Major Response Research Articles

Impact of baseline steroids on the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell carcinoma.

Immunochemotherapy involving the combination of programmed cell death 1/programmed cell death ligand 1 inhibitors with chemotherapy has advanced the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). The use of corticosteroids as pretreatment might reduce immunotherapy efficacy. To investigate the impact of baseline corticosteroid use on neoadjuvant immunochemotherapy (nIC) outcomes in locally advanced ESCC patients. Patients with locally advanced ESCC who received nIC at Sun Yat-sen University Cancer Center and the Third Affiliated Hospital of Sun Yat-sen University were included. Patients were divided into dexamethasone and antihistamine groups on the basis of the administered pretreatment. Antiallergic efficacy and safety were evaluated, as well as its impact on short-term efficacy [complete pathological response (pCR), major pathological response (MPR)] and long-term efficacy [overall survival (OS), progression-free survival (PFS)] of nIC. From September 2019 to September 2023, 142 patients were analyzed. No severe treatment-related adverse events or deaths were observed. Allergy occurrence was greater in the antihistamine group (P = 0.014). Short-term efficacy was not significantly different: The pCR rates were 29.9% and 40.0%, and the MPR rates were 57.9% and 65.7% in the dexamethasone and antihistamine groups, respectively. The long-term efficacy was not significantly different: The 2 years OS rates were 95.2% and 93.5%, and the 2 years PFS rates were 90.3% and 87.8%. Subgroup analysis revealed no difference in OS between the 20 mg dexamethasone group and the < 20 mg dexamethasone group, but PFS was significantly greater in the 20 mg dexamethasone group (93.9% vs 56.4%, P = 0.001). Dexamethasone or antihistamines can be used before nIC in locally advanced ESCC without affecting short- or long-term efficacy. Administering 20 mg dexamethasone before nIC may improve PFS in ESCC.

Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial.

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 .

Collaboration between DELLA and MED15 to regulate transcription in plants.

Gibberellins (GA) are diterpenoids that are categorized as one of main hormones that promote major developmental responses such as germination and stem elongation in plants. DELLA proteins act as the key repressors of GA responses. They interact with hundreds of different proteins. While the functioning of DELLA as transcriptional coactivators has also been reported earlier, the actual mechanism still remains elusive. One recent report describes interaction of DELLA with Mediator subunit MED15 as one of the mechanisms contributing to its transcription activation capability (Hernández-García et al. 2024). Interestingly, this mechanism of DELLA-MED15 module-mediated transcription regulation seems to be very ancient conserved from bryophyte Marchantia polymorpha to dicot Arabidopsis thaliana.

Identifying patients who benefit more from perioperative immunotherapy combinations for resectable non-small cell lung cancer based on clinical and molecular characteristics: a meta-analysis of randomized clinical trials.

This study aims to identify patient subgroups who benefit more from perioperative immunotherapy combined with chemotherapy (IO-CT) based on clinical and molecular characteristics in resectable non-small cell lung cancer (NSCLC). Randomized controlled trials (RCTs) on perioperative IO-CT were searched. Beneficial differences of IO-CT regimens across different patient subgroups were assessed by pooling trial-specific ratios in event-free survival (EFS), overall survival (OS), pathological complete response (pCR), and major pathological response (MPR). Six studies (n = 3003) involving five IO-CT regimens were included. Compared to CT alone, all IO-CT regimens significantly improved EFS, OS, MPR, and pCR, but increased toxicity. Toripa-chemo showed the best EFS and nivo-chemo showed the best OS. Patients with PD-L1 ≥ 1% had more EFS benefits compared to those with PD-L1 < 1% (HR [hazard ratio]: 1.55, 95% CI 1.17-2.04). Squamous NSCLC patients had significantly more pCR and MPR benefits than non-squamous NSCLC patients (pCR: OR [odds ratio] 0.68, 95% CI 0.49-0.95; MPR: OR 0.61, 95% CI 0.45-0.82). Former smokers had significantly higher pCR benefits than non-smokers (OR: 2.18; 95% CI 1.21-3.92). Additionally, OS benefit was significantly higher in patients < 65years compared to those ≥ 65years (HR ratio: 0.59, 95% CI 0.36-0.95). For MPR, males benefited significantly more from IO-CT compared to females (OR: 1.69, 95% CI 1.18-2.42). Perioperative IO-CT is more effective but more toxic than CT alone in resectable NSCLC. Patients with PD-L1 ≥ 1%, squamous NSCLC, a history of smoking, age < 65years and male gender may experience greater benefits from perioperative IO-CT.

