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Elucidating ligand interactions and small-molecule activation in the pyrrolnitrin biosynthetic enzyme PrnB

A cross-sectional analysis from a real-world cohort of patients with microsatellite instability colorectal cancer (MSI-CRC) with localized disease from the Spanish RETUD registry.

173 Background: Microsatellite instability (MSI) localized colorectal cancer (CRC) constitutes a subgroup of patients (pts) with different clinical and molecular characteristics and prognosis compared to microsatellite stable (MSS) disease. Here, we present our real world data regarding the management and clinical outcomes of a cohort of MSI-h localized CRC patients included in the Spanish Group of Treatment of Digestive Tumors (TTD) Registry (RETUD). Methods: RETUD is a national, multicenter registry for gastrointestinal tumors from the Spanish TTD Group. In this cross-sectional analysis we evaluated a real-world cohort of MSI-h localized CRC pts diagnosed from 1 st January 2017 to 29 th April 2024. Baseline characteristics and neo/adjuvant treatments are descriptively presented. Disease-free survival (DFS) and overall survival (OS) analyzed by Kaplan-Meier method are presented along with 95% confidence intervals (CI). Results: Five hundred and sixty-one (561) evaluable pts out of 679 MSI-CRC included in RETUD had a localized disease as initial diagnosis. Pts had a median age of 73.1 years and were predominantly Caucasian (97.7%) and female (52.6%). Fifty (12.4%) pts had Lynch Syndrome. Main tumor baseline characteristics are described (Table). Local-locoregional therapeutic procedures were: primary tumor resection in 531 (99.1%) pts and radiotherapy in 18 (3.2%) pts. A total of 198 (35.3%) pts received systemic therapy, mostly chemotherapy (n=165 83.3%) but 18 (9.1%) were treated with pembrolizumab due to unresectable disease. At database cut-off, 123 (21.9%) patients died, mostly due to not related intercurrent illness, and 96 (17.1%) pts developed metastasis. After a median follow up period of 28.5 months, the median (95% CI) OS was not reached and DFS was 78.2 (55.4-NA) months. The impact of adjuvant systemic therapy (chemotherapy vs. non-chemotherapy) for both stage II and stage III pts is under evaluation. Conclusions: Our work provides valuable real-world data from a cohort of MSI-h localized CRC pts treated under clinical practice conditions in Spain, reiterating the good disease prognosis exhibited by this subset of pts in contrast to MSS pts. Main tumor characteristics. Stage at initial diagnosis, n (%) I/II n (%) 55 (9.8) / 258 (46.0) III, n (%) 248 (44.2) Location of primary tumor a , n (%) right colon /left colon /rectum 447 (78.4) / 82 (14.4) / 41 (7.2) Type histological b , n (%) Intestinal 271 (48.9) Mucinous (colloid) adenocarcinoma (>50% mucinous) 115 (20.8) Signet ring cell carcinoma (>50% signet ring) 14 (2.5) Medullary carcinoma 18 (3.2) a Pts with more than 1 primary tumor; the percentage may be over 100%. b Unknown histology in 132 (23.8%) pts and missing data in 7 pts.

TAS102 in combination with oxaliplatin (TASOX) for refractory metastatic colorectal cancer.

