PURPOSE: To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node–positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m², once a day] on day 1 and capecitabine [1,000 mg/m², twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS: Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group ( P < .001). CONCLUSION: Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

KRAS mutation occurs in 35%-40% of colorectal cancer (CRC). The aim of our study was to evaluate the pathological and molecular features of specific KRAS mutated colorectal carcinomas. KRAS and BRAF V600E mutation tests were performed in 762 primary tumors from a consecutive cohort study of Chinese CRC patients. DNA mismatch repair (MMR) status was determined by immunohistochemistry (IHC) staining. Assessment of KRAS and BRAF V600E mutational status was performed using a multiplex allele-specific PCR-based assay. Mutations of KRAS (34.8%) and BRAF V600E (3.1%) were nearly mutually exclusive. Both KRAS- and BRAF- mutated tumors were more likely to be located at proximal colon than wild-type (WT) carcinomas. KRAS-mutated carcinomas were more frequently observed in female patients (47.5% vs 37.1%, p = 0.005) and mucinous differentiation (34.7% vs 24.8%, p = 0.004), but have no difference between lymph node (LN) metastases and among pTNM stages. Whereas, BRAF-mutated carcinomas more frequently demonstrated histologic features such as proximal location (60.9% vs 20.9%, p = 0.001), low-grade histology (43.5% vs 18.0%, p = 0.005), mucinous differentiation (69.6% vs 25.9%, p = 0.001) and deficient MMR (dMMR) (21.7% vs 7.6%, p = 0.03). In particular, KRAS codon 12 mutated carcinomas had increased lymph node metastasis (odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.04 to 1.65; P = 0.02) and were more likely in higher disease stage (III-IV) than that of WT carcinomas (OR = 1.30; 95% CI = 1.03 to 1.64; P = 0.03). However, there were no significant differences in lymph node metastasis and disease stage between KRAS codon 13 mutated carcinoma and WT carcinoma patients. In summary, KRAS codon 12 mutation, but not codon 13 mutation, is associated with lymph node metastasis and higher tumor stages.

Objectives The microscopic evaluation of slides has been gradually moving towards all digital in recent years, leading to the possibility for computer-aided diagnosis. It is worthwhile to know the similarities between deep learning models and pathologists before we put them into practical scenarios. The simple criteria of colorectal adenoma diagnosis make it to be a perfect testbed for this study. Design The deep learning model was trained by 177 accurately labelled training slides (156 with adenoma). The detailed labelling was performed on a self-developed annotation system based on iPad. We built the model based on DeepLab v2 with ResNet-34. The model performance was tested on 194 test slides and compared with five pathologists. Furthermore, the generalisation ability of the learning model was tested by extra 168 slides (111 with adenoma) collected from two other hospitals. Results The deep learning model achieved an area under the curve of 0.92 and obtained a slide-level accuracy of over 90% on slides from two other hospitals. The performance was on par with the performance of experienced pathologists, exceeding the average pathologist. By investigating the feature maps and cases misdiagnosed by the model, we found the concordance of thinking process in diagnosis between the deep learning model and pathologists. Conclusions The deep learning model for colorectal adenoma diagnosis is quite similar to pathologists. It is on-par with pathologists’ performance, makes similar mistakes and learns rational reasoning logics. Meanwhile, it obtains high accuracy on slides collected from different hospitals with significant staining configuration variations.

Background: The development of esophageal squamous cell carcinoma (ESCC) progresses a multistage process, collectively known as precursor lesions, also called dysplasia (DYS) and carcinoma in situ (CIS), subsequent invasive lesions and final metastasis. In this study, we are interested in investigating the expression of a variety of functional classes of proteins in ESCC and its precursor lesions and characterizing the correlation of these proteins with ESCC malignant progression. Methods: Fas, FADD, caspase 8, CDC25B, fascin, CK14, CK4, annexin I, laminin-5γ2 and SPARC were analyzed using immunohistochemistry on tissue microarray containing 205 ESCC and 173 adjacent precursor lesions as well as corresponding normal mucosa. To confirm the immunohistochemical results, three proteins, fascin, CK14 and laminin-5γ2, which were overexpressed in ESCC on tissue microarray, were detected in 12 ESCC cell lines by Western blot assay. Results: In ESCC and its precursor lesions, FADD, CDC25B, fascin, CK14, laminin-5γ2 and SPARC were overexpressed, while Fas, caspase 8, CK4 and annexin I were underexpressed. The abnormalities of these proteins could be classified into different groups in relation to the stages of ESCC development. They were "early" corresponding to mild and moderate DYS with overexpression of fascin, FADD and CDC25B and underexpression of Fas, caspase 8, CK4 and annexin I, "intermediate" to severe DYS and CIS with overexpression of FADD and CK14, and "late" to invasive lesions (ESCC) and to advanced pTNM stage ESCC lesions with overexpression of CK14, laminin-5γ2 and SPARC. Conclusion: Analyzing the protein expression patterns of Fas, FADD, caspase 8, CDC25B, fascin, CK14, CK4, annexin I, laminin-5γ2 and SPARC would be valuable to develop rational strategies for early detection of lesions at risk in advance as well as for prevention and treatment of ESCC.

GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas (TCGA). GADD45B expression features of 306 patients with stage II CRC and 201 patients with liver metastasis of CRC were investigated using immunochemical staining on tissue microarrays. Afterward, survival analysis and stratification analysis were performed in stage II to explore the prognostic and predictive significance of GADD45B. Overexpressed GADD45B is associated with poorer prognosis for CRC patients both in overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p = 0.001) based on the TCGA database. Analysis results according to the stage II CRC cohort and the liver metastatic CRC cohort revealed that GADD45B was gradually upregulated in normal mucosa including primary colorectal cancer (PCC). Colorectal liver metastases (CLM) tissues were arranged in order (normal tissue vs. PCC p = 0.005 and PCC vs. CLM p = 0.001). The low GADD45B group had a significantly longer five-year OS (p = 0.001) and progression-free survival (PFS) (p < 0.001) than the high GADD45B group for the stage II patients. The multivariate Cox regression analysis results proved that the expression level of GADD45B was an independent prognostic factor for stage II after radical surgery (OS: Hazard Ratio (HR) 0.479, [95% confidence interval (CI) 0.305–0.753] and PFS:HR 0.490, [95% CI 0.336–0.714]). In high GADD45B expression subgroup of stage II cohort, the patients who underwent adjuvant chemotherapy had longer PFS than those who did not (p = 0.008). High expression levels of GADD45B is an independent prognostic factor of decreased OS and PFS in stage II CRC patients. The stage II CRC patients with high GADD45B expression might benefit from adjuvant chemotherapy.