Impact of proton pump inhibitors on pathologic response rates following fluoropyrimidine-based neoadjuvant chemotherapy in pancreatic cancer patients.

Proton pump inhibitors (PPIs) negatively impact fluoropyrimidine-based chemotherapy efficacy in colorectal cancer. This study assessed PPI impact on major pathologic response (mPR) rates of pancreatic adenocarcinoma (PDAC) patients receiving fluoropyrimidine-based chemotherapy. An institutional retrospective review of resected PDAC patients receiving neoadjuvant fluoropyrimidine-based chemotherapy (98% FOLFIRINOX) from 2011 to 2021 was conducted. Outcomes were stratified by use or nonuse of PPIs within 6 months of neoadjuvant chemotherapy initiation. Primary outcome was mPR defined as complete or near complete response. Among 540 patients included, the median age was 64 (IQR: 60-70) years, 297 (55%) were male, and 202 (37%) were PPI users. 170 (31%) patients had mPR with similar rates among PPI users and nonusers (29% vs. 33%, p = 0.38). No difference in mPR was seen between PPI users and nonusers receiving chemoradiation (35% vs. 36%, p = 0.89) or ≥8 cycles of NAC (33% vs. 36%, p = 0.55). Median OS for PPI users was 30.9 versus 31.7 months for nonusers (p = 0.62). On multivariable analysis, PPI therapy was not associated with decreased survival. PPI usage did not significantly influence mPR or OS following neoadjuvant fluoropyrimidine-based chemotherapy in resected PDAC patients. Further analysis of all patients, not just those who underwent resection, is required.

WTAP weakens oxaliplatin chemosensitivity of colorectal cancer by preventing PANoptosis

As the most abundant post-transcriptional modification in eukaryotes, N6-methyladenosine (m6A) plays a crucial role in cancer cell proliferation, invasion and chemoresistance. However, its specific effects on chemosensitivity to oxaliplatin-based regimens and the impact of these drugs on m6A methylation levels in colorectal cancer (CRC) remain largely unexplored. In this study, we demonstrated that the m6A methyltransferase Wilms tumor 1-associating protein (WTAP) weakens oxaliplatin chemosensitivity in HCT116 and DLD1 cells. Mechanistically, oxaliplatin treatment upregulated WTAP expression, preventing multiple forms of cell death simultaneously, a process known as PANoptosis, by decreasing intracellular oxidative stress through maintaining the expression of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element, in an m6A-dependent manner. In addition, high WTAP expression in CRC patients is associated with a poor prognosis and reduced benefit from standard chemotherapy by clinical data analysis of The Cancer Genome Atlas (TCGA) database and patient cohort study. These findings suggest that targeting WTAP-NRF2-PANoptosis axis could enhance the antitumor efficacy of oxaliplatin-based chemotherapy in CRC treatment.

Monoubiquitinated H2B, a Main Chromatin Target of Formaldehyde, Is Important for S-Phase Checkpoint Signaling and Genome Stability.

Formaldehyde (FA) is a human carcinogen with ubiquitous environmental exposures and significant endogenous formation. Genotoxic activity of FA stems from its reactivity with DNA-NH2 groups. Histone lysines are another source of aldehyde-reactive amino groups in chromatin, however, chromatin/histone damage responses to FA and their biological significance are poorly understood. We examined histone posttranslational modifications in FA-treated human lung cells and found that the majority of the most prominent small lysine modifications associated with active or inactive chromatin were unchanged. FA moderately decreased H3K9 and H3K27 acetylation and H2A-K119 monoubiquitination but caused surprisingly severe losses of H2B-K120 monoubiquitination, especially in primary and stem-like cells. H2Aub1 decreases reflected its slower ubiquitination linked to a lower ubiquitin availability due to K48-polyubiquitination of FA-damaged proteins. Depletion of H2Bub1 resulted from its rapid deubiquitination in part by ATXN7L3-associated deubiquitinases and was independent on DNA damage signaling, indicating a direct chromatin damage response. Manipulations of H2Bub1 abundance showed that it was important for robust ATM and ATR signaling, efficient S-phase checkpoint, and suppression of mitotic transmission of unreplicated DNA and formation of micronuclei. Our findings identified H2B deubiquitination as a major FA-induced chromatin damage response that regulates S-phase checkpoint signaling and genome stability.

Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study.

To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling. A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%). Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

The utility of 18F-FDG PET/CT for predicting the pathological response and prognosis to neoadjuvant immunochemotherapy in resectable non-small-cell lung cancer

ObjectiveTo evaluate the potential utility of 18F-FDG PET/CT to assess response to neoadjuvant immunochemotherapy in patients with resectable NSCLC, and the ability to screen patients who may benefit from neoadjuvant immunochemotherapy.MethodsFifty one resectable NSCLC (stage IA–IIIB) patients were analyzed, who received two-three cycles neoadjuvant immunochemotherapy.18F-FDG PET/CT was carried out at baseline(scan-1) and prior to radical resection(scan-2). SULmax, SULpeak, MTV, TLG, T/N ratio, ΔSULmax%,ΔSULpeak%, ΔMTV%, ΔTLG%,ΔT/N ratio% were calculated. 18F-FDG PET/CT responses were classified using PERCIST. We then compared the RECIST 1.1 and PERCIST criteria for response assessment.With surgical pathology of primary lesions as the gold standard, the correlation between metabolic parameters of 18F-FDG PET/CT and major pathologic response (MPR) was analyzed. All metabolic parameters were compared to treatment response and correlated to PFS and OS.ResultsIn total of fifty one patients, MPR was achieved in 25(49%, 25/51) patients after neoadjuvant therapy. The metabolic parameters of Scan-1 were not correlated with MPR.The degree of pathological regression was negatively correlated with SULmax, SULpeak, MTV, TLG, T/N ratio of scan-2, and the percentage changes of the ΔSULmax%, ΔSULpeak%, ΔMTV%,ΔTLG%,ΔT/N ratio% after neoadjuvant therapy (p < 0.05). According to PERCIST, 36 patients (70.6%, 36/51) showed PMR, 12 patients(23.5%, 12/51) had stable metabolic disease(SMD), and 3 patients(5.9%, 3/51) had progressive metabolic disease (PMD). ROC indicated that all of scan-2 metabolic parameters and the percentage changes of metabolic parameters had ability to predict MPR and non-MPR, SULmax and T/N ratio of scan-2 had the best differentiation ability.The accuracy of RECIST 1.1 and PERCIST criteria were no statistical significance(p = 0.91). On univariate analysis, ΔMTV% has the highest correlation with PFS.ConclusionsMetabolic response by 18F-FDG PET/CT can predict MPR to neoadjuvant immunochemotherapy in resectable NSCLC. ΔMTV% was significantly correlated with PFS.

Metallothionein ameliorates airway epithelial apoptosis upon particulate matter exposure: role of oxidative stress and ion homeostasis

PurposeTo investigate the mechanism underlying particulate matter (PM) exposure-induced oxidative stress and potential rescue strategies against pulmonary damage in this context.MethodsA combination of omics technology and bioinformatic analysis were used to uncover mechanisms underlying cellular responses to PM exposure in human bronchial epithelia (HBE) cells and imply the potential rescue.ResultsOur results implicated that oxidative stress, metal ion homeostasis, and apoptosis were the major cellular responses to PM exposure in HBE cells. PM exposure disrupted oxidative phosphorylation (OXPHOS)-related gene expressions in HBE cells. Rescuing the expression of these genes with supplemental coenzyme Q10 (Co Q10) inhibited reactive oxygen species (ROS) generation; however, it only partially protected HBEs against PM exposure-induced apoptosis. Further, metallothionein (MT)-encoding genes associated with metal ion homeostasis were significantly induced in HBE cells, which was transcriptionally regulated by specificity protein 1 (SP1). SP1 knock-down (KD) aggravated PM-induced apoptosis in HBE cells, suggesting it plays a role in MT induction. Subsequent studies corroborated the protective role of MT by showing that exogenous MT supplement demonstrated effective protection against PM-induced oxidative stress and apoptosis in HBE cells. Importantly, exogenous MT supplement was shown to reduce ROS generation and apoptosis in airway epithelia in both HBE cells and a PM-inhaled murine model.ConclusionThis study demonstrates that the impact of MT on airway epithelia by suppressing oxidative stress and maintaining metal ion homeostasis is beneficial in attenuating damage to pulmonary cells undergoing PM exposure.

Histological Assessment and Interobserver Agreement in Major Pathologic Response for Non-Small Cell Lung Cancer with Neoadjuvant Therapy.

