Updated Data Research Articles

Long term emission and simulation on air quality from residential coal burning in China

Abstract Residential coal burning (RCB) is a notable contribution source of airborne pollution in China. To address this, a suite of control policies has been implemented, leading to a shift in the energy structure and a limitation in pollution emission within RCB sector. This study presents emission inventories for SO2, NOx, CO, and PM2.5 from RCB between 2010 and 2020, utilizing both published and measured emission factors (EFs). Furthermore, the emission amounts of pollution in year 2030 and 2050 were projected. Since 2010 to 2020, emission of pollution from RCB sector has demonstrated a noticeable decreasing trend, especially in policy priority regions. The emission amounts in policy priority regions are at a similar level to those in the South region. The most substantial reductions were observed in the Beijing-Tianjin-Hebei (BTH) region, with decreases of 69.8%, 74.2%, 74.8%, 79.8% 60.6% for SO2, NOx, CO, PM2.5 and BC respectively. Finally, the updated emission data used to calibrate the emission in GEOS-Chem model and to simulated national particle and gas pollution concentration in heating season emitted from RCB for year 2020 and 2030. The simulation results demonstrate a migration in the emission intensity center in the Northeast region. For SO₂, NO₂ and PM2.5, the RCB contribution decreased from 3.1, 18.3 and 19.9 μg/m³ in 2020 to 1.8, 11.6 and 9.8 μg/m³ in 2030, respectively. The SO2, NO2 and PM2.5 impact from RCB was -0.03 to 0.29, 0.61 to 7.04 and 1.2 to 2.9 μg/m3 on average in 2030 which shown a minor impact on ambient pollution in BTH region during heating season.

First-in-human phase 1/2 study (MYCHELANGELO I) of first-in-class epigenomic controller OTX-2002 targeting MYC oncogene in patients with hepatocellular carcinoma (HCC) and other solid tumors.

606 Background: The c-MYC (MYC) oncogene is a master transcription factor of tumor cell and microenvironment regulation; it is often dysregulated in cancer, including HCC. OTX-2002 is a MYC-targeted Epigenomic Controller (MYC-EC), an mRNA drug substance encapsulated in a clinical lipid nanoparticle (LNP), designed to downregulate MYC expression pre-transcriptionally with high specificity and durability, inhibiting tumor cell viability while sparing normal cells. Methods: A first-in-human dose-escalation study (NCT05497453) investigates OTX-2002 monotherapy in HCC and other solid tumors. Key outcomes include safety, tolerability, pharmacokinetics (PK) and the recommended dose for expansion. In addition to standard safety measures, LNP-associated safety measures including cytokine profiling and an assessment of the presence of anti-PEG antibodies (ADA) were included. Initial pharmacodynamic activity (PD) was assessed via measurement of DNA methylation at the MYC locus in cell-free DNA [cfDNA] from whole blood. Results: As of August 23, 2024, 24 patients were treated at 6 doses (19 HCC, 1 colorectal, 1 cervical, 1 pancreatic, 2 sarcoma). OTX-2002 was generally well-tolerated; most adverse events (89%) were low grade, with infusion-related reactions being the most common (30%). Consistent with known LNP profiles, OTX-2002 adverse events were transient and manageable, including cytokine and ADA expression levels. Plasma PK exposures of OTX-2002 were linear across the first five doses analyzed. Significant, on-target dose-dependent changes in MYC gene methylation were seen in cfDNA for all patients post-dose and were durable for at least 15 days, consistent with the designed durability of the MYC-EC. Updated data will be presented. Conclusions: OTX-2002 is well-tolerated and induces rapid and durable epigenomic changes to the MYC locus. These results provide clinical proof of mechanism of the epigenomic controller platform and support continued development of OTX-2002. Clinical trial information: NCT05497453 .

A phase 1 dose-escalation study of GCC19CART: A novel CAR T-cell therapy for metastatic colorectal cancer in the United States.

175 Background: GCC19CART, the first clinical candidate from the CoupledCAR solid tumor platform, pairs solid tumor CAR T-cells with CD19-targeting CAR T-cells to enhance proliferation, activation, and persistence against solid tumors. GCC19CART targets guanylate cyclase-C (GCC), a known mucosal marker. Building on the promising results from a clinical trial in China, a phase 1 study was initiated in the US for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy. As of August 14, 2024, a total of 9 subjects have been treated. Methods: Subjects were initially screened for GCC expression, however screening was discontinued after >95% of subjects with mCRC demonstrated GCC expression by immunohistochemistry (95/98). Eligible subjects underwent leukapheresis, lymphodepleting chemotherapy (fludarabine 30mg/m 2 and cyclophosphamide 300mg/m 2 on day-3), and then infusion of a single dose GCC19CART. Objective response was assessed by RECIST v1.1. Results: Four subjects have been enrolled at dose level 1 (1x10 6 cells/kg) and 5 subjects at dose level 2 (2x10 6 cells/kg). The most common adverse events were cytokine release syndrome (CRS) in 9/9 subjects (Grade 1: 6/9 [66.7%] and Grade 2: 3/9 [33.3%]) and diarrhea in 8/9 subjects (Grade 1: 3/9 [33.3%], Grade 2: 3/9 [33.3%], Grade 3: 2/9 [22.2%]). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2/9 subjects (Grade 2: 1/9 [11.1%] or Grade 3: 1/9 [11.1%]) and resolved rapidly with corticosteroid and dasatinib treatment. Three out of 9 subjects had a mild tremor (Grade 1) that resolved with corticosteroids. One subject experienced a dose-limiting toxicity (DLT) at dose level 2, presenting with Grade 3 diarrhea, Grade 4 enterocolitis and Grade 5 sepsis, and died from fungal sepsis 48 days post-infusion. At dose level 1, the overall response rate (ORR) was 50.0% (2/4). Two subjects demonstrated a partial response (PR) with one confirmed PR, while 1 additional subject had partial metabolic response on PET/CT with stable disease (SD) and 1 patient had progressive disease. At dose level 2, the ORR was 80% (4/5), including 1 subject with a pathological complete response, and 3 with a confirmed partial response, of which 1 had a complete metabolic response on PETCT. Conclusions: Preliminary results indicate that GCC19CART exhibits significant clinical activity in patients with refractory mCRC. Adverse events were related to GCC19CART mechanism and in line with what has been observed with other CAR T-cell products. Strategies to further optimize the management of treatment-related diarrhea are currently being implemented. The trial is ongoing and updated data will be presented. Clinical trial information: NCT05319314 .

