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Clinical study of radiotherapy combined with tegafur bolus synchronization in the treatment of inoperable elderly middle and advanced esophageal cancer.

460 Background: For patients with inoperable oesophageal cancer, simultaneous radiotherapy is the standard treatment option. However, elderly patients are often unable to tolerate CCRT, so a safe, effective and tolerable treatment option is needed. Tegafur, a derivative of 5-FU, has shown efficacy and safety in the treatment of oesophageal cancer. This clinical study evaluated the efficacy and toxicity of radiotherapy combined with a Tegafur bolus in elderly patients with oesophageal cancer. Methods: In this study, 62 patients with unresectable intermediate and advanced ESCC (stage IIA to IVA) between March 2022 and February 2024 were screened and divided into two groups: 32 in the experimental group (simultaneous radiotherapy and chemotherapy) and 30 in the control group (radiotherapy alone). The total radiotherapy dose was 50.4-64 Gy/5.6-6.4 wGy (1.8-2.0 Gy per fraction) in all cases, and the chemotherapy regimen: tegafur bolus (0.5 g, qd/bid, d1-14,q3w) was given from the first day of radiotherapy. The primary endpoint was near-term efficacy, and secondary endpoints included objective remission rate (ORR), disease control rate (DCR), T-cell subpopulation indices, and safety. Results: The CR, PR, SD and PD of radiotherapy combined with tegafur bolus synchronized treatment were 1 (3.1%), 17 (53.2%), 13 (40.6%) and 1 case (3.1%), respectively. The incidence of CR, PR, SD, and PD in the radiotherapy group was 0 (zero), 8 (26.7%), 19 (63.3%), and 3 (10%), respectively. The ORR of the simultaneous radiotherapy group and the control group were 56.3% and 26.7%(P=0.018), and the DCR of the two groups was 96.9% and 90% of the disease control rate of the patients in both groups (P=0.346). The results of univariate analysis showed that the influencing factor of ORR was the treatment regimen (P=0.018), and multivariate logistic regression analysis of variables with P<0.2 showed that the recent efficacy was correlated with the treatment regimen (P=0.039), and that the patients with radiotherapy synchronized with tigafluoroembolization chemotherapy had a better recent efficacy. After treatment, the levels of CD3 + , CD4 + , CD8 + , CD4 + /CD8 + were higher in the synchronized radiotherapy group than before treatment,CD3 + and CD8 + were higher in the control group than before treatment, and CD4 + and CD4 + /CD8 + were lower than before treatment. In terms of adverse reactions, the incidence of acute hematological toxicity (P=1), nausea and vomiting (P=1), radiation esophagitis (P=0.197), radiation pneumonitis (P=0.238), and esophageal fistula (P=0.613) were slightly increased in the simultaneous radiotherapy group compared with the control group. Conclusions: Radiotherapy synchronized with Tegafur suppositories is effective, with relatively mild side effects, convenient and safe for the treatment of inoperable advanced elderly patients with oesophageal cancer. Clinical trial information: ChiCTR2300073845.

Predicted missing information biases ensemble perception of temporally ordered facial expressions

Interplay of chromatin remodeling BAF complexes in mouse embryonic and epiblast stem cell conversion and maintenance

Clinical utility of nurses’ telephone follow-up program (Tsukiji Call) for resectable locally advanced esophageal squamous cell carcinoma patients received neoadjuvant DCF therapy.

