Good Pathological Response Research Articles

Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer with [68Ga]Ga-FAPI-04 PET, [18F]FDG PET, and Contrast-Enhanced MRI: Lesion-to-Lesion Comparison with Pathology.

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. 68Ga-labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI-04) PET/MRI, [18F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter's sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [68Ga]Ga-FAPI-04 PET/MRI and [18F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [68Ga]Ga-FAPI-04 change in SULpeak percentage, where SULpeak is SUVpeak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [68Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SULpeak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

Prediction of pathological response and lymph node metastasis after neoadjuvant therapy in rectal cancer through tumor and mesorectal MRI radiomic features

Establishing predictive models for the pathological response and lymph node metastasis in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) based on MRI radiomic features derived from the tumor and mesorectal compartment (MC). This study included 209 patients with LARC who underwent rectal MRI both before and after nCRT. The patients were divided into a training set (n = 146) and a test set (n = 63). Regions of interest (ROIs) for the tumor and MC were delineated on both pre- and post-nCRT MRI images. Radiomic features were extracted, and delta radiomic features were computed. The predictive endpoints were pathological complete response (pCR), pathological good response (pGR), and lymph node metastasis (LNM). Feature selection for various models involved sequentially removing features with a correlation coefficient > 0.9, and features with P-values ≥ 0.05 in univariate analysis, followed by LASSO regression on the remaining features. Logistic regression models were developed, and their performance was evaluated using the area under the receiver operating characteristic curve (AUC). Among the 209 LARC patients, the number of patients achieving pCR, pGR, and LNM were 44, 118, and 40, respectively. The optimal model for predicting each endpoint is the combined model that incorporates pre- and delta-radiomics features for both the tumor and MC. These models exhibited superior performance with AUC values of 0.874 (for pCR), 0.801 (for pGR), and 0.826 (for LNM), outperforming the MRI tumor regression grade (mrTRG) which yielded AUC values of 0.800, 0.715, and 0.603, respectively. The results demonstrate the potential utility of the tumor and MC radiomics features, in predicting treatment efficacy among LARC patients undergoing nCRT.

Evaluation of pathological response to neoadjuvant chemotherapy in locally advanced cervical cancer

Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.

Neoadjuvant pembrolizumab plus lenvatinib in patients with resectable stage III melanoma (NeoPele): Analysis of tumor microenvironment (TME) correlated to pathological response.

9566 Background: The phase II SWOG S1801 study showed an improved event-free survival with anti-PD-1 (PD1) neoadjuvant immunotherapy (neoIT) vs adjuvant PD1. One hypothesis explaining this benefit is the presence of tumor-draining lymph nodes (tdLN; defined as the nearest node to the tumor without direct involvement) as a potential reserve of stem-like (TCF7+) T cells, crucial to a good response to IT. We sought to analyze the immune infiltrate of the tumor-involved LN (ie TME) and tdLN from patients (pts) achieving major pathological response (MPR: complete [pCR] or near-complete [near-pCR] pathological response) vs non-MPR (partial [pPR] or no [pNR] pathological response). Methods: Pts with stage III melanoma treated with 6 weeks of PD1-based neoIT (PD1 + Lenvatinib) were included (NeoPele clinical trial; NCT04207086). Multiplex fluorescent immunohistochemistry of the TME before and after neoIT, and of the tdLN after neoIT was analyzed (T cell panel: CD3, TCF7, CD103, FoxP3, CD39 and Sox10; and B cell panel: CD20, CD21, CXCR5, TCF7, CD3 and SOX10). Lymphoid aggregates, characterized by clusters of CD21+ and CXCR5+ immune cells, were quantified. Results: Of the 20 pts, 11 (55%) had MPR (8 [40%] with pCR and 3 [15%] with near-pCR) and 9 (45%) had a non-MPR (4 [20%] with pPR and 5 [25%] with pNR). At baseline, MPR pts had a higher % of T cells (11% vs 3%, p = 0.0127) and follicular B helper T cells (CXCR5+; 29% vs 9%, p = 0.0293) than non-MPR pts in the TME. NeoIT led to an increase in the % of T cells, mainly in pts with MPR (median +30%; p = 0.0156) vs non-MPR (median +7%; p = 0.0312) pts, including an increase in the % of tumor-reactive (CD39+) T cells (p = 0.0195), but a decrease in % of tissue-resident stem-like (CD103+ TCF7+) T cells (p = 0.0195). Within the B cell compartment, there was an increase in the % of CD21+ B cells and mature (CD21+ CXCR5+) B cells in MPR vs non-MPR pts. At week 6, MPR pts maintained a higher % of T cells (36% vs 11%, p = 0.0172), follicular B helper T cells (20% vs 9%, p = 0.0133), and mature B cells (10% vs 2%, p = 0.0021) in the TME compared with non-MPR. NeoIT led to a significant increase in the number of lymphoid aggregates in the TME from MPR pts (median +42; p = 0,0156), but no difference in non-MPR pts. No differences were observed in the tdLN based on pathological response. Conclusions: MPR pts had a higher density of T cells in the TME at baseline, and a more differentiated and activated immune profile after neoIT compared with non-MPR pts. MPR pts had a significant increase in the number of lymphoid aggregates at week 6 compared to non-MPR pts; however, the role of these lymphoid aggregates, including the follicular B helper T cell subset and mature B cells, promoting a good pathological response to neoIT is yet to be clarified. Clinical trial information: NCT04207086 .