Short-course radiotherapy (SCRT) followed by fruquintinib plus adebrelimab and CAPOX in the total neoadjuvant therapy of locally advanced rectal cancer (LARC): A multicenter, single-arm, open-label, phase II study (UNION TNT).

192 Background: We have demonstrated that neoadjuvant SCRT followed by PD-1 inhibitor plus CAPOX for LARC patients (pts) showed a higher pCR rate and a well-tolerated safety profile in phase III UNION study. Fruquintinib is a potent and highly selective VEGFR inhibitor, which had been approved for previously treated mCRC pts. This study aimed to investigate the efficacy and safety of SCRT followed by fruquintinib plus adebrelimab and CAPOX as a total neoadjuvant therapy for high-risk LARC pts. Methods: In this prospective, open-label, multi-centers, single-arm phase 2 study (NCT06234007), pts diagnosed with newly diagnosed and high risk LARC were recruited. Pts received SCRT (25Gy/5f) followed by six cycles of fruquintinib (4mg, qd, po, q3w,for the initial 6 pts in the safety run-in period, dosage would be adjusted based on dose-limited toxicities in the 1st cycle) combined with adebrelimab (1200mg, iv, d1, q3w) and CAPOX (q3w). Primary endpoint was CR rate (including clinical CR & pathologic CR). Secondary endpoints included 3-year EFS rate, OS, R0 resection rate and safety. Results: As of 30 Aug 2024, 45 pts were enrolled (median age 59 years [range: 24-75], 26 males, 23 clinical T4 stage and 20 clinical N2 stage, 36 with EMVI positive, 31 with MRF positive, 22 tumor located ≤5cm from the anal verge). Up to 20 Sep 2024, all pts completed SCRT, 73.33% (33/45), 57.78% (26/45) and 31.11% (14/45) pts completed two, four and six cycles of combination therapy, respectively. At data cut-off, of 33 pts included in the efficacy analysis, 28 pts underwent MRI examination and mrTRG results were available, the remaining 5 pts had early surgery due to AEs/serious AEs. 35.7% (10/28) and 46.43% (13/28) pts were classified as mrTRG1 and mrTRG2, respectively. Of 19 pts who underwent surgery, R0 rate was achieved in all 19 pts (100%) and pCR was achieved in 12 pts (63.16%). Moreover, 1 pt achieved cCR during neoadjuvant therapy, thus the treatment strategy provided a CR rate of 65% (1 cCR plus 12 pCR divided by 20). Grade 3/4 adverse effects (AEs) occurred in 16 pts (47.06%), and most commonly were lymphocyte count decreased (n=6, 18.18%), diarrhea (n=5, 15.15%) and AST increased (n=2, 6.06%). 4 serious AEs reported with intestinal perforation and all achieved pCR after surgery therapy. No treatment related death was reported. Conclusions: SCRT followed by fruquintinib combined with adebrelimab and CAPOX as a total neoadjuvant therapy showed promising CR rate and favorable pCR for high-risk LARC pts, and the safety profile was generally manageable. This treatment strategy might be a potential option as neoadjuvant therapy for high-risk LARC pts. Updated data will be presented in the future. Clinical trial information: NCT06234007 .

Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors.