384 Background: The standard neoadjuvant treatment in Japan for resectable locally advanced esophageal squamous cell carcinoma (ESCC) is docetaxel (DTX) + cisplatin (CDDP) + 5-fluorouracil (5-FU) (DCF) based on the results of the JCOG1109 study. Neoadjuvant DCF therapy is administrated triweekly; in the first week in a hospital, and the remaining two weeks at hom. After the administration of neoadjuvant DCF therapy, patients might suffer from febrile neutropenia or gastrointestinal symptoms such as nausea, vomiting, constipation, diarrhea, and stomatitis even during remaining two weeks at home. Therefore, nurses in our hospital teach self-care at home for these patients who received neoadjuvant DCF therapy. However, some patients experienced emergency admission due to worsening adverse events. To prevent these events, nurses in our hospital conducted a telephone follow-up program (Tsukiji Call) for patients at home. Methods: This retrospective analysis included locally advanced ESCC patients who received neoadjuvant DCF therapy in our hospital between Feb 2023 and Jul 2024. Three courses of DCF (DTX [day 1]: 70 mg/m2, CDDP [day 1]: 70 mg/m2, 5-FU [continuous infusion on days 1-5]: 750 mg/m2, every three weeks) were planned as neoadjuvant treatment. On days 8-14 of the first course of neoadjuvant DCF therapy, Tsukiji Call was conducted by nurses in our hospital to check fever and nausea, vomiting, constipation, diarrhea, and stomatitis based on the CTCAE ver. 5.0 for patients at home before the first outpatient clinic. Eligible patients were divided into the Tsukiji Call and non-Tsukiji Call groups. We used Fisher's exact test to evaluate the frequency of grade 2 (Gr.2) or more adverse events (AEs) between two groups at the first outpatient clinic. Results: This study identified 90 patients (Tsukiji Call: 20, non-Tsukiji Call: 70). The median age (range) and gender male/female, PS 0/1/2, cStage I/II/III/IVA/IVB were 66.5 years (45-76 years) and 15 (75%)/5(25%), 19(95%)/1(5%)/0, 1(5%)/4(20%)/11(55%)/1(5%)/3(15%) in Tsukiji Call group, and were 64 years (46-79 years) and 49(70%)/21(30%), 67(95%)/2(2%)/1(1%), 1(1%)/13(18%)/50(71%)/0/6(8%) in non-Tsukiji Call group, respectively. In the first outpatient clinic, the frequency of Gr.2 or more AEs on fever, nausea, vomiting, constipation, diarrhea, stomatitis and any events between in Tsukiji Call and non-Tsukiji Call groups were 0/0(p = 1), 2(10%)/1(1%) (p = 0.123), 0/0 (p = 1), 0/0 (p = 1), 0/4(5%) (p = 0.572), and 0/10(14%) (p = 0.109), 2(10%)/15(21%) (p = 0.342), respectively. One patient in each group was emergently admitted within 7 days after discharge. Conclusions: Non-hematologic toxicities during DCF therapy may be reduced by Tsukiji Call by nurses in the hospital, which seemed to be in preventing the worsening of adverse events.

Phase II study of neoadjuvant chemotherapy with fluorouracil, leucovorin, oxaliplatin and docetaxel for resectable esophageal squamous cell carcinoma.

418 Background: Based on the JCOG1109 trial, neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) followed by surgery has become the standard of care for resectable locally advanced esophageal squamous cell carcinoma (ESCC). Although the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) demonstrated benefits for esophageal adenocarcinoma as a perioperative therapy, its safety and efficacy for locally advanced ESCC have not been evaluated. Methods: We conducted a multicenter phase II study of neoadjuvant FLOT therapy for ESCC. Patients with cT1N1-3M0-1 or cT2-3N0-3M0-1 (only supraclavicular lymph node (SCLN) metastasis is included as M1) based on the 8th edition of the UICC TNM staging system were eligible. Neoadjuvant chemotherapy consisted of oxaliplatin (85 mg/m 2 ), docetaxel (50 mg/m 2 ), and l-leucovorin (200 mg/m 2 ) on day 1, and continuous infusion of fluorouracil (2600 mg/m 2 /day) for 24 hours. This regimen was repeated every 2 weeks with a maximum of four cycles. The prophylactic antibody and G-SCF were not used mandatory. After completion of neoadjuvant chemotherapy, esophagectomy with extended lymphadenectomy was performed. Adjuvant treatment was prohibited for all patients. The primary endpoint was the pathological response rate (pRR), defined as the Grade 2 (more than two-thirds of the tumor is necrotic or fibrotic) or 3 (no viable tumor cells), based on the Japanese Classification of Esophageal Cancer. The sample size was determined based on an expected pRR of 38%, aiming for the lower bound of the 95% confidence interval to exceed the predetermined threshold of 20%. The expected number of patients to be enrolled was 60, with enrollment to be stopped when 45 patients with negative SCLN were enrolled. Results: Fifty-four patients were enrolled between September 2020 and January 2024. Patients with cStage I/II/III/IVB were 3/16/27/8. Of 54 patients, 45 patients were M0 without SCLN metastasis. Excluding 1 patient who did not receive any treatment after enrollment, 53 patients were included in the full analysis set. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (73.6%), and leukopenia (22.6%). Febrile neutropenia was observed in 1 patient (1.9%). Finally, 46 patients underwent surgery. No treatment-related deaths were observed and the incidence of operative morbidity was tolerable. The pRR was 43.4% (23/53) (95% CI 29.8-57.7, p=00002). This study met the primary endpoint. The radical resection rate was 83.0% (44/53). The pathological complete response rate was 13.2% (7/53). Conclusions: Neoadjuvant FLOT therapy showed a promising pathological response with acceptable toxicities. It was noteworthy that the incidence of febrile neutropenia was relatively lower with compared to neoadjuvant DCF therapy. This regimen might be a treatment option for locally advanced ESCC. Clinical trial information: jRCTs031200094.

