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Migratory behaviour of humpback whales in the southeastern Pacific under climate change

Replisomal coupling between the α-pol III core and the τ-subunit of the clamp loader complex (CLC) are essential for genomic integrity in Escherichia coli

Leading the way: How leading Chinese institutions drive MDT excellence in hepatocellular carcinoma.

563 Background: HCC MDTs involve specialists collaborating on patient cases to create personalized treatment plans. Implementing MDTs can be challenging in countries with limited resources and high disease burdens. In China, there were 368,000 new liver cancer cases in 2022 representative of 40% of global cases. Therefore, evaluating MDT practices at leading hospitals in China may offer valuable insights that could help improve HCC MDT practices worldwide. Methods: This study selected hospitals with distinct MDT models: one for all new patients and one for complex cases. Hospitals handling over 1,000 HCC cases annually were chosen. Desk research and virtual interviews with MDT members from three leading Chinese hospitals—The First Affiliated Hospital of USTC, The First Affiliated Hospital of SYSU, and Tongji Hospital—were conducted to analyze their MDTs and determine key best practices. Results: We identified 6 key best practice in HCC MDTs at these leading Chinese hospitals. 1) Quality Control on MDT process: Leading hospitals ensure the MDT’s efficient execution and effective outcomes. E.g., USTC established a quality control team to audit the MDT process. 2) Real-World Evidence: Leading hospitals prioritize the construction of real-world databases linked to MDT-care to inform impact on outcomes. E.g., SYSU's preliminary data shows impact of MDT care on survival rates (From 2006 to 2010, 5,627 patients who underwent radical liver cancer resection with MDT care saw their five-year survival rate reach 60%, a notable improvement over historical averages) 3) Comprehensive Teams: These hospitals typically have robust teams, involving around 10 specialties. E.g., Tongji Hospital’s MDTs involve ~10 specialties for holistic care. 4) Patient Journey Coverage: MDTs manage patients from diagnosis to rehabilitation, providing a holistic approach to patient management. 5) Guideline-based treatment decisions: They follow latest guidelines coupled with access to approved therapies to make treatment decisions 6) Training: Young physicians are invited to actively participate in MDT consultations (e.g., through case preparation and presentation, etc.). Conclusions: Evaluation of MDT practices at leading China institutes highlights key best practices that could be adopted to enhance care quality for patients with HCC. The ongoing efforts and successes of these institutions provide a model for broader adoption and standardization of MDT practices across the country.

Landscape of <i>MET</i> genomic alterations in colorectal cancer (CRC).

247 Background: MET signaling is implicated in the tumorigenesis of many solid tumors, including CRC. MET-targeted therapies are approved in non-small cell lung cancer with novel agents in clinical trials for tumors with MET exon 14 splice site mutations, MET amplifications, and recently MET expression. There is emerging therapeutic interest in targeting MET in CRC. Methods: Tumor samples from 50,500 cases of clinically advanced CRC were analyzed by hybrid capture-based comprehensive genomic profiling (CGP) that evaluated all classes of genomic alterations (GA). MSI-high status, tumor mutational burden (TMB), genomic ancestry, trinucleotide mutational signatures, and homologous recombination deficiency signature (HRDsig) were assessed for patients with activating MET GA. PD-L1 expression was determined by IHC (Dako 22C3 with TPS scoring system). Results were compared using the Fisher exact test with the Benjamini-Hochberg adjustment. Results: A total of 502 (1.0%) cases of activating GA of MET (METmut) were identified, including 418 cases (0.83%) with MET amplification (METamp), 10 (&lt;0.1%) rearrangements, and 78 (0.1%) short variant (SV) mutations with 19 (&lt;0.1%) cases of MET exon 14 splice site mutations. When compared with MET wild-type (METwt) CRC, the METmut CRC were of similar age (median 62 years), and numerically more likely to be male (61.4% vs 56.0%; P=.05). There were no differences in genomic ancestry (72% European ancestry for both groups). The METmut CRC featured more cases with a POLE signature (3.6% vs 0.4%; P=&lt;0.0001) and more GA per tumor (7 vs 5; P&lt;0.0001). MSI-high status was similar in both groups, with 4.2% in METmut and 6.0% in METwt (P=0.28). TMB levels were numerically higher in the METmut cases (TMB ≥ 10 mutations/Mb at 12.2% vs 9.0%; P=0.058). Low level PD-L1 expression (1-49% TPS) was similar in both groups (13.9% in METmut vs 13.3% in METwt), and while not statistically significant, high level PD-L1 expression (&gt;50% TPS) was higher in the METmut group (4.3% vs 1.6%; P=0.056). The frequencies of HRDsig+ CRC were rare and similar in both groups with 1.5% in METmut and 1.7% in METwt. METmut CRC had lower frequencies of GA in KRAS (34.7% vs 48.8%; P&lt;0.0001), NRAS (1.8% vs 4.2%; P=0.011), APC (72.5% vs 78.2%; P=0.009) and PIK3CA (12.2% vs 18.9%; P=0.0004), and higher frequencies of GA in CDK6 (10.2% vs 0.6%; P&lt;0.0001), EGFR (5.2% vs 0.2%; P=0.0002), ERBB2 (9.6% vs 5.2%; P=0.0004), HGF (8.0% vs 0.8%; P&lt;0.0001), POLE (4.2% vs 0.5%; P=0.005) and TP53 (84.1% vs 75.9%; P&lt;0.0001). In METmut CRC, ERBB2 alterations were 4.1% amplifications, 2.9% sequence mutations, 0.9% with more than one mutation. BRAF V600E was seen in 5.9% in METmut CRC and 8.4% of METwt. Conclusions: CGP reveals significant differences in the genomic landscapes of METmut CRC and METwt CRC, which may guide selection of potential rational drug combinations with novel MET-targeted therapies.

