Significant Improvement In Efficacy Research Articles

Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial

The interim analysis of the randomized phase 3 ESCORT-1st study demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) for camrelizumab-chemotherapy than placebo-chemotherapy in untreated advanced/metastatic esophageal squamous cell carcinoma (ESCC). Here, we present the final analysis of this study and investigate potential indicators associated with OS. Patients were randomized 1:1 to receive camrelizumab (200mg) or placebo, both in combination with up to six cycles of paclitaxel (175mg/m2) and cisplatin (75mg/m2). All treatments were administered intravenously every 3weeks. The co-primary endpoints were OS and PFS assessed by the independent review committee. As of April 30, 2022, the median OS was significantly longer in the camrelizumab-chemotherapy group compared to the placebo-chemotherapy group (15.6 [95% confidence interval (CI): 14.0-18.4] vs. 12.6months [95% CI 11.2-13.8]; hazard ratio [HR]: 0.70 [95% CI 0.58-0.84]; one-sided p<0.0001), with 3-year OS rates of 25.6% and 12.8% in the two groups, respectively. The 2-year PFS rates were 20.4% in the camrelizumab-chemotherapy group and 3.4% in the placebo-chemotherapy group. Adverse events were consistent with those reported in the interim analysis. Higher PD-L1 expression correlated with extended OS, and multivariate analysis identified sex and prior history of radiotherapy as independent indicators of OS. The sustained and significant improvement in efficacy with camrelizumab-chemotherapy compared to placebo-chemotherapy, along with the absence of accumulating or delayed toxicities, supports the long-term use of camrelizumab-chemotherapy as a standard therapy in untreated advanced/metastatic ESCC. This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

New target therapies in prostate cancer: from radioligand therapy, to PARP-inhibitors and immunotherapy.

Prostate cancer (PCa) remains a significant global health challenge, particularly in its advanced stages. Despite progress in early detection and treatment, PCa is the second most common cancer diagnosis among men. This review aims to provide an overview of current therapeutic approaches and innovations in PCa management, focusing on the latest advancements and ongoing challenges. We conducted a narrative review of clinical trials and research studies, focusing on PARP inhibitors (PARPis), phosphoinositide 3 kinase-protein kinase B inhibitors, immunotherapy, and radioligand therapies (RLTs). Data was sourced from major clinical trial databases and peer-reviewed journals. Androgen deprivation therapy and androgen-receptor pathway inhibitors remain foundational in managing castration-sensitive and early-stage castration-resistant PCa (CRPC). PARPi's, such as olaparib and rucaparib, have emerged as vital treatments for metastatic CRPC with homologous recombination repair gene mutations, highlighting the importance of personalized medicine. Immune checkpoint inhibitors (ICIs) have shown clinical benefit limited to specific subgroups of PCa, demonstrating significant improvement in efficacy in patients with microsatellite instability/mismatch repair or cyclin-dependent kinase 12 alteration, highlighting the importance of focusing ongoing research on identifying and characterizing these subgroups to maximize the clinical benefits of ICIs. RLTs have shown effectiveness in treating mCRPC. Different alpha emitters (like [225Ac]PSMA) and beta emitters compounds (like [177Lu]PSMA) impact treatment differently due to their energy transfer characteristics. Clinical trials like VISION and TheraP have demonstrated positive outcomes with RLT, particularly [177Lu]PSMA-617, leading to FDA approval. Ongoing trials and future perspectives explore the potential of [225Ac]PSMA, aiming to improve outcomes for patients with mCRPC. The landscape of PCa treatment is evolving, with significant advancements in both established and novel therapies. The combination of hormonal therapies, chemotherapy, PARPis, immunotherapy, and RLTs, guided by genetic and molecular insights, opens new possibilities for personalized treatment.

Lazertinib Versus Gefitinib as First-Line Treatment in Patients With EGFR-Mutated Advanced Non-Small-Cell Lung Cancer: Results From LASER301.

Lazertinib is a potent, CNS-penetrant, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This global, phase III study (LASER301) compared lazertinib versus gefitinib in treatment-naïve patients with EGFR-mutated (exon 19 deletion [ex19del]/L858R) locally advanced or metastatic non-small-cell lung cancer (NSCLC). Patients were 18 years and older with no previous systemic anticancer therapy. Neurologically stable patients with CNS metastases were allowed. Patients were randomly assigned 1:1 to lazertinib 240 mg once daily orally or gefitinib 250 mg once daily orally, stratified by mutation status and race. The primary end point was investigator-assessed progression-free survival (PFS) by RECIST v1.1. Overall, 393 patients received double-blind study treatment across 96 sites in 13 countries. Median PFS was significantly longer with lazertinib than with gefitinib (20.6 v 9.7 months; hazard ratio [HR], 0.45; 95% CI, 0.34 to 0.58; P < .001). The PFS benefit of lazertinib over gefitinib was consistent across all predefined subgroups. The objective response rate was 76% in both groups (odds ratio, 0.99; 95% CI, 0.62 to 1.59). Median duration of response was 19.4 months (95% CI, 16.6 to 24.9) with lazertinib versus 8.3 months (95% CI, 6.9 to 10.9) with gefitinib. Overall survival data were immature at the interim analysis (29% maturity). The 18-month survival rate was 80% with lazertinib and 72% with gefitinib (HR, 0.74; 95% CI, 0.51 to 1.08; P = .116). Observed safety of both treatments was consistent with their previously reported safety profiles. Lazertinib demonstrated significant efficacy improvement compared with gefitinib in the first-line treatment of EGFR-mutated advanced NSCLC, with a manageable safety profile.

