Prediction models of colorectal cancer prognosis incorporating perioperative longitudinal serum tumor markers: a retrospective longitudinal cohort study.

BACKGROUND: Current prognostic prediction models of colorectal cancer (CRC) include only the preoperative measurement of tumor markers, with their available repeated postoperative measurements underutilized. CRC prognostic prediction models were constructed in this study to clarify whether and to what extent the inclusion of perioperative longitudinal measurements of CEA, CA19-9, and CA125 can improve the model performance, and perform a dynamic prediction. METHODS: The training and validating cohort included 1453 and 444 CRC patients who underwent curative resection, with preoperative measurement and two or more measurements within 12 months after surgery, respectively. Prediction models to predict CRC overall survival were constructed with demographic and clinicopathological variables, by incorporating preoperative CEA, CA19-9, and CA125, as well as their perioperative longitudinal measurements. RESULTS: In internal validation, the model with preoperative CEA, CA19-9, and CA125 outperformed the model including CEA only, with the better area under the receiver operating characteristic curves (AUCs: 0.774 vs 0.716), brier scores (BSs: 0.057 vs 0.058), and net reclassification improvement (NRI = 33.5%, 95% CI: 12.3 ~ 54.8%) at 36 months after surgery. Furthermore, the prediction models, by incorporating longitudinal measurements of CEA, CA19-9, and CA125 within 12 months after surgery, had improved prediction accuracy, with higher AUC (0.849) and lower BS (0.049). Compared with preoperative models, the model incorporating longitudinal measurements of the three markers had significant NRI (40.8%, 95% CI: 19.6 to 62.1%) at 36 months after surgery. External validation showed similar results to internal validation. The proposed longitudinal prediction model can provide a personalized dynamic prediction for a new patient, with estimated survival probability updated when a new measurement is collected during 12 months after surgery. CONCLUSIONS: Prediction models including longitudinal measurements of CEA, CA19-9, and CA125 have improved accuracy in predicting the prognosis of CRC patients. We recommend repeated measurements of CEA, CA19-9, and CA125 in the surveillance of CRC prognosis.

A new magnetic resonance imaging tumour response grading scheme for locally advanced rectal cancer.

BACKGROUND: The potential of using magnetic resonance image tumour-regression grading (MRI-TRG) system to predict pathological TRG is debatable for locally advanced rectal cancer treated by neoadjuvant radiochemotherapy. METHODS: Referring to the American Joint Committee on Cancer/College of American Pathologists (AJCC/CAP) TRG classification scheme, a new four-category MRI-TRG system based on the volumetric analysis of the residual tumour and radiochemotherapy induced anorectal fibrosis was established. The agreement between them was evaluated by Kendall's tau-b test, while Kaplan-Meier analysis was used to calculate survival outcomes. RESULTS: In total, 1033 patients were included. Good agreement between MRI-TRG and AJCC/CAP TRG classifications was observed (k = 0.671). Particularly, as compared with other pairs, MRI-TRG 0 displayed the highest sensitivity [90.1% (95% CI: 84.3-93.9)] and specificity [92.8% (95% CI: 90.4-94.7)] in identifying AJCC/CAP TRG 0 category patients. Except for the survival ratios that were comparable between the MRI-TRG 0 and MRI-TRG 1 categories, any two of the four categories had distinguished 3-year prognosis (all P < 0.05). Cox regression analysis further proved that the MRI-TRG system was an independent prognostic factor (all P < 0.05). CONCLUSION: The new MRI-TRG system might be a surrogate for AJCC/CAP TRG classification scheme. Importantly, the system is a reliable and non-invasive way to identify patients with complete pathological responses.

Preoperative serum CA19-9 should be routinely measured in the colorectal patients with preoperative normal serum CEA: a multicenter retrospective cohort study.