Nelmastobart (hSTC810) combined with capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A phase 1b clinical trial.

162 Background: Treatment options for patients with metastatic colorectal cancer (mCRC) who experienced disease progression after receiving oxaliplatin and irinotecan-based chemotherapy are limited. Nelmastobart (hSTC810), a humanized anti-BTN1A1 (butyrophilin subfamily 1 member A1) monoclonal antibody of the IgG4 isotype, showed acceptable safety profile and the disease control rate was 39.3% in the first-in-human study, suggesting its potential efficacy. This phase Ib study was designed to evaluate the safety and explore synergistic anti-tumor activity of nelmastobart in combination capecitabine. The study aims to determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination therapy in patients with mCRC who are refractory to standard therapy. Methods: Dose escalation phases were conducted in patients with mCRC who were administered orally twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) and nelmastobart (400mg, 800mg intravenously every 3 weeks). Standard "3 + 3" dose escalation was used to define the MTD. In this phase 1b, 12 participants enrolled between February 5 2024 and June 11 2024 were 18 years of age or older with mCRC previously treated oxaliplatin and irinotecan in the metastatic setting. Results: The first 3 patients at the dose level 0 (nelmastobart 400mg, capecitabine 1,000 mg/m 2 twice daily) and level 1 (nelmastobart increased to 800 mg, capecitabine 1,000mg/m 2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 2 (nelmastobart 400mg, capecitabine 1,250mg/m 2 twice daily), 2 of 3 had DLTs (grade 3 hand-foot syndrome), which were attributed to capecitabine. When dose level 2 was expanded to 3 additional patients, 2 more patients experienced DLTs (grade 3 mucositis and hand-foot syndrome). Consequently, the combination of nelmastobart 800 mg once every three weeks and capecitabine 1,000 mg/m² twice daily (2 weeks on 1 week off) was established as the MTD/RP2D in patients with mCRC. The most common AEs were hand-foot syndrome (n=4), nausea (n=3) and stomatitis (n=2) which were related with capecitabine. Four patients experienced grade 1 fatigue, which was considered to be related to nelmastobart. Two patients (16.7%) out of 12 showed partial response and 8 patients have maintained stable disease for more than 4 months among 9 patients who had a median follow-up of more than 4 months (as of August 30). Conclusions: The combination of hSTC810 and capecitabine is well tolerated at the MTD, without unexpected AEs and shows promising antitumor activity in patients with heavily treated mCRC. The phase 2 study is currently in progress. Clinical trial information: NCT0599054 .

Pamrevlumab plus nab-paclitaxel/gemcitabine (Pam + GA) as first- and second-line therapy in metastatic pancreatic cancer (mPDAC): Results from Precision Promise (PrP) Bayesian platform trial.