189 Background: TAS102 (trifluridine/tipiracil hydrochloride) is approved for use alone or with bevacizumab in late line metastatic colorectal cancer (mCRC), with overall survival benefit in phase 3 trials (RECOURSE and SUNLIGHT). Oxaliplatin is frequently reintroduced after progression, resolution of limiting neuropathy, or disease recurrence post adjuvant therapy. In preclinical studies, oxaliplatin combined with TAS102 has shown synergism. We hypothesized TASOX may be an option for patients who have progressed/recurred after FOLFOX. Methods: We assessed safety and efficacy of TAS102 with oxaliplatin, enrolling patients with metastatic CRC progressed on ≥2 lines of therapy including 5FU, oxaliplatin and irinotecan. Patients with recurrence during or within 6 months of adjuvant chemotherapy were allowed. Exclusion: Prior TAS102 exposure, functional impairing peripheral neuropathy, ≥Grade 3 hypersensitivity to oxaliplatin, or uncontrollable grade 1-2 hypersensitivity to oxaliplatin. Treatment continued until disease progression or unacceptable toxicity. Patients received oxaliplatin 85 mg/m2 and TAS-102 35 mg/m2 bid days 1-5 every two weeks, and bevacizumab per MD choice. The primary endpoint was overall response rate (ORR) by RECIST (by independent radiologists). Secondary endpoints included disease control rate (DCR), safety and tolerability. Results: 54 patients enrolled; 53 received treatment on study and 48 had ≥1 disease assessment (median age 59, 58 % male, tumor RAS mutated 69%). Median time on study was 4 months (8 cycles; range 1-37 cycles). ORR was 6% (n=3), with average change in target lesions -45% (range -35 to -67%). 71% (n=34) had SD defined on study, with average change in target lesions -3% (range -29% to +20%). In those treated with bevacizumab (59%; n=28 ), 79% (n=22) had disease control vs. 75% (n=15). The most common reason for study discontinuation was progressive disease (23%, n=11). 68% (n=36) had a treatment-related adverse event (TRAE) ≥Grade 3 at any point during therapy. The most common G3 TRAEs were anemia 19% (n=10) and leukopenia 28% (n=15) at any time. Two (4%) developed grade 3 neuropathy. Conclusions: TASOX is effective as a 3rd line therapy for patients with mCRC. In our study, overall disease control rate was 77% with up to 19 months on study. Anemia and leukopenia are common but manageable. Bevacizumab did not seem to have as great an effect in our trial as observed in SUNLIGHT. Future studies would warrant TASOX in combination to bevacizumab in randomized trials in candidates for oxaliplatin retreatment. Clinical trial information: NCT02848079 .

Efficacy of immune checkpoint inhibitors in patients with advanced pancreatic NETs displaying high TMB and MMR alterations following treatment with alkylating agents.

662 Background: Alkylating-based chemotherapy (ALK) is one of the main treatments used in patients with advanced pancreatic neuroendocrine tumors (PanNETs). Its use has been associated with an increased risk of grade progression and acquisition of a hypermutator phenotype, associated with frequent alterations of the mismatch repair (MMR) genes. This suggests a potential benefit of immune checkpoint inhibitors (ICI) that are otherwise ineffective in ALK-naïve PanNETs, which are mostly hypomutated. We aimed to describe the efficacy of ICI in patients with advanced PanNET pretreated with ALK. Methods: We assembled an international retrospective cohort of patients with advanced PanNET who received at least one cycle of ICI, and who had previously received at least 3 months of ALK. Patients with poorly-differentiated neuroendocrine carcinoma were excluded. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was the objective response rate (ORR). The impact of tumor mutational burden (TMB, high being defined by >10 mut/Mb) and MMR alterations (mutations or IHC) was explored. Results: We included 39 patients (median age 58.7, male sex 62%). All PanNETs were progressive at baseline and presented a median of 3 (IQR, 2-4) metastatic sites. Tumors were predominantly classified as G2 (47%) or G3 (42%), with a median Ki-67 of 18.5% (IQR, 12-35). 23/27 patients with tumor tissue or ctDNA NGS testing had high TMB (median, 35 mut/Mb; IQR, 24-106) and 12/22 had MMR alterations. Patients had previously received an average of 14 cycles (IQR, 7-25) of ALK (temozolomide 78%, streptozotocin 18%, dacarbazine 4%), which had yielded objective response in 72% of cases. In addition, patients had received a median of 4 (IQR, 3-5) other treatments (including platinum drugs in 80% and PRRT in 51%). ICI mainly consisted in an anti-PDL1/PD1 + anti-CTLA4 combination (85%) or a monotherapy (15%), with a median of 3 (IQR, 2-8) cycles. The ORR was 18% and the disease control rate was 46%. Median PFS was 2.8 months (95% CI, 0.62-4.96) and 6-month PFS rate was 31%. 19% of patients had grade 3-4 toxicity. Patients with high TMB had higher ORR (30% vs. 0%, p=0.03) and longer median PFS (4.9 vs. 2.1 months, p=0.004) compared with patients with low/unknown TMB. Patients with altered MMR had higher ORR (42% vs. 7%, p=0.02) and longer median PFS (8.9 vs. 2.5 months, p=0.014) compared with patients with no/unknown MMR alterations. Conclusions: While ICI shows limited efficacy in unselected patients with advanced PanNETs pretreated with ALK, it may be an effective treatment option in case of high TMB and MMR alterations.