Phase II study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second‐line therapy for patients with metastatic colorectal cancer.

155 Background: Metastatic colorectal cancer (mCRC) patients have poor prognoses with limited response to second-line chemotherapy. Therefore, it is urgent to refine and design an optimal second-line treatment regimen to improve the response rate and prolong the survival of patients with mCRC. This study assessed the safety and efficacy of the trifluridine/tipiracil (TAS-102), irinotecan, and bevacizumab regimen in second-line settings for mCRC patients. Methods: This was a multicenter, single-arm, phase II trial. The mCRC patients who are refractory to standard first-line treatment, including fluoropyrimidine and oxaliplatin, are eligible. Based on the recommended phase II dose established in phase I, enrolled patients received TAS-102 (30 mg/m2 twice daily on days 1-5) and irinotecan (150 mg/m2 on day 1) combined with bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the objective response rate (ORR). Results: Between October 1, 2023, and August 31, 2024, 60 patients were enrolled, and all of them were evaluated for efficacy. As of August 31, 2024, efficacy was assessed in all 60 participants with an ORR of 18.3% (2 had complete response, CR; 9 had partial response, PR; 39 had stable disease, SD). Among the 39 patients with SD, 29 patients experienced tumor shrinkage. The disease control rate (DCR) was 83.3%. The median follow-up was 8.6 months (95% confidence interval [CI], 6.743-10.457). The six-month progression-free survival (PFS) was 59.6%. The median PFS was 6.9 months (95% CI 5.016-8.784), whereas the median overall survival (OS) was not reached. The 1-year OS rate was 92%. At the time of analysis, four patients have died, and 56 patients are still alive. All patients were evaluable for safety assessment. The most common treatment-related adverse events (TRAE) were nausea (100%), neutropenia (86.7%), and anemia (83.3%). The most frequent grade 3/4 TRAE were neutropenia (48.3%), febrile neutropenia (8.3%), nausea (3.3%), and anemia (3.3%). No treatment-related death occurred. Conclusions: The regimen of irinotecan, TAS-102, plus bevacizumab preliminarily demonstrated promising efficacy with tolerable toxicity for mCRC patients as second‐line treatment. This regimen warrants further exploration in refractory mCRC patients. Clinical trial information: NCT06202001 .

Spatial-domain combination of GRACE monthly time-variable gravity models based on multiple weighting strategies and comparison of models’ performance in the Caspian Sea

SETD7 promotes LC3B methylation and degradation in ovarian cancer

Incidence and survival trends in small bowel adenocarcinoma (SBA) from 2000-2019 in the United States.