Remarkable response as a new indicator for endoscopic evaluation of local efficacy of non-surgical treatments for esophageal cancer.

In Japan, standard of care of the patients with resectable esophageal cancer is neoadjuvant chemotherapy (NAC) followed by esophagectomy. Patients unfitted for surgery or with unresectable locally advanced esophageal cancer are generally indicated with definitive chemoradiotherapy (CRT). Local disease control is undoubtful important for the management of patients with esophageal cancer, therefore endoscopic evaluation of local efficacy after non-surgical treatments must be essential. The significant shrink of primary site after NAC has been reported as a good indicator of pathological good response as well as favorable survival outcome after esophagectomy. And patients who could achieve remarkable shrink to T1 level after CRT had favorable outcomes with salvage surgery and could be good candidates for salvage endoscopic treatments. Based on these data, "Japanese Classification of Esophageal Cancer, 12th edition" defined the new endoscopic criteria "remarkable response (RR)", that means significant volume reduction after treatment, with the subjective endoscopic evaluation are proposed. In addition, the finding of local recurrence (LR) at primary site after achieving a CR was also proposed in the latest edition of Japanese Classification of Esophageal Cancer. The findings of LR are also important for detecting candidates for salvage endoscopic treatments at an early timing during surveillance after CRT. The endoscopic evaluation would encourage us to make concrete decisions for further treatment indications, therefore physicians treating patients with esophageal cancer should be well-acquainted with each finding.

Digitally assessed lymphocyte infiltration in rectal cancer biopsies is associated with pathological response to neoadjuvant therapy

A frequently used treatment strategy in locally advanced rectal cancer (RC) is neoadjuvant therapy followed by surgery. Patients treated with neoadjuvant therapy achieve varying pathological response, and currently, predicting the degree of response is challenging. This study examined the association between digitally assessed histopathological features in the diagnostic biopsies and pathological response to neoadjuvant therapy, aiming to find potential predictive biomarkers. 50 patients with RC treated with neoadjuvant chemotherapy and/or radiotherapy followed by surgery were included. Deep learning-based digital algorithms were used to assess the epithelium tumor area percentage (ETP) based on H&E-stained slides, and to quantify the density of CD3+ and CD8+ lymphocytes, as well as the CD8+/CD3+ lymphocyte percentage, based on immunohistochemically stained slides, from the diagnostic tumor biopsies. Pathological response was assessed according to the Mandard method. A good pathological response was defined as tumor regression grade (TRG) 1–2, and a complete pathological response was defined as Mandard TRG 1. Associations between the ETP and lymphocyte densities in the diagnostic biopsies and the pathological response were examined. The density of CD8+ lymphocytes, and the CD8+/CD3+ lymphocyte percentage, were associated with both good and complete response to neoadjuvant therapy, while the density of CD3+ lymphocytes was associated with complete response. The ETP did not correlate with response to neoadjuvant therapy. It is well-known that infiltration of lymphocytes in colorectal cancer is a prognostic biomarker. However, assessment of CD8+ and CD3+ lymphocytes in the diagnostic tumor biopsies of patients with RC may also be useful in predicting response to neoadjuvant therapy.