Major pathologic response (MPR), defined as ≤10% of residual viable tumor (VT), is a prognostic factor in non-small cell lung cancer (NSCLC) after neoadjuvant therapy. This study evaluated interobserver reproducibility in assessing MPR, compared area-weighted and unweighted VT (%) calculation, and determined optimal VT (%) cutoffs across histologic subtypes for survival prediction. This retrospective study included 108 patients with NSCLC who underwent surgical resection after neoadjuvant chemotherapy or chemoradiation at Seoul National University Bundang Hospital between 2009-2018. Three observers with varying expertise independently assessed tumor bed and VT (%) based on digital whole-slide images. Reproducibility in tumor bed delineation was reduced in squamous cell carcinoma (SqCC) with smaller tumor bed, although overall concordance was high (Dice coefficient, 0.96; IoU score, 0.92). Excellent agreement was achieved for VT (%) (ICC=0.959) and MPR using 10% cutoff (Fleiss' kappa=0.911). Shifting between area-weighted and unweighted VT (%) showed only one case differing in MPR status out of 81 cases. The optimal cutoff was 10% for both adenocarcinoma (ADC) and SqCC. MPR+ was observed in 18 patients (17%), with SqCC showing higher MPR+ rates (p=0.044), lower VT (%) (p<0.001), and better event-free survival (p=0.015) than ADC. MPR+ significantly improved overall survival (p=0.023), event-free survival (p=0.001), and lung cancer-specific survival (p=0.012). While MPR assessment demonstrated robust reproducibility with minimal impact from the tumor bed, attention is warranted when evaluating smaller tumor beds in SqCC. A 10% cutoff reliably predicted survival across histologic subtypes with higher interobserver reproducibility.

MOY 1 - The Emergency General Surgeon: what should their future operative role be, and how can an EGS post be more attractive?

Abstract Aims Determine the desired future operative role of dedicated Emergency General Surgery (EGS) surgeons in the United Kingdom (UK) and the Republic of Ireland (ROI), and how to improve the attractiveness of an EGS post. Methods A live interactive online survey, designed and endorsed by ASGBI, was completed by attendees at two ASGBI conferences in 2023. The study was conducted according to CHERRIES and exempt from REC according to HRA. Consent was obtained from study participants, who were asked using a Likert scale which operations a dedicated EGS surgeon should perform and how an EGS post could be more attractive. Results The survey was completed by 156/371 eligible participants, of which 132 responses were analysed once duplicate responses (n=16), and non-UK/ROI respondents (n=8), were excluded. Participants included consultants (34%), surgical trainees (42%), and other doctors (23%), 61% were male and 39% were female, aged between 25 and 69. Respondents stated the desired future operative role of EGS surgeons included most EGS operations, including for torso trauma. Few believed EGS surgeons should perform emergency colonic resection for cancer (49%) or inflammatory bowel disease (37%), gastric volvulus (34%), bariatric complications (26%), or Boerhaaves (28%). The vast majority agreed that EGS posts could be improved by including elective general and subspecialty operating lists, continuing professional development, minimally-invasive (laparoscopic/robotic) opportunities, rest days post-on-call, family-friendly hours, EGS ambulatory and follow-up clinics, and major trauma responsibility. Conclusions EGS surgeons should operate on the majority of EGS patients. Job plans that include elective operating, professional development, and patient follow-up may improve recruitment and retention.

Secretome and immune cell attraction analysis of head and neck cancers

Immune checkpoint inhibitors are approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) but the response rate is only 13–18%. For an effective antitumor immune response, trafficking of immune cells to the tumor microenvironment (TME) is essential. We aimed to better understand immune cell migration as well as the involved chemokines in HNSCC. A transwell assay was used to study immune cell migration toward TME-conditioned medium. While T cell migration was not observed, conventional dendritic cell (cDC) migration was induced by TME-conditioned media. cDC migration correlated with various proteins in the TME secretome. CCL8, CXCL5, CCL13 and CCL7 were tested in validation experiments and addition of these chemokines induced cDC migration. Using single cell RNA-sequencing, we observed expression of CCL8, CXCL5, CCL13 and CCL7 in cancer-associated fibroblasts (CAFs). Depleting fibroblasts led to reduced cDC migration. Thus CAFs, while often seen as suppressors of antitumor immunity, play a role in attracting cDCs toward the head and neck cancer TME, which might be crucial for effective antitumor immunity and response to therapies. Indeed, we found RNA expression signatures of the indicated chemokines, cDC and CAF subpopulations, to be significantly higher in baseline tumor specimen of patients with a major pathological response to pre-surgical anti-PD-1 treatment compared to non-responding patients.