801 Background: SBA is a rare, poorly understood gastrointestinal malignancy. Adenocarcinomas are often grouped with other small bowel cancer histologies in epidemiologic and outcomes reports, which limits the ability to detect SBA-specific trends. Recent studies in European populations show increasing SBA incidence, but there are limited published data in American cohorts. Identifying trends in SBA can improve understanding of the population most at risk for developing SBA. This study describes U.S. trends in SBA incidence and outcomes from 2000 to 2019. Methods: Using the 2022 SEER research-limited dataset, we identified SBA cases and measured the incidence change from 2000-2019. We built linear regression models to evaluate changes in annual incidence by groups, including sex, race, and age of diagnosis, separately. We then compared the overall incidence and trends between subgroups. We investigated overall survival (OS) through the SEER research case listings for SBA patients diagnosed during the study period. Results: An average of 0.67 cases/100,000 SBA cases were reported annually from 2000-2019, with a median diagnosis age of 69 years. SBA incidence has increased annually by 0.3% per year from 2000-2019 (p=0.05). From 2000-2019, men were at a higher risk for SBA compared to women (p=0.02). In men, SBA cases increased at a rate of 0.004 cases/100,000/year from 2000-2019 (p=0.01) and a nonsignificant decrease in women of 0.00012 cases/100,000/year. There were no statistically significant differences in incidence or the change in incidence of SBA by race. The age-adjusted incidence was significantly higher each year between 2000 and 2019 in the > 70 cohort compared to the <70 cohort (p=0.02). Cases of SBA increased at a rate of 0.02 cases/100,000/year in adults >70 years (p=0.02). There were no differences in incidence rates in patients <70 years. There was no significant difference in OS for patients diagnosed with SBA in 2000, 2005, 2010, 2015, and 2019 (p=0.21). Conclusions: The overall annual incidence of SBA is increasing in the U.S. population. The most significant rate increases are in men and adults older than 70. In the SEER population, trends in SBA contrast with the recent rise of colorectal cancer in the young adult population, highlighting the unique nature of SBA compared to other gastrointestinal malignancies. Additionally, survival outcomes in patients diagnosed with SBA have remained stable over the past 20 years, while other malignancies have shown improvement in the same period. The small cohort size and the lack of a universal U.S. cancer registry limited this evaluation. Improved reporting of SBA cases and further research to identify risk factors are urgently needed to reduce the growing impact of SBA.

Clinical outcome after complete response with immunotherapy in hepatocellular carcinoma.

573 Background: Immunotherapy has shown great efficacy in hepatocellular carcinoma (HCC). No clear consensus exists on when to stop the immune checkpoint inhibitor (ICI) after complete response (CR), and clinical course after stopping ICI remains unknown. Methods: We identified 138 HCC patients who received ICI at Cedars-Sinai Medical Center and Mayo Clinic Rochester from 2016-2023. Modified Response Evaluation Criteria In Solid Tumors (mRECIST) was used to assess treatment response. We further described the clinical course of patients who achieved CR after ICI discontinuation, including cancer recurrence, subsequent treatment, liver transplantation (LT) listing and outcomes. Results: The median age at ICI initiation was 68 years; 79% were male; 55.9% were white; 51.5% were BCLC stage C. 9.4% CRs, 25.4% partial responses, 39.9% stable diseases, and 25.4% progressive disease. Hepatitis C etiology was associated with higher likelihood of CR (P=0.005). Among 13 patients who achieved CR, 10 stopped ICI (60% for LT evaluation, 40% for toxicity). After stopping ICI, 40% had recurrence (Table). 3 patients underwent local therapy for recurrent HCC within Milan criteria and 1 patient restarted ICI for recurrence beyond Milan criteria. Among CR patients, 9 patients underwent LT evaluation after stopping ICI and 7 patients were waitlisted. After listing, 3 dropouts were observed, due to recurrent HCC beyond Milan criteria, sepsis leading to death, and personal preference. 4 patients underwent LT. 2 patients underwent local therapy before LT for recurrent HCC (Table). All transplanted patients had the last dose of ICI more than 1 year before LT (12, 21, 24, and 29 months). On explanted livers, 2 patients had no residual viable tumor and 2 patients had residual HCC within Milan criteria. 1 patient developed acute cellular rejection and was treated with immunosuppressants and maintained stable graft function. None had graft loss or evidence of HCC recurrence in the follow-up period at 8, 20, 28, and 51 months. Conclusions: Immunotherapy demonstrated excellent effects on a subset of HCC patients, including 9.4% who achieved CR. After stopping ICI, 40% had cancer recurrence but 3 out of 4 were within Milan criteria. 4 underwent successful LTs (2.9%) with excellent post LT outcome. Larger prospective data is needed to establish a protocol for ICI use, especially to determine the optimal timing for ICI discontinuation after CR. BCLC at ICI initiation ICI cycles before stopping, ICI Recurrence after last ICI (days) Within Milan at recurrence Treatment(s) received after recurrence and outcomes OS (days) Patient 1 B 7, Nivolumab 730 No Nivolumab. Died from GI bleeding 1065 Patient 2 B 64, Atezo/Bev 149 Yes TACE with CR, followed by LT without recurrence. 1203 Patient 3 A 8, Nivolumab 1393 Yes Y90 with CR. No recurrence. 1984 Patient 4 C NA, Pembrolizumab 407 Yes TACE and MWA with CR, followed by LT without recurrence. 1722

Neoadjuvant adebrelimab plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma: A phase 2 trial.

