Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

NF-κB downstream miR-1262 disturbs colon cancer cell malignant behaviors by targeting FGFR1.

Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions in vitro using cancer cells and in vivo using a subcutaneous xenograft model. miRNA downstream targets are analyzed, and predicted binding and regulation are verified. miR-1262, an antitumor miRNA, is downregulated in colon cancer tissue samples and cell lines. miR-1262 overexpression suppresses colon cancer malignant behaviors in vitro and tumor development and metastasis in a subcutaneous xenograft model and a lung metastasis mouse model in vivo. miR-1262 directly targets fibroblast growth factor receptor 1 (FGFR1) and inhibits FGFR1 expression. FGFR1 overexpression shows oncogenic functions through the regulation of cancer cell proliferation, invasion, and migration; when cotransfected, lv-FGFR1 partially attenuates the antitumor effects of agomir-1262. NF-κB binds to the miR-1262 promoter region and inhibits transcription activity. The NF-κB inhibitor CAPE exerts antitumor effects; miR-1262 inhibition partially reverses CAPE effects on colon cancer cells. Conclusively, miR-1262 serves as an antitumor miRNA in colon cancer by targeting FGFR1. The NF-κB/miR-1262/FGFR1 axis modulates colon cancer cell phenotypes, including proliferation, invasion, and migration.

Rectal stump leakage: A neglected complication after Hartmann's procedure for colorectal cancer.

BACKGROUND: Hartmann's procedure is widely used in large bowel obstruction caused by colorectal cancer. However, rectal stump leakage, one of its serious complications, has not been well investigated in the literature. METHODS: Patients with colorectal cancer who underwent Hartmann's procedure between January 2015 and January 2022 were retrospectively assessed. Rectal stump leakage was diagnosed based on the clinical symptoms, nature of drainage fluid, and computed tomography characteristics. The patients were categorized into the following 2 groups: non-rectal stump leakage group and rectal stump leakage group. A multivariate logistic regression model was used to identify independent risk factors for rectal stump leakage. RESULTS: The incidence rate of postoperative rectal stump leakage was 11.6% in our patients. Univariate analysis revealed that male sex, body mass index (underweight), and tumor location (below the peritoneal reflection) were risk factors for rectal stump leakage (P < .05). Multivariate regression analysis confirmed these 3 factors were independent risk factors for rectal stump leakage (P < .05). Computed tomography imaging characteristics of patients with rectal stump leakage usually included inflammatory exudate and edema of the rectal stump, fluid, or gas-containing abscess around the rectal stump. The computed tomography imaging characteristics of a gas-containing abscess around the rectal stump and an abdominal drainage tube advanced into the rectum via the rectal stump could confirm the diagnosis of rectal stump leakage. The incidence rate of small bowel obstruction in group 2 (69.2%) was significantly higher than that in group 1 (15.7%) (P = .000). CONCLUSION: Male sex, body mass index (underweight), and tumor location (below the peritoneal reflection) were independent risk factors for rectal stump leakage after Hartmann's procedure. We suggested that rectal stump leakage be classified into inflammatory exudation and abscess stages on computed tomography imaging. Unexplained small bowel obstruction after Hartmann's procedure may be an important clue to the early diagnosis of rectal stump leakage.

Strong Metal Support Effect of Pt/g-C3N4 Photocatalysts for Boosting Photothermal Synergistic Degradation of Benzene.

Catalysis is the most efficient and economical method for treating volatile organic pollutants (VOCs). Among the many materials that are used in engineering, platinized carbon nitride (Pt/g-C3N4) is an efficient and multifunctional catalyst which has strong light absorption and mass transfer capabilities, which enable it to be used in photocatalysis, thermal catalysis and photothermal synergistic catalysis for the degradation of benzene. In this work, Pt/g-C3N4 was prepared by four precursors for the photothermal synergistic catalytic degradation of benzene, which show different activities, and many tests were carried out to explore the possible reasons for the discrepancy. Among them, the Pt/g-C3N4 prepared from dicyanamide showed the highest activity and could convert benzene (300 ppm, 20 mL·min-1) completely at 162 °C under solar light and 173 °C under visible light. The reaction temperature was reduced by nearly half compared to the traditional thermal catalytic degradation of benzene at about 300 °C.

