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Sufentanil enhances the cortical neurogenesis of rats with traumatic brain injury via PI3K/AKT signal pathway

Inhibition of L-threonine dehydrogenase from Trypanosoma cruzi reduces glycine and acetate production and interferes with parasite growth and viability

Impact of education on clinical confidence utilizing HER2-targeted therapies in colorectal cancer.

225 Background: Novel targeted therapies entered the treatment landscape in patients with HER2-positive metastatic colorectal cancer (mCRC). To ensure that these therapies are used effectively, clinicians must assess tumor HER2 status and recognize how HER2-directed treatment modalities fit into the current paradigm. To further enable clinicians to integrate HER2-targeted therapies, an educational program was designed in 2023. Methods: A one-hour online, video-based program was designed for clinicians and their teams and hosted on MedLive from February 2023 for one year. Knowledge and competence questions were administered pre-, and immediate post-activity. Additional questions assessed attitudes, barriers, and intended practice changes related to HER-positive mCRC. Results: Over 4,000 participants engaged in the educational activity, 67% of whom were physicians, and 63% noting their specialty as oncology. Approximately 68% identified as treaters seeing 14 patients with CRC per week with 78% of those patients have HER2-positive CRC. All pre-post questions showed significant improvements in knowledge and competence related to HER2 amplification testing methodologies, trial eligibility criteria, identification of patients who would benefit from anti-HER2 targeted regimens, and adverse events associated with anti-HER2 agents. Following the activity, 51% were more likely to incorporate testing for HER2 expression level or amplification prior to the selection of targeted therapy for their patients. The greatest challenges faced when managing patients with HER2-positive mCRC were affordability of therapy for patients (50%), adherence to treatment schedules (25%) and patient anxiety about treatment efficacy (24%). The most common barriers to patient enrollment in clinical trials identified by clinicians were lack of trials at their institutions (35%), lack of trials in their geographic region (21%), and patient lack of interest (20%). Qualitative insights on intended practice changes were shared by learners post-activity. Conclusions: The outcomes of this educational activity demonstrate the effectiveness of education in improving knowledge and confidence from testing to adverse event management to better integrate new regimens into practice. Encouraging practice changes were also seen from the write-in responses from learners. Additional needs were also identified to further solidify HER2 testing as a prerequisite for anti-HER2 targeted therapies, selecting eligible patients, and timely management of adverse events.

A multicenter retrospective study of salvage surgery for patients with residual or recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy: SURGES study.

422 Background: Salvage surgery is defined as an operation for patients with residual or recurrent tumors after definitive chemoradiotherapy (dCRT) with > 50 Gy. Although salvage surgery has been considered to improve prognosis, it is associated with a high incidence of postoperative morbidity and mortality. A previous meta-analysis by Faiz et al. reported anastomotic leakage, pulmonary disorder rates, and 90 day-mortality rates of 18.6%, 30.2%, and 8.8%, respectively. The aim of this study was to assess the efficacy and safety of salvage surgery in patients with residual or recurrent esophageal squamous cell carcinoma (ESCC) after dCRT and to explore the risk factors for postoperative complications and poor prognosis. Methods: This multi-institutional retrospective study enrolled patients treated with salvage surgery after dCRT between January 2017 and December 2021. The preoperative backgrounds of the patients were analyzed to assess their impact on survival or toxicity. Results: In total, 148 patients (59 with recurrent disease and 89 with residual disease) underwent salvage surgery at 10 leading hospitals in Japan. Post-dCRT ycT stages were T0/T1/T2/T3/T4: 12/25/30/78/3, and ycN stages were N0/N1/N2: 87/53/8. Among 136 patients who underwent esophagectomy, 108 underwent minimally invasive surgery and 28 underwent open surgery. Twelve patients had metastatic lymph nodes without primary disease. Severe postoperative complications (≧Clavien-Dindo Grade III) occurred in 39 (26.3%) patients and overall postoperative complications (≧Grade II) rate was 46.6%, including 19 (12.8%) anastomotic leakage and 25 (16.9%) pneumonia. Thirty- and 90-day mortality rates were observed in 0 and 5 (3.3%) patients, respectively. Multivariate logistic regression analysis showed that a total radiation dose ≥60 Gy (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.07-6.55) and residual disease (OR 3.04, 95%CI 1.32-7.00) were associated with severe postoperative complications. The 3-year overall survival (OS) and progression-free survival (PFS) rates were 48.9% and 40.0%, respectively (median follow-up time: 42.1 months). Multivariate analysis revealed that patients with a long interval between dCRT and salvage surgery (≥180 days) had significantly longer OS (hazard ratio [HR] 0.60, 95%CI 0.38-0.95, p=0.032), and ycN0 was associated with longer PFS (HR 0.56, 95%CI 0.36-0.87, p = 0.011). The total radiation dose was not an independent prognostic factor for either OS or PFS. Conclusions: Salvage surgery is safe and provides substantial long-term outcomes. In cases with a total radiation dose of ≥60 Gy and residual disease, special caution is required because of the higher incidence of postoperative morbidity. A longer interval between dCRT and salvage surgery and ycN0 were prognostic factors.