724 Background: RMC-9805 is a potent, oral, RAS(ON) G12D-selective, covalent, tri-complex inhibitor targeting the active, GTP-bound state of oncogenic RAS G12D isoforms. Despite low response rates to current standard of care (SOC), no RAS-targeted therapy is approved for G12D PDAC. Methods: In this Phase 1 study (NCT06040541), patients with previously treated, advanced KRAS G12D solid tumors received escalating RMC-9805 doses (150-1200 mg once daily [QD] or 300-600 mg twice daily [BID]). Treatment cycles were every 3 wks. Antitumor activity was assessed every 6 wks the first 24 wks then every 9 wks. Additional patients were enrolled at RMC-9805 doses that cleared the dose-limiting toxicity (DLT) evaluation to further characterize pharmacokinetics, safety, antitumor activity, and biomarkers. Plasma for ctDNA analysis was collected at baseline (BL; cycle 1, day 1 [C1D1] or screening), and on treatment (OT; C2D1 or C3D1). Results: As of Sept 2, 2024, 179 patients with KRAS G12D solid tumors (most having PDAC; n=104 [58%]) received 5 escalating dose levels of RMC-9805 (150-1200 mg daily). No DLTs or Grade 4 or 5 treatment-related adverse events (TRAEs) were reported, and the maximum tolerated dose (MTD) was not reached. Among patients who received a candidate recommended phase 2 dose (RP2D) of 1200 mg daily (1200 mg QD [n=60] or 600 mg BID [n=39]), the most common (≥10% of patients) TRAEs were nausea (27%), diarrhea (20%), vomiting (15%), and rash (10%), all of which were Grade 1 or 2 severity. One Grade 3 TRAE (ALT elevation) was observed in a patient with PDAC and a history of ALT elevation, biliary stenting, and liver metastasis. No patients treated with 1200 mg daily discontinued treatment due to TRAEs and 4% of patients had dose reductions due to TRAEs. In patients with PDAC receiving RMC-9805 daily at 1200 mg QD (n=20) or 600 mg BID (n=20) who enrolled at least 14 wks prior to data cutoff, the objective response rate (confirmed response or pending confirmation) was 30%, and the disease control rate was 80%. Of 28 patients who had KRAS G12D mutations detected in ctDNA at BL and were evaluable for OT assessment, 86% had an OT decrease >50% from BL of detectable KRAS G12D mutations, and 39% had a 100% OT clearance. Updated data will be presented. Conclusions: Oral RMC-9805 showed encouraging initial antitumor activity with early and deep reductions in KRAS G12D ctDNA in patients with KRAS G12D PDAC. Tolerability was favorable relative to SOC chemotherapy for PDAC and manageable. This overall safety profile and antitumor activity support continued evaluation as monotherapy in patients with KRAS G12D PDAC, and in combination with chemotherapy and targeted therapies, including the RAS(ON) multi-selective inhibitor RMC-6236. Clinical trial information: NCT06040541 .

Phage therapy in the management of respiratory and pulmonary infections: a systematic review.

Lower respiratory tract infections (LRTIs) pose a significant threat to global health, causing more than 2 million deaths worldwide. This menace is intensified by the alarming increase in drug resistance, which limits the availability of effective antibiotics for bacterial respiratory infections. Consequently, there is an urgent demand for alternative therapeutic options. Phage therapy (PT) has re-emerged as a promising therapeutic approach and as an adjunct to antibiotic treatment. This systematic review synthesises the application of PT for LRTIs in humans, providing unified and updated data on the evaluation of the safety and efficacy of PT for LRTIs. Systematic review. Following the PRISMA guidelines, a comprehensive search strategy was carried out (spanning January 2000 - February 2024) in four databases: PubMed, Scopus, ScienceDirect and Web of Science to retrieve published records of PT for LRTIs in humans only. The reference list of each included study was evaluated for possible inclusion of other relevant articles. Among the 18 records that fulfilled the inclusion criteria, 70 patients were administered PT. Microbiologically, 71.42% (n = 50/70) of the patients improved; with either the eradication of the pathogen or a decrease in bacterial load, whilst 15.71% (n = 11/70) did not record any improvement. About 5.71% (n = 4/70) recorded a partial/incomplete improvement, whilst 7.14% (n = 5/70) of the patients microbiological outcomes were unspecified. Clinically, up to 74.29% (n = 52/70) of the patients improved, whilst 10.00% (n = 7/70) of the patients showed no improvement. Another 2.86% (n = 2/70) recorded partial/incomplete improvement, whilst 12.86% (n = 9/70) were uncategorized. Phage titres that yielded positive outcomes ranged from 105 to 1012 PFU/mL. Studies that achieved a substantial phage titre at the site of infection frequently observed notable improvements. Regarding the safety of PT, 77.78% (N = 14/18) of the studies did not record any adverse effects after PT was administered, whilst 16.66% (n = 3/18) of the studies reported adverse effects. Based on recently published data originating mainly from observational studies, PT has shown considerable efficacy and safety in the treatment of LRTIs. However, there is a lack of uniform methodologies and protocols across different PT cases in the management of LRTIs. Consequently, there is a need for additional clinical studies to establish standardised pharmacokinetic elements and an overall protocol for PT. By doing so, we can fully unlock the potential of PT in effectively managing clinical bacterial infections, including LRTIs.

Preliminary phase 1/1b dose expansion results of the bifunctional EGFR/TGFβ inhibitor ficerafusp alfa (BCA101) with pembrolizumab in patients with squamous cell carcinoma of the anal canal.

4 Background: Anti-PD-1 monotherapy has limited efficacy in patients (pts) with advanced squamous cell cancer of the anal canal (SCAC). In KN-158, pembrolizumab (P) was reported to have an ORR of 10%, DCR of 25%, and a 12-month PFS rate of 15% in patients with incurable SCAC. TGFβ promotes immunosuppression within the tumor microenvironment, and inhibition of this pathway may improve tumor susceptibility to immune checkpoint blockade.Ficerafusp alfa (F)is a bifunctional EGFR/TGFβ inhibitor with manageable safety and favorable preliminary anti-tumor efficacy in advanced solid tumors (ESMO 2022 731MO). We evaluated the combination of F+P in pts with chemotherapy-refractory locally advanced/unresectable or metastatic SCAC. Methods: This single-arm, multicenter dose expansion from an ongoing phase I/Ib trial enrolled pts with ICI-naïve SCAC that was locally advanced/unresectable or metastatic, who had received 1-2 prior lines of chemotherapy. Pts received ficerafusp alfa (1500 mg IV on days 1, 8, 15) and pembrolizumab (200 mg IV on day 1) every 21-day cycle. The primary endpoint was safety (CTCAE v5), and secondary endpoints were radiographic response (RECIST 1.1), duration of response, progression-free survival, and overall survival. Results: Among 26 pts treated, 21 (81%) were female, and median age was 61 (range: 43-82). As of 7/2024, 22 pts are evaluable for efficacy. ORR was 32% (95% CI 13.9-54.9%). Six of the seven responses were confirmed, including one pt with a radiographic PR with pathologic CR to F+P. Seven pts (32%) achieved SD as best response, resulting in DCR of 64%. Median PFS was 2.8 months (95% CI 1.4-14.8) and the PFS rate at 12 months was 36%. G3 treatment-related adverse events were observed in 10/26 pts (38%, most common: Anemia (19%) and acneiform rash (12%)). TRAEs led to permanent discontinuation of study treatment in 2 pts (8%). The most common TRAEs of any grade were acneiform rash (13/26, 50%), epistaxis (46%) and headache (38%). Conclusions: The addition of ficerafusp alfa demonstrated encouraging efficacy, with increased ORR, DCR, and 12-month PFS relative to historical precedent with pembrolizumab alone. Safety and tolerability were acceptable. Further investigation of this combination in pts with advanced SCAC is warranted. Updated data will be presented. Study funded by Bicara Therapeutics Inc. with access to pembrolizumab in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (NCT04429542). Clinical trial information: NCT04429542 .