Combinatorial immune biomarkers of efficacy on buparlisib and paclitaxel in patients with SCCHN: BERIL-1 sub-analysis.

e18030 Background: Previous analysis of the BERIL-1 Phase 2 clinical trial (Soulieres et al, CCR, 2018), evaluating the efficacy of Buparlisib + Paclitaxel, was one of the largest genomic landscape analyses to date in metastatic SCCHN. With the recent approval of PD-1 in this indication, we sought to expand the analysis, focusing on combinatorial biomarkers of immune infiltration in addition to specific genomic alterations. The goal is to evaluate hierarchically prognostic and predictive biomarkers to select predefined analysis in the current Phase 3 clinical trial, BURAN (NCT04338399) post immune modulatory therapy. Methods: The results of this analysis focused on combination of genomic alterations in both tumor and plasma samples. Alterations found in tumor versus plasma revealed over 50 differentially altered genes. Combination of these sample types is more comprehensive of the patients’ true mutational and copy number status; no significant differences in alteration frequency between treatment and placebo treatment arms were identified. We evaluated correlations between select biomarkers and improvement in efficacy end points of Progression Free Survival (PFS) and Overall Survival (OS) between the treatment and control arms and within the treatment arm. Results: The most frequently altered genes were, TP53 (49%), NOTCH1 (21%), PIK3CA (19%), FAT1 (15%), and CDKN2A (13%). Previous analysis demonstrated that TP53 mutations as well as high immune infiltration (&gt; 10% intratumoral or stromal TILs) showed improvement in PFS &amp; OS. Further improvement to OS was observed in subjects with high immune infiltration and TP53 (p = .031, HR = 0.52), PIK3CA (p = .005, HR = 0.34), NOTCH1(p = .046, HR = 0.13) or FAT1(p = .007; HR = 0.28) alterations when compared to non-altered subjects in the treatment arm. Further improvement to PFS was observed in subjects with high immune infiltration and TP53(p = .031, HR = 0.52) or FAT1(p = .006, HR = 0.23) alterations when compared to non-altered subjects in the treatment arm; NOTCH1 alterations showed strong trends in improved PFS. Additionally, high tumor mutational burden (TMB) combined with alterations in the TP53 pathway showed significant OS improvement (p = .052, HR = 0.44) compared with the placebo arm. Conclusions: This analysis highlights unique insights into the mechanism of Buparlisib and Paclitaxel in of metastatic SCCHN patients; a significant improvement in efficacy observed when specific alterations are considered in the context of immune infiltration. These observations will be further explored in the ongoing Phase 3 clinical trial, BURAN. Additional analysis to be presented at the meeting include prognostic and predictive value of each biomarker and combination, differences between tumor and plasma samples, and comparison with end of treatment samples.

Abstract 828: DNA origami nanostructures as a targeted payload delivery system

Abstract DNA origami is a platform nanotechnology allows for the generation of nanostructures with precisely defined geometric shape that may be easily functionalized with a variety of payloads for therapeutic delivery. These payloads include nucleic acids (miRNA, siRNA, gene sequences), associated Cas protein molecules, therapeutic small molecules drugs, functional peptides (adjuvants or cell penetrating peptides), and incorporated targeting and/or therapeutic antibodies. Hence, DNA origami is a highly promising vehicle to deliver targeted therapeutic payloads to cancer cells or other diseases. Previous studies by our laboratory and others revealed DNA origami mediated drug delivery efficiently delivered daunorubicin or doxorubicin to cancer cells while outperforming free drug in both solid and liquid tumor model systems in vitro and in vivo. Our recent findings showed significant survival advantage by doxorubicin-loaded DNA origami over delivery of free doxorubicin in an aggressive, acute monocytic leukemia model. We also showed antibody-directed drug delivery by DNA origami may be directly targeted to monocytic leukemia cells expressing the target surface antigen, and superior efficacy in vitro against acute myeloid leukemia cells when loaded with daunorubicin relative to free drug at low concentrations. Thus, antibody targeted drug loaded DNA origami represent a promising novel precision medicine approach. Additionally, recent findings by our laboratory in vivo determined that DNA origami nanostructures alone administered at high dose (12.0mg/kg) distribute well, are non-toxic, and illicit mild immunogenicity, making them an attractive candidate for further development towards therapeutic applications. We recently developed a DNA origami structure functionalized at a high density with adjuvant (CpG) and antigenic peptides (OVA) to stimulate a directed antigen-specific immune response. We have shown this DNA origami vaccine platform displays significant improvement in efficacy by an OVA-pulsed antigen-killing assay in vivo relative to alum and CFA standard adjuvant formulations. Thus, our DNA origami vaccine platform represents a promising novel approach to optimize an anti-cancer immune response, a finding also shown by other laboratories.Collectively, DNA Nanobot technology offers 1) a promising a cancer drug delivery system that can deliver a high number of therapeutic drugs (100s of drug molecules per targeted delivery system) utilizing existing ADC conjugation methods; 2) An optimal vaccine delivery method to enhance efficacy; and 3) cell specific targeted delivery of therapeutic nucleic acids and genes to modify oncogene and/or tumor suppressor gene expression. Citation Format: Patrick Halley, Niksa Roki, Nicholas Vantangoli, Tom Zupancic, Jeff Spitzner, Meixiao Long, Karilyn Karilyn Larkin, John Byrd, Carlos Castro, Chris R. Lucas. DNA origami nanostructures as a targeted payload delivery system [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 828.