673 Background: Pamrevlumab (Pam) is a fully human recombinant monoclonal antibody against connective tissue growth factor. Early clinical data with Pam plus chemotherapy showed a favorable safety profile and potential efficacy in PDAC. In PrP, Pam + GA was tested as first line (Line 1) and second line (Line 2) therapy for mPDAC vs GA. PrP is a phase 2/3, innovative Bayesian adaptive platform trial sponsored by the Pancreatic Cancer Action Network testing multiple experimental arms efficiently against common controls (1). Methods: Randomization is 70% (adaptive amongst experimental arms in stage 1) and 15%:15% amongst two control arms (GA, mFOLFIRINOX). Pam + GA graduates from stage 1 to 2 if the Bayesian predictive power (PP) of eventual success is ≥ 35% for one of the arm’s signatures [Line 1, Line 2 or Line 1 &amp; 2 (All)]. All participants (pts) are followed for 12 months (mos) after last pt randomized and treated in Pam + GA. Stages 1 and 2 are combined for final analysis. Efficacy is defined by overall survival (OS) hazard ratio (HR, experimental vs control), by a Bayesian statistical model. Superiority (HR &lt; 1) is claimed at final analysis if the Bayesian probability of superiority is ≥ 98%. Results: Pam + GA entered PrP in Jun 2021. Between 6/2021 - 1/2023, at 23 US sites, 317 pts were treated and are included in the mITT analysis. 213 pts were treated in the Pam + GA arm (102 Line 1; 111 Line 2), 45 in the GA arm (23 Line 1; 22 Line 2), 31 in the mFOLFIRINOX arm and 28 in other experimental arms. All treated pts before and during Pam + GA enrollment were in the Bayesian model, with outcomes adjusted via a time machine to increase the trial’s statistical power. Baseline characteristics were balanced across the arms. Pam + GA met criteria to graduate to stage 2 in Sep 2022 in the All signature (Line 1 &amp; 2). At final analysis, Pam + GA did not meet the OS primary endpoint [model estimated HR: 1.18 (95% credible interval, 0.88, 1.56), posterior Pr(HR &lt; 1) = 0.14, below specified ≥ 0.98]. No benefit was seen in PFS nor ORR (Table). No new safety signals were seen. Conclusions: PrP, the first Bayesian platform trial in mPDAC, performed as designed; Pam + GA did not improve OS versus GA in Line 1 and Line 2 mPDAC. The novel Bayesian design warrants further study in mPDAC to enhance efficiency of drug development. Future designs should explore different strategies to allocate patients to control arm(s) vs experimental arms and accommodate novel agents intended to benefit subsets of mPDAC. 1. Picozzi, ASCO TPS 4188, 2022. Clinical trial information: NCT04229004 . Line 1 Line 2 GA Pam + GA Hazard Ratio GA Pam + GA Hazard Ratio Model Estimated mOS (mos) 11.3 9.7 1.18(95% CI* 0.88, 1.56) 7.8 6.6 1.18(95% CI* 0.88, 1.56) mPFS (mos) 5.3 5.9 0.64(95% CI^ 0.36, 1.14) 7.0 3.9 1.35(95% CI^ 0.78, 2.33) ORR (%) 26.1 35.3 4.5 9.0 *Credible Interval. ^Confidence Interval.

Alpha synuclein overexpression can drive microbiome dysbiosis in mice

Abstract Growing evidence indicates that persons with Parkinson disease (PD), have a unique composition of indigenous gut microbes. Given the long prodromal or pre-diagnosed period, longitudinal studies of the human and rodent gut microbiome before symptomatic onset and for the duration of the disease are currently lacking. PD is partially characterized by the accumulation of the protein α-synuclein (α-syn) into insoluble aggregates, in both the central and enteric nervous systems. As such, several experimental rodent and non-human primate models of α-syn overexpression recapitulate some of the hallmark pathophysiologies of PD. These animal models provide an opportunity to assess how the gut microbiome changes with age under disease-relevant conditions. Here, we used a transgenic mouse strain, which overexpress wild-type human α-syn to test how the gut microbiome composition responds in this model of PD pathology during aging. Using shotgun metagenomics, we find significant, age and genotype-dependent bacterial taxa whose abundance becomes altered with age. We reveal that α-syn overexpression can drive alterations to the gut microbiome composition and suggest that it limits diversity through age. Taxa that were most affected by genotype-age interaction were Lactobacillus and Bifidobacteria . In a mouse model, we showed direct link between alpha synuclein geneotype (hallmark of PD), a dysbiotic and low-diversity gut microbiome, and dysbiotic levels of Bifidobacteria and Lactobacillus (most robust features of PD microbiome). Given emerging data on the potential contributions of the gut microbiome to PD pathologies, our data provide an experimental foundation to understand how the PD-associated microbiome may arise as a trigger or co-pathology to disease.