Randomized study to assess colonic microbiome changes in response to energy drink consumption (ROSANNA Trial).

TPS325 Background: Colorectal cancer (CRC), the second leading cause of cancer deaths in the US, is increasingly diagnosed in individuals under 50. This rise in early-onset CRC (eoCRC) led the U.S. Preventative Services Task Force to recommend a reduction in the age to begin colorectal cancer screening in average-risk persons, from 50 to 45. The etiology of eoCRC is multifaceted, with one postulated theory pointing to alterations in the young adult colonic microbiome. Hydrogen sulfide (H 2 S) producing bacteria, like Bilophila wadsworthia , Fusobacterium nucleatum and Atopobium parvulum , are typically minor gut microbiota components but are overrepresented in CRC cases, linked to inflammation, and may promote a pro-carcinogenic environment. These bacteria preferentially use taurine, an essential amino acid, as a primary energy source. Energy drinks represent one of the largest dietary sources (6-16x normal daily intake) of taurine in contemporary diets. Our hypothesis is that high taurine levels in energy drinks could exacerbate CRC risk by promoting preferential growth and metabolic activities of already present H 2 S-producing bacteria, contributing to the rise of eoCRC. Methods: This randomized open-label trial is actively enrolling up to 60 young adults (18-40 years) without personal or family history of CRC, other major GI disease/distress, and baseline infrequent energy drink consumption. Group 1 (Arm A; n=30), will consist of subjects consuming at least one of two protocol-specified energy drinks daily for 4 weeks. Group 2 (Arm B; n=30), will consist of usual dietary intake. Enrollments are randomized 1:1 and stratified, by gender, age (18-25 vs. 26-40), and baseline energy drink consumption (rare/none vs. 1-2 per week). Every subject will complete: 1) a daily dietary and fitness log, 2) a weekly wellness log, 3) collection of stool/saliva/skin/urine at 3 sequential time points (baseline, after 2 weeks, after 4 weeks), and 4) blood collection at the same time points. The primary endpoint is the change in H 2 S-metabolizing bacterial communities between baseline and 1 month of energy drink exposure within Arm A and also compared to those in Arm B using microbiome analysis (diversity, taxonomy, sulfur-enriched gene pathways). Several secondary and exploratory assessments include changes related to subject demographic and dietary differences, concordance of microbiome changes with dietary logs and in other biospecimens beyond stool, H 2 S-production measurements, and analyses of subject metabolic and immune function. Trial opened in February 2024 with active enrollment ongoing. Updated data on trial status and any amendment modifications will be presented at the meeting. Clinical trial information: NCT06137248 .

A multicenter, prospective phase II trial of second-line aflibercept plus FOLFIRI in patients with metastatic colorectal cancer refractory to anti-EGFR agents (HGCSG1801): Updated analyses.

147 Background: The HGCSG1801 trial evaluated the treatment outcomes of aflibercept (AFL) plus FOLFIRI for patients(pts) with metastatic colorectal cancer (mCRC) refractory to an oxaliplatin-based regimen combined with an anti-EGFR agent. Here we report results of the updated efficacy, safety, and a biomarker analysis. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m 2 , leucovorin 200 mg/m 2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m 2 , and infusional 5-FU 2400 mg/m 2 /46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was 6-month progression-free survival (PFS) rate, and the secondary endpoints included overall survival (OS), PFS, overall response rate (ORR), disease control rate (DCR), and adverse events. Angiogenic factors were analyzed in plasma sample using a Luminex multiplex assay using the Cox proportional hazards model. This study was sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and supported by a grant from Sanofi. Results: Forty-three pts were enrolled between November 2019 and October 2022. The data cut-off date was April 30, 2024. The 6-month PFS rate was 59.0% (90% confidence interval [CI], 45.8–72.1%). Median PFS and OS were 7.3 months (95% CI, 5.5–11.0 months) and 18.8 months (95% CI, 12.9–26.6 months), respectively. The ORR was 20.9% (95% CI, 10.0–36.0%) and DCR was 88.4% (95% CI, 74.9–96.1%). No deaths and no new safety signals with a causal relation to the study treatment were observed. A biomarker analysis using pretreatment plasma samples showed a trend toward better PFS in pts with low VEGF-A (hazard ratio [HR] 0.40 [95% CI, 0.18-0.91]), TSP-2 (HR 0.40 [95% CI, 0.18-0.88]) or IL-8 levels (HR 0.43 [95% CI, 0.20-0.93]). There was also a trend toward better OS in pts with low levels of TSP-2 (HR 0.30 [95% CI, 0.11-0.81]) or TIMP-1 (HR 0.20 [95% CI, 0.06-0.69]). Conclusions: These updated data further support the activity and manageable safety profile of AFL plus FOLFIRI for pts with mCRC who failed an oxaliplatin-based regimen combined with an anti-EGFR agent. It was suggested the association between some angiogenic factors in plasma samples and the activity of AFL plus FOLFIRI in mCRC. Clinical trial information: jRCTs011190006 .