FP6.1 - Core Surgical Training in Northern Ireland: Regional Compliance with Quality Indicators

Abstract Aims Standards for training programmes are set by the GMC, with the Joint Committee for Surgical Training developing a curriculum and quality indicators (QIs) specific to Core Surgical Training. To ensure local training fits within these guidelines, placement quality is evaluated by NIMDTA, using specialty specific surveys sent to all Core Trainees in the region. Methods A survey, related to their current post, was sent to all Core Trainees in Northern Ireland. The responses were collated and cross-referenced against the 14 generic QIs for Core Surgery in order to assess compliance with published standards. Results Response rate from trainees was 70%. Compliance with the quality indicators was generally poor; 24% of trainees reported receiving the recommended 2 hours per week of formal teaching, 59% were able to complete a quality improvement project, 83% of trainees completed a learning agreement within the recommended 6 weeks from post commencement, 21% reported adequate exposure to simulation training and only 11% reported attending the expected one or more MDT meetings per week. Conclusions The level of adherence to the QIs for core surgery in Northern Ireland could be significantly improved. Despite some themes achieving a majority response in line with the QIs, overall alignment is poor. Subsequently we have developed key recommendations for focused improvement in the local Core Training programme in NI in an effort to better align our training with the JCST QI framework. A further survey will be conducted to assess the effect of these recommendations on compliance with JCST QIs.

Randomized clinical trial on accelerated preoperative hyperfractionated radiotherapy versus preoperative hyperfractionated radio-chemotherapy in locally advanced rectal cancer.

The aim of this study was to compare pathological response rates after preoperative hyperfractionated radiotherapy with co-administration of chemotherapy based on 5FU (HART-CT) versus preoperative hyperfractionated radiotherapy (HART) in patients with resectable rectal cancer. Patients with T2/N+ or T3/any N rectal cancer were randomized either to HART twice a day (28 fractions of 1.5 Gy) to total dose 42 Gy or to HART-CT. Tumour regression grade was postoperatively assessed according to the 4-point scale as recommended by the American Joint Committee on Cancer (AJCC). The secondary endpoints included overall survival (OS), disease-free survival (DFS), toxicity of preoperative treatment, locoregional, and distant failure rates. There were 187 patients eligible for analysis: 95 in HART and 92 in the HART-CT. Median follow-up was 5.6 years. The analysis demonstrated a significantly higher chance of achieving pathologic complete response in HART-CT arm: complete response was achieved in 4/95, 4% (HART) and 11/92, 12% (HART-CT) (P = .045). The differences in OS and DFS, while tending to favour HART-CT, were not significant: OS (P = .13, hazard ratio [HR] = 0.82, 95% CI, 0.63-1.06) and DFS (P = .32; HR = 0.88, 95% CI, 0.69-1.13). The locoregional failure and distant metastases rates did not statistically differ between the trial arms. The rate of late complications was similar (P = .51), grade 3+ being 8% versus 11% in the HART/HART-CT group, respectively. The hyperfractionated preoperative radiotherapy with concurrent 5-Fu-based chemotherapy (HART-CT) improved pathological response rate compared to HART. This translated into favourable OS and DFS in HART-CT, but the differences did not reach the threshold for significance. A new hyperfractionated chemo-RT scheme is proposed. Histopathological major response (TRG 0-1) is associated with better clinical outcome.

The short-term efficacy of neoadjuvant SOX versus SOX plus immune checkpoint inhibitor following laparoscopic gastrectomy for locally advanced gastric cancer: a multicenter retrospective cohort study in China