Sustained antigens delivery using composite microneedles for effective epicutaneous immunotherapy.

Allergen-specific immunotherapy (SIT) is a desirable way of therapy for various allergic diseases such as food allergy (FA). However, frequent visits for more than 3 years and potential adverse effects often hinder patient compliance. Recently, many researchers started focusing on microneedles (MNs) as a new method for SIT. In this study, we proposed an implantable MNs system produced by a two-step casting process, consisting of OVA (antigen)-loaded silk microneedles and a dissolvable, flexible polyvinyl alcohol (PVA) pedestal. Different from PVA, silk fibroin hydrogel has preferable vaccine release ability in vivo and in vitro. Once MNs are inserted into the skin, the PVA pedestal can dissolve in the interstitial fluid of the excised skin within 5 min and implant the OVA-loaded silk microneedle tips in dermal layer as a sustained antigen depot, thus inducing long-lasting immune response for at least 2 weeks. After receiving 3 doses of MN-based immunotherapy, the immune response in OVA-sensitized mice was successfully suppressed, with no apparent side effects. Compared to conventional subcutaneous immunotherapy (total dose of 150 [Formula: see text]g), MN immunotherapy ameliorated systemic anaphylaxis more effectively even at a lower dose (total dose of 30 [Formula: see text]g), demonstrating the antigen dose-sparing potential of the proposed MNs. Moreover, due to the prolonged release effect of silk-PVA composite MNs, the frequency of immunotherapy can be significantly reduced. To sum up, through prolonged skin exposure to antigen, this implantable designed MN may offer a new therapeutic strategy for FA treatment with significant improvements in efficacy and convenience. Schematic illustration of silk-PVA composite microneedles, consisting of OVA (antigen)-loaded silk microneedles and a dissolvable, flexible PVA pedestal. Once inserted into the skin, the PVA pedestal can dissolve in the interstitial fluid of the excised skin within 5 min. Subsequently, the OVA-loaded silk microneedle tips were implanted in the dermal layer as a sustained antigen depot and induced long-lasting immune response. This MNs-based immunotherapy can significantly modulate the Th1/Th2 imbalance of sensitized mice.

Health-Related Quality of Life in Patients With Advanced Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab or Treatment of Physician’s Choice

PurposeLenvatinib and pembrolizumab (LEN+PEMBRO) demonstrated clinically meaningful and statistically significant improvements in efficacy versus treatment of physician’s choice (TPC) in patients with advanced endometrial cancer (aEC) in the phase 3 Study 309/KEYNOTE-775. Health-related quality-of-life (HRQoL) is reported. Patients and MethodsPatients were randomly assigned to receive LEN+PEMBRO (n = 411; LEN 20 mg/day; PEMBRO 200 mg Q3W) or TPC (n = 416; doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 [weekly, 3 weeks on/1 week off]). Impact of treatment on HRQoL assessed by the global health status/quality of life (GHS/QoL) score of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) was a secondary objective; other scales of the Quality-of-Life Questionnaire (QLQ-C30), EORTC QLQ-Endometrial, 24 questions (EORTC QLQ-EN24), and EuroQoL 5 dimensions, 5 levels (EQ-5D-5L) were exploratory objectives. HRQoL was assessed on day 1 of each cycle. Completion/compliance, change from baseline, time to first and definitive deterioration were assessed. No multiplicity adjustments were applied for HRQoL endpoints. ResultsThe latest timepoint at which the predefined rates of completion (≥60%) and compliance (≥80%) were met was week 12. HRQoL at week 12 between treatment groups was generally similar. Time to first deterioration symptom scales favoured LEN+PEMBRO for QLQ-C30 dyspnoea, and QLQ-EN24 for poor body image, tingling/numbness, and hair loss; and TPC was favoured for QLQ-C30 pain, appetite loss, and diarrhoea, and QLQ-EN24 muscular pain. While the QLQ-C30 physical functional scale favoured TPC, other functional scales were generally similar between arms. Time to definitive deterioration favoured LEN+PEMBRO on most scales. ConclusionHRQoL data from Study 309/KEYNOTE-775, with previously published efficacy and safety results, indicate that LEN+PEMBRO has an overall favourable benefit/risk profile versus TPC for the treatment of patients with aEC. ClinicalTrials.govNCT03517449.

Opportunities of Electronic and Optical Sensors in Autonomous Medical Plasma Technologies

Low temperature plasma technology is proving to be at the frontier of emerging medical technologies with real potential to overcome escalating healthcare challenges including antimicrobial and anticancer resistance. However, significant improvements in efficacy, safety, and reproducibility of plasma treatments need to be addressed to realize the full clinical potential of the technology. To improve plasma treatments recent research has focused on integrating automated feedback control systems into medical plasma technologies to maintain optimal performance and safety. However, more advanced diagnostic systems are still needed to provide data into feedback control systems with sufficient levels of sensitivity, accuracy, and reproducibility. These diagnostic systems need to be compatible with the biological target and to also not perturb the plasma treatment. This paper reviews the state-of-the-art electronic and optical sensors that might be suitable to address this unmet technological need, and the steps needed to integrate these sensors into autonomous plasma systems. Realizing this technological gap could facilitate the development of next-generation medical plasma technologies with strong potential to yield superior healthcare outcomes.