VO2 based polarization-independent dual-wavelength plasmonic switches using U and C shaped nanostructures

PTEN loss in glioma cell lines leads to increased extracellular vesicle biogenesis and PD-L1 cargo in a PI3K-dependent manner

Neoadjuvant cadonilimab plus anlotinib followed by surgery for locally advanced esophageal squamous cell carcinoma: A single arm, phase 2 trial.

TPS506 Background: Esophageal cancer (EC) is the seventh most common cancer in China, where most of patients have locally advanced esophageal squamous cell carcinoma (LA-ESCC) at the time of diagnosis. Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) followed by surgery is standard treatment strategy for LA-ESCC in China. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of ESCC. Programmed death 1 (PD-1) inhibitors are the most commonly used ICIs in treatment of ESCC. Lately, the phase 3 ESCORT-NEO/NCCES01 trial demonstrates that neoadjuvant PD-1 inhibitor plus chemotherapy obtains superior pCR rates compared to chemotherapy alone for LA-ESCC. Except for PD-1 inhibitors, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitor is another effective ICI for ESCC, especially combined with PD-1 inhibitor according to the CHECKMATE-648 study. Although neoadjuvant immunotherapy plus chemotherapy has brought earth-shaking changes to the treatment of LA-ESCC, the chemo-based treatment modality still results in a high incidence of adverse events, reduces the quality of life and compliance of patients. Cadonilimab is a dual immune antibody drug comprised of PD-1 antibody and CTLA-4 antibody. Anlotinib is an oral, small molecule anti-angiogenic targeted agent that has been approved for use in advanced or metastatic ESCC in China. Therefore, we launched this trial to assess the efficacy and safety of cadonilimab plus anlotinib, a novel "chemo-free" strategy, followed by surgery for LA-ESCC. Methods: Study design: This is a single-arm, phase 2 study (NCT06426797). The primary endpoint of this study is the pCR rate. The secondary endpoints include safety, major pathological response (MPR) rate, objective response rate (ORR), R0 resection rate, and event-free survival (EFS). Study procedures: Cadonilimab will be intravenously administered at day 1 with a dose of 10 mg/Kg every three weeks for three cycles. Anlotinib will be orally administered daily at day 1 to day 14 with a dose of 12mg every three weeks for three cycles. In the end, the subjects will receive subtotal esophagectomy 4 to 6 weeks later after the last dose of cadonilimab. Major inclusion criteria: 1. Age > 18 years. 2. Histopathologically confirmed ESCC: c-stage II–IVA (8 th ed. AJCC). 3. Enough tissue for PD-L1 IHC test. 4. Eligible for anlotinib treatment. 5. ECOG performance status ≤ 2 points. Statistics: We hypothesized that the expected pCR rate would be 50%. 24 subjects are needed at an α-level of 0.05 (one-sided) and power of 80%. So, 25 subjects in total should be enrolled. The descriptive statistical method will be applied to the presentation of baseline characteristics, toxicities and measures of effectiveness. The Kaplan–Meier method will be used to calculate survival rates. Current enrollment: The study started on August 1 st , 2024, and 3 of planned 25 patients have been enrolled. Clinical trial information: NCT06426797 .

Temporal trends in rural vs urban colon cancer mortality in Texas: A SEER database analysis from 2012 to 2021.