Outcomes by transarterial chemoembolization (TACE) modality from participants (pts) with embolization-eligible hepatocellular carcinoma (HCC) treated with durvalumab (D) + bevacizumab (B) + TACE and placebos (PBO) + TACE: EMERALD-1 subgroup analysis.

575 Background: EMERALD-1 (NCT03778957) met its primary endpoint, showing improved progression-free survival (PFS) in pts with locoregional HCC treated with D + B + TACE versus PBO + TACE (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61–0.98). This analysis assessed the impact of TACE modality (conventional TACE [cTACE] or drug-eluting bead [DEB]-TACE) on efficacy and safety outcomes. Methods: Pts in this analysis received D (1500 mg) or PBO for D (Q4W) plus cTACE or DEB-TACE (investigator choice; TACE modality was a stratification factor). After completing the last TACE, pts received D (1120 mg) + B (15 mg/kg) or PBO for D + B (Q3W). PFS, time to progression (TTP), and overall response rate (ORR; BICR per RECIST v1.1) with D + B + TACE and PBO + TACE (intent-to-treat population) are reported by TACE modality. Safety was assessed in the safety analysis set (pts received ≥1 dose of study treatment [tx], regardless of randomization). Results: Overall, 59.3% of pts received cTACE and 40.7% received DEB-TACE in the D + B + TACE arm; similarly, 58.5% of pts received cTACE and 41.5% received DEB-TACE in the PBO + TACE arm. Most pts received 1 or 2 TACE procedures in both cTACE (60% in D + B + TACE arm; 67.2% in PBO + TACE arm) and DEB-TACE groups (55.6% in D + B + TACE arm; 53.6% in PBO + TACE arm). Baseline characteristics in the cTACE and DEB-TACE groups were similar, with some differences in the relative distribution of BCLC, HAP, and tumor burden (BCLC Score A; 29.0% vs 17.9%: HAP Score A; 36.5% vs 25.0%: tumor burden within up-to-7 criteria; 56.4% vs 37.5%, respectively). Baseline characteristics were generally well balanced across tx arms within the cTACE and DEB-TACE groups. PFS, TTP, and ORR improved with D + B + TACE versus PBO + TACE, regardless of TACE modality (Table). In the D + B + TACE and PBO + TACE arms, max Grade 3–4 adverse events possibly related to study tx were reported by 25/100 (25.0%) and 3/116 (2.6%) pts in the cTACE group, and 16/54 (29.6%) and 9/84 (10.7%) pts in the DEB-TACE group, respectively. Conclusions: Overall, pts receiving D + B + TACE had improved PFS, TTP, and ORR versus PBO + TACE regardless of TACE modality. Safety was manageable with both cTACE and DEB-TACE. Clinical trial information: NCT03778957 . D + B and cTACE (n=121) PBO and cTACE (n=120) D + B and DEB-TACE (n=83) PBO and DEB-TACE (n=85) Median (95% CI) PFS, months 19.4 (12.4–22.3) 11.1 (7.2–14.0) 11.1 (7.2–14.2) 6.7 (5.0–7.3) PFS HR (95% CI) 0.80 (0.59–1.10) 0.74 (0.51–1.06) Median (95% CI) TTP, months 22.3 (19.4–27.7) 13.6 (9.2–16.6) 15.0 (11.1–22.4) 6.9 (5.1–11.1) TTP HR (95% CI) 0.70 (0.49–0.98) 0.55 (0.36–0.83) Pts with measurable disease at baseline, n 119 119 83 84 ORR, n (%) pts with response* 62 (52.1) 43 (36.1) 26 (31.3) 17 (20.2) ORR, odds ratio (95% CI) 1.93 (1.15–3.27) 1.80 (0.89–3.69) *Includes confirmed complete or partial response.

