Worst Treatment Research Articles

W141 - Positive Methamphetamine Urinalysis Result During Treatment Intake is Not Associated With Worst Treatment Outcomes Amongst Opioid Users Initiating Medication-Assisted Opioid Treatment in Rural Communities

W141 - Positive Methamphetamine Urinalysis Result During Treatment Intake is Not Associated With Worst Treatment Outcomes Amongst Opioid Users Initiating Medication-Assisted Opioid Treatment in Rural Communities

NEMESIS - EXAMPLE OF OPEN ACCESS JOURNAL PROMOTING NEGATIVE RESULTS IN SCHOLARLY PUBLICATIONS

Nemesis (Negative Effects in MEdical ScIenceS) is peer-reviewed, free, open-access scientific University-founded journal (UCLouvain, Belgium in 2018). Currently most of the scientific journals accept to publish only ”positive effects”of experimental and clinical research. Only successful studies have the right to be published and cited. However, positive effects in research are frequently achieved after years of negative results. The negative results should also be accessible for scientific community as they represent the main source of progress, of inspiration, and of hope. In the open access journal all content is freely available without charge to the user or his/her institution. Users are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. There are no charges for authors neither for readers. Nemesis is using creative common license CC-BY-SA. The peer-review is performed by the Editorial Board. Nemesis accepts for publication: original contribution in the field of oral and craniomaxillofacial surgery, three-dimensional cone beam computed tomography (CBCT) dentomaxillofacial imaging, and physical anthropology and archaeology around the head. The first scope of Nemesis is to accept studies providing with negative results obtained after applying a correct methodology. Nemesis journal accepts also studies describing complications and their management, the worst cases, diagnostic and treatment failures, devices and implants failures, orphan diseases, neglected areas of research related to our journal scope, drugs adverse effects, technical problems, relapse and failures in oral and maxillofacial surgery. Nemesis is opened to multilingualism and provides translations of original articles in English and French into Polish and Ukrainian.

Prognostic Role of Multiparameter Flow Cytometry-Based Measurable Residual Disease Assessment in Acute Myeloid Leukemia Patients with FMS3-like Tyrosine Kinase-3 Internal Tandem Duplication (FLT3-ITD)

Introduction Measurable residual disease (MRD) monitoring is predictive in acute myeloid leukemia (AML). Assessment of FMS3-like tyrosine kinase-3 in-frame internal tandem duplications (FLT3-ITD) is usually performed at diagnosis by polymerase chain reaction (PCR). Due to its relative lower sensitivity of 2%, FLT3-ITD PCR is not routinely used during response assessment. Next-generation sequencing is similarly limited by technical difficulties in capturing tandem duplications using the short base pair-based sequencing method. Long base pair-based sequencing has been reported, but its use is limited by financial restrictions. Multiparameter flow cytometry (MFC) can be a useful tool for MRD monitoring in this AML subtype until such time that molecular techniques for detecting FLT3-ITD MRD are optimized. Patients and methods The study evaluated the outcomes of FLT3-ITD mutated AML patients diagnosed and treated from 2018 to 2022 at Princess Margaret Cancer Centre. We compared outcomes according to MFC-MRD post-induction and FLT3-ITD allele frequency (AF) status at diagnosis. MRD cut-off was 0.1%. Data were locked as of June 30, 2023. Clinical outcomes evaluated include overall survival (OS) and relapse-free survival (RFS). The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated considering competing risk. The Kaplan-Meier method using a log-rank test and a multivariate Cox proportional hazard model was used for analyses, while the Gray test and Fine-Grey model were used for uni- and multivariate analysis for CIR and NRM. Results A total of 111 patients with a mean age of 63.5 years were included, of whom 90 received treatment. Secondary AML accounted for 12.7% of patients. Risk stratification according to European LeukemiaNet (ELN) 2022 was favorable in 2 (1.8%), intermediate in 67 (60.4%), and adverse in 42 patients (37.8%). Nucleophosmin 1 (NPM1) co-mutation was observed in 55 patients (49.5%). Seventy-nine patients (87.8%) could be assessed for overall response, including 69 (76.7%) who achieved complete remission (CR) or CR with incomplete count recovery (CRi). Of these, 54 achieved first CR/CRi (CR1) with 1 induction cycle. MFC-MRD data were available in 61 patients, of whom 44 (72.1%) were MRD negative, while 17 (27.9%) were MRD positive. With a median follow-up of 437 days, 50 patients (45%) were still alive. Median OS and RFS were 3.42 years and 1.05 years, respectively. Among patients who achieved CR1, post-induction MFC-MRD positivity correlated with an inferior OS (HR 2.35 [1.06-5.26], p=0.037) and a trend for a shorter RFS (HR 2.08 [0.99-4.35], p=0.052). We examined the impact of FLT3-ITD AF at diagnosis on long-term outcomes. By applying a binary recursive partitioning method, the cut-off of FLT3-ITD AF with the best risk stratification power for RFS, was defined at 54.6%. The group with a higher FLT3-ITD AF showed inferior OS (HR 1.86 [1.01-3.44], p=0.047) and RFS (HR 1.91 [1.09-3.33], p=0.023). Taking together FLT3-ITD AF at diagnosis and MFC-MRD status at CR1, patients with low FLT3-ITD AF and negative MRD had the highest OS rate of 86.2% at 12 months (p=0.023), and the highest RFS at 72.4% (p=0.096), while the corresponding values for low FLT3-ITD AF/positive MRD patients were 87.5% and 50%, respectively. In contrast, those with high FLT3-ITD AF/negative MRD had an OS of 72.7% and a RFS of 45.5%, while those with high FLT3-ITD AF/positive MRD showed the lowest OS (16.7%) and the shortest RFS (16.7%). There was no statistical difference in CIR and NRM among groups. Multivariate analysis with stepwise selection was performed, considering age at diagnosis, ELN 2022 risk, MFC-MRD at CR1, FLT3-ITD AF at diagnosis, cytogenetics, and NPM1 co-mutation. Predictive factors for OS were MFC-MRD post-induction (HR 2.49 [1.11-5.61], p=0.027) and FLT3-ITD AF (HR 2.29 [1.03-5.11], p=0.043). For RFS, age at diagnosis (HR 1.03 [1.00-1.06], p=0.038) and FLT3-ITD AF (HR 2.40 [1.15-5.01], p=0.019) were predictive, while MFC-MRD was not significant (HR 1.59 [0.72-3.53], p=0.25). Conclusion Our data demonstrate that MFC-based MRD assessment is feasible in AML with FLT3-ITD. Although better outcomes are expected in patients with a lower FLT3-ITD AF, patients who failed to achieve MRD negativity at CR1 showed inferior outcomes. The presence of both poor risk factors, a high AF of FLT3-ITD at diagnosis and MRD positivity at CR1, correlated with the worst treatment outcomes.