PD‐L1 blockade by immune checkpoint inhibitors impairs sensitivity to osimertinib in EGFR‐mutant non‐small cell lung cancer cells

In the previous studies, it was shown that osimertinib plus durvalumab did not achieve satisfactory efficacy, even inferior to osimertinib alone. We found that PD-L1 blockade impaired the efficacy of osimertinib in EGFR-mutant NSCLC cells despite the presence of the tumor microenvironment. Therefore, durvalumab has no synergistic effect on osimertinib, and combination therapy will not enhance the efficacy of osimertinib. In recent years, the management of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation has developed rapidly. Osimertinib is a third generation EGFR tyrosine kinase inhibitor (TKI), which has achieved satisfactory efficacy and tolerability as the first-line (FLARUA study [ref]) and second-line (AURA series of studies [ref]) treatment of patients with EGFR-mutant NSCLC. This suggested that EGFR signaling is involved in the upregulation of programmed cell death ligand 1 (PD-L1) expression, which induces apoptosis of T cells, thereby promoting immune escape of tumor cells [1]. Therefore, several studies were conducted to explore the efficacy and safety of osimertinib combined with PD-L1 monoclonal antibody durvalumab in patients with EGFR-mutant NSCLC. The TATTON study is a phase Ib trial of osimertinib combination therapy, including durvalumab, in treatment of advanced EGFR-mutant NSCLC. Results showed that the combination of osimertinib and durvalumab resulted in an objective response rate (ORR) of 43%, but an increased incidence of interstitial lung disease (ILD) (22%). Another phase III study of osimertinib versus osimertinib plus durvalumab, the CAURAL trial, whose recruitment was terminated early due to the high incidence of ILD in the TATTON trial, showed an ORR of 80% in the osimertinib arm compared with an ORR of 64% in the combination arm [2]. Therefore, the combination of osimertinib plus durvalumab did not appear to provide a significant improvement in efficacy compared with osimertinib alone [3]. Regardless of the impact of durvalumab on the tumor microenvironment and the high incidences of adverse events, whether PD-L1 blockade itself has a synergistic effect on osimertinib treatment is still unknown. The role of PD-L1 blockade in the treatment of EGFR-mutant NSCLC with osimertinib, regardless of the effect on the tumor immune microenvironment, has not been reported. Here, we used a human EGFR-mutant NSCLC cell line HCC4006 (ATCC® CRL-2871™) to test the IC50 of osimertinib alone or in combination with different concentrations of durvalumab to explore the effect of osimertinib in blocking PD-L1. After seeding cells in 96-well plates, the cells were treated with a concentration gradient of osimertinib (manufacturer, city and country) ranging from 1 to 40 µm, diluted in serum-free medium alone or with 0.5 mg/mL durvalumab (manufacturer, city and country), 1 mg/mL durvalumab or 2 mg/mL durvalumab, respectively. After an additional 24 h of incubation, an MTS assay was performed to examine the IC50 of osimertinib against EGFR-mutant NSCLC cells using different solvents. It was proved that the IC50 of osimertinib continued to increase with the increase of durvalumab concentration compared with osimertinib alone, which was 6.202 µm, 9.28 µm, 13.37 µm, and 15.18 µm for osimertinib plus 0.5 mg/mL durvalumab, osimertinib plus 1 mg/mL durvalumab and osimertinib plus 2 mg/mL durvalumab, respectively (Figure 1). Currently, there is still a lack of evidence for first-line osimertinib combined with durvalumab or other immune checkpoint inhibitors (ICIs) in patients with EGFR-mutant NSCLC. In the above-mentioned previous studies, it was shown that combination therapy did not achieve satisfactory efficacy, even inferior to osimertinib alone. Durvalumab blocks PD-L1 on the surface of tumor cells and relieves the suppressive effect of immune cells in the tumor stroma. However, based on in vitro experiments, we found that PD-L1 blockade impaired the efficacy of osimertinib in EGFR-mutant NSCLC cells despite the presence of the tumor microenvironment. Therefore, durvalumab has no synergistic effect on osimertinib, and combination therapy will not enhance the efficacy of osimertinib. In summary, we should be cautious when choosing first-line EGFR-TKIs combined with immunotherapy. Conception/design: Dantong Sun and Junling Li. Collection and/or assembly of data: Dantong Sun and Puyuan Xing. Manuscript writing: Dantong Sun and Junling Li. Final approval of manuscript: All authors. None. The authors declare no conflict of interest. All experiments were carried out following the National Health and Family Planning Commission of the Professional Regulation Commission (PRC) guidelines. Not applicable. Data supporting this report are available from the corresponding authors on reasonable request.

Interim Update on the 'Watch' Registry, a Real-World Observational Study Using Clonoseq® to Monitor MRD in Lymphoid Malignancies