Efficacy and safety of albumin-bound docetaxel vs. docetaxel in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma: A multicenter, randomized, phase II study.

333 Background: Docetaxel has demonstrated promising activity in gastric cancer, both as monotherapy and in combination with other agents. Albumin-bound docetaxel (HB1801) is a new kind of taxane and has many advantages compared with docetaxel. Previous phase I study has demonstrated that HB1801 showed preliminary efficacy in patients with gastric cancer. Methods: In this phase II study, eligible patients were aged 18-75 years with histologically confirmed gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, who progressed on at least first line of combined chemotherapy of platinum and fluorouracil. Patients were randomized (1:1) to receive HB1801 (100 mg/m 2 ) or docetaxel (Taxotere, 75 mg/m 2 ) administered every 3 weeks by intravenous infusion. Stratified factors included previous treatment with immunotherapy (yes or no) and ECOG PS (0 or 1). Primary endpoint was progression free survival (PFS). Results: As of June 25, 2024, 128 patients were randomized to the HB1801 group ( n =65) or the docetaxel group ( n =63). The two groups were comparable on baseline characteristics. Overall, the median age was 59.0 (range 27-75) years, 106 (82.8%) patients had ECOG PS of 1. 76 (59.4%) patients had received previous treatment with immunotherapy. 76 (59.4%) patients had ≥ 2 metastatic sites. Median PFS was 4.0 months (95%CI 2.8-4.2) with HB1801 versus 2.7 months (95%CI 1.8-3.0) with docetaxel, HR = 0.81(95%CI 0.53, 1.21). Objective response rate and disease control rate were 21.5% (1CR and 13 PRs, 95%CI 12.3-33.5) and 56.9% (20 SDs, 95%CI 44.0-69.2) in the HB1801 group, compared with 14.3% (1 CR and 8 PRs, 95%CI 6.8-25.4) and 42.9% (17 SDs, 95%CI 30.5-56.0) in the docetaxel group. Median overall survival was 11.3 months with HB1801 versus 7.8 months with docetaxel (HR = 0.59 [95%CI 0.35, 1.01], p=0.025). Treatment-related adverse events (TRAEs) occurred in 93.8% of patients receiving HB1801, and 93.7% of patients receiving docetaxel. Alopecia (46.2% vs. 39.7%), fatigue (43.1% vs 23.8%), anemia (40.0% vs 39.7%), hypoalbuminemia (29.2% vs 12.7%), decreased appetite (21.5% vs 12.7%), peripheral edema (16.9% vs 12.7%) and nausea (15.4% vs 19.0%) were the most common TRAEs in the HB1801 group and the docetaxel group. 20 patients (30.8%) in the HB1801 group and 19 patients (30.2%) in the docetaxel group experienced ≥grade 3 TRAEs, with the most common being anemia and fatigue. 3 patients in the docetaxel group experienced treatment emergent adverse events (TEAEs) leading to death, which one was considered to be treatment-related. No patients in the HB1801 group had TEAEs leading to death. No new safety signal was observed in HB1801 group. Conclusions: Compared with Taxotere, HB1801 results in 41% reduction in risk of death with a manageable safety profile in patients with previously treated advanced G/GEJ cancer. Clinical trial information: NCT05705635 .

