Objective & Background Total neoadjuvant therapy (TNT) is a novel approach for locally advanced rectal cancer (LARC), which attempts to deliver both systemic chemotherapy and neoadjuvant chemoradiotherapy prior to surgery. However, its efficacy and safety remain controversial in randomized controlled trials (RCTs). We conducted this meta‐analysis to assess such concerns. Methods Head‐to‐head phase II/III RCTs were searched in Embase, PubMed, Web of Science and the Cochrane Library, as well as other sources. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were disease‐free survival (DFS), overall survival (OS), local recurrence‐free survival (LRFS), distant metastasis‐free survival (DMFS) and the R0 resection rate. Results Eight phase II/III RCTs involving 2,196 LARC patients were assessed. The primary analysis demonstrated a statistically significant improvement in the pCR rate for TNT treatment (OR = 1.77, 95% CI: 1.28 to 2.45, P = 0.0005). TNT treatment also showed improvements in DFS and OS outcomes compared with standard CRT (HR=0.83, 95% CI: 0.72 to 0.96, P = 0.03; HR=0.88, 95% CI:0.74 to 1.05, P = 0.15). In addition, TNT treatment showed significant efficacy in reducing the risk of distant metastasis (HR=0.81, 95% CI: 0.68 to 0.95, P = 0.012). Conclusion The overall pCR rate may be improved with TNT compared with standard treatment. The TNT strategy may also improve DFS and OS, and reduce the risk of distant metastasis. Implications for Practice Locally advanced rectal cancer (LARC) is a relatively common disease, with a poor prognosis due to its high metastatic potential. The role of total neoadjuvant therapy (TNT) has always been controversial. This meta‐analysis found that TNT in LARC is associated with a significant improvement in overall pCR rate, DFS, OS, and DMFS compared with standard treatment. TNT is a promising strategy for LARC, especially for patients who have little desire for surgery.

Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. The CLL-1 CAR-T cells specifically lysed CLL-1+ cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1+ myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.

Colorectal cancer (CRC) patients with mismatch repair (MMR)-deficient (dMMR) but not MMR-proficient (pMMR) tend to benefit from immune checkpoint blockade (ICB) therapy. To profile the tumor microenvironments (TME) underlying these varied therapeutic responses, we integrate spatial enhanced resolution omics-sequencing (Stereo-seq), single-cell RNA sequencing, and multiplexed imaging analysis to create high-definition spatial maps of tumors from treatment-naïve and ICB-treated CRC patients. Our results identify the spatial organization and immune status of the tumor-stroma boundary as a distinctive feature of dMMR and pMMR CRCs, which associates with ICB response. The physical interactions and abundance of LAMP3⁺DCs and CXCL13⁺T cells may shape the ICB-responsive tumor-stroma boundary, whereas CXCL14⁺cancer-associated fibroblasts tend to remodel extracellular matrix to form a structural barrier in non-responders. Our work therefore points out the importance of the molecular and cellular spatial structures of tumors in ICB response, raising the possibility of reprogramming tumor-stroma boundary for sensitizing immunotherapies in the majority of CRCs.

Objective: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). Background Data: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. Methods: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. Results: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm (P=0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm (P=0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P=0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P=0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. Conclusions: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Hand-foot syndrome (HFS) is the most common adverse event induced by capecitabine. Some clinicians think that HFS is a type of inflammation limited to the hands and feet and can be prevented with a COX-2 inhibitor (celecoxib). We designed a single-center, prospective randomized clinical trial to test the hypothesis. From August 2008 to December 2010, stage II and III colorectal cancer patients receiving capecitabine-based chemotherapy enrolled in the trial voluntarily. All patients were divided randomly into two groups treated with or without celecoxib. All adverse events were recorded. Grade 1 and grade 2 HFS were more common in the capecitabine group than in the capecitabine/celecoxib group (74.6% versus 57.4%, P = 0.034, 29.6% versus 14.7% P = 0.035). The use of celecoxib (P < 0.001, P = 0.003) and the level of dihydropyrimidine dehydrogenase (P = 0.048, P = 0.014) affected the incidence of grade 1 and 2 HFS, as determined by log-rank analysis. Multivariate Cox proportional hazards regression analysis indicated that the use of celecoxib was the only factor that affected the incidence of ≥ grade 1 HFS [Hazard Ratio (HR): 0.556, P = 0.001] and ≥ grade 2 HFS (HR: 0.414, P = 0.005). Celecoxib can be used effectively and safely to prevent capecitabine-related HFS.

Background: 5‐Fluorouracil (5‐FU) and capecitabine‐associated cardiotoxicity ranging from asymptomatic electrocardiography (ECG) abnormalities to severe myocardial infarction has been reported in a number of studies, but such cardiotoxicity in Chinese patients with malignant diseases has not been investigated to date. In the present study, we aimed to prospectively evaluate the incidence rates and clinical manifestations of 5‐FU‐ and capecitabine‐associated cardiotoxicity in cancer patients recruited from multiple centers in China. Methods: Among the 527 patients who completed the study, 196 received 5‐FU‐based chemotherapy and 331 received capecitabine‐based chemotherapy as either first‐line or adjuvant therapy. Adverse events were reported during the treatment and up to 28 days of follow‐up. Outcome measures included ECG, myocardial enzymes, cardiac troponin, brain natriuretic peptide and echocardiography. Univariate analysis and logistic regression were performed for subgroup analysis and identification of significant independent variables that are associated with cardiotoxicity of both agents. Results: In total, 161 of 527 patients (30.6%) experienced cardiotoxicity. The incidence rate of cardiotoxicity was 33.8% (112/331) in the capecitabine group, which was significantly higher than the rate of 25% (49/196) in the 5‐FU group ( P = 0.0042). 110/527 patients (20.9%) suffered arrhythmia, 105/527 (19.9%) developed ischemic changes, while only 20/527 patients (3.8%) presented heart failure and 6/527 patients (1.1%) had myocardial infarction. Pre‐existing cardiac disease, hypertension, capecitabine‐based chemotherapy and duration of treatment were identified as significant risk factors associated with cardiotoxicity. The odds ratio were 15.7 (prior history of cardiac disease versus no history), 1.86 (capecitabine versus 5‐FU), 1.06 (5–8 versus 1–4 chemotherapy cycles) and 1.58 (hypertension versus no hypertension), respectively. Conclusions: Cardiotoxicity induced by fluoropyrimidines in the Chinese population may be underestimated in clinical practice. Close monitoring of patients is recommended, especially for those patients at high risk for cardiotoxicity. Possible risk factors are duration of treatment, capecitabine‐based chemotherapy, pre‐existing cardiac diseases and hypertension. Trial registration This study was initiated on January 22, 2014 and has been retrospectively registered with the registration number ChiCTR1800015434