BackgroundThis study aims to evaluate the short-term efficacy for locally advanced gastric cancer (LAGC) who accepted laparoscopic gastrectomy (LG) after neoadjuvant SOX versus SOX plus immune checkpoint inhibitors (ICIs).MethodsLAGC patients who accepted LG after neoadjuvant SOX (SOX-LG, n = 169) and SOX plus ICIs (SOX + ICIs-LG, n = 140) in three medical centers between Jan 2020 and Mar 2024 were analyzed. We compared the tumor regression, treatment-related adverse events (TRAEs), perioperative safety between two groups, and explored the risk factors of postoperative complications (POCs) for LG after neoadjuvant therapy.ResultsThe baseline characteristics were comparable between two groups (P > 0.05). SOX + ICIs-LG group acquired a higher proportion of objective response (63.6% vs. 46.7%, P = 0.003), major pathological response (43.6% vs. 31.4%, P = 0.001), and pathological complete response (17.9% vs. 9.5%, P = 0.030). There were no significant differences in the TRAEs rates, operation time, R0 resection, retrieved lymph nodes, postoperative first flatus, and hospitalized days, overall and severe POCs between two groups (P > 0.05). Patients in the SOX-ICIs-LG group had lower estimated blood loss (EBL) compared with SOX-LG (P = 0.001). Multivariate analysis showed that more EBL (P = 0.003) and prognostic nutritional index (PNI) < 40 (P = 0.005) were independent risk factors of POCs for LG after neoadjuvant therapy.ConclusionNeoadjuvant SOX plus ICIs brings better tumor regression and similar TRAEs compared with SOX alone for LAGC. SOX + ICIs-LG is safe and feasible to conduct with less EBL. Surgeons should focus on the perioperative management to control POCs for patients with PNI < 40 and more EBL.

Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

413. LYMPH NODE MAJOR PATHOLOGIC RESPONSE IS A POTENTIAL PROGNOSTIC FACTOR AFTER NEOADJUVANT CHEMORADIOTHERAPY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Esophageal cancer ranks tenth in incidence and is the sixth most common cause of cancer-related deaths. Neoadjuvant chemoradiotherapy before and after surgery has been shown to improve ESCC patients' survival compared with surgery alone. However, the outcomes of nCRT are heterogeneous, and clinical or pathological methods that can predict nCRT responses have been extensively studied. There are currently no standard grading methods that assess the treatment response in lymph nodes after nCRT. We aimed to assess the clinicopathological relevance and determine the prognostic significance of lymph node major pathologic response (MPR) after nCRT in ESCC patients. Methods Patients who received nCRT for ESCC followed by surgery were retrospectively reviewed and classified into different lymph node stage (LNS) according to their pathological regression: LNS0 (no tumor cells in lymph node before nCRT); LNS1 (residual tumor cells in lymph node after nCRT≤50%; major pathologic response); LNS2 (residual tumor cells in lymph node after nCRT&amp;gt;50%; not major pathologic response). Results In total, 187patients, comprising 91,49 and 47 patients with LNS stage of 0(no tumor cells in lymph node before nCRT),1(major pathologic response), or 2(not major pathologic response), respectively, were included. The result showed that the higher LNS stage was strongly associated with decreased overall survival (P&amp;lt;0.001) and disease-free survival (P&amp;lt;0.001), and increased recurrence risks (P=0.002). The cox regression showed MPR was significantly an independent prognostic factor of OS and DFS. Among 96 patients with clinically positive LNs,54patients (56.3%) showed discordance between the PT and LN pathological regression grades. Conclusions Residual tumor cells in lymph node after nCRT≤50% could be defined as lymph node major complete response. The Lymph node MPR can be an independent prognostic indicator of ESCC patients who received nCRT plus curative surgery.

Moringa-based homestead to achieve Sustainable Development Goals: A case study from Jaintiapur of Sylhet, Bangladesh