Cough suppressant reverses lung scarring

The sex differences in diseases progression and prognosis among persons with HIV and HBV coinfection

Menaquinone-specific turnover by Mycobacterium tuberculosis cytochrome bd is redox regulated by the Q-loop disulfide bond

The efficacy of anamorelin in gastrointestinal cancer with cancer cachexia: Single center experience.

815 Background: Cancer cachexia is a catabolic syndrome that causes weight loss and loss of appetite in cancer patients. Anamorelin (ANAM) is an oral drug approved in Japan to treat cancer cachexia by selectively activating ghrelin receptors. There is limited real-world data available on the efficacy of ANAM for patients with gastrointestinal cancer. We assessed its efficacy and identified associated clinical features. Methods: We retrospectively collected data from medical records and questionnaires on gastric and colorectal cancer patients who received ANAM between April 2021 and March 2023. We evaluated the change in body weight, appetite, and oral intake from the time of initiation of ANAM. We judged the responder who gained more than 0.5 kg in body weight, improved appetite, and increased oral intake, respectively. The association between clinical features and the responders was also assessed using multivariate logistic regression analysis. Results: 72 patients were included in this study. Characteristics of the patients: median age: 68 years old (range 38-85), male/female: 35/37, gastric/colorectal cancer: 39/33, PS 0-1/2 or more: 63/9, median body mass index (BMI): 18.0 kg/m 2 (range 12.3-27.9), number of prior chemotherapy regimens 1/2/3 or more: 17/22/33, ascites none/mild/moderate/severe: 42/19/7/4, median serum albumin levels (Alb): 3.2 g/dl (range 2.0-4.2). The median treatment duration of ANAM was 47.5 days (3-450 days). 57 patients (79.2%) continued ANAM for more than 3 weeks, and 9 patients for more than 12 weeks. The main reasons for discontinuation were progressive disease (39.7%), ineffective (12.7%), effective (11.1%) and adverse events of ANAM (11.1%). 33 patients (45.8%) gained weight, 41 patients (56.9%) improved appetite and 34 patients (47.2%) increased oral intake. There was a correlation found between BMI ＜ 18.0 kg/m 2 and the responders (OR 3.43, p = 0.041). Conclusions: In this study, 68.0% of patients who received ANAM for showed response, that is, gained body weight, or improved appetite, or increased oral intake. And these observations suggested that BMI was associated with effects of ANAM. Further studies involving more patients needed.

Association between visceral adipose tissue radiodensity and overall survival among older adults with colorectal carcinoma.