Interface engineering of sandwich SiO2@α-Fe2O3@COF core-shell S-scheme heterojunctions for efficient photocatalytic oxidation of gas-phase H2S.

Hydrogen sulfide (H2S) is considered to be a broad-spectrum toxicant, and it is crucial to address this problem due to its serious health and climate change impacts. Photocatalysis can be effectively applied for the reduction of H2S molecules to S and other products. We synthesized sandwich-structured composite materials with internally immobilized SiO2 nanospheres and externally wrapped COF layers co-modified with iron oxide nanoparticles. Furthermore, originally looked at the efficiency of photocatalysis in reducing hydrogen sulfide to sulfur. In this paper, a sandwich structure of core-shell composite photocatalysts based on SiO2 was prepared by a multi-step method including Stöber and double ligand-regulated solvent heat, and these sandwich core-shell structures exhibited high hydrogen sulfide reduction and stability in applications. In addition, characterization, degradation studies, active substance trapping studies, and energy band structure analysis showed that S-type heterojunctions could effectively increase photo-generated carrier separation. This research advanced knowledge of photocatalytic hydrogen sulfide reduction and offered a novel approach for catalysts in COF sandwich core-shell structures.

Laparoscopic D3 lymph node dissection with left colic artery and first sigmoid artery preservation in rectal cancer.

BACKGROUND: D3 lymph node dissection with left colic artery (LCA) preservation in rectal cancer surgery seems to have little effect on reducing postoperative anastomotic leakage. So we first propose D3 lymph node dissection with LCA and first sigmoid artery (SA) preservation. This novel procedure deserves further study. METHODS: Rectal cancer patients who underwent laparoscopic D3 lymph node dissection with LCA preservation or with LCA and first SA preservation between January 2017 and January 2020 were retrospectively assessed. The patients were categorized into two groups: the preservation of the LCA group and the preservation of the LCA and first SA group. A 1:1 propensity score-matched analysis was performed to decrease confounding. RESULTS: Propensity score matching yielded 56 patients in each group from the eligible patients. The rate of postoperative anastomotic leakage in the preservation of the LCA and first SA group was significantly lower than that in the LCA preservation group (7.1% vs. 0%, P=0.040). No significant differences were observed in operation time, length of hospital stay, estimated blood loss, length of distal margin, lymph node retrieval, apical lymph node retrieval, and complications. A survival analysis showed patients' 3-year disease-free survival (DFS) rates of group 1 and group 2 were 81.8% and 83.5% (P=0.595), respectively. CONCLUSION: D3 lymph node dissection with LCA and first SA preservation for rectal cancer may help reduce the incidence of anastomotic leakage without compromising oncological outcomes compare with D3 lymph node dissection with LCA preservation alone.

CircDUSP1 regulates tumor growth, metastasis, and paclitaxel sensitivity in triple-negative breast cancer by targeting miR-761/DACT2 signaling axis.

Triple-negative breast cancer TNBC) is a malignant tumor with high incidence and high mortality that threaten the health of women worldwide. Circular RNAs (circRNAs) are a new class of noncoding RNAs that participate in the biological processes of various tumors, but the regulatory roles of circRNAs in TNBC have not been fully elucidated. In this study, the expression and characterization of circDUSP1 was detected via quantitative real-time PCR, nuclear-cytoplasmic fractionation assay, and fluorescence in situ hybridization. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circDUSP1 in TNBC. The interaction among circDUSP1, miR-761, DACT2 were confirmed by dual luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation experiments. We identified the circRNA named circDUSP1 that was inversely correlated with tumorigenesis and progression in TNBC. Overexpression of circDUSP1 significantly attenuated cell proliferation, migration, invasion, and epithelial-mesenchymal transition, while increased the sensitivity of TNBC cells to paclitaxel. In-depth mechanism analysis indicated that circDUSP1 acts as an endogenous sponge of miR-761 to reduce its suppression on target gene DACT2 expression in TNBC. Upregulation of miR-761 or downregulation of DACT2 partially reversed the biological process of TNBC and the prognosis of paclitaxel affected by circDUSP1. Taken together, our findings revealed a role for the regulation of the miR-761/DACT2 axis by circDUSP1 in the biological process of TNBC. These results provided new insights into the biological mechanism and targeted therapy of TNBC.