Enterobactin carries iron into Caenorhabditis elegans and mammalian intestinal cells by a mechanism independent of divalent metal transporter DMT1

Predictive factors for the efficacy of nal-IRI + 5FU/LV therapy in patients previously treated with conventional irinotecan.

737 Background: There were some reports that nal-IRI + 5FU/LV (NAPOLI) therapy was effective for patients with unresectable pancreatic cancer who had a history of treatment containing conventional irinotecan (IRI) though the others did not. We aimed to investigate the factors that contribute to the effectiveness of NAPOLI therapy for patients who have already received IRI-containing treatment. Methods: We retrospectively enrolled the consecutive patients who had previously treated with IRI-containing treatment and started NAPOLI therapy at our hospital between June 2020 and December 2022. We compared the patient backgrounds of patients who achieved CR, PR, or SD according to RECISTv1.1 (effective group) and those who did not (ineffective group). Continuous variables were divided into two groups by the median of the entire population, and factors contributing to the effectiveness of NAPOLI therapy were determined by logistic regression analysis. Results: The subjective were 52 patients. The reason for discontinuation of IRI-containing treatment was refractory and intolerant in 45 and 7 patients, respectively. The median age was 65 years. Twenty-three patients (44%) had ECOG PS of 0, and 41 patients (79%) had metastatic disease. The median albumin, CRP, CEA and CA 19-9 was 3.8 g/dL, 0.3 mg/dL, 8.5 ng/mL and 2082 U/mL, respectively. Twenty-one patients (40%) showed SD and they were allocated in the effective group whereas 31 patients were in the ineffective group. Of the 21 patients in the Effective Group, 16 patients(76%) were refractory, while of the 31 patients in the Ineffective Group, 29 patients (94%) were refractory. The factors contributing to disease control were PS of 0 (odds ratio, 5.79; 95% confidence interval, 1.34–25.0), CA 19-9 &lt;1000 U/mL (odds ratio, 5.53; 95% confidence interval, 1.26–24.3), and Alb &gt;3.8 g/dL (odds ratio, 5.19; 95% confidence interval, 1.14–23.7). Age, sex, disease stage, serum level of CRP, and CEA did not affect the effectiveness of NAPOLI therapy. Conclusions: Even in patients who have already received IRI treatment, the NAPOLI regimen is expected to be effective in patients with PS of 0, Alb &gt;3.8 g/dL, and CA 19-9 &lt;1000 U/mL.

The prevalence of Lynch syndrome and associated clinicopathologic features in patients with mismatch repair deficient gastric cancer.

380 Background: Approximately 2-4% of patients with primary colorectal cancer are estimated to be associated with Lynch syndrome. However, the prevalence of Lynch syndrome and associated clinicopathologic features in patients with mismatch repair-deficient (dMMR) gastric cancer (GC) is not well understood. In this study, we investigated the frequency of dMMR GCs in unselected GCs and the prevalence of Lynch syndrome, as well as associated clinicopathologic features and molecular alterations in dMMR GCs. Methods: A total of 847 cases of unselected GCs from 2010 to 2012 were collected at Jeju National University Hospital. Immunohistochemistry for mismatch repair proteins (MMR), including MLH1, MSH2, MSH6, and PMS2, and MSI analysis were performed on representative tumor sections of surgically resected specimens. Follow-up genetic counseling and genetic and/or epigenetic alterations of the MMR genes were also investigated. Results: Loss of one or more MMR proteins and microsatellite instability-high were observed in 72 patients; 67 patients showed loss of MLH1/PMS2, 2 patients showed loss of PMS2 alone, and 3 patients with MSH2/MSH6. Genetic counseling demonstrated that ten patients had a family history of LS-associated cancers and nine patients had a history of metasynchronous cancers. Of the 72 patients, 65 revealed hypermethylation of the promoter region of MLH1. The subsequent genetic germline tests demonstrated 2 patients with MLH1 mutation, 3 with MSH2 mutation, and 2 with PMS2 mutation. Conclusions: dMMR tumors were identified in 72 (8.5%) of 847 unselected primary GCs. This study estimated that 0.8% of patients with unselected GC and 9.7% of patients with dMMR GC fulfilled the revised Bethesda criteria and are associated with Lynch syndrome. The detection of dMMR GCs and necessary genetic counseling/tests based on revised Bethesda criteria would help find Lynch syndrome in patients with GC. Clinical and immunophenotypical features of patients with dMMR GC. Age ≤ 50 years 5 (6.9) &gt; 50 years 67 (93.1) Other malignancy history except GAC No 63 (87.5) Yes 9 (12.5) History of metachronous cancers Esophageal cancer 1 (1.4) Maxillary sinus cancer 1 (1.4) Papillary thyroid cancer 1 (1.4) Colorectal cancer 1 (1.4) Pancreatic cancer 1 (1.4) Breast cancer 1 (1.4) Breast cancer and malignant GIST 1 (1.4) Multiple HCCs 2 (2.8) History of Family with LS related cancers No 62 (86.1) Yes 10 (13.9) Fulfillment of the rBG No 63 (87.5) Yes 9 (12.5) MMR proteins Loss of MLH1 and PMS2 67 (93.1) Loss of PMS2 2 (2.8) Loss of MSH2 and MSH6 3 (4.2) Germline mutation test MLH1 mutations 2 (2.8) MSH2 mutations 3 (4.2) PMS2 mutations 2 (2.8)