43 Background: Central obesity is a known risk factor for colorectal carcinoma (CRC); however, the association between visceral adipose tissue (VAT) and survival outcomes remains unclear. This study aims to investigate the relationship between VAT and overall survival (OS) among older adults with CRC. Methods: We analyzed data from the Cancer and Aging Resilience Evaluation registry, including adults aged ≥ 60 years with newly diagnosed CRC who were seen at the University of Alabama at Birmingham for initial consultation between October 2017 and April 2024. Using single-slice computed tomography staging scans, we calculated visceral adipose tissue radiodensity (VATD; in Hounsfield units, HU) at the third lumbar vertebra (L3) using validated methods. A lower VATD (more negative score) indicates higher visceral adipose tissue. Participants were followed until death or the study cutoff date of July 10, 2024. Kaplan-Meier survival analysis was performed to estimate OS for those with low VAT (VATD ≥ median VATD) versus high VAT (VATD < median VATD). Additionally, Cox proportional hazards models were utilized to evaluate the association between VATD and OS, adjusting for age at diagnosis, sex, race/ethnicity, skeletal muscle index (SMI), skeletal muscle density (SMD), and cancer stage. Results: A total of 190 patients were included, with a median age at diagnosis of 68 years (IQR: 64-75), 56% male, 72% non-Hispanic White, and 40% diagnosed with Stage IV disease. The median SMI and SMD were 42.06 (IQR: 33.81 - 49.52) cm 2 /m 2 and 38.68 HU (IQR: 31.38 - 44.89) respectively. The median VATD was -86.14 HU (IQR: -93.78 – -76.39). Over a median follow-up of 60 months, 96 patients (51%) died. Median OS was 27 months for patients with low VAT and 62 months for those with high VAT (log-rank test, p < .001). After adjusting for confounders, VATD remained independently associated with OS (adjusted Hazard Ratio: 1.41 per IQR decrease; 95% CI: 1.06 – 1.86; p ≤ .05), indicating that each IQR decrease in VATD scores (implying an increase in VAT) is associated with a 41% increased risk of all-cause mortality. Conclusions: Our findings demonstrate that increased visceral adipose tissue, indicated by more negative VATD scores, is significantly associated with poorer survival outcomes among older adults with CRC. These results underscore the importance of dietary and weight loss interventions to improve outcomes in this population.

Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial.

LBA125 Background: Colorectal cancer (CRC) affects 1.9 million individuals globally each year. Among patients with stage II-III CRC, 20-40% develop metastatic disease. Aspirin lowers the incidence of adenomas and CRC in high-risk patients. In addition, observational studies suggest that post-diagnosis aspirin treatment improves disease-free survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response, but requires validation in randomized trials. Methods: The ALASCCA trial was a randomized, double-blind, multicenter, placebo-controlled trial with two parallel arms, across 33 hospitals in Sweden, Denmark, Finland, and Norway. Patients with stage I-III rectal cancer or stage II-III colon cancer exhibiting somatic alterations in the PI3K signaling pathway were included. Patients were randomized to receive either 160 mg of aspirin daily or placebo, initiated within three months post-surgery and continued for three years. To detect a hazard ratio (HR) of 0.36 for the primary outcome of time to recurrence (TTR) assessed at 3 years, with 80% power and a two-sided alpha of 0.05, 150 patients with PIK3CA mutations in exon 9 and/or 20 (“Group A”) were required per arm. An additional 300 patients with other somatic PI3K pathway driver alterations (PIK3CA outside exon 9/20, PIK3R1, or PTEN; "Group B") were required for secondary analyses. A stratified Cox proportional hazards model was fitted for the primary efficacy analysis. Results: A total of 3508 patients were screened for somatic alterations in the PI3K pathway. Of the 2980 patients with conclusive genomic analyses, 1103 patients (37%) had an alteration in the PI3K pathway: 515 patients (17.3%) in Group A and 588 patients (19.7%) in Group B. In total, 626 patients were randomized. After three years of follow-up, the HRs for TTR comparing aspirin to placebo were 0.49 (95% CI; 0.24-0.98; p=0.044) in Group A and 0.42 (95% CI; 0.21-0.83; p=0.013) in Group B. For DFS, the HRs were 0.61 (95% CI; 0.34-1.08; p=0.091) in Group A, and 0.51 (95% CI; 0.29-0.88; p=0.017) in Group B. Three patients experienced aspirin-related severe adverse events (one GI-bleeding, one hematoma, one allergic reaction). Conclusions: Primary endpoint was met. Adjuvant treatment with 160 mg aspirin daily for three years reduced recurrence rate in CRC patients with somatic alterations in the PI3K signaling pathway. These findings could lead to immediate changes in clinical praxis for about a third of CRC patients. Clinical trial information: NCT02647099 .

A phase II open-label study of sacituzumab govitecan in patients with previously treated locally advanced, recurrent, or metastatic cholangiocarcinoma (SIGNA).