LncRNA SNHG5 promotes the glycolysis and proliferation of breast cancer cell through regulating BACH1 via targeting miR-299.

BACKGROUND: Breast cancer (BC) is one of the most common malignant tumors in women. Accumulating studies have been reported that long non-coding RNA (lncRNA) SNHG5 is highly expressed in BC. However, the specific molecular mechanism of SNHG5 in BC is unclear. METHODS: Gene and protein expressions in BC cell were detected by qRT-PCR and western blotting. The proliferation and cell cycle were measured using colony formation assay and flow cytometry analysis, separately. The glucose consumption and lactate production were determined by using the glucose assay kit and lactate assay kit. A dual-luciferase reporter assay was performed to measure the interaction between miR-299 and SNHG5 or BACH1. RESULTS: SNHG5 and BACH1 expressions were increased in BC cell while miR-299 level was decreased. SNHG5 increased BACH1 expression by directly targeting miR-299. SNHG5 silencing or miR-299 overexpression suppressed the proliferation of BC cell, arrested the cell cycle in the G1 cell phase, and decreased the glucose consumption and lactate production of BC cell. However, inhibition of miR-299 or overexpression of BACH1 could reverse the inhibitory effects of sh-SNHG5 on cell proliferation and glycolysis in BC. CONCLUSION: SNHG5 promoted the BC cell growth and glycolysis through up-regulating BACH1 expression via targeting miR-299. These findings may improve the diagnostic and therapeutic approaches to BC.

MRI-based brain tumor segmentation using FPGA-accelerated neural network.

BACKGROUND: Brain tumor segmentation is a challenging problem in medical image processing and analysis. It is a very time-consuming and error-prone task. In order to reduce the burden on physicians and improve the segmentation accuracy, the computer-aided detection (CAD) systems need to be developed. Due to the powerful feature learning ability of the deep learning technology, many deep learning-based methods have been applied to the brain tumor segmentation CAD systems and achieved satisfactory accuracy. However, deep learning neural networks have high computational complexity, and the brain tumor segmentation process consumes significant time. Therefore, in order to achieve the high segmentation accuracy of brain tumors and obtain the segmentation results efficiently, it is very demanding to speed up the segmentation process of brain tumors. RESULTS: Compared with traditional computing platforms, the proposed FPGA accelerator has greatly improved the speed and the power consumption. Based on the BraTS19 and BraTS20 dataset, our FPGA-based brain tumor segmentation accelerator is 5.21 and 44.47 times faster than the TITAN V GPU and the Xeon CPU. In addition, by comparing energy efficiency, our design can achieve 11.22 and 82.33 times energy efficiency than GPU and CPU, respectively. CONCLUSION: We quantize and retrain the neural network for brain tumor segmentation and merge batch normalization layers to reduce the parameter size and computational complexity. The FPGA-based brain tumor segmentation accelerator is designed to map the quantized neural network model. The accelerator can increase the segmentation speed and reduce the power consumption on the basis of ensuring high accuracy which provides a new direction for the automatic segmentation and remote diagnosis of brain tumors.

Exosomal microRNA-503-3p derived from macrophages represses glycolysis and promotes mitochondrial oxidative phosphorylation in breast cancer cells by elevating DACT2.