Temporal and spatial variations in the physical and chemical properties of anaerobic granular sludge within a Pilot Spiral Symmetry Stream Anaerobic Bioreactor

Anaerobic granular sludge (AGS) determines the high performance of the bioreactor. To study the regionalization of granular sludge in the bioreactor, a Pilot Spiral Symmetry Stream Anaerobic Bioreactor (P-SSSAB) was established over 216 days, divided into three zones (I, II, and III) from bottom to top. AGS at the bottom of P-SSSAB had a higher porosity (60.35 %–83.27 %) and more suitable settling velocity (60 m/h) when the particle size range was 1.0–2.0 mm. This proved the better metabolic activity and superior settling performance in zone I than in zones II and III. In addition, the elemental composition of AGS in various zones was analyzed. The relative content of iron (5.66 %, 3.36 %, and 1.38 %, respectively) and sulfur (2.47 %, 2.19 %, and 1.49 %, respectively) in zone I, II, and III tended to decrease with the height of P-SSSAB. This also verified the better mass transfer performance and operational stability in lower zone than in upper zone. However, the monitoring of bed temperature in various zones revealed that the microbial activity in zone I was 6.7×10−12~3.5×10−2 times and 1.8×10−15~1.4×10−3 times that in zones II and III, respectively, which indicated that the unit activity of AGS in zone I was the worst. It indicated that AGS in lower zone had poor unit activity but had the highest unit capacity due to the high sludge concentration. Besides, the unit capacity of the upper zone was too weak to produce enough alkalinity to neutralize acid produced by excessive hydrolysis and acidification in lower zone, resulting in the worst treatment efficiency of the upper zone. Therefore, temperature and concentration ratios under various spatial distributions in bioreactors are vital to the overall sewage treatment stability and efficiency of bioreactors in actual engineering applications.

Pengaruh Wadah dan Lama Penyimpanan Terhadap Viabilitas dan Vigor Benih Hotong (Setaria italica (L) Beauv)

The aim of this research is that hotong seeds can be preserved for a long time so that they can be stored and used for cultivation in the next planting season. This research was conducted at the Tissue Culture Laboratory and Plant Physiology Laboratory at the Faculty of Agriculture, Pattimura University, Ambon, which took place from February to May 2021. Completely randomized design method, two factors, three replications. The first factor was seeds in open space (A0), seeds in aluminum foil (A1), seeds in glass bottles (A2), seeds in clear plastic (A3), and seeds in white cloth (A4). Another factor is the retention time (B) which consists of three stages, namely: 1 month (B1), 2 months (B2), and 3 months (B3) storage. BNJ test and Anova analysis at 95% confidence level. The treatment to maintain the quality of the hotong seeds was the 3rd month storage aluminum foil (A3B3) which could maintain a moisture content of 9.4%, PTM 80.67%, and the growth rate and vigor of hotong seeds at 81%, and the worst treatment in maintaining the quality of viability and vigor. seeds were calico fabric treated in the 3rd month of storage (A1B3).

Comparative safety of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis.