Background: Clinical trials of investigational agents in B-cell malignancies have demonstrated significant improvements in efficacy over the past several years. Despite often high complete response rates, many patients still relapse. All relapses are caused by residual tumor cells, whether detectable by standard clinical assessments or not. To detect low-level disease burdens, known as minimal/measurable residual disease (MRD), highly sensitive technologies are needed. The clonoSEQ® Assay has been cleared by the FDA to detect MRD in the bone marrow of patients with acute lymphoblastic leukemia (ALL) and multiple myeloma (MM) and in blood or bone marrow for patients with chronic lymphocytic leukemia (CLL). clonoSEQ is also available as a laboratory developed test (LDT) to detect MRD in other B-cell malignancies including non-Hodgkin lymphoma (NHL) and in additional sample types such as blood and plasma. Methods: The Watch Registry (NCT04545333; recruiting) is a prospective, multicenter observational study being conducted in the US to collect data from health care providers who use clonoSEQ as part of routine care for their ALL, MM, CLL, and NHL patients. Data collection is focused on understanding the timing of clonoSEQ MRD assessment and subsequent treatment decisions made based upon those results. The ultimate goal of the study is to describe the implementation and impact of the assay in patient management. Eligible patients are ≥ 18 years old, diagnosed with NHL, MM, ALL, or CLL, not enrolled in an interventional clinical study that dictates the frequency of their MRD testing, and whose treating physician is currently or planning to use clonoSEQ to monitor their MRD as part of their routine management. Patients may be in any phase of treatment at enrollment. Planned enrollment is 528 patients with a target of 476 who have ≥ 1 clonoSEQ MRD test during the course of the study. Results: From October 2020 through data cutoff of June 22, 2022, 328 patients have been enrolled across 18 sites (both academic and community). Twenty-three patients have discontinued for reasons including death (9), early site closure (5), failure to detect trackable sequences by clonoSEQ (4), insufficient "ID" sample material (2), enrollment on interventional study (1), site decision (1), patient decision (1). Patients range in age from 18-92 yrs with 136 females and 192 males. Patients have had 0-12 prior lines of therapy. Enrollment by tumor type is 52 ALL, 82 CLL, 94 MM, 82 NHL (32 FL, 27 DLBCL, 23 MCL), and 18 with less common lymphoid malignancies. Time on study ranges from 0.3 to 20.5 months with a median follow up of 6.0 months. To date, 295 clonoSEQ MRD tests have been ordered overall (Table 1) with 188 (63.7%) patients having had ≥ 1 MRD test on study and a range of 0-11 per patient. For those patients who have been tested to date, the most frequent use has been for patients with ALL (2.85 tests/pt) followed by NHL (1.30 test/pt), MM (1.11 tests/pt), and CLL (1.10 tests/pt). Most (74.9%) MRD tests have been ordered during remission (49.2%) or as the first MRD assessment post-hematopoietic cell transplant (HCT; 25.8%). Other timepoints include end of induction (2.7%), pre-HCT (2.7%), and other reasons (16.9%; includes post-chimeric antigen receptor T cell [CAR-T] monitoring). With 272 clonoSEQ results reported as of data cutoff (Table 2), there were 23 (8.5%) positive, 120 (44.1%) positive below limit of detection (LOD), and 129 (47.4%) negative results. Changes to a patient's treatment plan based upon MRD results have been made 31 (11.4%) times. Changes include initiating next line of therapy in 22 (8.1%) instances, intensifying ongoing treatment in 5 instances (1.8%), and reducing treatment intensity in 4 (1.5%) instances. The frequency of future MRD monitoring was changed based upon clonoSEQ results 29 (10.7%) times with 20 (7.4%) instances of an increase in monitoring frequency and 9 (3.3%) decreases. Details of treatment regimens and changes are being collected and will be reported at a later date. Conclusions: MRD is being measured by clonoSEQ across lymphoid malignancies in routine care, and reportedly, mostly for the purpose of monitoring MRD levels during remission (maintenance therapy or observation). With the readout of the many ongoing trials that are assessing the use of MRD to determine treatment regimen or discontinuation across these tumor types, using MRD to inform such decisions in real-world practice will become more common. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Manifold Learning and Nonlinear Homogenization

We describe an efficient domain decomposition-based framework for nonlinear multiscale PDE problems. The framework is inspired by manifold learning techniques and exploits the tangent spaces spanned by the nearest neighbors to compress local solution manifolds. Our framework is applied to a semilinear elliptic equation with oscillatory media and a nonlinear radiative transfer equation; in both cases, significant improvements in efficacy are observed. This new method does not rely on detailed analytical understanding of the multiscale PDEs, such as their asymptotic limits, and thus is more versatile for general multiscale problems.

RNAi Efficiency through dsRNA Injection Is Enhanced by Knockdown of dsRNA Nucleases in the Fall Webworm, Hyphantria cunea (Lepidoptera: Arctiidae).

RNA interference (RNAi) technology is a promising approach used in pest control. The efficiency of RNAi varies considerably among different insect species, and growing evidence suggests that degradation of double-stranded RNA (dsRNA) prior to uptake is an important factor that limits RNAi efficiency in insects. Our recent work on fall webworm (Hyphantria cunea), an important invasive pest in China, showed a relatively low silencing efficiency of RNAi through dsRNA injection, which is considered the most feasible dsRNA delivery method for inducing RNAi, and the factors involved in the mechanism remain unknown. Herein, we first detected the dsRNA-degrading activity in the hemolymph and gut content of H. cunea in ex vivo assays and observed rapid degradation of dsRNA, especially in the hemolymph, which was complete within only 10 min. To determine whether dsRNA degradation could contribute to the low effectiveness of RNAi in H. cunea, four dsRNA nuclease (dsRNase) genes, HcdsRNase1, HcdsRNase2, HcdsRNase3, and HcdsRNase4, were identified by homology searching against the H. cunea transcriptome database, and their transcript levels were subsequently investigated in different tissues, developmental stages, and after dsRNA injection. Our results show that HcdsRNases are highly expressed mainly in gut tissues and hemolymph, and the expression of HcdsRNase3 and HcdsRNase4 were significantly upregulated by dsGFP induction. RNAi-of-RNAi studies, using HcCht5 as a reporter gene, demonstrated that silencing HcdsRNase3 and HcdsRNase4 significantly increases RNAi efficacy via dsHcCht5 injection, and co-silencing these two HcdsRNase genes results in a more significant improvement in efficacy. These results confirm that the RNAi efficacy in H. cunea through dsRNA injection is certainly impaired by dsRNase activity, and that blocking HcdsRNases could potentially improve RNAi, providing a reference for related studies on insects where RNAi has low efficiency.

