Heparanase-1 is downregulated in chemoradiotherapy orbital rhabdomyosarcoma and relates with tumor growth as well as angiogenesis

AIM: To determine the role of heparanase-1 (HPSE-1) in orbital rhabdomyosarcoma (RMS), and to investigate the feasibility of HPSE-1 targeted therapy for RMS. METHODS: Immunohistochemistry was performed to analyze HPSE-1 expression in 51 cases of orbital RMS patients (including 28 cases of embryonal RMS and 23 cases of alveolar RMS), among whom there were 27 treated and 24 untreated with preoperative chemoradiotherapy. In vitro, studies were conducted to examine the effect of HPSE-1 silencing on RMS cell proliferation and tube formation of human umbilical vein endothelial cells (HUVECs). RD cells (an RMS cell line) and HUVECs were infected with HPSE-1 shRNA lentivirus at a multiplicity of infection (MOI) of 10 and 30 separately. Real-time PCR and Western blot were applied to detect the mRNA and protein expression levels of HPSE-1. Cell viability of treated or control RD cells was evaluated by cell counting kit-8 (CCK-8) assay. Matrigel tube formation assay was used to evaluate the effect of HPSE-1 RNAi on the tube formation of HUVECs. RESULTS: Immunohistochemistry showed that the expression rate of HPSE-1 protein was 92.9% in orbital embryonal RMS and 91.3% in orbital alveolar RMS. Tissue from alveolar orbital RMS did not show relatively stronger staining than that from the embryonal orbital RMS. However, despite the types of RMS, comparing the cases treated chemoradiotherapy with those untreated, we have observed that chemoradiotherapy resulted in weaker staining in patients' tissues. The expression levels of HPSE-1 declined significantly in both the mRNA and protein levels in HPSE-1 shRNA transfected RD cells. The CCK-8 assay showed that lentivirus-mediated HPSE-1 silencing resulted in significantly reduced RD cells viability in vitro. Silencing HPSE-1 expression also inhibited VEGF-induced tube formation of HUVECs in Matrigel. CONCLUSION: HPSE-1 silencing may be a promising therapy for the inhibition of orbital RMS progression.

Preoperative Chemoradiotherapy for Gastroesophageal Junction Adenocarcinoma Modified by PET/CT: Results of Virtual Planning Study

Background and Objectives: The treatment of gastroesophageal junction (GEJ) adenocarcinoma consists of either perioperative chemotherapy or preoperative chemoradiotherapy. Radiotherapy (RT) in the neoadjuvant setting is associated with a higher probability of resections with negative margins (R0) and better tumor regression rate, which might be enhanced by incrementing RT dose with potential impact on treatment results. This virtual planning study demonstrates the feasibility of increasing the dose to GEJ tumor and involved nodes using PET/CT imaging. Materials and Methods: 16 patients from the chemoradiotherapy arm of the phase II GastroPET study were treated by a prescribed dose of 45.0 Gray (Gy) in 25 fractions. PET/CT was performed before treatment. The prescribed dose was virtually boosted on PET/CT-positive areas to 54.0 Gy by 9 Gy in 5 fractions. Dose-volume histograms (DVH) were compared, and normal tissue complication (NTCP) modeling was performed for both dose schedules. Results: DVHs were exceeded in mean heart dose in one case for 45.0 Gy and two cases for 54.0 Gy, peritoneal space volume criterion V45Gy < 195 ccm in three cases for 54.0 Gy and V15Gy < 825 ccm in one case for both dose schedules. The left lung volume of 25 Gy isodose exceeded 10% in most cases for both schedules. The NTCP values for the heart, spine, liver, kidneys and intestines were zero for both schemes. An increase in NTCP value was for lungs (median 3.15% vs. 4.05% for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy, respectively, p = 0.013) and peritoneal space (median values for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy were 3.3% and 14.25%, respectively, p < 0.001). Conclusion: Boosting PET/CT-positive areas in RT of GEJ tumors is feasible, but prospective trials are needed.

O-OGC04 Peri-operative chemotherapy versus preoperative chemoradiotherapy in treatment of Esophago-gastric junctional adenocarcinomas: A 10-year cohort study