20. ADDITIONAL NEOADJUVANT IMMUNOTHERAPY DOESN’T INCREASE THE RISK OF ANASTOMOTIC LEAKAGE AFTER ESOPHAGECTOMY: A MULTICENTER RETROSPECTIVE COHORT STUDY

Abstract Background Neoadjuvant chemoimmunotherapy (nICT) is a promising therapy model for locally advanced esophageal squamous cell carcinoma (LA-ESCC), which brought good pathological response. However, there is still a lack of large cohot to confirm the impact of additional impact of additional neoadjuvant immunotherapy on short-term outcomes. The objective of this study lies on assessing the additional neoadjuvant immunotherapy making a difference in patients’ short-term outcomes, particularly the risk of anastomotic leakage (AL) and pathological response. Methods Patients with LA-ESCC who received neoadjuvant chemotherapy(nCT)/nICT combination with radical esophagectomy were enrolled from three medical centers in China. Baseline data were matched using propensity score matching (1:1, caliper = 0.01) and inverse probability processing weighting(IPTW). Conditional logistic regression and weighted logistic regression analysis were used to further evaluate whether additional neoadjuvant immunotherapy would increased the risk of postoperative AL. Results A total of 331 patients LA-ESCC receiving nCT or nICT were enrolled. The application of PSM as well as IPTW ensured baseline data equilibrium. After matching, there were no significant difference in the AL incidence between the two groups (p = 0.68, after PSM; p = 0.97 after IPTW), and the incidence of AL was 15.85% vs. 18.29%, and 14.79% vs. 15.01%, respectively. Weighted logistic regression analysis showed that additional neoadjuvant immunotherapy wasn’t responsible for AL. The nICT group had dramatically higher pCR in primary tumor than the nCT group (9.76% vs. 28.05% after PSM and 7.72% vs. 21.17% after IPTW). Conclusions Additional neoadjuvant immunotherapy can benefit pathological reactions without increasing the risk of AL and pulmonary complications. We require further randomized controlled research to validate whether additional neoadjuvant immunotherapy would make a difference in other complications, and determine whether pathologic benefits could translate into prognostic benefits, which would require longer follow-up.

Potential of damage associated molecular patterns in synergising radiation and the immune response in oesophageal cancer.

There is an intimate crosstalk between cancer formation, dissemination, treatment response and the host immune system, with inducing tumour cell death the ultimate therapeutic goal for most anti-cancer treatments. However, inducing a purposeful synergistic response between conventional therapies and the immune system remains evasive. The release of damage associated molecular patterns (DAMPs) is indicative of immunogenic cell death and propagation of established immune responses. However, there is a gap in the literature regarding the importance of DAMP expression in oesophageal adenocarcinoma (OAC) or by immune cells themselves. To investigate the effects of conventional therapies on DAMP expression and to determine whether OAC is an immunogenic cancer. We investigated the levels of immunogenic cell death-associated DAMPs, calreticulin (CRT) and HMGB1 using an OAC isogenic model of radioresistance. DAMP expression was also assessed directly using ex vivo cancer patient T cells (n = 10) and within tumour biopsies (n = 9) both pre and post-treatment with clinically relevant chemo(radio)therapeutics. Hypoxia in combination with nutrient deprivation significantly reduces DAMP expression by OAC cells in vitro. Significantly increased frequencies of T cell DAMP expression in OAC patients were observed following chemo(radio)therapy, which was significantly higher in tumour tissue compared with peripheral blood. Patients with high expression of HMGB1 had a significantly better tumour regression grade (TRG 1-2) compared to low expressors. In conclusion, OAC expresses an immunogenic phenotype with two distinct subgroups of high and low DAMP expressors, which correlated with tumour regression grade and lymphatic invasion. It also identifies DAMPs namely CRT and HMGB1 as potential promising biomarkers in predicting good pathological responses to conventional chemo(radio)therapies currently used in the multimodal management of locally advanced disease.

IMMUNOREACT 0: Biopsy-based immune biomarkers as predictors of response to neoadjuvant therapy for rectal cancer-A systematic review and meta-analysis.