Precision Combination Therapies Based on Recurrent Oncogenic Coalterations.

We developed the predictive bioinformatics platform REFLECT and a multiomics- based precision combination therapy resource. The REFLECT-selected therapies lead to significant improvements in efficacy and patient survival in preclinical and clinical settings. Use of REFLECT can optimize therapeutic benefit through selection of drug combinations tailored to molecular signatures of tumors. See related commentary by Pugh and Haibe-Kains, p. 1416. This article is highlighted in the In This Issue feature, p. 1397.

Analysis of the Therapeutic Effects of Percutaneous Compression Plate for Femoral Neck Fractures in Young and Middle-Aged Patients: A Retrospective Multicenter and 2-Year Follow-Up Study

Introduction: Traditional internal fixators include hollow compression screw (HCS) and sliding hip screw for femoral neck fractures have a high incidence of complications, and are not conducive to postoperative early rehabilitation and weight-loading of patients. Therefore, femoral neck fractures are referred to as ‘unresolved fractures’. However, single-center results of percutaneous compression plate (PCCP) have showed a significant improvement in efficacy. We retrospectively analyzed the therapeutic effects of PCCP for femoral neck fractures in young and middle-aged patients in a multi-center and &gt;2-year follow-up.&#x0D; Materials and Methods: Between January 2010 and December 2017, 331 patients with femoral neck fractures in young and middle-aged patients fixed with HCS and PCCP in four hospitals were studied retrospectively.&#x0D; Results: There were 182 men and 149 women, with an average age of 47.69 years (age range, 20-65 years). HCS group vs. PCCP group (170 vs. 161). There was no significant difference in the baseline data between the two groups (P&gt;0.05). All patients were followed-up for 24-60 months (mean, 36 months). The operative time and intraoperative bleeding were significantly decreased, whereas the hospital stay significantly longer in HCS group than those in PCCP group (P&lt;0.05). Nonunion in 17 cases and fixation failure in 14 cases in HCS group, whereas 3 and 0 cases, respectively, in PCCP group, showing significant difference (P&lt;0.05). Avascular necrosis (AVN) in 17 cases in HCS group while 15 cases in PCCP group, showing no significant difference (P&gt;0.05). The overall complications in HCS group were greater than that in PCCP group (P&lt;0.05). The Harris hip scores at 6- and 12-month follow-up in group PCCP were significantly improved than those in group HCS (P&lt;0.05), but not significant at 18-, 24- month and last follow-up between the two groups (P&gt;0.05).&#x0D; Conclusion: Our results suggest that PCCP is a stable and reliable internal fixation device with sliding compression effect for femoral neck fractures, which has satisfactory short and mid-term therapeutic effects, but AVN remains unsolved.

Clinical Characteristics and Survival Outcomes of Primary Effusion Lymphoma: A National Cancer Database Study

IntroductionPrimary effusion lymphoma (PEL) is a rare HHV8(+) non–Hodgkin lymphoma associated with HIV infection or other causes of immunosuppression. Large-scale studies describing the natural history of this entity are lacking. Materials and MethodsNational cancer database (NCDB) was queried for patients diagnosed with PEL between 2004 and 2016. All patients age ≥ 18 years diagnosed with PEL were included. We excluded patients with multiple primary malignancies or lost follow-up. Kaplan-Meier and multivariate cox regression were used in the analyses. ResultsOf the 219 PEL patients included in the analysis, 179 (82%) were males, 161 (74%) Caucasian and 49 (22%) African American. Median age at diagnosis was 60 ± 19 years and median OS (mOS) was 8.5 months. One hundred and fifteen were HIV+, 63 HIV-, 111 received chemotherapy, and 101 did not. Patients who received chemotherapy had better mOS compared to patients who did not receive chemotherapy (13 vs. 3 months, P < .001). This difference was observed in HIV+ patients (22.97 vs. 1.97 months, P = .006), but not in HIV- patients (6.24 vs. 8.20 months, P = .752). On multivariate analysis, chemotherapy treatment was associated with better OS (HR 0.502 95% CI 0.324-0.777; P = .002), whereas HIV status did not affect the OS (HR 0.6 95% CI 0.3-1.4; P = .258). ConclusionThis largest retrospective analysis on PEL revealed that current chemotherapeutic approach is significantly beneficial for HIV+ patients but not for HIV- patients. The rapid advancement in HIV treatment might be playing a role in survival improvement among HIV+ patients. Novel therapies are needed to improve the survival of patients with PEL, especially in HIV- patients. MicroabstractPEL is a rare HHV8(+) non–Hodgkin lymphoma. Using national cancer database, we studied clinical characteristics, and outcomes of 219 PEL patients. We found that chemotherapy significantly improved overall survival in HIV+ patients. However, a similar survival improvement was not seen in HIV- patients. Significant improvement in efficacy of antiretroviral therapy is likely contributing to the survival improvement in HIV+ patients.

Dual-Frequency Intravascular Sonothrombolysis: An In Vitro Study.