Real world characteristics and outcomes of patients with BRAFV600E-mutant metastatic colorectal cancer in Australia: The COALA project.

70 Background: BRAFV600E-mutant metastatic colorectal cancer (mCRC) represents a unique molecular subset with poor prognosis and less responsiveness to chemotherapy. The BEACON CRC study demonstrated that encorafenib plus cetuximab (EC) significantly improved overall survival (OS) compared to FOLFIRI plus cetuximab in BRAF-mutant mCRC as 2 nd or 3 rd line therapy. This combination was reimbursed in Australia from January 2022. Methods: We analysed data from the Australian TRACC mCRC clinical registry, encompassing patients (pts) with BRAF-mutant mCRC diagnosed in Australia from 2009 to 2024 at 31 hospitals. We assessed baseline demographics, uptake of EC following reimbursement and efficacy analysis of progression-free survival (PFS) and OS for pts that received EC and those who did not. Pts receiving EC on a clinical trial were excluded. Results: Among 2,800 pts with known BRAF mutation status, 365 (13%) were BRAF mutated. The BRAF mutant cohort had a median age of 63 years, with a significantly higher mutation rate in the 20-39 age group than other age groups (age 20-39, 25.5%; age 40-59, 10%; age 60+, 13.2%; P&lt;0.001); 54.5% were female, 58% right-sided tumours, 64% with synchronous metastatic disease and 21.7% deficient mismatch repair (dMMR). Overall, 314 (86%) pts with BRAF mutant tumours and 2,079 (85%) BRAF wild-type (WT) tumours received 1 st line treatment, and 156 (43%) BRAF mutant and 1,144 (47%) BRAF WT pts received 2 nd line therapy. The median OS from diagnosis was 17.3 months for BRAF mutant pts versus 34.7 months for BRAF WT pts (p &lt; 0.0001). All dMMR BRAF mutant pts received 1 st line pembrolizumab since its reimbursement in August 2021. Among 41 BRAF mutant pts progressing on 1 st line therapy since January 2022,(32 pMMR, 9 dMMR), 33 (80%) were subsequently treated with EC, and 4 (10%) did not receive further treatment. OS from the start of 2 nd line therapy was 9.6 months (95% CI: 7.2-12.5) for pts who received EC and 7.1 months (95% CI: 6.4-8.6) for those who received other systemic treatment. Median PFS for pts receiving EC was 4.6 months (95% CI: 3.4-5.8) and 3.3 months (95% CI: 2.5-5.3) for other 2 nd line treatments. Conclusions: mCRC pts younger than 40 have a high rate of BRAF mutation, where 1 in 4 tumours harbour the mutation. BRAF mutant mCRC has a poorer outcome than BRAF WT despite a similar proportion receiving 1 st and 2 nd line treatment. The majority of eligible BRAF mutant mCRC pts received EC following reimbursement in Australia, with PFS and OS outcomes consistent with the BEACON CRC trial.