443 Background: Several clinical trials have demonstrated the enhanced pathological response with the addition of immune checkpoint inhibitor to neoadjuvant chemotherapy in patients with resectable esophageal squamous cell carcinoma (ESCC), including the phase 3 ESCORT-NEO trial. Adebrelimab, an anti-programmed cell death-ligand 1 antibody, has shown potential as neoadjuvant monotherapy in the phase 1b NATION-1907 trial of resectable ESCC, with a 2-year overall survival rate of 92% in 30 patients. This study evaluated the efficacy and safety of adebrelimab plus chemotherapy as neoadjuvant therapy in patients with resectable locally advanced ESCC. Methods: In this single-center phase 2 trial (NCT06178211), patients aged 18-75 years with stage II-III (cT2N1-2M0 or cT3N0-2M0) ESCC received adebrelimab (1200 mg, day 1) plus albumin-bound paclitaxel (100 mg/m 2 , days 1, 8, and 15) and carboplatin (area under the curve of 5 mg/mL/min, day 1) every 3 weeks for 2 cycles. Esophagectomy was performed 4-6 weeks after neoadjuvant therapy. The primary endpoint was pathological complete response (pCR; ypT0N0) rate. Secondary endpoints were clinical complete response (cCR) rate (defined as no residual tumor after neoadjuvant therapy, based on computed tomography, positron emission tomography-computed tomography [PET-CT], endoscopic biopsy, and endoscopic ultrasound-guided fine-needle aspiration [EUS-FNA]), margin-free (R0) resection rate, major pathological response (MPR; ≤10% residual tumor cells) rate, event-free survival, overall survival, and safety. Results: Between January 2024 and May 2024, a total of 36 patients were enrolled. Most patients (75.0%) had clinical stage III ESCC. Thirty-five patients completed 2 cycles of neoadjuvant therapy, while one patient refused the last dose of albumin-bound paclitaxel. Two patients refused surgery while 34 underwent esophagectomy. The pCR rate was 38.9% (95% confidence interval [CI], 23.1-56.5) in all patients and 41.2% (95% CI, 24.6-59.3) in the surgery set; the R0 resection rate was 94.4% (95% CI, 81.3-99.3) and 100% (95% CI, 89.7-100), and the MPR rate was 63.9% (95% CI, 46.2-79.2) and 67.6% (95% CI, 49.5-82.6), respectively. The cCR rate was 47.2% (95% CI, 30.4-64.5) in all patients. Of 36 patients, grade ≥3 treatment-emergent adverse events during neoadjuvant therapy included decreased neutrophil count (2 [5.6%]), decreased white blood cell (2 [5.6%]), decreased platelet count (1 [2.8%]), impaired hearing (1 [2.8%]), hyponatremia (1 [2.8%]), immune-mediated hepatitis (1 [2.8%]), intestinal obstruction (1 [2.8%]), and esophageal ulcer (1 [2.8%]). Surgical complications occurred in 17 (50%) of 34 patients. Conclusions: Neoadjuvant adebrelimab plus chemotherapy shows promising pathological response and favorable safety profile in patients with resectable locally advanced ESCC. Survival follow-up is ongoing. Clinical trial information: NCT06178211 .

Mid-term outcomes of percutaneous pulmonary valve replacement with Edwards-Sapien bioprosthesis in native right ventricular outflow tract

Interaction of unphosphorylated PtsN with the K+/H+ antiporter YcgO inhibits its activity in Escherichia coli

The impact of nutritional status on recurrence-free survival (RFS) in patients with locally advanced oesophagogastric adenocarcinoma (LA-OGA) treated with FLOT therapy.