Thrombo-occlusive disease is one of the leading causes of death worldwide. There has been active research on safe and effective thrombolysis in preclinical and clinical studies. Recently, the dual-frequency transcutaneous sonothrombolysis with contrast agents [microbubbles (MBs)] has been reported to be more efficient in trigging the acoustic cavitation, which leads to a higher lysis rate. Therefore, there is increasing interest in applying dual-frequency technique for more significant efficacy improvement in intravascular sonothrombolysis since a miniaturized intravascular ultrasound transducer typically has a limited power output to fully harness cavitation effects. In this work, we demonstrated this efficacy enhancement by developing a new broadband intravascular transducer and testing dual-frequency sonothromblysis in vitro. A broadband intravascular transducer with a center frequency of 750 kHz and a footprint size of 1.4 mm was designed, fabricated, and characterized. The measured -6-dB fractional bandwidth is 68.1%, and the peak negative pressure is 1.5 MPa under the driving voltage of 80 Vpp. By keeping one frequency component at 750 kHz, the second frequency component was selected from 450 to 650 kHz with an interval of 50 kHz. The in vitro sonothrombolysis tests were conducted with a flow model and the results indicated that the MB-mediated, dual-frequency (750+500 kHz) sonothrombolysis yields an 85% higher lysis rate compared with the single-frequency treatment, and the lysis rate of dual-frequency sonothrombolysis increases with the difference between the two frequency components. These findings suggest a dual-frequency excitation technique for more efficient intravascular sonothrombolysis than conventional single-frequency excitation.

A new approach for CW-TSCPC to improve its safety and efficacy in glaucoma treatment

The goal of our study was to compare the outcomes of transscleral diode cyclophotocoagulation using a new protocol with new settings. In fact, we targeted the ciliary body guided by transillumination, reduced the energy applied at each spot, and enlarged the treatment area posteriorly from the pars plicata to the pars plana. Data were collected retrospectively from two groups of glaucoma patients. The first group of patients underwent transscleral diode laser cyclophotocoagulation as usual, with one-row applications of a maximum of 1200mW of energy and a duration of 2000ms. The second group was treated in three rows, using the same settings as the first group. Transillumination was used continuously during all of our procedures, to focus accurately on the location of the ciliary body. Outcome measures included intraocular pressure (IOP) and visual acuity (VA) at baseline and at a minimum of 3 months postoperatively, as well as complications occurring up until last follow-up visit. Patients were considered successfully treated if their intraocular pressure was lowered by at least 25% compared to their baseline or if their intraocular pressure was less than 21mmHg after the procedure, with or without glaucoma medications. Sixty eyes were treated with the one-row protocol, followed by 508 eyes treated with the three-row protocol. The mean follow-up was 19 (range 3-31) months. Success rates were 62% and 86% for the one-row group and three-row group, respectively. The IOP decrease was 40.5% (a mean reduction from 37.5±8.1mmHg to 22.3±10.2mmHg) in the one-row group and 57.6% in the three-row group (mean reduction from 36.05±10.4mmHg to 15.7±7.3mmHg), which was statistically significant in each group (P=0.0001). Additionally, a significant improvement in efficacy was found in the 3-row compared to the 1-row group (P=0.0001) No significant difference was found in VA before or after the procedure or between the 2 groups. No serious complications were reported. Diode laser TSCPC is a practical, rapid and well-tolerated procedure. The treatment protocol used, with lower energy levels applied to the eye, guided systematically by transillumination and targeting a wider area, appears to be safer and more effective.

802P A machine learning-based framework for efficacy and safety analysis of PD-1PD-L1 inhibitor application in gynaecological cancer on incomplete post-marketing surveillance dataset

Post-marketing surveillance of antineoplastic agents is performed to evaluate the efficacy and safety in patients aiming at expanding drug indications and discovering potential adverse reactions. The real-world data is fraught with multiple missing values. Literature addressing different strategies for dealing with missing data in such a situation is scarce. Using machine learning algorithms for predicting therapeutic response to PD-1/PD-L1 Inhibitor has attracted attention in recent years. However, training a predictive model usually requires imaging or biomarker information, which is rarely available in the post-marketing surveillance data. To address these challenges, we propose an ensemble learning-based framework that utilizes a multi-model fusion strategy at the stages of both data imputation and outcome prediction. The proposed method is evaluated on a gynecological cancer post-marketing surveillance dataset with 118 patient samples, collected from Sep 2019 to Feb 2021. Compared to several existing imputation algorithms, our method demonstrates a superior capability to obtain high-quality imputed values, effectively boosting the overall performance of outcome prediction. The study also compares three PD-1 inhibitors, including Camrelizumab (with 51 patient samples), Sintilimab (44 samples), and Toripalimab (23 samples). Statistical results show that Toripalimab presents a significant efficacy improvement in the RECIST metric, with 48% CR, 35% PR, 4% SD, and 13% PD, compared to Camrelizumab (29% CR, 22% PR, 14% SD, 24% PD) and Sintilimab (18% CR, 48% PR, 20% SD, 14% PD). The death rates for Camrelizumab, Sintilimab, and Toripalimab, are 17.6%, 13.6%, and 0%. With respect to adverse reactions (AE), the rates of organ dysfunction are 62.7%, 50.0%, and 43.5%, and the rates of general discomfort are 17.6%, 47.7%, and 17.4%, for Camrelizumab, Sintilimab, and Toripalimab, respectively. Our method can be used as an effective analytical tool for efficacy and safety evaluation on an incomplete post-marketing surveillance dataset.