Background Esophago-gastric junctional (EGJ) cancers have been considered recently as distinct tumour entity with characteristic genetic profiles. However, the optimal multimodal therapy of advanced EGJ cancers is still debatable. In this comparative study, we analysed the outcomes of peri-operative chemotherapy (CT) versus pre-operative chemoradiotherapy (CRT) in treatment of advanced EGJ adenocarcinomas. Methods This study included patients with locally advanced but resectable EGJ adenocarcinomas who underwent surgical resection after oncological therapy between 2010 till 2019, at our institution. Follow up till May 2021 was done. The outcomes between CT and CRT groups were retrospectively analysed. The long-term follow up data was obtained via direct contact with the patients during our oncological clinics, cross-checked with our hospital/national patients’ electronic databases. Results 107 patients had EGJ cancers; 90 (84%) patients met our inclusion criteria. Peri-operative chemotherapy was received in 65 (72%) patients. Overall median survival rate was 2.2 years in CRT-group compared to 2.4 years in CT-group (p-value 0.29), with comparable recurrence rates (48% vs 36% respectively). R0-resections were higher in CRT-group (84%) compared to CT-group (71%), yet insignificant p-value 0.197. Preoperative chemoradiotherapy achieved higher complete pathological response (28% vs 6%, p-value 0.009) and negative lymph nodes rates (64% vs 37%, p-value 0.014) compared to CT-group. Short-term outcomes (postoperative complications, morbidity rates and length of hospital stay) were similar across both groups. Conclusions Preoperative chemoradiotherapy was associated with higher complete pathological response and negative lymph nodes rates for EGJ adenocarcinomas compared to peri-operative chemotherapy, without increase in postoperative complications or morbidity rates. However, it wasn’t associated with improved overall or disease-free survival rates. These findings supported the use of CRT in treatment of advanced EGJ adenocarcinomas.

A Novel Scoring System for Response of Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer Using Early-Treatment Blood Features Derived From Machine Learning

BackgroundPreoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (LARC). However, individual responses to preoperative CRT vary from patient to patient. The aim of this study is to develop a scoring system for the response of preoperative CRT in LARC using blood features derived from machine learning.MethodsPatients who underwent total mesorectal excision after preoperative CRT were included in this study. The performance of machine learning models using blood features before CRT (pre-CRT) and from 1 to 2 weeks after CRT (early-CRT) was evaluated. Based on the best model, important features were selected. The scoring system was developed from the selected model and features. The performance of the new scoring system was compared with those of systemic inflammatory indicators: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and the prognostic nutritional index.ResultsThe models using early-CRT blood features had better performances than those using pre-CRT blood features. Based on the ridge regression model, which showed the best performance among the machine learning models (AUROC 0.6322 and AUPRC 0.5965), a novel scoring system for the response of preoperative CRT, named Response Prediction Score (RPS), was developed. The RPS system showed higher predictive power (AUROC 0.6747) than single blood features and systemic inflammatory indicators and stratified the tumor regression grade and overall downstaging clearly.ConclusionWe discovered that we can more accurately predict CRT response by using early-treatment blood data. With larger data, we can develop a more accurate and reliable indicator that can be used in real daily practices. In the future, we urge the collection of early-treatment blood data and pre-treatment blood data.

Impact of the distal resection margin on local recurrence after neoadjuvant chemoradiation and rectal excision for locally advanced rectal cancer

We aimed to evaluate whether a short distal resection margin (< 1 cm) was associated with local recurrence in patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy. Patients with rectal cancer who underwent preoperative chemoradiotherapy followed by curative surgery were divided into two groups based on the distal resection margin (≥ 1 cm and < 1 cm). In total, 507 patients were analyzed. The median follow-up duration was 48.9 months. The 3-year local recurrence rates were 2% and 8% in the ≥ 1 cm and < 1 cm groups, respectively (P < 0.001). Multivariable analysis revealed that a distal resection margin of < 1 cm was a significant risk factor for local recurrence (P = 0.008). Subgroup analysis revealed that a distal resection margin of < 1 cm was not an independent risk factor for local recurrence in the ypT0–1 group. However, among patients with tumor stages ypT2–4, the cumulative 3-year incidences of local recurrence were 2.3% and 9.8% in the ≥ 1 cm and < 1 cm groups, respectively (P = 0.01). A distal resection margin of < 1 cm might influence local recurrence rates in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy, especially in patients with tumor stages ypT2–4.

Prognoses in Pathologically Confirmed T1 Lower Rectal Cancer Patients with or without Preoperative Therapy: An Analysis Using the Surveillance, Epidemiology, and End Results Database

Introduction Preoperative chemoradiotherapy (CRT) is the standard therapy for downstaging in locally advanced lower rectal cancer. However, it remains unclear whether rectal cancers down-staged by preoperative therapy show similar prognoses to those of the same stage without preoperative therapy. We previously demonstrated that preoperative CRT did not affect prognosis of rectal cancer with pathological T1N0 (pT1N0) stage in a single institute. Here, using a larger dataset, we compared prognoses of (y)pT1 rectal cancer stratified by the use of preoperative therapy and analyzed prognostic factors. Methods Cases of pT1N0 rectal cancer, registered between 2004 and 2016, were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized as the ‘ypT1 group’ if they had undergone preoperative therapy before surgery or as the ‘pT1 group’ if they had undergone surgery alone. overall survival (OS) and cancer-specific survival (CSS) between these groups of patients was compared. Factors associated with CSS and OS were identified by univariate and multivariate analyses. Results Among 3,757 eligible patients, ypT1 and pT1 groups comprised 720 and 3,037 patients, respectively. While ypT1 patients showed poorer CSS than ypT1 patients, there was no significant difference in OS. Preoperative therapy was not an independent prognostic factor for CSS or OS. Multivariate analysis identified age and histological type as significant factors associated with CSS. Sex, age, race, and number of lymph nodes dissected were identified as significant factors associated with OS. Conclusions Prognosis among patients with (y)p T1N0 rectal cancer was similar irrespective of whether they underwent preoperative therapy, which is consistent with our previous observations.

