DCE-MRI radiomics nomogram can predict response to neoadjuvant chemotherapy in esophageal cancer

Objectives To assess volumetric DCE-MRI radiomics nomogram in predicting response to neoadjuvant chemotherapy (nCT) in EC patients. Methods This retrospective analysis of a prospective study enrolled EC patients with stage cT1N + M0 or cT2-4aN0-3M0 who received DCE-MRI within 7 days before chemotherapy, followed by surgery. Response assessment was graded from 1 to 5 according to the tumor regression grade (TRG). Patients were stratified into responders (TRG1 + 2) and non-responders (TRG3 + 4 + 5). 72 radiomics features and vascular permeability parameters were extracted from DCE-MRI. The discriminating performance was assessed with ROC. Decision curve analysis (DCA) was used for comparing three different models. Results This cohort included 82 patients, and 72 tumor radiomics features and vascular permeability parameters acquired from DCE-MRI. mRMR and LASSO were performed to choose the optimized subset of radiomics features, and 3 features were selected to create the radiomics signature that were significantly associated with response (P < 0.001). AUC of combining radiomics signature and DCE-MRI performance in the training (n = 41) and validation (n = 41) cohort was 0.84 (95% CI 0.57–1) and 0.86 (95% CI 0.74–0.97), respectively. This combined model showed the best discrimination between responders and non-responders, and showed the highest positive and positive predictive value in both training set and test set. Conclusions The radiomics features are useful for nCT response prediction in EC patients.

Serum apolipoprotein B to apolipoprotein A-I ratio is an independent predictor of liver metastasis from locally advanced rectal cancer in patients receiving neoadjuvant chemoradiotherapy plus surgery

Background The ratio of serum apolipoprotein B (apoB) to apolipoprotein A-I (apoAI) had been reported as a prognostic factor in colorectal cancer. This retrospective study aimed to assess the implication of apoB-to-apoAI ratio in predicting liver metastasis from rectal cancer (RC). Methods The clinical data of 599 locally advanced RC patients treated with chemoradiotherapy followed by surgery were reviewed. Serum apoAI, apoB and apoB-to-apoAI ratio were analyzed for their correlation with the liver-metastasis-free, other-metastasis-free and overall survivals, together with the pretreatment and postsurgical pathoclinical features of the patients. Univariate and multivariate survival analyses were realized through the Kaplan-Meier approach and Cox model, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for independent predictors. Results Carbohydrate antigen 19 − 9 ≥ 26.3 U/ml, apoB-to-apoAI ratio ≥ 0.63, tumor regression grade 5 − 3, pT4 and pN + stage emerged as independent predictors of poorer liver-metastasis-free survival. The hazard ratios were 1.656 (95% CI, 1.094–2.506), 1.919 (95% CI, 1.174–3.145), 1.686 (95% CI, 1.053–2.703), 1.890 (95% CI, 1.110–3.226) and 2.012 (95% CI, 1.314–2.077), respectively. Except apoB-to-apoAI ratio, the other 4 factors were also independent predictors of poorer other-metastasis-free and overall survivals. And the independent predictors of poorer overall survival also included age ≥ 67 years old, distance to anal verge < 5 cm. Conclusions Serum apoB-to-apoAI ratio could be used as a biomarker for prediction of liver metastasis risk in locally advanced RC.

SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy

Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochemistry in preoperative tumor tissue. In an expanded study group (n = 378), a set of SMAD3 polymorphisms (rs35874463, rs1065080, rs1061427, rs17228212, rs744910, and rs745103) was analyzed. Association with tumor regression grade (TRG) and patient prognosis (progression-free survival [PFS] and overall survival [OS]) was assessed. Patients with high tumor expression of SMAD3 had a significantly increased risk of poor response (TRG≥2) [cellularity &gt;55% (OR:10.36, p = 0.0004), or moderate/high intensity (OR:5.20, p = 0.0038), or an H-score≥1 (OR:9.84, p = 0.0004)]. Patients carrying the variant SMAD3 rs745103-G allele had a poorer response (OR:0.48, p = 0.0093), a longer OS (HR:0.65, p = 0.0307), and a trend for longer PFS (HR:0.75, p = 0.0944). Patients who carried both high SMAD3 tumor expression and the wild-type rs745103-A allele had an extremely high risk of not achieving a complete response (OR:13.45, p = 0.0005). Host and tumor SMAD3 status might be considered to improve risk stratification of LARC patients to facilitate selection for alternative personalized neoadjuvant strategies including intensified regimens.

