PURPOSE: To assess whether the integration of PD-1 inhibitor with total neoadjuvant therapy (iTNT) can lead to an improvement in complete responses (CRs) and favors a watch-and-wait (WW) strategy in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). PATIENTS AND METHODS: We conducted a prospective, multicenter, randomized, open-label, phase II trial using a pick-the-winner design. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly assigned to group A for short-course radiotherapy (SCRT) followed by six cycles of consolidation immunochemotherapy with capecitabine and oxaliplatin and toripalimab or to group B for two cycles of induction immunochemotherapy followed by SCRT and the rest four doses. Either total mesorectal excision or WW was applied on the basis of tumor response. The primary end point was CR which included pathological CR (pCR) after surgery and clinical CR (cCR) if WW was applicable, with hypothesis of an increased CR of 40% after iTNT compared with historical data of 25% after conventional TNT. RESULTS: Of the 130 patients enrolled, 121 pMMR/MSS patients were evaluable (62 in group A and 59 in group B). At a median follow-up of 19 months, CR was achieved at 56.5% in group A and 54.2% in group B. Both groups fulfilled the predefined statistical hypothesis ( P < .001). Both groups reported a pCR rate of 50%. Respectively, 15 patients in each group underwent WW and remained disease free. The most frequent grade 3 to 4 toxicities were thrombocytopenia and neutropenia. Patients in group A had higher rate of cCR (43.5% v 35.6%) at restaging and lower rate of grade 3 to 4 thrombocytopenia (24.2% v 33.9%) during neoadjuvant treatment. CONCLUSION: The iTNT regimens remarkably improved CR rates in pMMR/MSS LARC compared with historical benchmark with acceptable toxicity. Up-front SCRT followed by immunochemotherapy was selected for future definitive study.

Gastric cancer (GC) is one of the most common malignancies. Immunotherapy is a promising targeted treatment. The immune regulatory programmed death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis has been used as a checkpoint target for immunotherapy. Currently, considerable discrepancies exist concerning the expression status of PD‐L1 and its prognostic value in GC. We aimed to evaluate the expression rates of PD‐L1 in GC, and further assess its relationship with mismatch repair (MMR), and human epidermal growth factor receptor 2 (HER2) status. We retrospectively collected 550 consecutive cases of GC in Fudan University Shanghai Cancer Center from 2010 to 2012. PD‐L1, MMR protein, and HER2 status were detected by immunohistochemistry (IHC). Fluorescence in situ hybridization was further used in HER2 IHC 2+ cases. Cases with at least 1% membranous and/or cytoplasmic PD‐L1 staining in either tumor cells (TCs) or tumor‐infiltrating immune cells (TIICs) were considered as PD‐L1 positive. The correlation between clinicopathological parameters, HER2, MMR, and PD‐L1 expression status was determined using chi‐squared tests. About 37.3% cases (205/550) showed PD‐L1 expression in TCs and/or TIICs. 17.3% cases (95/550) showed PD‐L1 expression in TCs, 34.5% (190/550) cases showed PD‐L1 expression in TIICs. There were 45 deficient MMR (dMMR) cases (8.2%), which showed higher rates of PD‐L1 expression compared with MMR‐proficient carcinomas (60.0% vs. 35.2%, P = 0.001). HER2 was positive in 66 (12.0%) cases. The expression of PD‐L1 occurred more frequently in HER2‐negative group than HER2‐positive cohorts (39.0% vs. 24.2%, P = 0.020). The survival analysis revealed that PD‐L1 was not associated with prognosis. This study evaluated the association between the PD‐L1 expression and a specific subgroup (dMMR and HER2‐negative) in a large Asian cohort of GC. GC patients with dMMR and HER2‐negative status exhibited higher PD‐L1 expression rates. Our finding indicated that MMR and HER‐2 status might be potential biomarkers for anti‐PD‐L1 therapy.

Collagen triple helix repeat containing (CTHRC1), which was identified as a cancer‐related factor, is a promigratory protein involved in multiple processes, including vascular remodeling, antifibrosis, metabolism, bone formation, and cancer. In this study, we aimed to investigate the clinical significance and possible role of CTHRC1 in the process of epithelial‐mesenchymal transition (EMT) in colorectal cancer (CRC). Here, we revealed that CTHRC1 mRNA and protein levels are both upregulated in CRC tissues compared with those of paired noncancerous tissues. Moreover, the overexpression of CTHRC1 correlated with poor prognosis in patients with CRC (especially colon cancer). Furthermore, we showed that CTHRC1 induced EMT and promoted cell motility in CRC cells. Importantly, we demonstrated that CTHRC1 promoted EMT by activating transforming growth factor‐β (TGF‐β) signaling, revealing a possible effective therapeutic treatment for patients with CRC.