A phase 1b dose escalation trial of gemcitabine and nab-paclitaxel in combination with lixumistat in patients with advanced pancreatic cancer.

743 Background: Despite recent advances, there are limited effective therapeutic options for pancreatic ductal adenocarcinoma (PDAC). Conventional chemotherapy can be difficult to tolerate and offers modest survival benefits. Lixumistat is a small molecule biguanide that inhibits the first and rate-limiting step of the oxidative phosphorylation pathway, which is critical to the survival of PDAC tumor cells. A first-in-human dose escalation trial of Lixumistat in solid tumors demonstrated a favorable safety profile and a recommended phase 2 dose (RP2D) of 800 mg per day (QD) (1). Methods: A single center Phase 1b study is currently enrolling patients with treatment-naïve metastatic PDAC to evaluate the safety and tolerability of Lixumistat when combined with standard-of-care gemcitabine (Gem) plus nab- paclitaxel (NP) (NCT05497778). The initial escalation cohort received oral Lixumistat at 400 mg QD; the subsequent escalation cohort received oral Lixumistat at 800 mg QD. All patients also receive fixed doses of intravenous (IV) NP (125 mg/m 2 ) and IV Gem (1000 mg/m 2 ) on Days 1, 8, and 15 (28 day cycle). Here we report the preliminary results from the escalation phase of the trial. Results: Thirteen patients have been treated: 7 at 400 mg and 6 at 800 mg. There were no grade 4-5 toxicities. Two patients experienced a DLT at the 800 mg dose (grade 3 diarrhea and grade 3 fatigue); no DLTs were observed at the 400 mg dose. The most common Lixumistat related toxicities were Grade 1/2 nausea/vomiting (controlled with anti-emetics), skin rash, fatigue, and diarrhea. Grade 1-3 thrombocytopenia, neutropenia, and peripheral sensory neuropathy events were no more than expected with this combination and managed with Gem/NP dose reduction, omission of day 8, or therapy hold until resolved to Grade 1. Based on toxicities observed at 800 mg, 400 mg is the RP2D. Among 6 response-evaluable patients treated at the RP2D, 2 achieved an objective partial response (ORR = 33%, 95% CI: 4.3%-77.3%); 4 patients had stable disease with tumor shrinkage observed in 3 of these patients (12%, 22% and 23% reduction); and the DCR was 100% (95% CI: 54.1%-100%). Notably, a patient from the 800 mg cohort who was dose reduced to 400 mg after DLT achieved a complete response in their target lesions. Current median follow-up time is 13.2 months, and 2 patients have died. Estimated median PFS is 12.9 months (95% CI: 3.65, NA) and estimated median OS is 18 months (95% CI: 6.42, NA). Four patients remain on active treatment at the time of analysis. Conclusions: When combined with Gem and NP; a dose of 400 mg of Lixumistat QD was demonstrated to be safe, tolerable and identified as the RP2D. This trial is currently enrolling patients at the RP2D in the expansion cohort. Updated data on safety and efficacy will be presented at the meeting. 1. Janku 2022. Clinical trial information: NCT05497778 .

Practical management of adverse events in patients receiving tarlatamab, a delta-like ligand 3-targeted bispecific T-cell engager immunotherapy, for previously treated small cell lung cancer.

Tarlatamab is a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 (DLL3) and the cluster of differentiation 3 (CD3) molecule. In the phase 2 DeLLphi-301 trial of tarlatamab for patients with previously treated small cell lung cancer, tarlatamab 10 mg every 2 weeks achieved durable responses and encouraging survival outcomes. Analyses of updated safety data from the DeLLphi-301 trial demonstrated that the most common treatment-emergent adverse events were cytokine release syndrome (53%), pyrexia (38%), decreased appetite (36%), dysgeusia (32%), and an emia (30%). Cytokine release syndrome was mostly grade 1 or 2 in severity, occurred primarily after the first or second tarlatamab dose, and was managed with supportive care, which included the administration of antipyretics (e.g., acetaminophen), intravenous hydration, and/or glucocorticoids. Other treatment-emergent adverse effects of interest included neutropenia (16%) and immune effector cell-associated neurotoxicity syndrome and associated neurologic events (10%). Given that tarlatamab is the first T-cell engager approved for the treatment of small cell lung cancer, raising awareness with regard to the monitoring and management of tarlatamab-associated adverse events is essential. Here, the authors describe the timing, occurrence, and duration of these adverse events and review the management and risk-mitigation strategies used by clinical investigators during the DeLLphi-301 trial.