36 Background: Colorectal cancer is a major concern for the U.S. healthcare system, being the fourth most common cancer by incidence in the country with 152,810 cases in 2024. Measuring the burden this disease places on patients and health resources may serve to optimize our approach to the detection, management and resource allocation for combating this ailment. Methods: Our study is a population-based study cohort of colon cancer deaths in Texas. We queried the National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) for colon cancer deaths in Texas over the most recent available decade, 2012 through 2021. The National Center for Health Statistics Urban-Rural Classification Scheme was used to classify counties according to the 2013 US Census classification: urban (≥ 50,000) and rural (< 50,000). We calculated age-adjusted mortality rates (AAMRs) per 100,000 population using the direct standardization method based on the age group weights from the 2000 standard US population. Confidence intervals for AAMR were derived by estimating the standard error as the AAMR divided by square root of number of mortalities. Differences between AAMR were tested by comparing the 95% confidence intervals (95% CI) for the individual rates. The annual percent change (APC) in AAMR was tested using negative binomial regression. Subgroup analyses included age group, sex, and race/ethnicity. Results: Over the study period, 10.8% of the study population lived in rural areas and 89.2% lived in urban areas. A total of 33,591 colon-cancer deaths were reported during the study period with 5,423 (16.1%) in rural counties and 28,168 (83.9%) in urban counties. At the beginning of the study period the rural AAMR (13.9 [12.7 to 15.1]) was significantly higher than urban AAMR 12.1 [95% CI 11.7 - 12.6]). The rural AAMR rose significantly over the study period (APC 1.1% [95% CI 0.3% - 1.9%]; p = 0.0050) to AAMR 14.9 (95% CI 13.7 to 16.1). In contrast, the urban AAMR did not change over study period (APC -0.3% [95% CI -0.7 to 0.1]; p = 0.1444) and was equal to the initial AAMR 12.1 (95% CI 11.7 to 12.5). On subgroup analyses, males, people ages 25-64 years, Hispanics, Non-Hispanic Blacks, Non-Hispanic Asians, and Non-Hispanic Native Americans in rural areas each had significant and increasing trends in AAMR. Conclusions: Our analysis revealed an increase in AAMR in rural counties of Texas, reflecting a concerning trend with regard to colorectal cancer in this region. This may be due to higher poverty rates, lower level of education, more distance from healthcare facilities and difficulties with transportation faced by rural counties. Furthermore, rural areas also report higher rates of obesity and poor dietary habits. Rural areas also face a shortage of Primary Care Physicians (PCP’s), with metropolitan counties retaining 1.7 times as many PCP’s as rural counties, and 82.5% of counties without a PCP being rural.

Definitive local therapy in solitary liver metastatic anal squamous cell carcinoma.

5 Background: Metastatic anal squamous cell carcinoma is rare and associated with a poor prognosis. There is limited evidence on the impact of local interventions on survival outcomes in patients with metastatic disease. We aimed to evaluate the survival of patients with liver-only metastatic anal cancer following definitive local management of liver lesions. Methods: This is a single-institution retrospective cohort study of patients with liver-limited metastatic anal cancer who underwent curative-intent local therapy. Clinical characteristics were collected and analyzed. The Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival (OS). Prognostic factors associated with DFS and OS were assessed using Cox-proportional hazards models. Results: Twenty-five patients were included, median age was 59 years, and 92% were female. None of the patients had known HIV infection, 92% had HPV-positive disease and 76% had metachronous liver metastases following locoregional disease. All patients received chemoradiation for the primary lesion Unilobar hepatic involvement was present in 76% of the patients, with 56% having a single metastatic lesion. Pre-intervention systemic therapy was provided to 52% of the patients, including 8 who received carboplatin and paclitaxel, with a median duration of 3 months and ORR of 69%. Definitive treatment of metastatic disease included surgical resection (60%), non-surgical interventions (20%), and multimodal therapy (20%). All patients had viable tumor in the pathological specimen. With a median follow-up of 22 months, median DFS was 7.3 months, and median OS was 51.3 months. An ECOG performance status of 2, poorly differentiated histology, and extrahepatic recurrence were identified as significant prognostic factors in the univariate analysis, but not in the multivariate analysis. Conclusions: Our results demonstrate potential for long-term survival in liver-limited metastatic anal squamous cell carcinoma amenable to local therapeutic intervention combined with systemic therapy. These findings warrant further prospective study of local therapy in oligometastatic anal cancer. Characteristics N=25 (%) Median number of liver metastases (range), lesions- 1- 2-3- >3 1 (1-20)14 (56)8 (32)3 (12) Median maximal diameter of liver metastases (range), cm 3 (0.9-11.9) Best response of liver metastases to chemotherapy (N=13)- Complete response- Partial response- Stable disease- Progressive disease 2 (15)7 (54)3 (23)1 (8) Surgical procedure (N=20)- Right/left hemi-hepatectomy- Segmentectomy- Wedge resection 4 (20)14 (70)2 (10) Non-surgical procedure (N=10)- Local ablation- Radiotherapy- Other 5 (50)3 (30)2 (20) Hepatic surgical margins (N=20)- Positive margins- Close margins (<1mm)- Negative margins 02 (10)18 (90) Recurrent disease- Yeso Intrahepatico Extrahepatic- No 20 (80)14 (70)6 (30)5 (20)