TPS651 Background: Cholangiocarcinoma (CCA) is a highly aggressive cancer with limited treatment options. Trop-2, a transmembrane calcium signal transducer, plays a key role in cellular self-renewal, proliferation, and transformation, thereby promoting tumorigenesis. Its overexpression has been associated with disease progression and shorter survival in several epithelial tumors, including CCA. Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of a humanized anti-trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody coupled to SN-38, the active metabolite of the topoisomerase inhibitor, irinotecan. Based on the results from the Phase III ASCENT trial, SG was approved by the FDA for treating relapsed or refractory triple-negative breast cancer and hormone receptor-positive breast cancer, regardless of Trop-2 expression. Given Trop-2's expression in CCA, SG is being investigated as a potential treatment option in this setting. Methods: This Phase II, non-randomized, open-label, single-arm study is being conducted at the University of Kansas Cancer Center and its affiliated sites. Eligibility : Key inclusion criteria include patients with locally advanced, recurrent, or metastatic CCA who have undergone at least one line of prior therapy, have adequate archival tissue for biomarker evaluation or are willing to undergo a biopsy, and have an ECOG performance status of 0-1. Key exclusion criteria include known homozygosity for the UGT1A1*28 allele, which is associated with irinotecan toxicity, and prior treatment with topoisomerase I inhibitors. Treatment Plan : SG is administered at 10 mg/kg intravenously on Days 1 and 8 of every 21-day cycle. Imaging will be performed every 6 weeks. Biopsies will be required both prior to treatment and on-treatment (between Days 15-21 of Cycle 1). Objectives : Primary objective: To determine the anti-tumor activity of SG as measured by the overall response rate (ORR) according to RECIST 1.1. Secondary objectives: To assess treatment safety in participants who have received at least one dose of SG, and to evaluate anti-tumor activity based on progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). Statistical Plan : The sample size (n=22) was calculated using a modified Simon two-stage design, hypothesizing an improvement in ORR to 25%, compared to a baseline value of 8%. In the first stage, 14 patients will be enrolled. If ≤1 participant demonstrates an ORR, the study will be stopped for futility. If ≥2 participants show ORR, an additional 8 patients will be enrolled (total n=22). The study will be deemed successful if ≥4 participants achieve an ORR. This design provides 80.9% power with an 8.5% type I error rate. Stopping rules include halting the trial if the grade 4-5 treatment-related toxicity rate reaches 10%. Enrollment is ongoing. Clinical trial information: NCT06178588 .

Sodium channel blocker reduces skin inflammation

Investigating the prevalence and associated factors of elevated liver enzymes and dyslipidemia during pregnancy

N-terminal fragment shedding contributes to signaling of the full-length adhesion receptor ADGRL3

Outcomes of simultaneous, adaptive, MRI-guided liver SBRT in patients with heavily pretreated colorectal cancer and four or more liver metastases.