The main therapy for rectal cancer patients is neoadjuvant therapy (NT) followed by surgery. Immune biomarkers are emerging as potential predictors of the response to NT. We performed a meta-analysis to estimate their predictive significance. A systematic literature search of PubMed, Ovid MEDLINE and EMBASE databases was performed to identify eligible studies. Studies on patients with rectal cancer undergoing NT in which the predictive significance of at least one of the immunological markers of interest was assessed by immunohistochemistry (IHC) in pretreatment biopsies were included. Seventeen studies reporting sufficient data met the inclusion criteria for meta-analysis. High levels of total CD3+, CD4+ and CD8+ tumor infiltrating lymphocytes (TILs), as well as stromal and intraepithelial CD8+ compartments, significantly predicted good pathological response to NT. Moreover, high levels of total (tumoral and immune cell expression) PD-L1 resulted associated to a good pathological response. On the contrary, high levels of intraepithelial CD4+ TILs were correlated with poor pathological response. FoxP3+ TILs, tumoral PD-L1 and CTLA-4 were not correlated to the treatment response. This meta-analysis indicated that high-density TILs might be predictive biomarkers of pathological response in patients that underwent NT for rectal cancer.

Evaluation of the role of inflammatory blood markers in predicting the pathological response after neoadjuvant chemoradiation in patients with locally advanced rectal cancer.

This study aimed to evaluate the role of inflammatory blood markers in predicting the pathological response rate after neoadjuvant chemoradiation (neo-CRT) in patients with locally advanced rectal cancer (LARC). In this prospective cohort study, we analyzed the data of patients with LARC who underwent neo-CRT and surgical removal of the rectal mass between 2020 and 2022 in a tertiary medical center. Patients were examined weekly during chemoradiation and neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and systemic immune inflammation index (SII) were calculated from weekly laboratory data. Wilcoxon signed-ranks and logistic regression analysis were utilized to determine whether any laboratory parameters during different time point assessments or their relative changes could predict the tumor response based on a permanent pathology review. Thirty-four patients were recruited for the study. Eighteen patients (53%) achieved good pathologic response. Statistical analysis by Wilcoxon signed-ranks method indicated significant rises in NLR, PLR, MLR, and SII on weekly assessments during chemoradiation. Having an NLR over 3.21 during chemoradiation was correlated with the response on a Pearson chi-squared test (p = 0.04). Also, a significant correlation was found between the PLR ratio over 1.8 and the response (p = 0.02). NLR ratio over 1.82 marginally missed a significant correlation with the response (p = 0.13). On multivariate analysis, a PLR ratio over 1.8 showed a trend for response (odds ratio = 10.4; 95% confidence interval, 0.9-123; p = 0.06). In this study, PLR ratio as an inflammatory marker showed a trend in the prediction of response in permanent pathology to neo-CRT.

Radiomics from Mesorectal Blood Vessels and Lymph Nodes: A Novel Prognostic Predictor for Rectal Cancer with Neoadjuvant Therapy.

The objective of our study is to investigate the predictive value of various combinations of radiomic features from intratumoral and different peritumoral regions of interest (ROIs) for achieving a good pathological response (pGR) following neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). This retrospective study was conducted using data from LARC patients who underwent nCRT between 2013 and 2021. Patients were divided into training and validation cohorts at a ratio of 4:1. Intratumoral ROIs (ROIITU) were segmented on T2-weighted imaging, while peritumoral ROIs were segmented using two methods: ROIPTU_2mm, ROIPTU_4mm, and ROIPTU_6mm, obtained by dilating the boundary of ROIITU by 2 mm, 4 mm, and 6 mm, respectively; and ROIMR_F and ROIMR_BVLN, obtained by separating the fat and blood vessels + lymph nodes in the mesorectum. After feature extraction and selection, 12 logistic regression models were established using radiomics features derived from different ROIs or ROI combinations, and five-fold cross-validation was performed. The average area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of the models. The study included 209 patients, consisting of 118 pGR and 91 non-pGR patients. The model that integrated ROIITU and ROIMR_BVLN features demonstrated the highest predictive ability, with an AUC (95% confidence interval) of 0.936 (0.904-0.972) in the training cohort and 0.859 (0.745-0.974) in the validation cohort. This model outperformed models that utilized ROIITU alone (AUC = 0.779), ROIMR_BVLN alone (AUC = 0.758), and other models. The radscore derived from the optimal model can predict the treatment response and prognosis after nCRT. Our findings validated that the integration of intratumoral and peritumoral radiomic features, especially those associated with mesorectal blood vessels and lymph nodes, serves as a potent predictor of pGR to nCRT in patients with LARC. Pending further corroboration in future research, these insights could provide novel imaging markers for refining therapeutic strategies.