Trends in the Incidence and Survival Outcomes in Patients With Small Cell Lung Cancer in the United States: An Analysis of the SEER Database

ABSTRACTBackgroundThere has been a lack of updated epidemiological data on the incidence and survival outcomes for patients with small cell lung cancer (SCLC) in the United States over the last two decades.MethodsA retrospective, population‐based study was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) program to identify patients with SCLC from 2000 to 2020. Trends in cancer incidence, incidence‐based mortality rates, 1‐year relative survival rates and 1‐year observed survival were evaluated utilizing the SEER database.ResultsThe database identified a total of 188,426 SCLC patients during the study period from 2000 through 2020. The age‐adjusted incidence rate slowly declined, on average, by 3% (95% CI: −3.2% to −2.8%) each year from 9 per 100,000 in 2000 to 4.6 per 100,000 in 2020. The decline is evident for all age groups, sexes, and races. Incidence‐based mortality also declined slowly from 6.6 in 2005 to 3.5 in 2020. However, survival outcomes, including 1‐year relative survival and 1‐year observed survivals, have not improved significantly over the last two decades.ConclusionThis study found that the incidence of SCLC has decreased from 2000 to 2020, likely due to a reduction in smoking rates, underscoring the importance of smoking abstinence. An improvement in incidence‐based mortality is likely related to an enhanced medical care and a decrease in the incidence of SCLC, but the lack of improvement in survival outcomes reflects the need for more effective systemic therapy.

Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line treatment in patients with RAS-mutant metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.

151 Background: Anti-angiogenic drugs combined with chemotherapy could bring good clinical benefit to patients (pts) with mCRC, but the efficacy in pts with RAS mutant mCRC was limited. Fruquintinib is a highly selective oral inhibitor of vascular endothelial growth factor receptors (VEGFRs -1, -2, and -3) and was approved for previously treated mCRC. Our study was to explore the efficacy and safety of fruquintinib combined with FOLFIRI/mFOLFOX6 in the second line treatment of RAS-mutant mCRC (NCT05634590). Methods: Eligible pts with histologically confirmed RAS-mutant mCRC who had received first-line standard chemotherapy regimens were included in the study, and pts received Fru (4 mg, p.o. qd, 3 weeks on/1 week off, q4w) plus FOLFIRI/mFOLFOX6 (d1-15, q4w) until disease progression, unacceptable toxicities, or withdrew consent. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS)and safety. Results: As of Aug 30, 2024, 25 eligible pts were enrolled and received at least one time treatment. Baseline characteristics included median age (66.0 [range: 35-73]), female/male (56.0% / 44.0%), ECOG PS 1(68.0%), left-sided and right-sided colon (72.0% / 28.0%), liver metastasis (64.0%), prior anti-VEGF therapies (76.0%). 14 pts had received at least one tumor assessment. Five pts achieved partial response (PR), 9 pts achieved stable disease (SD), and the ORR was 35.7% (5/14) (95% confidence interval [CI]: 12.8-64.9), the DCR was 100.0% (14/14) (95% CI: 76.8-100.0). Compared to liver metastases, the ORR was higher without liver metastases (42.9% [95%CI 9.9-81.6]). The median PFS was 6.41 months (95% CI: 6.37 - NA), and median OS was not reached yet. In the subgroup analysis, Median PFS was also longer without liver metastases pts than with liver metastases (8.84 mo vs 6.41 mo; HR=1.230; 95%CI 0.2462-6.148; p=0.7775). Additionally, Grade ≥3 treatment-emergent adverse events (TEAEs) included platelet count decreased (18.2%), hypertension (9.1%) and neutrophil count decreased (9.1%). Conclusions: Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line in patients with RAS-mutant mCRC achieved a promising clinical benefit, with a manageable safety profile. This trial is ongoing and more updated clinical data will be presented in the future. Clinical trial information: NCT05634590 .

Efficacy, safety and DNA methylation analysis of cadonilimab combined with taxane and cisplatin as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Updated results from an open-label, multicenter phase II trial (AK104-IIT-014).

463 Background: Immune checkpoint inhibitors combined with chemotherapy had become the first-line standard treatment for advanced ESCC and cadonilimab, as a bispecific antibody simultaneously targeting PD-1 and CTLA-4, may further boost anti-tumor activity with a satisfied safety profile. Here, we present the updated data for the safety and efficacy of cadonilimab combination therapy as the first-line treatment in advanced ESCC. The correlation between DNA methylation and clinical response was also investigated. Methods: Treatment-naïve patients (pts) with unresectable locally advanced or metastatic ESCC were enrolled. Cadonilimab (10mg/kg, iv, d1, q3w) combined with paclitaxel or nab-paclitaxel (175 mg/m 2 , iv, d1, q3w) and cisplatin (65 to 75 mg/m 2 , iv, d1, q3w) were administrated for up to 6 cycles, then Cadonilimab (10mg/kg, iv, d1, q3w) monotherapy continued as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Plasma cell-free DNA samples were collected before and after treatment and prepared for methylation level sequencing. Results: As of September 20, 2024, 43 pts were enrolled with a median age of 61 years (range 44-75), 81.4% were male, 39.5% had PD-L1 CPS≥10 and 95.3% had metastatic diseases. All pts were evaluable for safety and efficacy. The ORR was 81.4% (95%Cl: 66.1%-91.1%) and DCR was 97.7% (95%Cl: 86.2%-99.9%). The median PFS (mPFS) was 7.05 months (mo) (95%Cl: 5.86-8.24) and OS analysis was immature. In the PD-L1 CPS≥10 pts, the ORR was 100.0% (95%Cl: 77.1%-100.0%) and mPFS was 7.05 mo (95%Cl: 5.19-8.91). In the PD-L1 CPS＜10 pts, the ORR was 77.3% (95%Cl: 54.2%-91.3%) and mPFS was 7.05 mo (95%Cl: 5.87-8.24). Six hyper-methylated CpG sites, EPTIN9、PKNOX2、DLEU7、SOX7、CNRIP1 and LINC00554 might be the candidate biomarkers as the mean pretreatment methylation levels were significantly higher in the PR pts than those in the non-PR pts (p=7.8×10 -7 ). Grade 3-4 treatment-related adverse events (TRAEs) were reported in 44.2% (19/43) pts, mainly including neutropenia (25.6%), leukopenia (9.3%) and hyponatremia (7.0%). The infusion-related reactions (IRR) occurred in 14.0% (6/43) and grade ≥3 IRR occurred in 4.7% (2/43) pts. 7 pts discontinued cadonilimab administration due to TRAEs. Conclusions: The updated results suggested that bispecific antibody cadonilimab combined with taxane and cisplatin as first-line treatment continued to show encouraging anti-tumor activity and manageable safety in pts with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes. Clinical trial information: NCT05522894 .