160 Background: About one-third of colorectal cancer (CRC) patients (pts) develop metastases, most commonly in the liver (CRLM). Ablative treatment of multiple liver lesions is difficult and often not done with conventional CT-based radiation therapy, but feasible with MRI-guided adaptive radiation. This study reviews our experience treating pts with high burden CRLM using MRI-guided stereotactic body radiation therapy (MRgRT). Methods: This study identified pts with 4 or more CRLM treated with MRgRT between 7/2019 and 4/2024, all of whom had progressive disease during or after standard-of-care therapy. Ablative radiation was delivered to all sites of disease with no concurrent systemic therapy. All with Child-Pugh score 5-6 (class A) liver function. Local control was defined as no progression in any treated lesion on a per-patient basis. Descriptive statistics summarized the data. A Cox proportional hazards model was used to identify predictors of survival, while the Kaplan-Meier method was used to estimate survival functions. Statistical analysis was performed using SPSS. Results: Seventeen pts with 110 lesions were included, with a median follow-up of 10.7 months (range, 1.7–36.9). The majority (n=15) received systemic therapy in the year before MRgRT. The median number of prior lines of systemic therapy was 2 (range, 1–5). Eight pts (47.1%) had nodal and/or lung progression in addition to CRLM, and 4 pts (23.5%) had at least one prior course of MRgRT. A median of 6 liver lesions (range, 4–11) were prescribed a median dose of 60 Gy (range, 60–80), each delivered in 5 fractions. Median total gross tumor volume per pt was 23.8 cm 3 (range, 0.97–60.1). Seventy-four fractions were available for radiation delivery analysis, of which 55 (74.3%) were adapted. At least one target was modified in 51 (92.7%) of the adapted fractions. Acute toxicity occurred in 7 pts, all with self-limited fatigue and nausea. Progression in Child-Pugh classification from A to B occurred in three pts 3-6 months post-MRgRT. Late toxicity occurred in 1 patient with mild, possibly radiation-related peripheral biliary dilation. Two pts developed malignant biliary strictures. Per-patient local control was 50.8% and 34.8% at 1 and 2 years, respectively, while liver control was 28.7% at 2 years. Six-month systemic therapy-free survival was 31.9%. Two-year overall survival (OS) was 43.9%, with a median of 17.1 months (range, 8.6–25.7). The size of the largest tumor correlated with OS (HR 1.23, p=0.014). Conclusions: In this small series of CRC pts with 4+ CRLM, MRgRT is well-tolerated and shows promise as astrategy to consolidate disease and delay the immediate need for systemic therapy changes. Patient selection is critical to identify those most likely to benefit, though the overall impact on survival and disease trajectory remains uncertain.

Reply to: Disparities in Allograft Access in the Era of Post-Transplant Cyclophosphamide-Based Mismatched Unrelated Donor Transplantation

Anlotinib plus benmelstobart as adjuvant therapy in patients with esophageal squamous cell carcinoma: A phase II clinical trial (ALTER-E005).

459 Background: Surgery represents a primary radical treatment for esophageal cancer, However, the risk of recurrence remains noteworthy after surgical resection, underscoring the need for more effective and tolerable postoperative regimens for esophageal squamous cell carcinoma (ESCC). Benmelstobart, a novel PD-L1 blockade, demonstrated promising antitumor activity when combined with anlotinib, an antiangiogenic agent, in the treatment of various tumors including advanced ESCC (NCT05038813) and biliary tract cancer (NCT03996408). Therefore, ALTER-E005 study aimed to evaluate the efficacy and safety of combining anlotinib with benmelstobart as adjuvant therapy in patients (pts) with ESCC. Methods: This was a single-arm, multi-center phase Ⅱ clinical trial. Thirty pts (≥18 years) with histologically confirmed T1-2N1-3M0 or T3-4NanyM0 ESCC who had undergone radical (R0) resection with no recurrence 6 to 12 weeks after surgery and an ECOG PS ≤ 1 were eligible for enrollment. Enrolled pts received oral anlotinib (12 mg, days 1-14) and intravenous benmelstobart (1200 mg, day 1) every 3 weeks for up to 16 cycles or until disease recurrence. The primary endpoint was disease recurrence free (DFS). while secondary endpoints included safety, 1-year DFS rate, 3-year DFS rate, 1- year overall survival (OS) rate, and 3-year OS rate. Results: As of the data cut-off date (September 20, 2024), a total of 30 patients were enrolled with a median age of 67. Among the 30 surgically resected patients with ESCC, 26 (86.7%) had an ECOG score of 1, and 25 (83.3%) were male. According to the eighth edition of the AJCC Cancer Staging Manual, 9 (30.0%) were classified as stage Ⅱ, and 21 (70.0%) were classified as stage Ⅲ. As of the data cut-off date, the median follow-up time was 8.9 months (95% CI: 7.9-12.3). Four pts experienced disease recurrence, and the median duration of DFS has not yet been reached, with 6-month and 1-year DFS rates of 95.7% (95% CI, 72.9%-99.4%), 84.0% (95% CI, 57.7%-94.6%) respectively. Currently, 13 pts are still undergoing therapy. Out of the total 30 patients, 9 (30%) experienced grade 3 treatment-emergent adverse events (TEAEs). No grade 4 or higher TEAEs were observed. The grade 3 TEAEs included hand-foot syndrome (10.0%), hypertension (3.3%), abnormal liver function (3.3%), immune-related hepatitis (3.3%), pneumonia (3.3%), hyperglycemia (3.3%) Lymphocyte count decreased (3.3%), acute cholecystitis (3.3%) and syncope (3.3%). Conclusions: This study highlighted the promising efficacy and safety preliminarily of combining anlotinib with benmelstobart as adjuvant therapy in patients with ESCC who underwent radical (R0) resection and showed no recurrence 6 to 12 weeks after surgery. Clinical trial information: NCT05252078 .