MicroRNAs (miRNAs) are emerging drivers in tumor progression, while the role of miR-503-3p in breast cancer (BC) remains largely unknown. We aimed to explore the impact of macrophage-derived exosomal miR-503-3p in the development of BC by regulating disheveled-associated binding antagonist of beta-catenin 2 (DACT2). miR-503-3p and DACT2 expression in BC tissues and cells was assessed, and the expression of Wnt/ß-catenin signaling pathway-related proteins in BC cells was also evaluated. Macrophages were induced and exosomes were extracted. The screened BC cell lines were, respectively, treated with exosomes, miR-503-3p inhibitor/mimic or upregulated/inhibited DACT2, and then the phenotypes, glucose intake, oxygen consumption rate, and adenosine-triphosphate (ATP) level of BC cells were determined. Cell growth in vivo was also observed. MiR-503-3p was elevated, DACT2 was reduced, and Wnt/ß-catenin signaling pathway was activated in BC cells. Macrophage-derived exosomes, upregulated miR-503-3p or inhibited DACT2 promoted malignant behaviors of BC cells, glucose intake, and activity of the Wnt/ß-catenin signaling pathway, while repressed oxygen consumption rate and ATP level in BC cells. Reversely, reduced miR-503-3p or upregulated DACT2 exerted opposite effects. This study revealed that reduction of macrophage-derived exosomal miR-503-3p repressed glycolysis and promoted mitochondrial oxidative phosphorylation in BC by elevating DACT2 and inactivating Wnt/ß-catenin signaling pathway. Our research may provide novel targets for BC treatment.

Prognostic factors for T1-2 colorectal cancer after radical resection: Lymph node distribution is a valuable predictor of its survival.

OBJECTIVE: The prognostic factors for patients with T1-2 colorectal cancer (CRC) after radical resection and the predictive value of lymph node distribution (LND) system compared with TNM system for these patients have not been well studied. METHODS: From September 2009 and June 2016, a total of 541 consecutive patients with T1-2 CRC who accepted radical resection in two centers were included in this study. Their clinicopathological characteristics and prognosis were analyzed using univariate and multivariate Cox regression analyses. The predictive value of LND system for these patients were compared with the TNM system. RESULTS: Univariate analysis revealed that patients' gender, tumor size, LNM and lymphovascular or nerve invasion were prognostic factors for the disease-free survival (DFS) (p < 0.05). Multivariate regression analysis confirmed the gender, LNM and lymphovascular or nerve invasion were independent prognostic factors for the DFS (p < 0.05). The LND system had a better predictive value than the TNM system in lymph node-positive T1-2 CRC patients (P = 0.026 vs p = 0.148). CONCLUSIONS: The gender, LNM and lymphovascular or nerve invasion were independent prognostic factors for the patients with T1-2 CRC after radical resection. The LND system had a better predictive value than the TNM system in T1-2 CRC patients.

CXCR4/TGF-ß1 mediated self-differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and promoted colorectal carcinoma development.

Background: Tumor microenvironment (TME) is a crucial part of tumor hallmarks. Mesenchymal stem cells (MSCs), important components of TME, are the main source of Carcinoma-associated fibroblasts (CAFs), but the mechanism of transformation regulation is still unclear. Transforming growth factor-ß1 (TGF-ß1), chemokine Stromal cell-derived factor-1 (SDF-1) and its endogenous receptor CXCR4 may play important roles during this process.Methods: Co-culture technique was used to explore the effects of MSCs on the proliferation, migration and invasion of colorectal carcinoma (CRC) cells and how they induced MSCs to differentiate into CAFs. The expression of α-SMA, Vimentin, S100A4 and FAP were detected as CAFs markers. Inhibitors AMD3100 and cyclophosphamide (Cy) were pre-treated in MSCs to verify the functions of CXCR4/TGF-ß1. Finally, the xenograft models in nude mice were generated to further verify this process in vivo.Results: MSCs promoted the CRCs proliferation, invasion and migration, and induced SDF-1 expression and secretion, which dramatically up-regulated CXCR4 and TGF-ß1 expression in MSCs. The levels of CAFs markers elevated in MSCs, indicating CAFs differentiation occurred in MSCs. AMD3100 and Cy treatment significantly blocked this differentiation process of MSCs by suppressing CXCR4 expression and TGF-ß1 secretion. In vivo xenograft experiments also demonstrated that MSCs promoted differentiation into CAFs through CXCR4/TGF-ß1 signaling in either primary tumor tissues or hepatic metastatic tissues of CRC.Conclusion: Our studies have revealed the essential role of CXCR4/TGF-ß1 axis playing in the transformation of tumor microenvironment by mediating MSCs differentiation into CAFs, promoting CRCs growth and metastasis.