Updated efficacy results of ASKB589 combined with CAPOX and PD-1 inhibitor as first-line treatment for metastatic gastric/gastro-esophageal junction (G/GEJ) adenocarcinoma from a phase Ib/II study.

454 Background: ASKB589 is a non-fucosylated fully human IgG1 monoclonal antibody that binds CLDN18.2 with high affinity, specificity, and improved ADCC and CDC activities. Previous findings indicated that ASKB589 exhibited a well-tolerated safety profile at doses up to 20 mg/kg and demonstrated promising antitumor effects. A dose of 6 mg/kg has been selected for further evaluation. Here, we present the updated data from dose expansion part in NCT05632939 study. Methods: This phase 1b/2 study was consisted of dose-escalation part and dose-expansion part. The expansion part aimed to assess the safety and efficacy of ASKB589 combined with CAPOX plus a PD-1 inhibitor as the initial treatment for advanced G/GEJ cancer with CLDN18.2 positive, regardless of PD-L1 expression. CLDN18.2 and PD-L1 expression were evaluated through IHC analysis using clone DS-3 and clone E1L3N at a central lab. All pts were given ASKB589 intravenously at a dosage of 6 mg/kg. Responses were assessed by RECIST 1.1 every 6 weeks. Adverse events were graded using CTCAE v5.0. Results: As of July 29, 2024, 49 evaluable pts with CLDN18.2 M/H expressions (≥2+ membrane staining intensity in ≥40% of tumor cells) regardless of PD-L1 CPS score. Forty pts (81.6%) achieved a partial or complete response, with a confirmed objective response rate (cORR) of 73.5% (95%CI: 58.9, 85.1). The median duration of response was 11.14 months (6.93, NE). Three subjects underwent surgical treatment as a result of tumor reduction following treatment. All 49 pts achieved SD or better with a disease control rate of 100%. cORR was 76.2% and 74.1% in the CPS<1 and CPS<5 groups, respectively. Of all treated pts (N=50), PFS rate at 9 months was 58.1% (95% CI: 42.2, 71.0) and OS rate at 12 months was 77.1% (95% CI: 61.2, 87.2). Mature PFS and OS data will be reported at the time of the conference. The safety profile of the triplet is generally consistent with the safety data of ASB589 plus CAPOX combination in first-line G/GEJ cancer pts presented previously, which was mainly characterized by manageable on-target-off-tumor effects, including hypoalbuminemia, nausea, and vomiting. Conclusions: The combination of ASKB589 with CAPOX and a PD-1 inhibitor as the initial treatment for pts with G/GEJ cancer was well tolerated with no unexpected safety signals. It has shown a high confirmed ORR, 100% disease control, deep and durable antitumor activity, regardless of PD-L1 expression levels. A phase 3 study of the triple regimen for the 1L G/GEJ cancer is actively enrolling pts in China. Clinical trial information: NCT05632939 . cORR based on CLDN18.2 and PD-L1 expression. n/N (%) PD-L1CPS<1 PD-L1CPS 1-5 PD-L1 CPS≥5 Total CLDN18.2 M&HcORR 16/21(76.2%) 7/10 (70.0%) 13/18 (72.2%) 36/49 (73.5%) CLDN18.2 Moderate cORR 2/3(66.7%) 0/1(0.0%) 6/9(66.7%) 8/13(61.5%) CLDN18.2 High cORR 14/18(77.8%) 7/9(77.8%) 7/9(77.8%) 28/36(77.8%)

Refining the Florida ecological greenways network for improved landscape planning and conservation prioritization

ContextThe Florida Ecological Greenways Network (FEGN), established in the mid-1990s, was developed to combat habitat loss and fragmentation from rapid population growth. Over the past 30 years, the FEGN has been pivotal in identifying areas essential for biodiversity and ecosystem services to support conservation land acquisition programs including Florida Forever and the Rural and Family Lands Protection Program. It also underpins the Florida Wildlife Corridor Act, demonstrating its critical role in shaping state legislation. Continuous updates to the FEGN have ensured its relevance by integrating new geospatial data and advanced modeling techniques.ObjectivesThis paper examines the methodology delineating and prioritizing the FEGN’s statewide ecological network. Using geospatial data to interface with environmental policy for strategic conservation planning, we demonstrate its cumulative importance for protecting the state’s biodiversity and ecosystem services.MethodsWe describe the data and methodological framework used to prioritize and refine the FEGN, including focal species, ecosystem services, connectivity models, and distribution of natural communities. We also compare the 2021 and 2016 versions of the FEGN to demonstrate the impact of updated data and land protection progress.ConclusionsOur findings emphasize the importance of regularly updating connectivity conservation plans to account for land use changes and advancements in geospatial modeling tools. The involvement of a Technical Advisory Group (TAG) has ensured objective data inclusion and building trust in the planning process. The FEGN provides essential guidance for stakeholders in landscape conservation planning, including government agencies, land trusts, and private landowners. The state legislature’s recognition and funding of the Florida Wildlife Corridor underscore the effectiveness of long-term scientific integration in conservation efforts.