Immune features of ovarian tumors with a good response to neo-adjuvant chemotherapy in combination with an anti-PD-L1 alone or with an anti-CTLA4: Data from the randomized IneOV trial (a GINECO study).

5586 Background: We have shown that chemotherapy may have immunomodulatory properties and prime the tumor microenvironment (TME) by recruiting cytotoxic immune cells. We previously reported that neoadjuvant chemotherapy (NACT) associated with Durvalumab (D) +/- Tremelimumab (T) resulted in encouraging complete resection (70%) and complete pathological response (18%) rates in patients with unresectable ovarian cancer. Here, we aimed to 1) characterize the immune TME at baseline of responders compared to non-responders and 2) describe changes in immune TME in paired tumor samples at diagnosis and after 3 cycles of NACT with D +/- T in the randomized IneOV trial. Methods: Tumor samples from IneOV trial (55 at diagnosis, 40 after treatment) were analyzed for CD3+, CD68+ and CD20+ by multiplexed immunohistochemistry. Stromal and intra-epithelial TILs were scored as percentage of positive surface. Patients were classified as good pathological responders (pR) (CRS3) or pathological non-responders (pNR) (CRS1 or 2). Intra-tumoral T cell infiltration was described as High or Low (intraepithelial (ie)CD3+ > median vs < , respectively). Non parametric statistical tests were used. We evaluated the correlation of the markers with each others (Spearman test) and with pathological response rate (Mann-Withney test). Results: At diagnosis, in the intra-epithelial compartment of the TME, the most abundant cells were macrophages (median ieCD68+ = 3,4) compared to T (ieCD3+ = 1.1), B (ieCD20+ ND) ANOVA p-value = 0.002 and < 0.0001 respectively . In individual tumors, infiltration by the 3 different immune subsets was poorly correlated suggesting immune TME heterogeneity in OC. Pathological response was evaluable in 64 patients: 19 pR and 45 pNR. At diagnosis, CD3+ (p = 0.02) and CD68+ (p = 0.006) infiltration was significantly higher in pR tumors compared to pNR. Most of pR (76%) had high intra-tumoral CD3+ infiltration versus 39% in pNR (p = 0.011). After treatment, tumors with pR showed significantly greater CD3+ intra-epithelial infiltration compared to pNR (p = 0.047). Conclusions: Our results suggest that good pathological response to NACT +D+/-T is associated with high levels of both T cells and macrophages in iTME at baseline, and increased intratumoral T cell infiltration post-treatment. Work is ongoing to further characterize the iTME, especially in pNR to identify other strategies to enhance the anti-tumor immune response. Clinical trial information: NCT03249142 .

Predictive Biomarkers of Pathological Response to Neoadjuvant Chemoradiotherapy for Locally Advanced Soft Tissue Sarcomas.

Marginally resectable and unresectable soft tissue sarcomas (STS) remain a therapy challenge due to the lack of highly active treatment. The aim of the study was to identify a biomarker to predict the pathological response (PR) to preplanned treatment of these STSs. In the phase II clinical trial (NCT03651375), locally advanced STS patients received preoperative treatment with a combination of doxorubicin-ifosfamide chemotherapy and 5 × 5 Gy radiotherapy. PR to the treatment was classified using the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group recommendations. We have chosen HIF-1α, CD163, CD68, CD34, CD105, and γH2AFX proteins, rendering different biological phenomena, for biomarker study. Nineteen patients were enrolled and in four cases a good PR was reported. The high expression of HIF-1α before surgery showed a negative correlation with PR, which means a poor response to therapy. Furthermore, the samples after surgery had decreased expression of HIF-1α, which confirmed the correlation with PR. However, high expression of γH2AFX positively correlated with PR, which provides better PR. The high number of positive-staining TAMs and the high IMVD did not correlate with PR. HIF1α and γH2AFX could be potential biomarkers for PR prediction after neoadjuvant treatment in STS.