388 Background: Malnutrition and weight loss were reported as poor prognostic factors in operable OGA. This study examines the relationship between oncological outcomes and nutritional status in LA-OGA patients under the current standard of care, perioperative FLOT therapy. Methods: From 2017 to 2023, 423 patients who had radical resection at Royal Marsden Hospital were screened. Inclusion criteria included LA-OGA (cT2≤ and Nany or Tany and N+), at least one cycle of neoadjuvant chemotherapy (NAC), and ECOG PS 0–2. Nutritional status was assessed by body weight and prognostic nutritional index (PNI), with significant weight loss defined as a 5% loss within six months before diagnosis or during NAC. PNI was calculated as serum albumin (g/L) + 0.005 × lymphocyte count /μL, with categories of severe (<45), mild to moderate (45–49.9), and normal (≥50). The primary endpoint was 3-year recurrence-free survival (3y-RFS). Restricted mean survival time (RMST) at 36 months was calculated to analyze survival time. Multivariate analyses were performed to identify prognostic factors for RFS. The pathological response was assessed using tumour regression grade (TRG) (Mandard criteria). Results: Of the 423 patients, 210 met the inclusion criteria. Primary tumour sites were the oesophagus (52.4%), the oesophagogastric junction (18.1%), and the stomach (29.5%). The median follow-up was 26.5 months. Weight loss at baseline and after NAC, as well as PNI, did not significantly impact RFS (p=0.13, p=0.91, p=0.69, p=0.45). However, a PNI decrease from baseline was associated with significantly shorter 3y-RFS (46% vs. 69%, p<0.001), and the RMST difference was 5.46 months (p<0.001). Multivariable analyses showed ypN positivity (p<0.001), R1 resection (p<0.001), and PNI decrease (p=0.03) as negative prognostic factors for RFS. Pathological response did not differ regardless of PNI change (28.2% vs. 30.4%, p=0.75). Conclusions: A decrease of PNI is a significant poor prognostic factor for RFS in LA-OGA patients undergoing FLOT, suggesting that maintaining nutritional status during NAC could enhance survival outcomes.

Long-term outcomes and surgical conversion following immunotherapy in MSI-H biliary tract cancers.

592 Background: Deficient mismatch repair/microsatellite instability (MSI-H) in biliary tract cancers (BTC) is rare, estimated to be 1-5%. MSI-H across solid tumors has shown unprecedented durable response to immune checkpoint inhibitors (ICI) regardless of anatomic location. Here we describe the clinical outcomes of unresectable BTC patients with MSI-H treated with ICIs and their conversion to surgery. Methods: We conducted a multicenter, retrospective analysis of patients (pts) with advanced BTC who had been identified with MSI-H by molecular analysis performed between 2017 and 2024 at Mayo Clinic and University Hospitals Seidman Cancer Center. The outcomes of interest were overall survival (OS), defined as time from initiation of first-line systemic treatment to death; Time-to-treatment failure (TTF), defined as time from initiation of treatment to cessation due to any cause; and response. All analyses were done descriptively. Results: We identified 22 MSI-H pts with BTC, 19 with cholangiocarcinoma and 3 with gallbladder cancer. Median age at diagnosis was 61 (range 26-86), 20 (90.9%) were Caucasian, 9 (40.9%) were male gender, and 5 (22.7%) had etiology as Lynch syndrome. Twelve (54.5%) pts had metastatic disease at diagnosis. Twenty pts (90.9%) received first line systemic therapy, of whom 11 (55%) continued onto second line. Among the 20 pts that received first line therapy, median TTF was 7.6 months (95% CI: 4.8-14.3), objective response was observed in 7 (35%) pts, and disease control was observed in 15 pts (75%). Among the 11 pts that continued onto second line systemic treatment, objective response was observed in 4 pts (36%) and disease control was observed in 6 pts (55%). Among the 20 pts that received first line therapy, 19 (95%) ever received ICI +/- chemotherapy as a part of their treatment plan. Two-year OS for pts who ever received ICI was 63% (95% CI: 41%-96%). In total, 4 pts (20%) were restaged to resectable following treatment with an ICI, underwent resection, and currently have no evidence of disease. Conclusions: Administration of ICI during treatment plan in pts with MSI-H confirmed durable response and even downstage pts to resectable stage for curative intent. Testing for MSI-H should be performed upfront to guide treatment decision.

Neoadjuvant immune checkpoint blockade in resectable hepatocellular carcinoma: A systematic review and meta-analyisis.