Temporal variations of metals and trace elements in tuna spines from the canary islands from 1990s to 2000s

Mutations in histones dysregulate copper homeostasis leading to defect in Sec61-dependent protein translocation mechanism in Saccharomyces cerevisiae

The incidence and risk of cardiovascular events among gastroesophageal cancer patients receiving immune-checkpoint inhibitors.

374 Background: Immune checkpoint inhibitors (ICIs) have been associated with an increased risk of cardiovascular events. However, these data were mostly derived from patients with lung cancer or melanoma. To date, there is limited data describing the incidence and risk of cardiovascular adverse events associated with the use of ICIs among patients with gastroesophageal cancers. Methods: We performed a propensity score-matched cohort study using the TriNetX Analytics Network database, which comprises de-identified data from over 120 participating institutions and 101 million individuals. We defined the ICI cohort as patients who received any of the ICIs and chemotherapy. We defined the control cohort as patients who received only chemotherapy but not an ICI. We matched 2 cohorts based on predetermined variables including age, race, gastroesophageal cancer-directed therapy, cardiovascular agents, underlying comorbidities, and surgical history. The outcomes were myocarditis, pericarditis, myocardial infarction, heart failure, cerebral ischemia/infarction, atrial fibrillation, conduction disorders, and venous thromboembolism (VTE). All outcomes were captured within 1-year of the start of ICI therapy and identified using the International Classification of Diseases (ICD)-10 codes. Results: We identified 2005 patients who received ICI and chemotherapy (ICI cohort) and 14048 patients who received chemotherapy only (control cohort). We matched 952 patients in 2 cohorts. The mean age was 62.8 ± 12.7 and 62.8 ± 12.3 for the ICI and chemotherapy cohorts, respectively. We observed a significant increase in cardiovascular events in the ICI cohort compared to the chemotherapy cohort. In particular, the risk of myocarditis (4 cases in the ICI cohort and no cases in the chemotherapy cohort), pericarditis (Hazard ratio (HR), 2.53 [95% CI: 1.52-4.19]), conduction disorders (HR, 1.64 [95% CI: 1.04-2.59]), and VTE (HR, 1.56 [95% CI: 1.17-2.10]) were higher in the ICI cohort than the chemotherapy cohort. Conclusions: The use of ICI was associated with an increased risk of cardiovascular events, particularly myocarditis, pericarditis, conduction disorders, and VTE among patients with gastroesophageal cancer. Further studies are needed to identify strategies to stratify patients at high risk of developing ICI-associated cardiovascular events. Outcomes ICI + Chemotherapy(ICI cohort) Chemotherapy only(Control cohort) Hazard ratio(95% CI) Cases At risk patients Cases At risk patients Myocarditis 4 952 0 952 - Pericarditis 52 952 21 952 2.53 (1.52-4.19) Myocardial infarction 18 952 12 952 1.49 (0.72-3.11) Cerebral Ischemia/Infarction 22 952 17 952 1.30 (0.69-2.44) Atrial fibrillation 56 952 48 952 1.16 (0.79-1.71) Conduction disorder 49 952 30 952 1.64 (1.04-2.59) Venous thromboembolism 112 952 73 952 1.56 (1.16-2.10) Heart Failure 118 952 114 952 1.04 (0.80-1.34)

Impact of time to surgery on outcomes in patients with advanced esophageal squamous cell carcinoma following neoadjuvant therapy: An exploratory analysis of phase III trial JCOG1109.

