank sum test, differential expression for each feature was calculated between patients experiencing treatment failure (LRF and DF) and those with no evidence of disease progression. A similar process was done with baseline clinical features including performance status, tumor stage, age, p16 status and smoking history. Where required, a chi-squared test was used for categorical clinical variables. <h3>Results</h3> 95 patients were analyzed (45 definitive, 50 adjuvant). There were 17 LRF (17.9%) and 16 DF (16.8%) events. 304 radiomic features were extracted from CTV HR and CTV Necks (the latter was only performed for patients with bilateral neck contours). 2 features extracted from CTV HR ROIs were significantly associated with LRF and 29 features with DF (p < 0.05). 30 features extracted from CTV Necks ROIs were significantly associated with LRF and 0 features with DF (p < 0.05). There were no statistically significant clinical features associated with LRF or DF. <h3>Conclusion</h3> CT-based radiomic features derived from specific ROIs in simulation images were associated with both LRF and DF events, which was not the case for canonical clinical features. Interestingly, the CTV HR was more prominently associated with DF, whereas the CTV Necks was associated with LRF. Further studies with larger, more diverse datasets are needed to refine this model and provide a path for clinical validation.

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Emulating a Target Trial of Dynamic Treatment Strategies for Major Depressive Disorder Using Data From the STAR∗D Randomized Trial

BackgroundClinical guidelines recommend adding a second drug for patients with major depressive disorder who have a partial response and switching antidepressants for those who show no response or intolerance. This guidelines-based strategy was compared with other strategies for the management of unresponsive depression. MethodsA total of 1436 individuals experiencing treatment failure with citalopram and still requiring antidepressant therapy were identified in the STAR∗D (Sequenced Treatment Alternatives to Relieve Depression) trial. A (hypothetical) target trial was then designed and emulated. The following strategies for decision making were compared: sequential monotherapy, sequential dual non–selective serotonin reuptake inhibitor therapy (SD), and a guidelines-based strategy. The primary outcome was symptomatic remission defined as a Hamilton Depression Rating Scale score ≤7 or 2 consecutive scores ≤5 on the 16-item Quick Inventory of Depressive Symptomatology–Clinician Rated. Secondary outcomes were serious events (hospitalizations, suicide, and mortality). Inverse probability weighting was used to control for possible confounding. ResultsA total of 971 patients were eligible for our emulation. Patients initiating SD had the lowest levels of depression at baseline. The estimated 9-month probability of remission was 43.5% for the sequential monotherapy group, 47.6% for the SD group, and 53.2% for the guidelines-based strategy group. Compared with the sequential monotherapy group, the difference in 9-month probability of remission was −4.2% (95% CI, −15.6 to 4.6) for the SD group and −9.7% (−19.3 to 1.9) for the guidelines-based strategy group. The 9-month relative risks of remission were 1.09 (0.90 to 1.38) and 1.22 (0.96 to 1.46), respectively. Results were consistent across sensitivity analyses. The 9-month relative risks of serious events were 0.77 (0.38 to 1.40) and 0.62 (0.33 to 1.00), respectively. ConclusionsUsing the guidelines-based strategy was associated with an increased probability of remission and a lower risk of serious adverse events. The potential implications are substantial given the large number of patients experiencing treatment failure to antidepressants.

Primary extranodal diffuse large B‐cell lymphoma: Molecular features, treatment, and prognosis