Objective: This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment of adult patients with metastatic clear cell renal cell carcinoma (RCC). Methods: A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously untreated adult patients with metastatic clear cell RCC. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration tool. The P score was used to determine the treatment ranking. The mean probability of an event along with the relative measures of the NMA was considered with the treatment rankings. Results: A total of 13 RCTs were included in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy were the best treatment options. Sorafenib achieved the highest P score for treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting of any grade, and hypertension of any grade or grade ≥3. Tivozanib achieved the highest P score for AEs, grade ≥3 AEs, dose modifications due to AEs, and grade ≥3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + pembrolizumab-in terms of grade ≥3 fatigue, nausea, and vomiting. TKIs used in combination were shown to have a poorer safety profile than those used as monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms of any AEs, grade ≥3 AEs, treatment discontinuation due to AEs, dose modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade ≥3 nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, grade ≥3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst option in terms of grade ≥3 vomiting. Interestingly, among the other safety endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and hypertension of any grade. Conclusion: The general safety profile, including common AEs, is better when TKIs are used as monotherapy vs. in combination with immunological agents. To confirm these findings, further research is needed, including large RCTs.

Global parameter optimisation and sensitivity analysis of antivenom pharmacokinetics and pharmacodynamics

In recent years it has become possible to design snakebite antivenoms with diverse pharmacokinetic properties. Owing to the pharmacokinetic variability of venoms, the choice of antivenom scaffold may influence a treatment's neutralisation coverage. Computation offers a useful medium through which to assess the pharmacokinetics and pharmacodynamics of envenomation-treatment systems, as antivenoms with identical neutralising capacities can be simulated. In this study, we simulate envenomation and treatment with a variety of antivenoms, to define the properties of effective antivenoms. Systemic envenomation and treatment were described using a two-compartment pharmacokinetic model. Treatment of Naja sumatrana and Cryptelytrops purpureomaculatus envenomation was simulated with a set of 200,000 theoretical antivenoms across 10 treatment time delays. These two venoms are well-characterised and have differing pharmacokinetic properties. The theoretical antivenom set varied across molecular weight, dose, kon, koff, and valency. The best and worst treatments were identified using an area under the curve metric, and a global sensitivity analysis was performed to quantify the influence of the input parameters on treatment outcome. The simulations show that scaffolds of diverse molecular formats can be effective. Molecular weight and valency have a negligible direct impact on treatment outcome, however low molecular weight scaffolds offer more flexibility across the other design parameters, particularly when treatment is delayed. The simulations show kon to primarily mediate treatment efficacy, with rates above 105 M−1s−1 required for the most effective treatments. koff has the greatest impact on the performance of less effective scaffolds. While the same scaffold preferences for improved treatment are seen for both model snakes, the parameter bounds for C. purpureomaculatus envenomation are more constrained. This paper establishes a computational framework for the optimisation of antivenom design.

Biopsychosocial treatment response among youth with continuous headache: A retrospective, clinic-based study.

Youth with continuous (always present) headache are vastly understudied; much remains to be understood regarding treatment response in this population. To describe and explore biopsychosocial factors related to initial clinical outcomes among treatment-seeking youth with continuous headache. This retrospective cohort study extracted data of 782 pediatric patients (i.e., aged <18 years) with continuous headache from a large clinical repository. Youth in this study had experienced continuous headache for ≥1 month before presenting to a multidisciplinary headache specialty clinic appointment. Extracted data from this appointment included patients' headache history, clinical diagnoses, and headache-related disability, as well as information about biopsychosocial factors implicated in headache management and/or maintenance (e.g., healthy lifestyle habits, history of feeling anxious or depressed). Additional data regarding patient headache characteristics, disability, and lifestyle habits were extracted from a subset of 529 youth who returned to clinic 4-16 weeks after their initial follow-up visit. After characterizing initial treatment response, exploratory analyses compared youth with the best and worst treatment outcomes on several potentially influential factors. Approximately half of youth (280/526; 53.2%) continued to have continuous headache at follow-up, ~20% of youth (51/526) reported a significant (≥50%) reduction in headache frequency. Improvements in average headache severity (e.g., percentage with severe headaches at initial visit: 45.3% [354/771]; percentage with severe headaches at follow-up visit: 29.8% [156/524]) and headache-related disability were also observed (e.g., percentage severe disability at initial visit: 62.9% [490/779]; percentage severe disability at initial follow-up visit: 34.2% [181/529]). Individuals with the worst headache frequency and disability had a longer history of continuous headache (mean difference estimate = 5.76, p = 0.013) and worse initial disability than the best responders (χ2 [3, 264] = 23.49, p < 0.001). They were also more likely to have new daily persistent headache (χ2 [2, 264] = 12.61, p = 0.002), and were more likely to endorse feeling depressed (χ2 [1, 260] = 11.46, p < 0.001). A notable percentage of youth with continuous headache show initial improvements in headache status. Prospective, longitudinal research is needed to rigorously examine factors associated with continuous headache treatment response.

Clinicians' preferences for managing aneurysmal subarachnoid hemorrhage using endothelin receptor antagonists.