A study was conducted in Sylhet at Jaintiapur Upazila to determine the prospects of Moringa-based homestead concerning Sustainable Development Goals. A household survey was conducted following a simple random sampling of 135 farmers and following a semi-structured questionnaire and interview schedule with 100 farmers (40 identified Moringa-based adopters and 60 non-adopters). The final questionnaire was prepared after pilot testing, which contained data on common species diversity, and the perception of farmers regarding SDGs indicators of “no poverty, zero hunger, good health, and well-being, gender equality, affordable and clean energy, decent work and economic growth”. The extent of agreement was recorded following the points Likert scale high (3) to no change (0), and the SDG index (SDGI) value was calculated. The 10 key informant interviews were conducted with non-adopters to get insights into their perception regarding Moringa-based homesteads. The findings revealed that the status of plant species diversity such as betel nut (100 %), mango (100 %), bean (99 %), and arjun (90 %) was higher in comparison to non-adopters where the status of the respective species was 92 %, 99 %, 89 %, and 73 % respectively. The perception assessment revealed that 100 % of adopters and 90 % of non-adopters believed that Moringa-based homesteads had the potential to increase access to food, nutrition, and medicinal resources. While the majority of 70 % of adopters, and 90.5 % non-adopters disagreed that it had the potential to ensure government access and non-government credit resources. Among the Moringa-based homestead adopters, the gross income derived from Moringa sales was 2828.57 ± 1481.45, where 55 % of homesteads were identified to have Moringa plants between 3 and 5, and homesteads solely supplied fuel materials for 40 % of households. Gender participation was quite evident for homestead farming activities, where female participation was higher in planting, weeding, irrigation, and fencing. Homesteads provided both on-farming and off-farming income opportunities where major responses were found for poultry farming (96 %), vegetable farming (95 %), and day labor (97 %). Farmers were found to practice climate-smart practices of homestead agroforestry (100 %), rainwater harvesting (99 %), weeding (98 %), and management of debris (95 %) in their respective homesteads. The results disclosed that Moringa-based homestead in Sylhet can be a potential option for attaining SDGs indicators of escalation of household income (SDGI = 90), access to food, nutrition, and medicinal resources (SDGI = 103.6), facilitation of natural treatment of diseases (SDGI = 104.6), de-escalation of gender discrepancy in terms of production activities (SDGI = 103.64), own source of fuel (SDGI = 58.44), both off-farm and on-farm income opportunity (SDGI = 100.52), ecosystem health maintenance by resilient practices (SDGI = 104.6). Farmers ranked food security capacity as a major motivational factor, while the low economic return was a major demotivational factor. The escalation of Moringa-based homesteads needs to be prioritized while facilitating credit, and institutional support to extend encouragement to non-adopters for wider integration of Moringa-based homesteads, and appropriate utilization of the existing resources for greater profitability.

575. PATHOLOGIC RESPONSE AND RESIDUAL LYMPH NODE PATTERNS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA PATIENTS UNDERGOING NEOADJUVANT IMMUNOCHEMOTHERAPY COMPARED TO NEOADJUVANT CHEMORADIOTHERAPY

Abstract Background Concurrent chemoradiotherapy is the cornerstone treatment for locally advanced esophageal cancer. Immunochemotherapy, established as the standard treatment for advanced esophageal cancer, concurrently exhibits excellent short-term efficacy in the neoadjuvant stage. Combining concurrent chemoradiotherapy with immunochemotherapy may enhance control over primary tumor and metastatic lymph nodes, potentially improving patients’ outcomes and survival. Therefore, comparing the pros and cons of these two treatment modalities in controlling primary lesions and lymph node metastasis is crucial for guiding clinical treatment. Methods Our study enrolled a total of 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant immunochemotherapy (NICT) and 151 ESCC patients who underwent neoadjuvant chemoradiotherapy (NCRT) between January 2019 and March 2022. We documented baseline patient characteristics, including clinical TNM stage, tumor location, and clinical metastatic lymph nodes, as well as pathologic outcomes such as pathological stage, pathologic complete response (pCR), tumor regression grade (TRG), and pathological metastatic lymph nodes. To balance baseline patient characteristics, we employed inverse probability of treatment weighting (IPTW) to adjust for confounding in different neoadjuvant treatment groups. Results After balancing baseline characteristics, there was no statistically significant difference in pathologic outcomes, including pCR rate, major pathologic response rate, TRG, yp-TNM stage, and R0 resection rate between NCRT and NICT. However, patients with clinical N2-3 stage (OR 2.66; 95% CI 1.05 to 6.79) or lower thoracic esophageal tumors (OR 2.31; 95% CI 1.05 to 5.04) had a higher chance of achieving pCR after NICT compared to NCRT. For patients undergoing NICT, the ypN0 rates for clinically N0 patients were 100.0% (5/5), while only 65.0% (13/20) of clinical N0 patients achieved ypN0 in the NCRT group. Even after adjusting for differences in clinical stage, tumor location, and baseline lymph node metastasis rates in various locations, the NICT group still demonstrated a lower rate of abdominal lymph node metastasis during surgery (p=0.030). Conclusion In comparison to concurrent chemoradiotherapy, immunochemotherapy exhibits comparable overall disease control for primary lesions and lymph node metastasis. Notably, patients with clinical N2-3 and lower thoracic esophageal cancer may derive greater benefits from NICT. The potential of immunochemotherapy in enhancing the effectiveness of chemoradiotherapy is evident in its ability to improve the control of occult metastatic lymph nodes and reduce abdominal lymph node metastasis.