AbstractDiffuse large B‐cell lymphoma (DLBCL) is the most common subtype of non‐Hodgkin's lymphoma and represents a heterogeneous entity. One‐third of DLBCL arises from extranodal organs and its prognosis often varies with regard to the sites involved. Molecular features are important to elucidate the differences in clinical features, predict the disease prognosis, and improve effective targeted therapeutic strategies. Extranodal DLBCLs originated from the breast, skin, uterus, immune‐privileged sites such as the central nervous system and testes, often show a high proportion of non‐germinal center B‐cell‐like (non‐GCB) phenotypes, with a high frequency of MYD88/CD79B mutations. In contrast, extranodal DLBCLs originated from the thyroid gland and stomach show a relatively low proportion of non‐GCB phenotype, with a considerably excellent prognosis. Immunochemotherapy with rituximab is the standard of care in both nodal and extranodal DLBCLs. However, approximately 40% of the patients experience treatment failure. It is critical to optimize the treatment strategy, including radiotherapy, autologous stem cell transplantation and targeted therapy according to the clinical characteristics and molecular heterogeneity. In this review, we present an overview of the key molecular pathways, prognosis assessment and innovative therapies in primary extranodal DLBCLs.

Long-term outcomes and circulating tumor DNA analysis from a phase I/II study of lenalidomide and obinutuzumab with CHOP for newly diagnosed diffuse large B-cell lymphoma.

7553 Background: Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP), but a third of patients (pts) experience treatment failure. Randomized trials comparing RCHOP with modified regimens, including replacing R with obinutuzumab (O, CD20 antibody, Vitolo JCO 2017) and adding lenalidomide (L) to RCHOP (Nowakowski JCO 2021), have not significantly improved outcomes. The combination of L and O may have synergy via an enhanced NK-cell mediated antibody dependent cellular cytotoxicity. We hypothesized combining L and O with CHOP (LOCHOP) would be an effective and well tolerated treatment of DLBCL. Methods: In this single center phase Ib/II study (NCT02529852) pts with untreated CD20+ DLBCL received 6 cycles of CHOP with O 1000mg IV on days (D) 1, 8, and 15 during cycle 1 and D1 during cycles 2-6, and L 15 mg orally on D1-14 of each cycle. Growth factor and thromboembolism prophylaxis were mandated. The primary objectives were to determine the maximum tolerated dose (MTD) of L and efficacy of LOCHOP. Plasma samples were collected for circulating tumor DNA (ctDNA) analysis. Results: Fifty-three pts were enrolled, 6 in phase Ib and 47 in phase II. No dose limiting toxicities were experienced in phase Ib at an MTD of 15 mg of L. Median age was 62 years, 35 (66%) pts had stage III/IV disease, 12 (23%) an IPI &gt; 2, and 26 (49%) and 22 (42%) were germinal center (GC) and non-GC subtype (5 not classified) by Hans algorithm. At end of therapy, 50 pts were evaluable, overall response: 49 (98%), complete response: 45 (90%). Median follow up was 4.5 years and 4-year progression free and overall survival rates were 87.4% and 91.3%. No characteristics were associated with differences in outcomes. Any grade and grade 3-4 adverse events (AEs) were experienced by 100% and 70% of pts. Grade 3-4 AEs included neutropenia (38%), thrombocytopenia (17%), fatigue (13%), neutropenic fever (13%), and infection (9%). Four (8%) pts developed venous thromboembolism. At study entry, 31/33 (94%) profiled pts had detectable ctDNA with CAPP-Seq, 24% had high ctDNA ( &gt; log 2.5 hGe/ml) and 24/31 (77%) were evaluable by LymphGen classifier: molecular subtypes included EZB (5, 21%), ST2 (5, 21%), MCD (4, 17%), and other (9, 38%). All 5 EZB and 4/5 ST2 pts were GC subtype while 2/4 MCD pts were non-GC (1 GC, 1 not classified). With LOCHOP, 13/18 (72%) and 11/15 (73%) pts achieved early and major molecular response (Kurtz JCO 2018). By PhasED-Seq (Kurtz Nat Biotechnol 2021), 16/18 (89%) had no detectable ctDNA after ≥5 cycles. Conclusions: LOCHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA. Noninvasive molecular subtyping is feasible as a supplement to tissue diagnosis and should be incorporated in future studies aiming to improve on RCHOP. Clinical trial information: NCT02529852.