IMMULAB: A phase II trial of immunotherapy with pembrolizumab in combination with local ablation for patients with early stage hepatocellular carcinoma (HCC)—The IKF-IMMULAB trial.

582 Background: Ablation of neoplastic tissue through radiofrequency ablation (RFA), microwave ablation (MWA), or brachytherapy is a potentially curative option for patients with early stage hepatocellular carcinoma (HCC); however, recurrence rates are high. While updated results from IMbrave050 do not support the use of adjuvant therapy following resection or local therapy, the potential of peri-interventional systemic treatment as a potentially more effective approach to increase recurrence free and long-term survival remains to be determined. We propose that peri-interventional treatment with pembrolizumab may improve outcomes following local ablative therapies. Methods: This single arm phase II trial investigates peri-interventional treatment with pembrolizumab combined with RFA/MWA or brachytherapy, or - as recommended for tumors ≥ 3 cm - by combination with TACE in early stage HCC with maintained liver function. 200 mg of pembrolizumab (q3w) was administered intravenously for 2 cycles followed by radiologic imaging and local therapy. Pembrolizumab was continued for up to 12 months. Primary endpoint was radiological response rate according to RECIST 1.1 prior to local therapy. Results: 30 pts (ECOG 0 or 1) were enrolled in 9 centers in Germany with a median age of 70 years (73.3% males, median tumor size 25 mm with minimum of 10 mm and maximum of 72 mm, 60% solitary lesions). All pts received at least 1 dose of study treatment and the median number of cycles was 13. ORR was 13.3% with 6.7% CR and 6.7% PR after two cycles. After a median follow-up of 34.5 months, median time to recurrence (TTR) was 16.43 months, with 8 pts remaining free of recurrence. mOS was not reached, with a 2y OS rate of 76% and a 3y OS rate of 66%. No new safety signs were observed. Subsequent local ablation was performed in 13 pts, and 10 pts started on systemic therapies (5 TKI, 3 ICI and 2 pts received TKI and ICI). Conclusions: In the IKF-IMMULAB trial the expected objective response rate of 30%, according to RECIST1.1., prior to local therapy was not reached. However, with recent evidence that radiologic response underestimates pathological response in ICI-treated HCC patients and supported by a 2y OS rate of 76% and a 3y OS rate of 66%, there is evidence for the efficacy of peri-interventional treatment with pembrolizumab without new safety signals. Clinical trial information: NCT03753659 .

HIV/AIDS and HBV co-infection with optimal control strategies and cost-effectiveness analyses using integer order model

Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding

Exploration of novel biomarkers and novel therapies for immune checkpoint inhibitors (ICIs) in genetic variants of esophageal squamous cell carcinoma (ESCC): A study of 1,059 Japanese cases.

495 Background: In Japan, cancer genome profiling (CGP) tests will be covered by insurance in 2019, and more than 1,000 ESCC cases have been accumulated in the national database. ICIs are currently the key drugs for esophageal cancer, and MSI and TMB status can work as biomarkers for ICIs in solid tumors. Therefore, to improve the prognosis of esophageal squamous cell carcinoma (ESCC), we aim to search for gene variants that may predict the efficacy of ICIs and explore the possibility of new treatment from genetic data accumulated in the Japanese nation-wide C-CAT database. Methods: We retrospectively analyzed 1,059 ESCC cases from C-CAT data accumulated from June 2019 to February 2024. We used the registered clinical and genetic information to examine gene variants and carcinogenic pathways that could serve as biomarkers for ICIs. Results: Of the 1059, 152 (14.4%) had TMB-H and 3 (0.3%) had MSI-H, with a median TMB of 5.0 Muts/Mb (range: 0-268). XPO1 and TP53 were found to be positively and negatively correlated as genes affecting TTF in nivolumab monotherapy (FDR P value &lt; 0.01). TMB has the potential to be a biomarker for ICI, but TMB was significantly higher in the group with variants in the ARID family ( ARID2 , ARID1A plus ARID5B ) (median TMB 5.0 vs 8.0 Muts/Mb, P&lt;0.001). In addition, 709 patients (66.9%) had any variants in three pathways (TP53, RTK and cell cycle), which are thought to be involved in the carcinogenesis of ESCC. PIK/Akt/mTOR and epigenetic modulation pathways were also found to be abnormal in many cases, and abnormalities in the epigenetic modification pathway were found to contribute significantly to TMB-H (FDR P value&lt;0.01, Logarithmic value=19.2). Conclusions: This is the first case-specific report on the relationship between mutations in the ARID family and TMB in ESCC and the signalling pathways leading to carcinogenesis. In the present study, the association between the ARID family and TMB, and between abnormalities in the epigenetic modification pathway and TMB, which has been previously reported in other cancer types but not in esophageal cancer, suggests that multiple pathological mutations including these may be new biomarkers for ICI in 1059 Japanese patients. Furthermore, multiple pathways are often involved in ESCC carcinogenesis at the same time, and a separate, combined approach that takes these into account may be necessary in the development of new drugs.