The endothelin receptor antagonist (ERA) clazosentan is being investigated for the medical prevention of cerebral vasospasm and associated complications, such as delayed cerebral ischemia (DCI), after aneurysmal subarachnoid hemorrhage (aSAH). This study quantified how clinicians weigh the benefits and risks of ERAs for DCI prevention to better understand their treatment needs and expectations. An online choice experiment was conducted to elicit preferences of neurologists, intensivists, and neurosurgeons treating aSAH in the US and UK for the use of ERAs. The design of the choice experiment was informed by a feasibility assessment (N = 100), one-on-one interviews with clinicians (N = 10), a qualitative pilot (N = 13), and a quantitative pilot (N = 50). Selected treatment attributes included in the choice experiment were: one benefit (likelihood of DCI); and three risks (lung complications, hypotension, and anemia). In the choice experiment, clinicians repeatedly chose best and worst treatment options based on a scenario of a patient being treated in the ICU after aneurism repair. A correlated mixed logit model determined the relative attribute importance (RAI) and associated highest density interval (HDI) as well as acceptable benefit-risk trade-offs. The final choice experiment was completed by 350 clinicians (116 neurologists, 129 intensivists/intensive care clinicians, and 105 neurosurgeons; mean age, 47.4 years). Reducing the likelihood of DCI (RAI = 56.5% [HDI, 53.6-59.5%]) had the largest impact on clinicians' treatment choices, followed by avoiding the risks of lung complications (RAI = 29.6% [HDI, 27.1-32.3%]), hypotension (RAI = 9.2% [HDI, 7.5-10.8%]), and anemia (RAI = 4.7% [HDI, 3.7-5.8%]). Clinicians expected the likelihood of DCI to decrease by ≥8.1% for a 20% increase in the risk of lung complications, ≥2.4% for a 20% increase in the risk of hypotension, and ≥1.2% for a 20% increase in the risk of anemia. Clinicians were willing to accept certain increased risks of adverse events for a reduced risk of DCI after aSAH. The likelihood of DCI occurring after aSAH can therefore be considered a clinically relevant endpoint in aSAH treatment development. Thus, evaluations of ERAs might focus on whether improvements (i.e., reductions) in the likelihood of DCI justify the risks of adverse events.

The efficacy and safety of different endovascular modalities for infrapopliteal arteries lesions: A network meta-analysis of randomized controlled trials

Endovascular treatment has become the first-line therapy for infrapopliteal artery occlusive disease (IPOD), while the optimal endovascular method remains to be determined. We performed a network meta-analysis (NWM) of randomized controlled trials (RCTs) to simultaneously compare the outcomes of different endovascular modalities for IPOD. The Pubmed, Embase, and Cochrane databases were used as data sources. The NWM approach used random-effects models based on the frequentist framework. In total, 22 eligible RCTs (44 study arms; 1,348 patients) involving nine endovascular modalities or combinations [balloon angioplasty (BA), drug-coated balloon (DCB), drug-eluting stent (DES), atherectomy device + BA (AD + BA), AD + DCB, balloon-expandable bare metal stent (BMS), self-expanding stent (SES), absorbable metal stents (AMS), and inorganics-coated stent (ICS)] were included. BA had a lower 12-month primary patency rate than DCB (RR 0.50, CI 0.27, 0.93) and AD + DCB (RR 0.34, CI 0.12, 0.93). AD + DCB decreased 6-month TLR compared with AMS (RR 0.15, CI 0.03, 0.90), and DES decreased it compared with BMS (RR 0.25, CI 0.09, 0.71). DCB had a lower 6-month TLR rate than AMS (RR 0.26, CI 0.08, 0.86) and BA (RR 0.51, CI 0.30, 0.89). BA had a higher 12-month TLR rate than DCB (RR 1.76, CI 1.07, 2.90). According to the value of the surface under the cumulative ranking curve (SUCRA), AD + DCB was considered the best treatment in terms of primary patency at 6 months (SUCRA = 87.5) and 12 months (SURCA = 91). AD + BA was considered the best treatment in terms of 6-month TLR (SUCRA = 83.1), 12-month TLR (SURCA = 75.8), and 12-month all-cause mortality (SUCRA = 92.5). In terms of 12-month major amputation, DES was considered the best treatment (SUCRA = 78.6), while AD + DCB was considered the worst treatment (SUCRA = 28.8). Moreover, AD + BA always ranks higher than AD + DCB in the comparison including these two combinations. Subgroup analyses of modalities without stenting did not significantly change the primary outcomes. ADs showed noteworthy advantages in multiple terms for IPOD except for 12-month major amputation. AD + BA may be a better method for IPOD than AD + DCB. The efficacy and safety of ADs are worthy of further investigation. [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022331626].

Inconsistent clinical outcomes following afatinib treatment in NSCLC patients harboring uncommon epidermal growth factor receptor mutation.