Diagnostic performance of MRI and endoscopy for assessing complete response in rectal cancer after neoadjuvant chemoradiotherapy: a systematic review of the literature

Background The diagnostic performance of magnetic resonance imaging (MRI) modalities and/or endoscopy for assessing complete response in rectal cancer after neoadjuvant chemoradiotherapy (nCRT) is unclear. Purpose To summarize existing evidence on the diagnostic performance of diffusion-weighted MRI, perfusion-weighted MRI, T2-weighted MR tumor regression grade, and/or endoscopy for assessing complete tumor response after nCRT. Material and Methods MEDLINE and Embase databases were searched. The PRISMA guidelines were followed. Sensitivity, specificity, negative predictive, and positive predictive values were retrieved from included studies. Results In total, 81 studies were eligible for inclusion. Evidence suggests that combined use of MRI and endoscopy tends to improve the diagnostic performance compared to single imaging modality. The positive predictive value of a complete response varies substantially between studies. There is considerable heterogeneity between studies. Conclusion Combined re-staging tends to improve diagnostic performance compared to single imaging modality, but the vast majority of studies fail to offer true clinical value due to the study heterogeneity.

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

Overexpression of MLPH in Rectal Cancer Patients Correlates with a Poorer Response to Preoperative Chemoradiotherapy and Reduced Patient Survival

Data mining of a public transcriptomic rectal cancer dataset (GSE35452) from the Gene Expression Omnibus, National Center for Biotechnology Information identified the melanophilin (MLPH) gene as the most significant intracellular protein transport-related gene (GO:0006886) associated with a poor response to preoperative chemoradiation. An MLPH immunostain was performed on biopsy specimens from 172 rectal cancer patients receiving preoperative chemoradiation; samples were divided into high- and low-expression groups by H-scores. Subsequently, the correlations between MLPH expression and clinicopathologic features, tumor regression grade, disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS) were analyzed. MLPH expression was significantly associated with CEA level (p = 0.001), pre-treatment tumor status (p = 0.022), post-treatment tumor status (p < 0.001), post-treatment nodal status (p < 0.001), vascular invasion (p = 0.028), and tumor regression grade (p < 0.001). After uni- and multi-variable analysis of five-year survival, MLPH expression was still associated with lower DSS (hazard ratio (HR), 10.110; 95% confidence interval (CI), 2.178–46.920; p = 0.003) and MeFS (HR, 5.621; 95% CI, 1.762–17.931; p = 0.004). In conclusion, identifying MLPH expression could help to predict the response to chemoradiation and survival, and aid in personal therapeutic modification.

Patterns and timing of recurrence in esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiotherapy plus esophagectomy