458 Background: JCOG1109, a multicenter three-arm phase III trial, evaluated three neoadjuvant treatment regimens for advanced esophageal squamous cell carcinoma (ESCC), cisplatin and 5-fluorouracil (CF), docetaxel, cisplatin, and 5-fluorouracil (DCF), and cisplatin, 5-fluorouracil, and radiation therapy (CF-RT). The trial demonstrated the superiority of neoadjuvant DCF therapy in improving overall survival (OS). This exploratory analysis investigates the impact of the interval time from completion of neoadjuvant therapy to surgery (time to surgery, TTS) on both short- and long-term outcomes across different neoadjuvant therapy regimens. Methods: This analysis included patients from JCOG1109 who underwent surgery after neoadjuvant therapy. Patients were categorized into four TTS subgroups within each arm, based on quartiles of the overall cohort. Short-term outcomes such as perioperative complications, as well as long-term outcomes including OS and progression-free survival (PFS) were evaluated across these TTS subgroups. Results: Of the 601 patients enrolled in JCOG1109, 546 patients proceeded to surgery following neoadjuvant therapy. The median TTS was 35 days (range: 16-81) for the CF arm, 38 days (range: 17-109) for the DCF arm, and 41 days (range: 14-98) for the CF-RT arm. Baseline characteristics were well-balanced across all TTS subgroups in each treatment arm. Short-term outcomes revealed that operative time and overall proportions of postoperative complications were comparable. However, in the CF-RT arm, a longer TTS was associated with increased blood loss (200 ml, 210 ml, 300 ml, 370 ml; p-value for trend test = 0.010) and tended to increase the risk of anastomotic leakage (6%, 7%, 14%, 18%; p-value for trend test = 0.073). No significant differences in OS or PFS were observed across TTS subgroups in any treatment arm, with hazard ratios indicating no clear trend toward improved or worsened long-term outcomes. Conclusions: The timing of surgery following neoadjuvant therapy does not appear to affect long-term prognosis in patients with advanced ESCC, irrespective of the neoadjuvant therapy regimen. However, for patients undergoing neoadjuvant CF-RT, earlier surgery may be advantageous in reducing the risk of increased surgical complexity and anastomotic leakage.

Safety and preliminary efficacy of ATG-022 in patients with advanced/metastatic gastric cancer (CLINCH).