Abstract 3806: Investigating the role of miRNA-34a in the resistance of esophageal adenocarcinoma to neoadjuvant chemoradiation therapy

Abstract Background: The current standard of care for locally advanced esophageal adenocarcinoma (EAC) involves neo-adjuvant chemoradiation therapy (neo-CRT) followed by surgery. However, response to neo-CRT is poor and resistance remains a significant barrier to effective treatment. There are currently no clinical biomarkers to predict treatment response in EAC. Evidence supports a role for microRNA-34a (miR-34a) as a tumor suppressor in cancer, however, the role of miR-34a in the tumor response to therapy in EAC is largely unknown. Methods: Irradiation of EAC cell lines was performed using an Xstrahl RS225 X-ray irradiator at a clinically-relevant dose of 2 Gy. Radiosensitivity of EAC cell lines (OE33 P, OE33 R, OE33, OE19, Flo-1Par and Flo-1LM) was assessed by the gold standard clonogenic assay. miR-34a expression was assessed by qPCR. EAC tumor biopsies were obtained from consenting patients undergoing diagnostic endoscopy. Pathological response of the resected tumor was assigned by a pathologist using the Mandard Tumor Regression scale. miRTarBase and KEGG pathway analysis were used to identify predicted target genes and pathways of miR-34a. Results: miR-34a was demonstrated to be expressed in a panel of EAC cell lines (OE33 P, OE33 R, OE19, Flo-1Par and Flo-1LM cells). Interestingly, miR-34a expression was significantly decreased in EAC cell line models of both acquired radioresistance (OE33 R) and inherent radioresistance (OE19). miR-34a was also significantly decreased in a model of radioresistant metastatic EAC (Flo-1LM). Supporting in vitro data, in pre-treatment tumor biopsies from EAC patients (n=18), miR-34a was significantly decreased in patients having a subsequent poor pathological response to neo-CRT, when compared to patients having a good pathological response to neo-CRT. Target and pathway analysis demonstrated miR-34a-mediated regulation of genes and pathways associated with treatment resistance, including the complement system, cellular metabolism and p53 signaling, among others. Conclusion: Decreased miR-34a expression is associated with radioresistance across a panel of in vitro EAC models and in pre-treatment tumor biopsies from EAC patients having a poor pathological response to neo-CRT. This highlights a potential role for miR-34a as a novel biomarker predicting response to neo-CRT in EAC. Analysis of validated and predicted gene targets of miR-34a identified a number of pathways associated with treatment resistance. We are currently investigating the functional role of miR-34a in modulating tumor response to radiation in vitro to determine its potential as a novel therapeutic target to boost treatment response in EAC. Citation Format: Christina Cahill, Stephen G. Maher, Rebecca O'Brien, Wei-Lin Winnie Wang, John V. Reynolds, Jacintha O'Sullivan, Niamh Lynam-Lennon. Investigating the role of miRNA-34a in the resistance of esophageal adenocarcinoma to neoadjuvant chemoradiation therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3806.

The role of magnetic resonance tumour regression grade in the prediction of regression and survival of rectal adenocarcinoma after long-course chemoradiotherapy: a cohort study.

Between 2011 and 2016, patients with rectal cancer who underwent LCCRT and had post-LCCRT MRI were included in the study. Both mrTRG and pTRG were dichotomised into good responders (mrTRG 1-3 and pTRG 0-1) and poor responders (mrTRG 4-5 and pTRG 2-3). Correlation between mrTRG and pTRG was assessed with Cohen κ analysis. Survival analysis was performed with Kaplan-Meier test and Cox proportional hazard models. There were 59 patients included in this study. There were significant reductions in anal sphincter and circumferential resection margin involvement in post-LCCRT MRI. Fair agreement was found between mrTRG and pTRG (κ=0.345). Sensitivity, specificity and accuracy of mrTRG 1-3 to predict good pathological response were 100%, 46.3% and 62.7%, respectively. On survival analysis, mrTRG 1-3 was not associated with improved overall survival and recurrence-free survival. While there is fair agreement in correlation between mrTRG and pTRG, MRI remains an objective, noninvasive assessment of tumour response. Further studies are required to improve the ability of mrTRG to predict good responders to LCCRT and evaluate its role as a prognostic marker for survival.

Efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A retrospective study.

This study aims to compare the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) with different radiotherapy doses (45Gy and 50.4Gy) in patients with locally advanced rectal cancer (LARC). Herein, 120 patients with LARC were retrospectively enrolled between January 2016 and June 2021. All patients underwent two courses of induction chemotherapy (XELOX), chemoradiotherapy, and total mesorectum excision (TME). A total of 72 patients received a radiotherapy dose of 50.4 Gy, while 48 patients received a dose of 45 Gy. Surgery was then performed within 5-12 weeks following nCRT. There was no statistically significant difference between the baseline characteristics of the two groups. The rate of good pathological response in the 50.4Gy group was 59.72% (43/72), while in the 45Gy group achieved 64.58% (31/48) (P>0.05). The disease control rate (DCR) in the 50.4Gy group was 88.89% (64/72), compared to 89.58% (43/48) in the 45Gy group (P>0.05). The incidence of adverse reactions for radioactive proctitis, myelosuppression, and intestinal obstruction or perforation differed significantly between the two groups (P<0.05). The anal retention rate in the 50.4Gy group was significantly higher in contrast to the 45Gy group (P<0.05). Patients receiving a radiotherapy dose of 50.4Gy have a better anal retention rate but also a higher incidence of adverse events such as radioactive proctitis, myelosuppression, and intestinal obstruction or perforation, and a comparable prognosis to patients treated with a radiotherapy dose of 45Gy.

The beginning of a new era in induction treatment for operable non-small cell lung cancer: a narrative review.

The survival benefit of induction therapy for non-small cell lung cancer (NSCLC) remains controversial. Recently, the outcomes of systemic therapy for NSCLC have dramatically changed with the advent of molecular target drugs and immune checkpoint inhibitors (ICIs). The present review was conducted to investigate the outcomes of induction therapy with reference to randomized control trials (RCTs). We reviewed RCTs and ongoing clinical trials between 1990 and 2022 using relevant databases: PubMed, Web of Science, and EMBASE database. We investigated the outcomes of induction therapy. Induction therapy was associated with longer overall survival in comparison to surgery alone in several RCTs for stage III disease. However, its benefit in early-stage (I-II) disease was unclear. Regarding induction chemotherapy and chemoradiotherapy, the safety and survival outcomes did not differ between the two arms. Epidermoid growth factor receptor (EGFR) tyrosine kinase inhibitors as induction therapy in patients with proven EGFR mutations may be a sufficient choice for the improvement of overall survival. In ongoing single arm clinical trials and a randomized control study, the administration of ICIs as induction therapy was associated with a good pathological response and satisfactory safety, which will lead to a better survival outcome. Long-term observation is needed to evaluate the toxicity and survival impact of induction therapy with ICIs. Induction chemotherapy and EGFR-TKIs for stage IIIA NSCLC may contribute to the improvement of survival outcomes although the effect of systemic therapy on stage I-II remains controversial. ICIs may be considered as a valuable treatment option because of their feasibility and safety for induction therapy.

Quantitative Diffusion-Weighted Imaging Analyses to Predict Response to Neoadjuvant Immunotherapy in Patients with Locally Advanced Head and Neck Carcinoma.