Uncommon epidermal growth factor receptor (EGFR) mutations consist of a heterogeneous population of molecular alterations, and the available clinical data on the outcomes of patients with non-small-cell lung cancer (NSCLC) harboring uncommon EGFR mutations following afatinib treatment are limited. The purpose of this pooled analysis was to investigate the clinicopathological features of patients with uncommon EGFR mutations (um-EGFRms) along with their treatment response and survival outcomes following afatinib treatment. We performed a literature search in the NCBI PubMed database to identify relevant articles and conducted this pooled analysis based on 70 studies. The relationships between patient clinical characteristics, EGFR mutation type and the response to afatinib treatment were analyzed using univariate chi-square analysis, and survival analysis was performed using the Kaplan-Meier method. Data from a total of 99 patients were included in the pooled analysis. The objective response rate (ORR) to treatment with afatinib was53.5%, with a median progression-free survival (mPFS) of 9.0 months. For patients administered first-line afatinib treatment, the ORR and median PFS were 73.5% and 15.6 months, respectively, which were both superior to those of patients treated with second- or later-line treatments (ORR:37.0%, p < 0.001; mPFS: 6.0months, p = 0.001). Moreover, patients with a single um-EGFRm were more likely to have a favorable response and prognosis benefit after treatment with afatinib than patients with multiple one (ORR: 63.3% vs 38.5%, p=0.017; mPFS: 15.6 months vs 6.0 months,p=0.010). Moreover, single um-EGFRm were independent predictive factors for better treatment response and superior PFS. Subgroup analysis indicated that patients harboring major um-EGFRms (i.e., L861Q, G719X, and S768I) exhibited the best treatment responses and prognoses (ORR: 74.1%, mPFS: 15.6 months), by contrast, patients harboring multiple um-EGFRms comprising 19del/L858R had the worst treatment responses and prognoses (ORR: 23.5%, mPFS: 5.6months). Patients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following afatinib treatment, which closely related to the mutation pattern and cooccurring partner mutant genes. Administering afatinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances, but this recommendation requires further clinical studies for verification.

Development and validation of a multivariable prognostic model in de novo metastatic castrate sensitive prostate cancer.

Metastatic castrate sensitive prostate cancer (mCSPC) is a heterogeneous disease state with variable prognosis. Although several life-prolonging systemic agents are available, there is no robust multivariable model to predict prognosis and improve risk stratification in mCSPC. The objective of this study was to build and validate a multivariable prognostic model to predict overall survival (OS) in mCSPC. We used data from LATITUDE, a phase III randomized controlled trial in which men with de novo mCSPC were randomly allocated to either ADT plus abiraterone or ADT with placebo. Patients with non-missing data (n = 1,058) were randomly split in a 70:30 ratio to training (n = 743) and testing (n = 315) sets. Elastic net regression was used for variable selection. A multivariable Cox regression model for OS was then fitted using the selected variables. The predictive accuracy of the model was assessed on the testing set using the time-dependent area under curve (tAUC) with bootstrapped confidence intervals [CI] primarilyfor OS and secondarily forradiographic progression-free survival (rPFS). The 11 prognostic variables in the final model were performance status, number of skeletal metastases, Gleason score, presence of liver metastasis, worst pain score, albumin, lactate dehydrogenase, prostate-specific antigen, hemoglobin, and treatment regimen. The tAUC for predicting OS at 2- and 3-years was 0.74 (95%CI, 0.67-0.80) and 0.72 (95%CI, 0.65-0.77), respectively. The tAUC for rPFS at 2- and 3-years was 0.72 (95%CI, 0.65-0.77) and 0.77 (95%CI, 0.70-0.82), respectively. A prognostic model for men with de novo mCSPC was developed and validated in an independent testing set. Our model had high accuracy for predicting OS and rPFS. The model includes commonly used clinical and laboratory parameters and can guide risk stratification of these patients for participation in future trials.

P1221: DIFFUSE LARGE B-CELL LYMPHOMA RICHTER SYNDROME IN CHRONIC LYMPHOCYTIC LEUKEMIA – A RETROSPECTIVE ANALYSIS OF TREATMENT OUTCOMES IN POLISH ADULT LEUKEMIA STUDY GROUP