590 Background: Hepatocellular carcinoma (HCC) presents a significant therapeutic challenge due to its high recurrence rates after curative-intent resection. Neoadjuvant immune checkpoint blockade (ICB) has emerged as a promising strategy to improve tumor control by modulating the immune microenvironment prior to surgery. This systematic review and meta-analysis aim to assess the safety and efficacy of neoadjuvant ICB in improving clinical outcomes for patients with resectable HCC. Methods: A systematic search of PubMed, EMBASE, and Cochrane databases was conducted to identify clinical trials examining neoadjuvant ICB in resectable HCC. Primary endpoints included pathological complete response (pCR), major pathological response (mPR), overall response rate (ORR), and grade 3-4 treatment-related adverse events (TRAE). Prespecified subgroup analyses were conducted for studies combining ICB with tyrosine kinase inhibitors (TKIs) or dual ICB therapies. Pooled proportions were calculated using a random-effects model via the R package "meta." Inter-study heterogeneity was assessed using the I² statistic and test for subgroup differences were conducted. Results: Out of 1,321 studies screened, 14 clinical trials involving 252 patients with resectable HCC were included. Most studies were phase II trials (57%), and patient median age ranged from 57.5 to 68.0 years, with 88.3% of patients being male. The pooled prevalence of mPR was 32% (95% CI, 24–42%; I² = 9%)while pCR was achieved in 24% (95% CI, 17–34%; I² = 29%)of patients. The ORR was 27% (95% CI, 18–39%; I² = 49%), and severe adverse events (grade 3-4 TRAE) had a pooled prevalence of 24% (95% CI, 17–34%; I² = 16%). Subgroup analysis of trials combining ICB with TKIs showed an ORR 34% (95% CI, 20–55%; I² = 60%), an mPR rate of 27% (95% CI, 19–40%; I² = 0%), and a pCR rate of 20% (95% CI, 14–30%; I² = 0%). Dual ICB therapies demonstrated a higher mPR rate of 42% (95% CI, 26–67%; I² = 16%) and a pCR rate of 41% (95% CI, 29–59%; I² = 29%), but were associated with a higher incidence of severe TRAE (41%; 95% CI, 29–60%; I² = 0%). Conclusions: Neoadjuvant ICB demonstrates promising efficacy in resectable HCC, particularly when combined with TKIs or dual ICB therapies. While dual ICB enhances pathological response rates, it is associated with higher rates of severe TRAE. These results highlight the need of further studies to optimize combination strategies that balance efficacy and safety for patients with resectable HCC.

The role of footwear in improving running economy: a systematic review with meta-analysis of controlled trials

Cabozantinib selectively induces proteasomal degradation of p53 somatic mutant Y220C and impedes tumor growth

Long-term survival outcomes of atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma.

600 Background: Immunotherapy combinations such as atezolizumab plus bevacizumab (Atezo-Bev) or STRIDE have been established as standard therapies for patients with advanced hepatocellular carcinoma (HCC). After dual immunotherapy treatment, durable responders and long-term survivors had been reported. However, the longevity of such outcomes following Atezo-Bev treatment remains to be evaluated. Methods: We analyzed medical records of four medical centers in Taiwan for patients with Child-Pugh class A liver reserve who received first-line Atezo-Bev treatment for advanced HCC from January 2018 to May 2021, to evaluate their survival outcomes after a long-term follow-up. Results: We enrolled 54 patients, predominantly male (90.7%) with the median age of 65 years. The main hepatitis etiology was viral hepatitis (92.6%), including 68.5% chronic hepatitis B. After a median follow-up of 61.9 months, the median overall survival (OS) was 21.0 months (95% confidence interval 10.4 – 31.6 months). The 3-year, 4-year and 5-year OS rate was 36.4%, 25.7% and 25.7%, respectively. For patients with tumor response (N = 19, 34.5%) or disease control (N = 44, 80.0%), the 3-year, 4-year, and 5-year OS rates are listed at Table 1. In univariate analysis, younger age (≤ 70 years), absence of intrahepatic tumor, lack of macrovascular invasion (MVI), and ALBI grade 1 were associated with an OS > 3 years. In multivariate analysis, after adjusting sex, viral hepatitis, MVI, extrahepatic spread, and initial alpha-fetoprotein > 400 ng/ml, the absence of intrahepatic tumor (Odds ratio [OR] = 5.36, p = 0.047) and ALBI grade 1 (vs grade 2, OR = 10.02, p = 0.037) remained independent predictors for OS > 3 years. Conclusions: In patients with advanced HCC, Atezo-Bev treatment led to a notable proportion achieving long-term survival, especially in patients with good response to the treatment. Absence of intrahepatic tumors and preserved liver function are predictive of prolonged survival. 3-year, 4-year and 5-year OS rate of patients who receive Atezo-Bev treatment, stratified by treatment response. Landmark survival OS rate (%) by treatment response Disease control Responder 3 years 35.6 52.2 4 years 30.3 52.2 5 years 30.3 47.7 Responder: patients who achieved a best response of complete response or partial response after treatment with Atezo-Bev. Disease control: includes responders and patients who achieved a best response of stable disease following Atezo-Bev treatment.