Evaluation of EpiSwitch in predicting immunotherapy response in hepatocellular carcinoma and gastrointestinal tumors.

623 Background: The EpiSwitch Checkpoint Inhibitor Response Test (CiRT) is a blood-based assay that analyzes DNA conformations in immune cells to predict responses to immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1. CiRT has demonstrated superior predictive accuracy compared to traditional biomarkers, such as tumor mutational burden (TMB) and PD-L1 immunohistochemistry (IHC), for predicting responses in urothelial cancer (ESMO 2022). However, its role in hepatocellular carcinoma (HCC) and other gastrointestinal (GI) tumors remains unclear. As immunotherapy becomes more common in these cancers, identifying reliable predictive biomarkers is essential to optimize treatment outcomes. Methods: This retrospective study evaluates CiRT-predicted immunotherapy responses and clinical outcomes in patients with HCC and GI tumors, including cholangiocarcinoma, pancreatic adenocarcinoma, and gastric cancer. All patients received one or more lines of immunotherapy. CiRT responses were categorized into high probability (HP) and low probability (LP). Treatment response was assessed per RECIST 1.1 criteria. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), overall survival (OS), and progression-free survival (PFS) were analyzed. Results: 43 patients (24 HP, 19 LP) were included. HCC patients (n = 33) received varied immunotherapy regimens, such as combinations of bevacizumab with atezolizumab, tremelimumab with durvalumab, and nivolumab with ipilimumab. Non-HCC patients (n = 10) received combinations of immunotherapy and chemotherapy such as durvalumab with cisplatin and gemcitabine and nivolumab with oxaliplatin and capecitabine. Across all patients, CiRT revealed a sensitivity of 73.91%, a specificity of 65%, a PPV of 70.83%, and an NPV of 68.42%. In HCC, sensitivity was 70.59% and specificity was 68.75%. In non-HCC, sensitivity was 83.33% and specificity 50%. HP responders showed better treatment outcomes compared to LP responders, with higher rates of complete response (CR: 12.5% vs 0%), partial response (PR: 29.2% vs 21.1%), and stable disease (SD: 29.2% vs 10.5%), and a lower rate of progressive disease (PD: 29.2% vs 68.4%) (p = 0.0467). Overall, 70.83% of HP achieved CR, PR, or SD vs. 31.58% of LP (p = 0.0098). PFS was significantly better in HP (p = 0.044, Log-rank test; median PFS = 2.0 months for the LP group, mPFS not reached for the HP group). No statistically significant OS difference was noted due to the lack of events in the HP group. Conclusions: CiRT HP status was associated with improved response rates to immunotherapy, longer PFS, and better treatment outcomes in HCC and GI tumors. HP responders experienced notably better outcomes, suggesting that CiRT could serve as a promising predictive biomarker for immunotherapy response, addressing a critical unmet need for reliable biomarkers to treat HCC and other GI tumors.