Implementation and analysis of hybrid communication for monitoring and control for android-based smart farming

Farmers are forced to water each crop individually or wait to switch off the water pump. to avoid this, water management needs to be optimized—that is, it needs to be done on schedule, in the appropriate quantity, and throughout a wide area in an effective manner. That is hybrid communication between online and offline communication. To run this system will use 3 nodes, for details 1 node in the irrigation section, 1 node in the monitoring section of land and soil quality, and 1 node in the section to control data or can be said to be a semi-server to give commands to 2 nodes offline. To see if the system still communicates with each other and runs according to the block diagram that has been designed, an Android application will be made to monitor the system. Where if there is a failed data update or data change in the results of the automation system, a notification will come out to check the system as a whole. To support this research, several sensor calibrations were carried out which resulted in an average accuracy level above 90 percent. For the overall system test, 10 experiments were carried out at different times to see the reliability of the system

The impact of updated imaging software on the performance of machine learning models for breast cancer diagnosis: a multi-center, retrospective study.

Artificial Intelligence models based on medical (imaging) data are increasingly developed. However, the imaging software on which the original data is generated is frequently updated. The impact of updated imaging software on the performance of AI models is unclear. We aimed to develop machine learning models using shear wave elastography (SWE) data to identify malignant breast lesions and to test the models' generalizability by validating them on external data generated by both the original updated software versions. We developed and validated different machine learning models (GLM, MARS, XGBoost, SVM) using multicenter, international SWE data (NCT02638935) using tenfold cross-validation. Findings were compared to the histopathologic evaluation of the biopsy specimen or 2-year follow-up. The outcome measure was the area under the curve (AUROC). We included 1288 cases in the development set using the original imaging software and 385 cases in the validation set using both, original and updated software. In the external validation set, the GLM and XGBoost models showed better performance with the updated software data compared to the original software data (AUROC 0.941 vs. 0.902, p < 0.001 and 0.934 vs. 0.872, p < 0.001). The MARS model showed worse performance with the updated software data (0.847 vs. 0.894, p = 0.045). SVM was not calibrated. In this multicenter study using SWE data, some machine learning models demonstrated great potential to bridge the gap between original software and updated software, whereas others exhibited weak generalizability.

Modbus RTU Protocol Timing Evaluation for Scattered Holding Register Read and ModbusE-Related Implementation

In parallel with the development of data transmission in the telecommunications sector to connect peripheral devices, hardware engineers have defined interfaces for independent communication systems. The basic idea of having standardized interfaces for external devices was quickly extended to control and instrumentation equipment, as the real-time characteristic of distributed systems became a challenge in the field. The proposed Modbus Extension (ModbusE) builds on these new techniques introduced in the UART interface, so that the newly introduced extension retains all the characteristics of the Modbus RTU except for the character bit structure. The validation of the ModbusE protocol allowed the proposal of a new communication message structure, a description of Modbus devices, an acquisition cycle to attain a deterministic temporal response behavior and the definition of an architecture for IIoT integration. In this work, practical research is based on data update times in SMARTConvert software when between 1 and 50 registers are accessed. These registers can, in the most favorable case, be at consecutive addresses and can all be read in a single bus query request, or at addresses 1 to 50, or the registers must be read in separate requests. The contributions of this paper are related to highlighting cases where Modbus modules are incorporated, the addressed registers are not consecutive and the Modbus reads 1 or more holding register records and the ModbusE proposal. As these registers must not be on consecutive addresses, it is necessary to make several requests, defining the function of a Modbus acquisition cycle, adapting the equations to the purpose of the tests carried out, measuring the Modbus communication signals and describing the ModbusE communication concept.

Sleep Quality Among a Sample of Medical Students and the Association with Academic Performance: An Updated Data

Sleep is influenced by various factors, including social, economic, genetic, and medical factors, and work and study schedules. Medical students are highly susceptible to sleep-related problems. In this study, we aimed to evaluate the sleep patterns and quality of medical students and determine their correlation with academic achievement. This cross-sectional study was conducted at the King Abdulaziz University between November 2022 and April 2023. The participants completed an online questionnaire distributed to all medical students via social media channels. The questionnaire included the Pittsburgh Sleep Quality Index to assess sleep quality and Epworth Sleepiness Scale to measure excessive daytime sleepiness (EDS). Academic performance was self-reported by students based on their grade point average. Of the 274 participants, 54.0% were males with a mean age of 22.81 years. Only 21.5% of students reported normal sleep quality during the previous month, with almost 78.5% reporting poor sleep quality and 40.9% experiencing EDS. Notably, no associations were observed between the sleep quality and sleep–wake patterns and academic performance of the students (p = 0.324 and 0.784, respectively). These findings highlight the substantial prevalence of poor sleep quality and EDS among Saudi medical students, consistent with global trends. Unexpectedly, no significant correlation was observed between sleep quality and student academic performance. These findings suggest that the demanding nature of medical education significantly impacts the sleep patterns and overall well-being of students.