Role of neoadjuvant therapy(chemotherapy and/or radiotherapy) in lymph node and primary rectal tumor regression and prognosis (Preprint)

UNSTRUCTURED Background: Rectal tumors are important malignancies and prediction of prognosis after neoadjuvant therapy is important to improve the prognosis process. The purpose of this study was to determine therole ofneoadjuvant therapy in lymph node regression and primary rectal tumor as well as its association with prognosis. Methods and materials: In this descriptive study, 40 consecutive patients with rectal tumor who were referred toTaleghani Hospital for surgery from 2011 to 2018 were enrolled. Moreover, theneoadjuvant therapy role in lymph node regression and primary rectal tumor was determined as well as its association with prognosis. Results: The results of this study demonstrate that there was no tumor regression in 20% of patients and it wasalso less than 25%, 25-50%, 50-75%, and complete in 22.5%, 35%, 20%, and 2.5% of the patients,respectively. The lymph node regression was complete in 5% of the patients and it wasalso less than 25% in 20% and more than 25% in 50% of them. In addition, it was with no regression in 25% of the patients. The lymph node regression was related to N stage (P=0.018), primary tumor regression grade (P=0.001), yPT (P=0.008), and yPN (P=0.020); however, it was not related to prognosis (P > 0.05). Conclusions: Totally, according to the obtained results, it can be concluded thatneoadjuvant therapy plays a good role in lymph node regression and primary rectal tumor, but it has no association with prognosis. Keywords:Neoadjuvant therapy, Lymph node regression, Primary rectal tumor, Prognosis

Endoscopic submucosal dissection for rectal neoplastic lesions: experience from a European center.

IntroductionNowadays, various endoscopic resections including polypectomy, endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD) are well known first-line approaches for early neoplastic rectal tumors.Material and methodsIn this case series study, we analyzed 320 ESD procedures performed in a high-volume colorectal center in Poland, Europe. The aim of this study was to retrospectively evaluate ESD procedure in cases of rectal carcinoma performed by a single trained operator in a referral center provided with endoscopy.ResultsOverall, en bloc resection was observed in 92.5% of patients (296/320). The en bloc resection rate was at a similar level in those lesions with involved anal sphincters versus tumors without involvement (93.85% vs. 92.16%; p=0.644). R0 resection was noted in 89.4% of patients (286/320). The overall curative ESD rate was 85.94% (n=275). The curative ESD rate in the invasive cancer group reached 52.6% (n=20). We observed ESD-related adverse events, such as bleeding and perforation, in 3.4 % of patients (n=11).ConclusionsWe have demonstrated that ESD in rectal tumors is an efficient and safe procedure with a high curative rate, even in difficult lesions. Anal sphincter localization and recurrent character of the lesion have no impact on the final outcomes. The ESD approach should have been considered for all rectal tumors, especially those lesions suspected of superficial mucosal invasion, as it can serve as a staging method and may have been curative for adenomas and cancers limited to mucosa.

New Artificial Intelligence Score and Immune Infiltrates as Prognostic Factors in Colorectal Cancer With Brain Metastases

Incidence of brain metastases has increased in patients with colorectal cancer (CRC) as their survival has improved. CD3 T-cells and, lately, DGMate (DiGital tuMor pArameTErs) score, have been identified as prognostic factors in locally advanced CRC. Until now, there is no data concerning the prognostic value of these markers in patients with CRC-derived brain metastases. All consecutive patients with CRC-derived brain metastases diagnosed between 2000 and 2017 were retrospectively included. Staining for CD3, CD8, PD-1, PD-L1 and DGMate analyses were performed using tissue micro-array from primary tumors and, if available, brain metastases. All in all, 83 patients were included with 80 primary tumor samples and 37 brain metastases samples available. CD3 and CD8 T-cell infiltration was higher in primary tumors compared to brain metastases. We observed a significant higher DGMate score in rectal tumors compared to colon tumors (p=0.03). We also noted a trend of higher CD3 T-cell infiltration in primary tumors when brain metastases were both supra and subtentorial compared to brain metastases that were only subtentorial or supratentorial (p=0.36 and p=0.03, respectively). No correlation was found between CD3 or CD8 infiltration or DGMate score in primary tumors or brain metastases and overall survival (OS) in the overall population. In patients with rectal tumors, a high DGMate score in brain metastases was associated with longer OS (13.4 ± 6.1 months versus 6.1 ± 1.4 months, p=0.02). High CD3 T-cell infiltration in brain metastases was associated with lower OS in patients with supratentorial brain metastases (9.8 ± 3.3 months versus 16.7 ± 5.9 months, p=0.03). PD-L1 overexpression was rare, both in primary tumors and brain metastases, but PD-L1 positive primary tumors were associated with worse OS (p=0.01). In contrast to breast and lung cancer derived brain metastases, CD3 and CD8 infiltration and DGMate score are not major prognostic factors in patients with CRC-derived brain metastases.