CXCR4/TGF-ß1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer.

Background: Liver metastasis of colon cancer is strongly affected by the tumor microenvironment (TME), with interactions between tumor cells and cancer-associated fibroblasts (CAFs) in particular. TGF-ß is well known for its ability to mediate the CAF phenotype, and CXCR4 expression is closely correlated to poor prognosis in CRC. The relationship between these two signaling pathways remains to be delineated in liver metastasis of colon cancer.Methods: Immunohistochemistry was employed to investigate CXCR4 expression in 45 human specimens of primary colorectal cancer (CRC) and liver metastasis. The functions of SDF-1 released by hepatic stellate cells (HSCs) on CXCR4 and TGF-ß1 in CRC cells were investigated in vitro. The effects of CRC on HSCs differentiation into CAFs were confirmed using co-culture technology and expression analysis of CAFs markers by qPCR, western blot and immunofluorescence. The involvement of CXCR4 and TGF-ß1 was verified with addition of CXCR4 inhibitor AMD3100 and TGF-ß1 inhibitor cyclophosphamide (Cy) both in vitro and in vivo.Results: There were more CXCR4-positive cells at the liver metastatic tissues compared to the primary sites. CRC cells activated and transformed HSCs to CAFs after co-cultivating with HSCs. Activated HSCs stimulated TGF-ß1 secretion from CRC cells after co-culture with CRC cells in vitro. Moreover, the expression of CAFs markers was increasing in the activated HSCs. In a mouse hepatic metastasis model, treated with AMD3100 or Cy blocked the metastatic potential of HCT116 cells and the hepatic CAFs differentiation.Conclusions: These results indicated that CXCR4/TGF-ß1 axis plays an important role in CRC liver metastasis through mediating HSCs differentiation into CAFs, providing preclinical evidences that blockade of the axis might be beneficial for anti-metastasis therapy in CRC.

Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial.

PURPOSE: In the multicenter, open-label, phase III FOWARC trial, modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus radiotherapy resulted in a higher pathologic complete response rate than fluorouracil plus radiotherapy in Chinese patients with locally advanced rectal cancer. Here, we report the final results. METHODS: Adults ages 18 to 75 years with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). RESULTS: In total, 495 patients were randomly assigned to treatment. After a median follow-up of 45.2 months, DFS events were reported in 46, 39, and 46 patients in the fluorouracil plus radiotherapy, mFOLFOX6 plus radiotherapy, and mFOLFOX6 arms. In each arm, the probability of 3-year DFS was 72.9%, 77.2%, and 73.5% (P = .709 by the log-rank test), the 3-year probability of local recurrence after R0/1 resection was 8.0%, 7.0%, and 8.3% (P = .873 by the log-rank test), and the 3-year overall survival rate was 91.3%, 89.1%, and 90.7% (P = .971 by log-rank test), respectively. CONCLUSION: mFOLFOX6, with or without radiation, did not significantly improve 3-year DFS versus fluorouracil with radiation in patients with locally advanced rectal cancer. No significant difference in outcomes was found between mFOLFOX6 without radiotherapy and fluorouracil with radiotherapy, which requires additional investigation of the role of radiotherapy in these regimens.