Real-world genomic testing performance in colorectal cancer (CRC): The MultiTEAM Systems Framework Precision Oncology Reflex Testing (TEAMSPORT).

108 Background: Genomic testing plays a pivotal role in personalizing treatment for CRC patients. Despite recommendations from NCCN, adoption remains uneven. Research indicates that only 64.7% of patients with metastatic CRC (mCRC) underwent molecular testing nationwide. TEAMSPORT seeks to address this gap by evaluating the feasibility of reflex testing and examining how pathology and oncology teams integrate genomic testing into routine practice. Methods: This quasi-experimental study tracks testing over time. Eligible patients were 18 years or older, with a histological diagnosis of adenocarcinoma, who received treatment at the University of Kansas Health System (TUKHS). Exclusion criteria included patients discharged to hospice after diagnosis, those whose last contact with TUKHS occurred within 30 days of diagnosis, and patients who passed away within 30 days of diagnosis. Testing rates were calculated as the number of tests performed divided by the number of testing opportunities, where "testing opportunities" refer to NCCN-recommended tests based on cancer stage. An intervention to increase adherence to NCCN-recommended testing began in December 2022. Results: From January 2022 to December 2023, 564 colorectal cancer (CRC) cases were eligible for genomic testing, resulting in 1,525 testing opportunities. In localized CRC, testing rates steadily improved, from 92% in January-June 2022 to 98% by July-December 2023 for patients diagnosed outside of TUKHS. At TUKHS, the rates remained high, reaching 100% in the first two periods and staying over 90% in subsequent periods. Patients with mCRC saw similar trends, particularly in the control arm where rates went from 61% to 71%. Specific molecular NCCN-recommended tests were assessed. At TUKHS, testing rates were high for microsatellite instability (MSI - 98%) which is caused by deficiency of the DNA mismatch repair (dMMR) system. Lower testing rates were observed for other markers like KRAS (70%), BRAF (67%) and HER2 (48%). Testing rates were assessed based on primary insurance. At TUKHS, the testing rates for Medicaid patients reached 94%, private insurance patients at 78%, and Tricare/VA at 100%. Outside of TUKHS, Medicaid patients had lower testing rates at 21%, private insurance patients at 74%, and CMS patients at 66%. Time to test by processing lab will be presented at the meeting. Conclusions: Despite the high testing rates for MSI/dMMR, the overall genomic testing in CRC remains imperfect, with lower rates for BRAF and HER2 . This discrepancy may be related to the fact that targeted therapies for BRAF and HER2 are not yet part of first-line treatment for CRC. Causes for the discrepancy in testing rates by primary insurance have yet to be determined. Future research should address these gaps to enhance precision oncology in CRC management.

A safety trial of antibiotic fecal microbiota transplantation for esophageal and gastric cancer patients treated with immune checkpoint inhibitors (Biorich2 trial).