Search of Predictors of Radiosensitivity in Rectal Adenocarcinoma

Purpose: To analyze a number of immunohistochemical markers as predictors of the radiosensitivity of rectal adenocarcinoma. Material and methods: The study included 122 patients with histologically verified rectal adenocarcinoma, varying degrees of differentiation, and the stage of the tumor process I-IIIC, T2-T4b /N0-N2b/ M0, with the localization of the tumor in the lower-middle-ampullary parts of the rectum. Predictors included in the research: Ki67, p53, EGFR, Bcl2, COX2, P21, E-cadherin. Preoperative chemoradiotherapy was performed up to 48–50 Gy with the use of medications (5-FU, Cisplatin) as a radio modifiers. The analysis was carried out according to the degree of severity of therapeutic pathomorphosis (according to Mandard), a decrease in the stage before surgery. Results: A full course of preoperative chemoradiotherapy followed by surgery was performed at 121 patients, one patient died of concomitant cardiac pathology during the break. The first degree of Mandard pathomorphosis (complete resorption) registered at 12 patients. The second degree (preservation of a few tumor cells against the background of fibrotic changes) – at 27 patients. The third degree (a large number of preserved tumor cells against the background of the predominance of fibrosis) – at 38 patients. The fourth degree (tumor cells predominate over fibrotic changes) – at 27 patients. The fifth degree (complete absence of signs of tumor regression, absence of fibrosis) – at 2 patients. A decrease in the stage of the tumor process according to the preoperative comprehensive examination registered in 114 (94.2%) patients, in 9 (7.4%) patients – there was no dynamics. During the observation period from 2006 until nowadays, 10 people are known to have died. Years in remission range from 3 months to 22 years. According to the results of multivariate and multiple regression analyses, it is possible to successfully predict the effectiveness of chemoradiotherapy, both with the use of biomarkers (Ki67, p53, EGFR, Bcl2, COX2, P21, E-cadherin), and traditional indicators (histological type, stage of the disease, gender, degree of differentiation). It turned out, that both traditional indicators and immunohistochemical indicators work equally well, regardless of each other. Conclusion: Studied immunohistochemical predictors of radiosensitivity of rectal adenocarcinoma, allow to assess the degree of radiosensitivity or radioresistance of the tumor in each patient before the start of preoperative chemoradiotherapy by doing so, it warns us about the effectiveness or ineffectiveness of chemoradiotherapy in a specific clinical situation, which allows us to individualize the approach to treatment, choosing a more suitable treatment method for the patient: neoadjuvant chemotherapy or surgery.

Circulating miRNA Signature Predicts Response to Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer

PURPOSE Patients with locally advanced rectal cancer (LARC) are recommended to receive preoperative chemoradiotherapy (PCRT) followed by surgery. Response to PCRT varies widely: 60%-70% of patients with LARC do not derive therapeutic benefit from PCRT, whereas 15%-20% of patients achieve pathologic complete response (pCR). We sought to develop a liquid biopsy assay for identifying response to PCRT in patients with LARC. MATERIALS AND METHODS We analyzed two genome-wide microRNA (miRNA) expression profiling data sets from tumor tissue samples for in silico discovery (GSE68204) and validation (GSE29298). We prioritized biomarkers in pretreatment plasma specimens from clinical training (n = 41; 15 responders and 26 nonresponders) and validation (n = 65; 29 responders and 36 nonresponders) cohorts of patients with LARC. We developed an integrated miRNA panel and established a risk assessment model, which was combined with the miRNA panel and carcinoembryonic antigen levels. RESULTS Our comprehensive discovery effort identified an 8-miRNA panel that robustly predicted response to PCRT, with an excellent accuracy in the discovery (area under the curve [AUC] = 0.95) and validation (AUC = 0.92) cohorts. We successfully established a circulating miRNA panel with remarkable diagnostic accuracy in the clinical training (AUC = 0.82) and validation (AUC = 0.81) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to conventional clinical factors in both cohorts ( P < .01) and the risk assessment model was superior (AUC = 0.83). Finally, we applied our model to detect patients with pathologic complete response and showed that it was dramatically superior to currently used pathologic features (AUC = 0.92). CONCLUSION Our novel risk assessment signature for predicting response to PCRT has a potential for clinical translation as a liquid biopsy assay in patients with LARC.