The time Interval Between the End of Radiotherapy and Surgery Does Not Affect Outcomes in Rectal Cancer

Introduction The ideal time interval between the completion of chemoradiotherapy and subsequent surgical resection of advanced stage rectal tumors is highly debated. Our aim is to study the effect of the time interval between the completion of chemoradiotherapy and surgical resection on postoperative and oncologic outcomes in rectal cancer. Methods Patients who underwent neoadjuvant chemoradiotherapy for resected locally advanced rectal tumors between 2004 and 2015 were included in this analysis. The time interval was calculated from the date of radiation completion to date of surgery. Patients were split into 2 groups based on the time interval (<8 weeks and >8 weeks). Postoperative outcomes (anastomotic leak, pathologic complete response (pCR), and readmission) and survival were assessed with multivariable logistic regression and Cox regression models while adjusting for relevant confounders. Results 200 patients (62% male) underwent resection with a median time interval of 8 weeks from completion of radiotherapy. On multivariable logistic regression, there was no significant increase in odds between time interval to surgery and anastomotic leak (aOR = .8 [.27-2.7], P = .8), pCR (aOR = 1.2[.58-2.6] P = .6), or readmission (aOR = 1.02, 95% CI:0.49-2.24, P = .9). Time interval to surgery was not an independent prognostic factor for overall (HR = 1.04 CI = .4-2.65, P = .9) and disease-free survival (HR = 1.2 CI = .5-2.9, P = .6). Conclusion The time interval between neoadjuvant radiotherapy completion and surgical resection does not affect anastomotic leak rate, achievement of pCR, or overall and disease-free survival in patients with rectal cancer. Extended periods of time to surgical resection are relatively safe.

Rectal Tumor Stiffness Quantified by In Vivo Tomoelastography and Collagen Content Estimated by Histopathology Predict Tumor Aggressiveness

PurposeTo investigate the significance of collagen in predicting the aggressiveness of rectal tumors in patients, examined in vivo based on tomoelastography quantified stiffness and ex vivo by histologically measured collagen volume fraction (CVF).Experimental Design170 patients with suspected rectal cancer were prospectively enrolled and underwent preoperative magnetic resonance imaging (MRI) and rectal tomoelastography, a technique based on multifrequency magnetic resonance elastography. Histopathologic analysis identified eighty patients with rectal cancer who were divided into subgroups by tumor-node (TN) stage, prognostic stage, and risk level. Rectal tumor stiffness was correlated with histopathologic CVF. Area-under-the-curve (AUC) and contingency analysis were used to evaluate the performance of rectal stiffness in distinguishing tumor stages which was compared to standard clinical MRIResultsIn vivo tomoelastography revealed that rectal tumor stiffened significantly with increased TN stage (p&lt;0.05). Tumors with poorly differentiated status, perineural and lymphovascular invasion also displayed higher stiffness than well-to-moderately differentiated, noninvasive tumors (all p&lt;0.05). Similar to in vivo stiffness, CVF indicated an abnormally high collagen content in tumors with perineural invasion and poor differentiation status. CVF was also positively correlated with stiffness (p&lt;0.05). Most importantly, both stiffness (AUROC: 0.82) and CVF (AUROC: 0.89) demonstrated very good diagnostic accuracy in detecting rectal tumors that have high risk for progressing to an aggressive state with poorer prognosis.ConclusionIn human rectal carcinomas, overexpression of collagen is correlated with increased tissue stiffness and high risk for tumor advancing more aggressively. In vivo tomoelastography quantifies rectal tumor stiffness which improves the diagnostic performance of standard MRI in the assessment of lymph nodes metastasis. Therefore, in vivo stiffness mapping by tomoelastography can predict rectal tumor aggressiveness and add diagnostic value to MRI.

Liver-First Approach for Synchronous Colorectal Metastases: Analysis of 7360 Patients from the LiverMetSurvey Registry

Background The liver-first approach in patients with synchronous colorectal liver metastases (CRLM) has gained wide consensus but its role is still to be clarified. We aimed to elucidate the outcome of the liver-first approach and to identify patients who benefit at most from this approach. Methods Patients with synchronous CRLM included in the LiverMetSurvey registry between 2000 and 2017 were considered. Three strategies were analyzed, i.e. liver-first approach, colorectal resection followed by liver resection (primary-first), and simultaneous resection, and three groups of patients were analyzed, i.e. solitary metastasis, multiple unilobar CRLM, and multiple bilobar CRLM. In each group, patients from the three strategy groups were matched by propensity score analysis. Results Overall, 7360 patients were analyzed: 4415 primary-first, 552 liver-first, and 2393 simultaneous resections. Compared with the other groups, the liver-first group had more rectal tumors (58.0% vs. 31.2%) and higher hepatic tumor burden (more than three CRLMs: 34.8% vs. 24.0%; size > 50 mm: 35.6% vs. 22.8%; p < 0.001). In patients with solitary and multiple unilobar CRLM, survival was similar regardless of treatment strategy, whereas in patients with multiple bilobar metastases, the liver-first approach was an independent positive prognostic factor, both in unmatched patients (3-year survival 65.9% vs. primary-first 60.4%: hazard ratio [HR] 1.321, p = 0.031; vs. simultaneous resections 54.4%: HR 1.624, p < 0.001) and after propensity score matching (vs. primary-first: HR 1.667, p = 0.017; vs. simultaneous resections: HR 2.278, p = 0.003). Conclusion In patients with synchronous CRLM, the surgical strategy should be decided according to the hepatic tumor burden. In the presence of multiple bilobar CRLM, the liver-first approach is associated with longer survival than the alternative approaches and should be evaluated as standard.