TPS510 Background: The development of immune checkpoint inhibitors (ICIs) has improved the prognosis of unresectable advanced or recurrent esophageal and gastric cancer. However, the prognosis remains poor. The human intestinal microbiota plays various roles in digestion, immunomodulation, and metabolism and is known to influence tumor suppression. Previous studies reported that intestinal microbiota can impact immune responses and the effectiveness of ICIs. Therefore, this study investigates the safety and efficacy of antibiotic fecal microbiota transplantation (A-FMT) in patients with unresectable advanced or recurrent esophageal or gastric cancer. Methods: Eligible patients are diagnosed with unresectable advanced or recurrent esophageal squamous cell carcinoma or gastric adenocarcinoma. The primary endpoint is to examine the dose-limiting toxicity (DLT) of A-FMT. Secondary endpoints include response rate, disease control rate, progression-free survival, overall survival, and biomarkers of efficacy and adverse events. This trial consists of two parts: safety confirmation, which assesses DLT incidence, and an expansion part, which examines efficacy and safety. The safety confirmation part will enroll 3-6 patients in cohort 1 (combination therapy with ICIs and chemotherapy) and cohort 2 (combination of anti-PD-1 and anti-CTLA4 antibodies). The expansion part will enroll untreated patients: 10 for esophageal cancer (ICIs + chemotherapy), 10 for anti-PD-1 + anti-CTLA4 antibodies, and 11 for gastric cancer (ICIs + chemotherapy). After enrollment, patients receive antibacterial agents for 1 week before FMT. Patients then undergo total colonoscopy after bowel cleaning with polyethylene glycol plus ascorbic acid. A 200 mL fecal suspension from a healthy donor is transferred to the patient's cecum, and ICIs with/without chemotherapy are initiated thereafter. Biomarker analysis explores diagnostic or surrogate biomarkers, aiming to identify molecular targets, cell populations, microbial species, and functions involved in efficacy by analyzing the effects of A-FMT and ICIs on the tumor microenvironment and intestinal microbiota using methods such as proteome analysis. This trial is registered in the Japan Registry of Clinical Trials as jRCTs031240170 and was initiated in August 2024, with enrollment ongoing. Clinical trial information: jRCTs031240170.

Analyzing disease control through testing game approach embedded with treatment and vaccination strategies

MAP3K4 signaling regulates HDAC6 and TRAF4 coexpression and stabilization in trophoblast stem cells

The impact of protein-energy malnutrition on outcomes in patients with cholangiocarcinoma admitted with sepsis: Insights from a national database.

535 Background: Patients with cholangiocarcinoma (CCA) are prone to infection and related complications. Protein-energy malnutrition (PEM) is common among these patients, arising from either the malignancy or its treatments. PEM is linked to worse medical and surgical outcomes and longer hospital stays across various cancers. The impact of PEM on CCA patients with sepsis, however, remains underexplored. This study aims to fill this gap by assessing how PEM affects in-hospital outcomes in CCA patients admitted with sepsis. Methods: We queried the Healthcare Cost and Utilization Project National Inpatient Sample and identified adult patients with CCA admitted with the principal diagnosis of sepsis from 2018 to 2021, using the ICD-10 code. We categorized the cohort based on the presence or absence of PEM and applied complex sampling weights for national representativeness. We compared socio-demographic characteristics and comorbidities between CCA patients with sepsis who have PEM and those who do not. The primary outcome studied was all-cause in-hospital mortality. Secondary outcomes examined were acute kidney injury (AKI), renal replacement therapy (RRT), respiratory failure (RF), invasive ventilation (IV), septic shock, vasopressor requirement (VP), mean length of hospital stay (LOS), and mean total hospitalization charges (THC). Multivariate regression models assessed outcome disparities between groups, adjusting for patient characteristics and comorbidities, with statistical significance set at p &lt; 0.05. Results: We identified a total of 22,680 adults with CCA who were admitted with the principal diagnosis of sepsis from 2018 to 2021. Among these, 7,245 patients (31.9%) had a concurrent diagnosis of PEM. The PEM group had a higher proportion of female (47.3% vs 44.1%, p=0.04) and non-white (41.7% vs 37.2%, p&lt;0.001) patients and patients with Charlson Comorbidity Index &gt; 3 (86.5% vs 83.3%, p&lt;0.001). Patients with PEM had higher odds of all-cause in-hospital mortality with an adjusted odds ratio (aOR) of 1.26 (95% confidence interval (CI) 1.05-1.51). They also had higher odds of AKI with an aOR of 1.32 (95% CI 1.16-1.50), RF with an aOR of 1.30 (95% CI 1.09-1.51), and septic shock with an aOR of 1.22 (95% CI 1.06-1.40). Patients with PEM also had a higher LOS (9.0 vs 6.3 days) with an adjusted incidence rate ratio (aIRR) of 1.41 (95% CI 1.33-1.49) and THC ($115,971 vs $83,176) with aIRR of 1.35 (95% CI 1.25-1.45). Conclusions: Our study revealed that CCA patients with PEM admitted with sepsis had significantly higher odds of in-hospital mortality, AKI, RF, and septic shock compared to those without PEM. They also experienced longer hospital stays and higher hospitalization charges. These findings highlight the urgent need to address PEM in CCA patients and tailor inpatient management to reduce complications in this high-risk group.