Background Tumor regression grade (TRG) after neoadjuvant therapy is reportedly predictive of prognosis in esophageal cancer patients, as lack of a response to neoadjuvant therapy is associated with a poor prognosis. However, there is little information available on the timing and pattern of recurrence after esophagectomy for thoracic esophageal squamous cell carcinoma (TESCC) that takes into consideration TRG after neoadjuvant chemoradiotherapy (NACRT). Here, in an effort to gain insight into a treatment strategy that improves the prognosis of NACRT non-responders, we evaluated the patterns and timing of recurrence in TESCC patients, taking into consideration TRG after NACRT. Methods A total of 127 TESCC patients treated with NACRT and esophagectomy between 2009 and 2017 were enrolled in this observational cohort study. TRGs were assigned based on the proportion of residual tumor cells in the area (TRG1, ≥1/3 viable cancer cells; 2, < 1/3 viable cancer cells; 3, no viable cancer cells). We retrospectively investigated the timing and patterns of recurrence and the prognoses in TESCC patients, taking into consideration TRG after NACRT. Results The 127 participating TESCC patients were categorized as TRG1 (42 patients, 33%), TRG2 (56 patients, 44%) or TRG3 (29 patients, 23%). The locoregional recurrence rate was higher in TRG1 (36.4%) patients than combined TRG2–3 (7.4%) patients. Patients with TRG3 had better prognoses, though a few TRG3 patients experienced distant recurrence. There were no significant differences in median time to first recurrence or OS among patients with locoregional or distant recurrence. There was a trend toward better OS in TRG2–3 patients with recurrence than TRG1 patients with recurrence, but the difference was not significant. Conclusions NACRT non-responders (TRG1 patients) experienced higher locoregional recurrence rates and earlier recurrence with distant or locoregional metastasis. TRG appears to be useful for establishing a strategy for perioperative treatments to improve TESCC patient survival, especially among TRG1 patients. (303 words).

Neoadjuvant Therapy of Metformin is Associated with Good Tumor Response After Preoperative Concurrent Chemoradiotherapy for Rectal Cancer

Metformin is associated with good tumor response in preoperative concurrent chemoradiotherapy (CCRT) for rectal cancer. This study aims to demonstrate that the timing of metformin is related to the tumor response on preoperative CCRT for rectal cancer. From January 2010 to December 2017, 232 patients who underwent curative resection after preoperative CCRT were reviewed. Patients were divided into groups with or without diabetes or metformin. The timing of metformin administration was divided based on before and after initiation of chemoradiotherapy. Multivariate logistic regression analysis was used to identify predictors for tumor response. Tumor downstaging (p = 0.02) and good response rates of tumor regression grade (TRG) (p = 0.008) were significantly higher in the group administered metformin before CCRT than other groups. In the multivariate analysis, metformin administration before CCRT was a significant factor in predicting tumor downstaging (odds ratio [OR] 10.31, 95% confidence interval [CI]: 1.76 - 102.08, p = 0.02) and good TRG (OR 12.55, 95% CI: 2.38 - 80.24, p = 0.004). In patients with rectal cancer who underwent preoperative CCRT, neoadjuvant therapy of metformin before CCRT was significantly associated with good tumor response and tumor downstaging.

Significance of chemotherapy-free interval and tumor regression grade in patients with recurrent esophageal squamous cell carcinoma receiving chemotherapy with fluorouracil and platinum after esophagectomy following preoperative chemotherapy

Background In Japan, standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC) includes preoperative chemotherapy with fluorouracil plus cisplatin followed by esophagectomy. However, its efficacy is unclear in patients with recurrent disease with < 6 months of chemotherapy-free interval (CFI) after preoperative chemotherapy followed by esophagectomy and in those with ≥ 6 months of CFI and poor pathological response to prior preoperative chemotherapy. Method We retrospectively evaluated the efficacy of fluorouracil plus platinum in patients with recurrent ESCC who received preoperative chemotherapy followed by curative esophagectomy. Results Among 105 patients with recurrent ESCC after preoperative chemotherapy followed by esophagectomy, a total of 55 patients received fluorouracil plus platinum for recurrent disease. Patients with a CFI < 6 months (n = 20) had significantly shorter overall survival (OS) (median, 7.1 vs 14.5 months, P = 0.008) compared with those with a CFI ≥ 6 months (n = 35). Multivariate analysis showed that OS was worse in patients with a CFI < 6 months or a tumor regression grade (TRG) ≤ 1a. Furthermore, in patients with a CFI ≥ 6 months, TRG ≤ 1a was associated with significantly shorter OS (11.1 months vs. not reached, P = 0.001). Conclusion Fluorouracil plus platinum was ineffective for recurrent ESCC in patients with a CFI < 6 months and in those with a CFI ≥ 6 months and a TRG ≤ 1a. Alternate regimens including nivolumab or pembrolizumab might be considered for the treatment for recurrence in these patients.