Endoscopic Ultrasound Elastography in the Assessment of Rectal Tumors: How Well Does It Work in Clinical Practice?

Endorectal ultrasound applications in the evaluation of rectal tumors could be a useful tool in achieving proper staging of rectal cancer. The purpose of this study was to compare the efficacy of rectal tumor staging by flexible endoscopic ultrasound (EUS) with real-time elastography (RTE) using the gold standard post-surgery histological analysis of the resected tissue as the control. The second aim of our research was to establish cutoff values for the EUS-RTE strain ratio corresponding to stages by independently comparing the stiffness values obtained with histology and EUS-RTE staging in order to minimize observation bias. We evaluated the records of 130 patients with a rectal tumor confirmed by biopsy. EUS was used in 70 patients, EUS-RTE—in the other 60. We found no statistically significant differences in staging accuracy when comparing EUS to EUS-RTE. Through a correspondence method between staging assessment and the EUS-RTE stain ratio, we identified cutoff intervals for T2, T3, and T4 staging that were nonoverlapping and proved to be statistically significant in terms of EUS-RTE values (significantly different ascending values from one interval to the other). We found that EUS-RTE offers slightly better, although not statistically significant sensitivity and specificity for T and N stage predictions compared to 2D EUS. Our results showed that EUS-RTE offers slightly higher sensitivity and specificity compared to EUS. Reliable cutoff intervals were found for strain rate elastography, previously available only for shear wave elastography (SWE) which is currently unavailable on any EUS system. Thus, these commonly available EUS-RTE systems can serve as a complementary tool in the staging of rectal tumors.

Genes copy number as a marker of low-invasive assessment of rectal tumors radiotherapy effectiveness.

3025 Background: Radiotherapy (RT) is a key component of rectal cancer (RC) treatment, however, nonresponsiveness in patients to preoperative RT is very common, usually due to the tumor cells radioresistance, mediated by their molecular characteristics, such as gene expression. The features of mRNA rapid degradation in extracellular environment make this indicator unsuitable for low invasive diagnostics. The solution to this problem is possible by switching to a more stable marker - the copy number variation (CNV), which can be determined in the extracellular DNA (cfDNA) circulating in the blood plasma. Therefore, the aim of the study was to identify the relationship between the level of genes CNV in the cfDNA of blood plasma with the effectiveness of rectal tumors RT. Methods: We used cfDNA preparations from blood plasma obtained before RT from 200 patients with RC, as well as from blood plasma of 50 apparently healthy donors (AHD, without cancer). RT was carried out on a linear accelerator Novalis TX (SFD = 2.4 Gy, TFD = 54.0 Gy). Blood samples were separated into plasma and cell fraction by centrifugation. Isolation of cfDNA from blood plasma was performed using the phenol-chloroform method. Determination CNV of 5 genes (BRCA2, H2AX, CASP9, RBBP8 and BCL2) was performed using Real-Time qPCR method. Differences were assessed using Mann-Whitney test; the Bonferroni correction was used to correct multiple comparisons. Results: RT results for 200 patients allowed them to be divided into 2 groups. After RT, 120 patients showed complete tumor regression (group 1), 50 patients showed insignificant tumor regression and 30 patients did not regress (group 2). In cfDNA of group 1 patients was found CNV decrease (p < 0.05) of H2AX and RBBP8 genes by 2.5 and 2.0 times, respectively, relative to AHD group. In the cfDNA of group 2patients an increase (p < 0.05) of BRCA2, H2AX, RBBP8 and BCL2 genes CNV was found by 2.0, 2.2, 2.0 and 2.0 times, respectively, relative to AHD group. Only 2 genes CNV differed in group 1 from group 2: the CNV of H2AX and RBBP8 was 5.4 and 4.0 times less respectively (p < 0.005). Conclusions: Thus, it has been found that increased CNV of genes BRCA2, H2AX, BCL2, RBBP8 in blood plasma cfDNA is associated with low efficiency of RT. At the same time, the CNV of H2AX and RBBP8 genes in cfDNA of patients with RC has the greatest potential as a marker of the RT effectiveness.