Background: Richter syndrome (RS) is a recognized uncommon manifestation and evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with a dismal prognosis. It occurs in 2-10% of CLL patients. It is associated with a clonal evolution and progression, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or, less frequently, to Hodgkin Lymphoma (HL). Despite the advances in understanding pathogenesis of the disease, the DLBCL variant of RS (DLBCL-RS) is associated with a dismal prognosis with a median survival < 1 year. The treatment options and risk factors of worse outcome for RS still need to be further expanded. Aims: To study the characteristic and treatment outcomes of patients with DLBCL-RS. Methods: The retrospective analysis of 99 patients diagnosed with DLBCL-RS treated in hematology centers of the Polish Adult Leukemia Study Group (PALG) between 2011 and 2021. Results: Clinical data of 124 patients with Richter syndrome was collected. Ninety-nine patients were diagnosed with DLBCL-RS (79.8%) and further analyzed. Median time since CLL diagnosis to Richter transformation was 43.0 months (range 0-252.0). At the time of transformation 31.3% patients had CLL Rai stage IV, 74.7% were ECOG< 2, while the median Cumulative Illness Rating Scale (CIRS) was 4 (range 0-16). Thirty-seven patients transformed during CLL treatment, 56.7% of them were receiving novel agents (Brutons tyrosine kinase inhibitor or BCL2 inhibitor). Median time of observation after transformation was 10.7 months (range 0-98.6). Median overall survival (OS) after DLBCL-RS diagnosis was 17.3 months (95% Cl 11.9-46.8) and median progression-free survival (PFS) 13.5 months (95% Cl 9.6-22.7). Seventy-six patients (76.8%) had RS treated with intensive chemotherapy protocols, mainly R-CHOP-like regimens for the first line treatment. Only 42.3% had response to the treatment (25/76 complete responses and 11/76 partial responses). Worth mentioning is that in the group of patients with response two patients had ibrutinib monotherapy and one had rituximab-ibrutinib. In forty patients RS was primarily resistant to administered treatment and 65% of them died due to progression or treatment related complications. In the primary resistant DLBCL-RS p53 pathway aberration was noted in 47.5% of patients (17p deletion in 13 patients or TP53 mutation in 6 patients). Better results were achieved for patients who proceeded to autologous hematopoietic stem cell transplantation (auto-HSCT; n=8) and allogeneic HSCT (allo-HSCT; n=10). The median OS in auto-HSCT recipients was 46.1 months, while in allo-HSCT the median OS reached 18.3 months (3 patients died due to allo-HCST-related complications). Significantly lower OS (3.4 months, 95% Cl 14.13-not reached) was observed for RS in heavily pretreated CLL patients (>3 lines of therapy preceding transformation) compared to those treated with up to 3 lines of therapy (23.7 months) (p=0.0002). Median OS for treatment naïve patients at DLBCL-RS diagnosis was not reached. Other factors identified as predictors of poor OS in univariate analysis were ECOG ≥2 (p=0.0014), hemoglobin level <10 g/dl (p=0.017) and platelet count <100x109/L (p=0.0065). Summary/Conclusion: Our study represents the largest dataset of DLBCL-RS patients in Polish hematology centers and confirms the poor outcomes and prognosis associated with RS. The worst treatment results were observed in RS receiving >3 lines of CLL therapy preceding transformation. Only proceeding to hematopoietic stem cell transplantation may improve the prognosis.

Abstract 1246: Consensus molecular subtypes (CMS) of colorectal cancer predict anti-EGFR response irrespective of tumor sidedness

Abstract Background: Activating mutations in KRAS, NRAS, and BRAF are known to cause resistance to anti-EGFR therapy. However, only ~40% of colorectal cancer (CRC) patients with RASWT tumors respond to that treatment. We aim to leverage tumor transcriptomes to predict response to anti-EGFR antibody (e.g., cetuximab) treatment and understand intrinsic resistance mechanisms in CRC. Experimental Design: Transcriptomic profiles with RAS mutation status from two clinical (Okita et al., n = 135; Khambata-Ford et al., n = 68), and preclinical cohorts of CRC cell lines (Medico et al., n = 146) and PDX models (Bertotti et al., n = 216) treated with cetuximab were downloaded from Gene Expression Omnibus (GEO). Each cohort was divided into RASWT and RASMut groups, and transcriptomic profiles were used to assign consensus molecular subtypes (CMS) to each sample. Gene Set Enrichment Analysis (GSEA) was performed to identify resistant pathways in each CMS RASWT group. Results: Restricting to RASWT patients (n = 80) in Okita et al. cohort, we observed that CMS2 tumors had significantly higher disease control rates (DCR) [92% (33/36); chi-square p = 0.03] with cetuximab in combination with doublet chemotherapy relative to CMS1 [50% (2/4)], CMS3 [59% (13/22)], and CMS4 [83% (15/18)] tumors. RASWT CMS2 tumors (n = 43) also showed significantly higher DCR [68% (15/22); chi-square p = 0.03] with single-agent cetuximab compared to CMS1 [0% (0/4)], and CMS4 [29% (5/17)] tumors in Khambata-Ford et al. cohort. In multivariate analysis including both CMS and tumor sidedness, only CMS2 (HR = 0.62, p = 0.03) was significant predictor of cetuximab response in Okita et al. cohort. CMS1 tumors showed worst treatment response irrespective of tumor sidedness [DCR, left: 50% (1/2) vs right: 50% (1/2)]. In contrast both left and right-sided CMS2 tumors responded well [DCR, left: 91% (31/34) vs 100% (2/2)] to cetuximab plus chemotherapy [PFS, 7.9 vs 7 months; log-rank test p = 0.7]. In microsatellite stable (MSS) RASWT cell lines (n = 27), CMS2 cells lines were most sensitive [59% (7/17)] relative to CMS4 [0% (0/10)]. In MSS RASWT PDX models (n = 60), CMS2 had highest DCR [75% (18/24)] than CMS1 [36% (4/11)], CMS3 [55% (5/9)], CMS4 [62% (10/16)]. We found Myc, E2F, and mTOR gene sets/pathways were consistently enriched in resistant patients, cell lines, and PDX models (Normalized enrichment score &amp;gt; 1, FDR &amp;lt; 0.25). Small molecule inhibitors of Myc (JQ1), E2F (AZD7762 &amp; MK-8776), and mTOR (Everolimus) pathways in resistant CRC cell line (HT55) exhibited additive, but not synergistic, effects with cetuximab. Conclusions: These data suggest that tumor transcriptional profiles are a better predictor of anti-EGFR response than tumor-sidedness. Use of CMS to predict anti-EGFR response should be validated in a larger, prospective study. Activation of Myc, E2F, and mTOR pathways are associated with cetuximab resistance in colorectal cancer cells. Citation Format: Saikat Chowdhury, Ria Gupta, Valsala Haridas, Mohammad A. Zeineddine, Scott Kopetz, John Paul Shen. Consensus molecular subtypes (CMS) of colorectal cancer predict anti-EGFR response irrespective of tumor sidedness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1246.