Background: Programmed death-ligand 1 (PD-L1) expression determines the eligibility for anti-PD-1 treatment in patients with advanced gastric cancer, but evidence indicates that PD-L1 staining is heterogeneous. Patients who are ineligible for radical surgery could be tested for PD-L1 expression with biopsy staining, but it is unclear if a small biopsy is representative of the PD-L1 status of the whole tumor. The aim of our study was to determine how many biopsy specimens are needed to accurately reflect the objective status of PD-L1 expression in whole sections. Methods: We built tissue microarrays (TMAs) as substitutes for core biopsies, collecting 6 cores per case from 152 gastric cancer specimens. All of the slides and TMAs underwent PD-L1 immunohistochemical staining, and PD-L1 expression in at least 1% of tumor cells or immune cells was defined as positive. Results: It was necessary to randomly select multiple cores from TMAs to reach a suitable agreement rate (> 90%) and Cohen’s κ value (> 0.8) between TMAs and whole sections. We defined the PD-L1 staining status from the whole section as the standard. The evaluation of five randomly selected cores from TMAs agreed well with the evaluation of whole sections. The sensitivity, specificity and the area under the curve (AUC) of the receiver-operating characteristic (ROC) were 0.93, 0.92, and 0.922 (95% confidence interval (CI) 0.863–0.982), respectively. Conclusions: We conclude that PD-L1 expression among TMA samples had different degrees of relevance to the corresponding surgical specimens, which indicates that at least five biopsies might be necessary to characterize patients taking anti-PD-1 treatment.

Background: Both AJCC 7th and 8th TNM systems have included tumor deposits (TDs) in nodal staging when lymph nodes metastases (LNMs) are negative in colorectal cancer (CRC). However, the prognostic role of TDs has not been determined in the presence of positive LNMs. Methods: Two independent large-scale cohorts of CRC patients from the Surveillance Epidemiology and End Results (SEER) database (n=69,178) [2010–2013] and Fudan University Shanghai Cancer Center (FUSCC) (n=3,137) [2010–2014] were retrospectively analyzed. Kaplan-Meier method was used to estimate survival curves and univariate and multivariate analyses were performed by Cox proportional hazard model. Results: TDs were observed in 12.3% (n=8,480) and 14.8% (n=463) of patients in the SEER and FUSCC cohorts, respectively. Multivariate analysis suggested TDs were an independent adverse prognostic factors for overall survival (OS) (P<0.001). Remarkably, both cohorts showed the presence of TDs was significantly associated with OS, but not was the number of TDs (P=0.982 and P=0.252 for the SEER and FUSCC cohorts, respectively). In the presence of LNMs, positive TDs were associated with a shorter OS [hazard ratio (HR): 2.69, 95.0% confidence interval (CI): 2.597–2.778; P<0.001]. Further analysis combining TDs with LNMs demonstrated that the prognosis of patients with N1TD (N1 with positive TDs) was same as the N2 patients, and N2TD (N2 with positive TDs) patients had much worse prognosis than N2 (P<0.001). Conclusions: Our results have shown the unique features of TDs in patients with CRC, different from LNMs. In the presence of LNMs, TDs should also be considered in TMN system.

Background and aim: Amphicrine carcinoma, in which endocrine and epithelial cell constituents are present within the same cell, is very rare. This study characterized the clinicopathologic and survival analysis of this tumor, further compared the genetic diversities among amphicrine carcinoma and other tumors.Materials and methods: The clinicopathologic characteristics and survival outcomes of amphicrine carcinoma in this study were analyzed. The pan-cancer transcriptome assay was utilized to compare the genetic expression profile of this entity with that of conventional adenocarcinoma or neuroendocrine tumors.Results: Ten cases (all in male patients) were identified in the stomach or intestine, with a median patient age of 62 years. There were characteristic patterns in the tumors: tubular, fusion or single-file growth of goblet- or signet ring-like cells. Four tumors were classified as low-grade and 6 as high-grade according to the histologic architecture. All cases were positive for neuroendocrine markers (synaptophysin and chromogranin A) and showed intracellular mucin in the amphicrine components. Four cases exhibited mRNA expression patterns showing transcriptional homogeneity with conventional adenocarcinomas and genetic diversity from neuroendocrine tumors. During the follow-up period, 3 patients died of disease, all of whom had high-grade tumors. Patients with high-grade amphicrine carcinoma had worse outcomes than those with low-grade tumors.Conclusions: This study confirms the morphological, immunostaining and transcriptome alterations in amphicrine carcinoma distinct from those in conventional adenocarcinomas and neuroendocrine tumors, but additional studies are warranted to determine the biological behavior and therapeutic response.