456 Background: ATG-022 is an antibody-drug conjugate (ADC) targeting Claudin 18.2 (CLDN 18.2) tumor antigen broadly expressed in gastric and other solid tumors. ATG-022 consists of a humanized monoclonal antibody that binds to CLDN 18.2 with high affinity of sub-nM grade and a conjugated linker-payload VC-MMAE, demonstrating activity across a wide range of CLDN18.2 expression levels, including both high and low/ultra-low expression levels. Methods: The CLINCH study included dose escalation phase and dose expansion phase. In the dose escalation, patients(pts) with advanced solid tumors regardless of CLDN 18.2 expression received ATG-022 once every three weeks (0.3-3.0 mg/kg Q3W) to evaluate the safety, tolerability, and pharmacokinetics. CLDN 18.2-positive patients were enrolled in dose expansion to receive ATG-022 at recommended phase 2 doses (RP2D) to evaluate the efficacy and safety. The primary endpoints included dose-limiting toxicity (DLT) and adverse events (AEs). The efficacy endpoints included objective response rate (ORR) and disease control rate (DCR), evaluated per RECIST1.1 criteria. Results: As of Aug 21, 2024, 16 pts with advanced solid tumors, including 7 gastric cancer (GC), were treated with ATG-022 from 0.3 to 3.0 mg/kg in dose escalation, with 1 DLT of grade 3 nausea found at 3 mg/kg among 6 pts, and 21 GC pts were enrolled in dose expansion to receive RP2D of 2.4 mg/kg Q3W. Among all 37 pts, median age was 61 years. Baseline ECOG were 0 (9 pts) and 1 (28 pts); 33 (89.2%) pts had stage IV disease; 26 (70.3%) pts had received ≥ 2 prior lines of systemic therapy and 14 (37.8%) pts had prior anti-PD-1/L1 therapy. At 2.4 mg/kg in expansion, 3 (14.3%) pts had ≥ 1 Serious TRAEs; 8 (38.1%) pts had grade ≥ 3 TRAEs; the most common TRAEs included neutrophil count decreased (47.6%), nausea (38.1%) and white blood cell count decreased (33.3 %). In dose escalation, 7 GC pts were enrolled, including 3 CLDN 18.2-positive pts. One PR and 1 CR was observed in pts with GC at the dosage of 1.8 mg/kg and 2.4 mg/kg, respectively. Among 12 GC pts who had at least 1 tumor evaluation in dose expansion, 5 PR and 7 SD were observed, resulting in an ORR of 41.7%, and a DCR of 100%. One CR and 1 PR were observed among 3 GC pts receiving 2.4 mg/kg and with CLDN 18.2 expression < 2+, 5%. The Cmax of both total antibody and ADC drug is increased as dose increased from dose 0.3 – 3.0 mg/kg. No pronounced exposure accumulation was found after multiple dose treatment. Preliminary data showed Dose-Normalized AUC of MMAE for ATG-022 is comparable with other vcMMAE ADC drugs. Conclusions: ATG-022 demonstrated a manageable safety profile, comparable PK properties in current dosing levels, and encouraging preliminary antitumor effects in GC pts from high CLDN 18.2 expression to low CLDN 18.2 expression, suggesting further clinical investigation in pts with variable CLDN 18.2 expression. The enrollment of GC and other solid tumors are ongoing. Clinical trial information: NCT05718895 .

Vaccines for cancer prevention: exploring opportunities and navigating challenges

High-Precision computational solutions for nonlinear evolution models in graphene sheets

Abstract This study investigates the analytical solutions of a nonlinear evolution model governing the dynamics of graphene sheets, a material renowned for its exceptional electronic properties and versatile applications in nanotechnology. Three advanced analytical approaches-the Khater II (Khat II) method, the Khater III (Khat III) method, and the Generalized Rational (GRat) approach-are employed to derive exact solutions for this model with high precision. The accuracy and reliability of these solutions are validated by comparing them to numerical results obtained via He’s Variational Iteration (HVI) method, which serves as a benchmark for numerical verification. The analysis reveals a remarkable agreement between the analytical and numerical solutions, highlighting the robustness and effectiveness of the proposed methodologies. Furthermore, this study provides new insights into the nonlinear dynamics and physical properties of graphene sheets, while also identifying connections to other prominent nonlinear evolution equations. The innovative use of these analytical techniques offers practical frameworks for addressing complex nonlinear models in mathematical physics, thus advancing solution methodologies for such equations. This research contributes significantly to applied mathematics, material science, and nanotechnology by delivering accurate solutions and enhancing our understanding of graphene’s nonlinear behavior. Finally, the findings have far-reaching implications, offering potential applications in designing advanced materials with tailored properties to support technological advancements, thereby pushing the boundaries of nanotechnology and materials engineering.

Enhanced dynamic coupling in a nuclear receptor underlies ligand activity

Phase II trial of sintilimab in cancer of unknown primary.