MP12-16 OPTIMIZING TARGETED DRUG SELECTION IN COMBINATION THERAPY FOR PATIENTS WITH ADVANCED OR METASTATIC RENAL CELL CARCINOMA: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS OF SAFETY

You have accessJournal of UrologyCME1 May 2022MP12-16 OPTIMIZING TARGETED DRUG SELECTION IN COMBINATION THERAPY FOR PATIENTS WITH ADVANCED OR METASTATIC RENAL CELL CARCINOMA: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS OF SAFETY Ruiyang Xie, Bingqing Shang, Weixing Jiang, Chuanzhen Cao, Hongzhe Shi, and Jianzhong Shou Ruiyang XieRuiyang Xie More articles by this author , Bingqing ShangBingqing Shang More articles by this author , Weixing JiangWeixing Jiang More articles by this author , Chuanzhen CaoChuanzhen Cao More articles by this author , Hongzhe ShiHongzhe Shi More articles by this author , and Jianzhong ShouJianzhong Shou More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002534.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Targeted therapies were often applied in the combination with immune checkpoint inhibitors for patients with advanced or metastatic renal cell carcinoma (RCC). A network meta-analysis was carried out to provide a categorized safety ranking profile and assess the adaptability for combination choice of targeted therapies. METHODS: Randomized controlled trials comparing vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) and mammalian target of rapamycin (mTOR) inhibitors were included in a Bayesian network meta-analysis. RESULTS: 19 relevant trials with 10,615 patients and 11 treatments were included. For grade ≥3 adverse events, lenvatinib plus everolimus showed worse safety than other treatments except for lenvatinib when compared to placebo (placebo versus OR 0.23, 95% CI 0.07-0.78), whereas the OR of everolimus versus placebo was relatively low (OR 1.23, 95% CI 0.50-3.14). Temsirolimus was demonstrated to cause the most severe renal and urinary disorders compared to placebo (placebo versus OR 0.08, 95% CI 0.00-2.61) among the treatments, and lenvatinib plus everolimus was observed with a low OR of 0.17 95% CI 0.01-1.02 as well. In contrast, sorafenib showed an OR that was lower than 1 for renal and urinary disorders compared to other VEGF-TKIs. For gastrointestinal symptoms, lenvatinib was found to be correlated with much higher toxicity than other treatments. Tivozanib and axitinib were the worst two in terms of respiratory disorders, and all the OR values of other treatments were statistically significant except the comparison between these two. In terms of hepatobiliary disorders, cabozantinib was found to be the worst treatment compared to placebo (OR 9.33, 95% CI 3.78-28.56). CONCLUSIONS: Lenvatinib plus everolimus had the worst and the second worst in terms of adverse events related to renal disorders and grade ≥3 adverse events, respectively. Everolimus, with the best ranking of safety, was more likely to be selected for combination therapies. This study will guide treatment choice and optimize the future trial design for advanced or metastatic RCC. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e174 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ruiyang Xie More articles by this author Bingqing Shang More articles by this author Weixing Jiang More articles by this author Chuanzhen Cao More articles by this author Hongzhe Shi More articles by this author Jianzhong Shou More articles by this author Expand All Advertisement PDF DownloadLoading ...

Disinfectants effectiveness in Tomato brown rugose fruit virus (ToBRFV) transmission in tobacco plants

&lt;p&gt;The importance of the &lt;em&gt;Tomato brown rugose fruit virus &lt;/em&gt;(ToBRFV) in the tomato and pepper crops in the world has created the need to investigate and test alternatives for its management. Preventive tactics are the best option to manage a viral disease, so the objective of this study was to evaluate the effectiveness of sodium hypochlorite, ethyl alcohol, quaternary ammonium salts, liquid soap and milk powder dissolved in water, applied by spraying and immersion of razor blades infested with the virus and inoculating mechanically on &lt;em&gt;Nicotiana rustica &lt;/em&gt;and &lt;em&gt;N. benthamiana &lt;/em&gt;leaves. A completely randomized design with five repetitions was used and the experimental unit was the area of a tobacco leaf delimited by a rectangle, and the response variable was the number of local lesions/ cm2 (LL/cm2). A non-parametric analysis and a Kruskal Wallis test for comparison of means were used to evaluate the treatments, and significative differences were found (Ji&amp;lt;.0001). Sodium hypochlorite (spraying) and the subsequent application of milk prevented the appearance of local lesions and the transmission of ToBRFV. While the worst treatments were ethyl alcohol (immersion) with an average of 12 LL/cm2, and quaternary ammonium salts (immersion) with 3.22 LL/cm2. The rest of the treatments significantly reduced the number of LL/cm2 (&amp;lt;1), but did not prevent the appearance of systemic symptoms in the inoculated plants.&lt;/p&gt;

Food Addiction in Eating Disorders: A Cluster Analysis Approach and Treatment Outcome.