Neoadjuvant immune checkpoint blockade (ICB) prior to surgery may induce early pathological responses in head and neck squamous cell carcinoma (HNSCC) patients. Routine imaging parameters fail to diagnose these responses early on. Magnetic resonance (MR) diffusion-weighted imaging (DWI) has proven to be useful for detecting HNSCC tumor mass after (chemo)radiation therapy. 32 patients with stage II-IV, resectable HNSCC, treated at a phase Ib/IIa IMCISION trial (NCT03003637), were retrospectively analyzed using MR-imaging before and after two doses of single agent nivolumab (anti-PD-1) (n = 6) or nivolumab with ipilimumab (anti-CTLA-4) ICB (n = 26). The primary tumors were delineated pre- and post-treatment. A total of 32 features were derived from the delineation and correlated with the tumor regression percentage in the surgical specimen. MR-DWI data was available for 24 of 32 patients. Smaller baseline tumor diameter (p = 0.01-0.04) and higher sphericity (p = 0.03) were predictive of having a good pathological response to ICB. Post-treatment skewness and the change in skewness between MRIs were negatively correlated with the tumor's regression (p = 0.04, p = 0.02). Pre-treatment DWI tumor diameter and sphericity may be quantitative biomarkers for the prediction of an early pathological response to ICB. Furthermore, our data indicate that ADC skewness could be a marker for individual response evaluation.

¿Es la actividad metabólica del tejido adiposo un predictor de respuesta histopatológica al tratamiento neoadyuvante en el cáncer de mama?

Introduction and objectivePrediction of the pathologic response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer is essential for optimal treatment strategy. The current approach of adjuvant or neoadjuvant treatment is based on the molecular subtype. Obesity may have affected chemotherapy response. This study aims to evaluate the relationship between metabolic activity of adipose tissue (AT) and pathological responses to NAC. And to define the association with body mass index (BMI) and metabolic parameters of standardized uptake value (SUV) of adipose tissue measured by positron emission computed tomography (PET/CT). Material and methodsOne-hundred and sixteen consecutive patients with stage II and III breast cancer who underwent PET/CT before receiving NAC, were evaluated in the study. Metabolic parameters of visceral adipose tissue (VAT-SUV), subcutaneous adipose tissue (SAT-SUV), and calculated SUV of visceral-to-subcutaneous ratio (V/S-ratio) were regarded. The relationship between SUV of AT and pathologic response was evaluated from medical records retrospectively. ResultsUnivariate-analysis revealed that good pathological response was significantly associated with clinical stage (p<0.001), HER-2 positivity (p<0.001), VAT-SUV (p=0.037), VAT-density (p=0.043) and V/S-ratio (p=0.003). In multivariate-analysis clinical stage, HER-2 positivity and V/S-ratio were found to have statistically effect on pathological response. VAT-volume (p<0.001), VAT-SUV (p=0.016), SAT-volume (p<0.001) and SAT-SUV (p<0.001) has positive correlation with BMI value. On the other hand, V/S-ratio (p=0.039) and SAT-density (p=0.003) has negative correlation with BMI. ConclusionMetabolic activity of AT is associated with BMI and effected chemotherapy responses. Low V/S ratio was associated with high BMI and poor pathological response to NAC. V/S ratio may be a useful marker for the prediction of NAC responses.

Clinical and biochemical predictors of tumor response after neoadjuvant therapy in rectal cancer.

Patients who have a good clinical and/or pathologic response to neoadjuvant chemoradiotherapy (nCRT) for rectal cancer have better long-term outcomes and can potentially be spared morbid surgery. This study aimed to identify pretreatment clinical and biochemical predictors of response to neoadjuvant treatment for rectal cancer. Patients undergoing neoadjuvant therapy for rectal cancer between 2007 and 2022 were retrospectively included. Those patients who achieved a complete clinical response were offered a nonoperative management strategy and the remaining patients underwent surgical resection. The primary endpoint was tumor regression grade (TRG) based on radiological imaging (mrTRG) or pathology (pTRG). Patient response was classified as good (mrTRG 1-2 or pTRG 0-1) versus poor (mrTRG 3-4 or pTRG 2-3). Logistic regression was performed to determine predictors of TRG. A total of 984 patients with rectal cancer were identified of which 274 met the inclusion criteria. Of 274 patients, 228 (83%) underwent surgical resection. A good TRG response was observed in 119 (41%) patients, and a complete response was achieved in 53 (17%) patients. On univariable and multivariable logistic regression, clinical T2 stage and body mass index of ≥25kg/m2 were significant predictors of a good TRG. Clinical T2 stage and a personalised total neoadjuvant therapy regimen were significant predictors of complete response. Clinical T2 stage and a BMI≥25kg/m2 were predictors of good response to neoadjuvant therapy for rectal cancer. Future prospective studies are required to confirm these findings and evaluate their potential use in better targeting of nCRT.