825 Background: CUP is an aggressive rare malignancy accounting for 2-4% of all cancers. Beyond frontline therapy, predominantly systemic cytotoxic chemotherapy, no clear standard of care exists. Preliminary data suggests that immune-checkpoint inhibitors have encouraging activity in patients with CUP. Prior anti-PD1 agents have demonstrated response rates of 21-23%. We studied the role of sintilimab, an anti-PD1 antibody, in CUP. Methods: In this phase II study (NCT05024968)10 patients (of planned 40) were enrolled prior to closure of the study due to sponsor funding. Patients were eligible if they were refractory or intolerant to one line of systemic therapy or had a contraindication for cytotoxic chemotherapy. Patients received sintilimab 200 mg IV every 3 weeks. Paired tumor biopsies were collected for biomarker analysis. The primary endpoint was confirmed objective response rate (cORR) by RECISTv1.1 assessed by independent radiology review. Key secondary endpoints were safety, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and Quality of Life (QOL). Median PFS and OS were calculated according to the Kaplan-Meier method. Adverse events (AEs) were assessed according to CTCAE v5.0. Results: Between 10/2021 and 2/2023, 10 patients were enrolled and treated. Median age was 65 years and 30% of patients were female. Seven (70%) had poorly differentiated carcinoma. Patients received a median of 1 line of therapy prior to enrollment. Median follow-up was 19.8 months. All patients were evaluable for toxicity and response. The cORR was 40% (95% CI, 12.2 to 73.8); one (10%) patient with a complete response and 3 (30%) with partial responses. The median DOR was 15.7 months. Three patients (30%) had Grade ≥ 3 (no grade 4/5) treatment-related AEs including 2 patients with sepsis and 1 patient with leukocytosis. Median PFS and OS were 4.4 months (95% CI, 2.0 to 25.4) and 25.4 months (95% CI, 4.0 to 27.4), respectively. Conclusions: Anti-PD1 therapy with Sintilimab demonstrated significant anti-tumor activity for select patients with refractory CUP with safety profile consistent with other anti-PD1 agents. Ongoing correlative studies may inform the role of biomarker selection for immunotherapy in CUP. Clinical trial information: NCT05024968 .

Postoperative exercise in gastric cancer patients undergoing gastrectomy: A randomized controlled trial.

358 Background: Faster physical recovery after gastrectomy may lead to better physical and psychological health in patients with gastric cancer. Post-surgical exercise may prevent physical dysfunction and improve recovery, but its effects on physical function are not fully explored. Methods: In this trial, 52 gastric cancer patients (Stage 1-3) were randomly assigned to early postoperative exercise rehabilitation or usual care (1:1 ratio). Interventions Inpatient Supervised Exercise sessions were conducted for 15 minutes once a day on Postoperative Day (POD) 1 and 2 in the ward. Home-based Exercise involved 30-minute remote exercise sessions at home once a week following discharge, with additional recommendations for daily 30-minute sessions of low to moderate-intensity aerobic exercises and bodyweight exercises. Moreover, the exercise group was provided with an exercise log and instructional videos to record the duration of bodyweight exercises and aerobic exercises. Measurements were taken three times (baseline, POD3, and the first outpatient visit 1 month after surgery). The primary outcome was a Short Physical Performance Battery (SPPB), with secondary outcomes including grip strength, 30-second sit-to-stand (STS), body composition, C-reactive protein (CRP), and quality of life (QOL). Results: A total of 46 (88%) participants (mean [SD] age, 60.2 [12.24] years; 26 [57%] male) completed the trial. Compliance with intervention in-patient exercise was 96% and remote exercise was 79%. The significant difference in SPPB scores of 11.4±1.3 in the exercise group compared with 10.7±1.43 usual care group (mean difference, -1.09 score; 95%CI, -1.7 to -0.4; p=<.001). Moreover, there were significant differences between groups in the STS exercise group 14.3±2.8 usual care group 13.6±4.5 (mean difference, 1.86; 95%CI, -3.3 to -0.4; p=.028), and CRP in POD3 exercise group 66.9±40.73 usual care group 103.7±54.25 (mean difference, -22.54 score; 95%CI, -46.5 to 1.4; p=.016). However, there was no significant difference in grip strength, body composition, and QOL. Conclusions: Postoperative exercise presents as a beneficial strategy to enhance physical recovery in patients undergoing gastrectomy, improving key physical function markers and reducing inflammation. Clinical trial information: NCT06260293 .

Combination Immunotherapy for Advanced Melanoma—How to Choose?