Background: A first approach of a phenotypic characterization of food addiction (FA) found three clusters (dysfunctional, moderate and functional). Based on this previous classification, the aim of the present study is to explore treatment responses in the sample diagnosed with Eating Disorder(ED) of different FA profiles. Methods: The sample was composed of 157 ED patients with FA positive, 90 with bulimia nervosa (BN), 36 with binge eating disorder (BED), and 31 with other specified feeding or eating disorders (OSFED). Different clinical variables and outcome indicators were evaluated. Results: The clinical profile of the clusters present similar characteristics with the prior study, having the dysfunctional cluster the highest ED symptom levels, the worse psychopathology global state, and dysfunctional personality traits, while the functional one the lowest ED severity level, best psychological state, and more functional personality traits. The dysfunctional cluster was the one with lowest rates of full remission, the moderate one the higher rates of dropouts, and the functional one the highest of full remission. Conclusions: The results concerning treatment outcome were concordant with the severity of the FA clusters, being that the dysfunctional and moderate ones had worst treatment responses than the functional one.

A Comparison of Biosolids Production and System Efficiency between Activated Sludge, Moving Bed Biofilm Reactor, and Sequencing Batch Moving Bed Biofilm Reactor in the Dairy Wastewater Treatment

Dairy industry wastewater is rich in organic content, presenting a high biodegradability, and therefore biological treatments are widely employed. This study aimed to evaluate biosolids production in three systems: activated sludge (AS), movingbed biofilm reactor (MBBR), and sequencingbatch movingbed biofilm reactor (SBMBBR). Simulated dairy wastewater was used at different organic load rates (OLRs): 1.22, 2.87, and 5.44 gCOD L−1d−1. Besides biosolids production, COD, total carbon (TC), and total nitrogen (TN) removal efficiency was evaluated. Biosolids production was measured in the mixed liquor, carrier-adhered biomass, treated wastewater, and surplus sludge. The operational conditions were kept similar for the three systems, with a carrier filling ratio of 50% for MBBR and SBMBBR. The SBMBBR proved to have better performance in the removal efficiencies of COD, TC, and TN for all OLRs studied. The MBBR presented a similar COD and TC removal efficiency as the SBBR for the two highest OLRs (2.87 and 5.44 gCOD L−1d−1). Concerning biosolids production, the MBBR system produced less biomass and delivered the lowest amount of adhered biomass inside the carriers. The AS treatment generated the highest amount of sludge and offered the worst treatment capability for all OLRs evaluated.

Use of Triggers on in vitro Fertilization and Evaluation of Risk Factors for Sub-Optimal Maturation Rate.

To compare the oocyte maturation rate in the treatment of in vitro fertilization (IVF) in terms of the use of human chorionic gonadotropin (hCG), agonist gonadotropin-releasing hormone (GnRH) and dual trigger and to evaluate the associated risk factors for sub-optimal maturation rates. A retrospective cohort study with 856 women who underwent IVF. They performed oocyte retrieval and were classified into 3 groups (1 - hCG, 2 - GnRH agonist, 3 - dual trigger). The primary outcome was maturation rate per trigger, and the secondary outcomes were the pregnancy rate per oocyte retrieval and the correlations between low maturation rate as well as the clinical and treatment characteristics of women. The maturation rate was 77% in group 1; 76% in group 2, and 83% in group 3 (p = 0.003). Group 2 showed women with better ovarian reserve, greater number of oocytes collected, and more mature oocytes and embryos compared with the other groups (p < 0.001). The cumulative clinical pregnancy rate was no different between the groups (p = 0.755). Low ovarian reserve and low doses of follicle-stimulating hormone (FSH) administered during the stimulus were associated with a higher chance of null maturation rate. The oocyte maturation rates and IVF results were similar in all groups. Low ovarian reserve is associated with the worst treatment results.

Effect of surface treatment materials on frost resistance of damaged concrete

In order to study the effect of silicate infiltration agent, tetraethyl orthosilicate and nano-SiO2 surface treatment materials on the freezing resistance of damaged concrete, the peeling condition of damaged concrete after soaking in salt water was tested by single-side freeze-thaw method. The results showed that tetraethyl orthosilicate and silicon infiltration agent can effectively improve the damaged concrete frost resistance and can reduce the 7 d water quantity of concrete, the most significant is the effect of tetraethyl orthosilicate, 7 d water quantity reduced rate of 65%, after 28 times freeze-thaw cycle exfoliation volume is 679 g/m2. Silicon infiltration agent surface treatment also has a good effect, can increase the number of freeze-thaw cycles 8 times. Nano-SiO2 has the worst treatment effect and can not improve the number of freeze-thaw cycles of damaged concrete.