Cost-Effectiveness of Daratumumab Plus Lenalidomide Plus Dexamethasone Versus Lenalidomide Plus Dexamethasone for Treatment of Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy: An Analysis of the Pollux Trial

Background: Daratumumab has been approved in the United States (US) for patients with multiple myeloma (MM). In the POLLUX trial of MM patients who had received at least one prior line of therapy, daratumumab plus lenalidomide plus dexamethasone (DRd) showed significant improvements in efficacy compared to lenalidomide plus dexamethasone (Rd) (Dimopoulos, NEJM, 2016). However, limited information is available on the cost-effectiveness of DRd. A decision-analytic model was developed to consider direct medical costs from a US payer perspective and to explore the cost-effectiveness of DRd versus Rd in previously treated MM and in a subgroup of patients with only one prior line of therapy (first relapse).Methods: The model structure took the form of a partitioned survival analysis with three health states: progression-free survival (PFS), progressive disease, and death. A range of parametric survival functions were fitted to patient-level PFS data from the POLLUX trial with (1) selection based on the Akaike and Bayesian information criteria and (2) priority given to the external validity of extrapolations with conservative survival projections. Diagnostic plots were used to assess the validity of the proportional hazards assumption between DRd and Rd. Due to the number of data events and the follow-up time of the trial, overall survival (OS) was not estimated via parametric extrapolation of trial data but rather by its relationship to PFS, based on a retrospective analysis of approximately 23,000 MM patients (Felix, BMC Cancer, 2013). Drug costs were taken from wholesale acquisition costs (Red Book, 2017). Dosing information was extracted from the POLLUX trial. Drug-administration costs were sourced from Centers for Medicare and Medicaid Services, 2017 and health-state costs, subsequent therapy utilization patterns, and utility weights were sourced from published literature. Cost-effectiveness was estimated over a lifetime horizon, with costs and outcomes discounted at 3% per annum. Incremental cost-effectiveness ratios were calculated, specifically the incremental cost per quality-adjusted life-year (QALY) gained and the incremental cost per life-year gained. One-way and probabilistic sensitivity analyses (PSA) were conducted, as well as scenario analyses around parametric curve selection. All analyses were performed for the overall trial population and for the subgroup of patients with a first relapse.Results: The best-fit, conservative parametric function for all patients was Weibull and for first relapse patients, exponential. All results were presented as discounted values (Table 1). In the overall trial population, the mean PFS was estimated to be 4.12 and 1.84 years for DRd and Rd, respectively. DRd resulted in an average of 4.24 additional life-years (8.43 life-years - 4.19 life-years) and 3.66 additional QALYs (7.12 QALYs - 3.46 QALYs) over Rd. Costs increased for DRd; the majority were related to drug acquisition of daratumumab and to longer time on treatment due to a longer PFS period. Incremental cost-effectiveness ratios in the overall trial population were $153,110 per life-year gained and $177,499 per QALY gained. Overall, survival (life-years), PFS, and QALYs were greater in the first relapse subgroup for both DRd and Rd than in the overall trial population. Mean PFS was estimated to be 5.02 and 2.09 years for DRd and Rd, respectively. DRd resulted in an average of 4.83 additional life-years (9.51 life-years - 4.68 life-years) and 4.17 additional QALYs (8.06 QALYs - 3.89 QALYs) over Rd. Incremental cost-effectiveness ratios in the first relapse subgroup were $165,167 per life-year gained and $191,024 per QALY gained. One-way and scenario analyses indicated the most sensitive parameters to be PFS distribution, the relationship between PFS and OS, discount rates, utility weights, and drug-acquisition costs. PSA was summarized in the form of scatter plots and cost-effectiveness acceptability curves.Conclusion: Based on the range of plausible cost-effectiveness ratio thresholds ($183,000-$264,000 per life-year gained and $109,000-$297,000 per QALY gained) reported in the 2003 cost-effectiveness decision rules for the US (Braithwaite, Med Care, 2008), this analysis suggests that DRd is cost-effective compared to Rd in the treatment of previously treated MM. DRd offers a clinically superior and cost-responsible treatment option for previously treated MM. [Display omitted] DisclosuresMaiese:Janssen: Employment; Johnson & Johnson, LLC: Equity Ownership. Graham:Janssen: Research Funding; RTI Health Solutions: Employment. Hawe:RTI Health Solutions: Employment; Janssen: Research Funding. Le Moine:RTI Health Solutions: Employment; Janssen: Research Funding. Abraham:Janssen Oncology (Johnson & Johnson, LLC): Consultancy. Senbetta:Johnson & Johnson, LLC: Equity Ownership; Janssen: Employment.

Comparison of efficacy and safety of topical luliconazole with topical fluconazole against tinea corporis in a tertiary care hospital

Background: Dermatophytosis is a common cutaneous infection worldwide with prevalence varying from 20% to 25%. Luliconazole is a newer topical antifungal applied once daily with greater reservoir property in stratum corneum. Objective of the study was to compare the clinical efficacy and safety of luliconazole 1% cream with Fluconazole 1% cream in patients with mild to severe grades of tinea corporis.Methods: A total of 100 patients with mycologically confirmed tinea corporis were randomised into group A and B respectively. Group A, 50 patients received luliconazole 1% for 2 weeks and group B, 50 patients received fluconazole 1% cream for 4 weeks. Patients were clinically and mycologically evaluated on 0, 2nd and 4th week of treatment and followed up on 8th week for any relapse.Results: Significant improvement in efficacy was seen in Luliconazole while compared with fluconazole group against tinea corporis infection. Mycological cure and clinical improvement showed significant difference in group A. The safety and tolerability profile of both groups were good and statistically comparable.Conclusions: Luliconazole 1% cream is found to be safe, effective and tolerable with low incidence of relapse than fluconazole 1% cream.