LAPIS: Randomized phase 3 trial of chemotherapy (CTX) with and without pamrevlumab (PAM) for locally advanced pancreatic cancer (LAPC).

675 Background: PAM improved response, surgical eligibility, and resection rates when combined with CTX in phase 1/2 LAPC trials (NCT01181245; NCT02210559). LAPIS (NCT03941093) evaluated efficacy and safety of PAM + CTX in unresectable LAPC. Methods: LAPIS was a global, double-blind, placebo-controlled phase 3 trial of adults with treatment-naïve, -confirmed unresectable LAPC. Patients received (randomized 1:1) PAM (35 mg/kg Q2W) or placebo (PBO) plus CTX (gemcitabine + nab-paclitaxel [GnP] or FOLFIRINOX [FFX] per standard protocol) for up to six 28-day cycles. based on changes in -9, on FDG-PET, resectability, with final surgical decision made by surgeon. Primary endpoint: overall survival (OS); secondary endpoints: event-free survival (EFS), progression-free survival (PFS), and objective response rate (ORR. Safety (including treatment-emergent adverse events [TEAEs]) was evaluated in patients who received treatment. Results: 143 and 141 patients (median [range] age, 65.0 [31–90] yrs; 53.2% male) were randomized to PAM and PBO arms. 142 and 141 received treatment: GnP, 114 (79.7%) and 112 (79.4%); FFX, 28 (19.6%) and 29 (20.6%). PAM (64.8%) and 96 PBO (68.1%) patients completed 6 treatment cycles. . Survival similar for PAM and PBO arms (Table) and did not differ by. For PAM + FFX vs PBO + FFX, respiratory, thoracic and mediastinal disorders (39.3% vs 27.6%) and skin and subcutaneous tissue disorders (53.6% vs 37.9%) occurred >10% more with PAM; TEAE frequencies were similar with PAM + GnP and PBO + GnP. One treatment-related death occurred in PAM arm. Conclusions: LAPIS contained important LAPC trial innovations: pre/post-CTX FDG-PET imaging, objective criteria for surgical intervention, external surgical review panel, and composite EFS measurement. Addition of PAM to CTX was not associated with additional toxicity but did not improve survival outcomes for unresectable LAPC. Clinical trial information: NCT03941093 . LAPIS endpoints. PAM arm (n=143) PBO arm (n=141) OS, months, median (95% CI) events=118 (82.5%)17.25 (15.47, 18.89) events=112 (79.4%)17.94 (14.59, 20.34) HR (95% CI)1.08 (0.83, 1.41)p=0.55 EFS, a months, median (95% CI) events=99 (69.2%)5.72 (5.59, 6.01) events=102 (72.3%)5.78 (5.62, 6.37) HR (95% CI)1.05 (0.78, 1.39) PFS, months, median (95% CI) events=48 (33.6%)9.36 (7.75, 11.79) events=44 (31.2%)9.40 (7.69, 10.84) HR (95% CI)1.01 (0.65, 1.56) ORR, n (%) 43 (30.1) 64 (45.4) OR (95% CI)0.50 (0.31, 0.82) Complete response 0 0 Partial response 43 (30.1) 64 (45.4) CI, confidence interval; HR, hazard ratio; OR, odds ratio. a Earliest of 1) failure to achieve local disease-free status at end of treatment and/or after surgery; 2) local or distant recurrence/progression; or 3) death.