OBJECTIVE: Whether preoperative serum carbohydrate antigen 19-9 (CA19-9) is an independent prognostic factor and there are interactions of serum CA19-9 with carcinoembryonic antigen (CEA) on the risk of recurrence in colorectal cancer (CRC) patients are still not clarified. METHODS: Consecutive patients with CRC who underwent curative resection for stage II-III colorectal adenocarcinoma at five hospitals were collected. Based on Cox models, associations of preoperative CA19-9 with recurrence-free survival (RFS) and overall survival (OS) were evaluated in patients with or without elevated CEA, and interactions between CEA and CA19-9 were also calculated. Restricted cubic spline (RCS) curves were used to evaluate the associations between preoperative CA19-9 and CRC outcomes on a continuous scale. RESULTS: A total of 5048 patients (3029 [60.0%] men; median [interquartile range, IQR] age, 61.0 [51.0, 68.0] years; median [IQR] follow-up duration 46.8 [36.5-62.4] months) were included. The risk of recurrence increased with the elevated level of preoperative CA19-9, with the slope steeper in patients with normal CEA than those with elevated CEA. Worse RFS was observed for elevated preoperative CA19-9 (> 37 U/mL) (n = 738) versus normal preoperative CA19-9 (≤ 37 U/mL) (n = 4310) (3-year RFS rate: 59.4% versus 78.0%; unadjusted hazard ratio [HR]: 2.02; 95% confidence interval [CI]:1.79 to 2.28), and significant interaction was found between CA19-9 and CEA (P for interaction = 0.001). Increased risk and interaction with CEA were also observed for OS. In the Cox multivariable analysis, elevated CA19-9 was associated with shorter RFS and OS regardless of preoperative CEA level, even after adjustment for other prognostic factors (HR: 2.08, 95% CI:1.75 to 2.47; HR: 2.25, 95% CI:1.80 to 2.81). Subgroup analyses and sensitivity analyses yielded largely similar results. These associations were maintained in patients with stage II disease (n = 2724). CONCLUSIONS: Preoperative CA19-9 is an independent prognostic factor in CRC patients. Preoperative CA19-9 can be clinically used as a routine biomarker for CRC patients, especially with preoperative normal serum CEA.

Significance of tumor deposits combined with lymph node metastasis in stage III colorectal cancer patients: a retrospective multi-center cohort study from China.

PURPOSE: The study aimed to explore the value of tumor deposits in stage III colorectal cancer (CRC) and verify whether patients with more tumor deposit numbers have higher risk of recurrence. METHODS: The retrospective cohort analysis was performed at two cancer centers of China. Stage III CRC patients who underwent radical resection at the center between April 2008 and February 2019 were identified. The Univariate/Multivariate Cox regression, Kaplan-Meier analysis, and PSM were recurrence-free survival (RFS) used. RESULTS: Total 1080 stage III CRC patients (634 [58.7%] men; median [IQR] age, 60 [50-68] years) who underwent radical surgical resection were identified for inclusion in this study. Patients with tumor deposits had a 12.8% lower 3-year RFS (n = 236 [69.9%]) than the patients without tumor deposits (n = 844 [82.7%]) (P ≤ 0.0001). The 3-year RFS of patients with stage N2 (n = 335 [61.2%]) was 18.6% lower (P ≤ 0.0001) than the original cohort of patients with stage N1 (n = 745 [79.8%]), but it was similar to the RFS of patients with 4 or more tumor deposits plus lymph node metastases (n = 58 [61.4%]) (P = 0.91). The RFS for patients with 4 or more tumor deposits plus number of lymph node metastases (n = 58 [61.4%]) was 15.8% lower than the cohort of patients with 1-3 tumor deposits + number of lymph node metastases (n = 687 [77.2%]) (P = 0.001). Multivariate analysis confirmed that patients with 4 or more tumor deposits + the number of lymph node metastases (hazard ratio [HR], 1.88; 95% CI, 1.24-2.87) were independently associated with a shorter RFS. CONCLUSION: The number of tumor deposits is an indicator of poor postoperative prognosis. It is necessary to incorporate the number of tumor deposits combined with the number of lymph node metastases to stratify postoperative stratification of stage III CRC, which may provide a new theoretical basis for adjuvant therapy for patients with N1 stage CRC after surgery.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

BACKGROUND: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. MATERIALS AND METHODS: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. RESULTS: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. CONCLUSION: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. IMPLICATIONS FOR PRACTICE: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

Effects of neoadjuvant chemotherapy with or without intensity-modulated radiotherapy for patients with rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision and adjuvant chemotherapy is the standard regimen for patients with locally advanced rectal cancer (LARC). However, whether and to which extent neoadjuvant radiotherapy could be removed from nCRT for patients with LARC is still unclear. This was a multicenter, retrospectively recruited, prospectively maintained cohort study. A propensity score matching model was employed to minimize potential confounding factors between subgroup patients treated with neoadjuvant chemotherapy (nCT) or nCRT. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed between subgroup patients by Kaplan-Meier analysis, log-rank test, and Cox regression model. In total, 3233 consecutive patients, consist of 571 nCT and 2662 nCRT-treated cases, were included. After propensity score matching (1:4), 565 nCT-treated patients were matched to 1852 nCRT-treated patients. Compared with nCT, nCRT treatment indeed decreased 3-y local recurrence (10.0% vs 6.6%, P = .026), but had no impact on OS, DFS and DMFS (all P > .05) for LARC. Stratified analysis further confirmed that nCRT treatment was associated with higher 3-y LRFS and 3-y DFS than nCT treatment for baseline high-risk subgroup (cT4, cN+, and cIII stage) patients (all P < .05). Conversely, for the baseline low-risk subgroup patients (cT3, cN0, and cII stage), nCRT and nCT treatment had similar 3-y OS, LRFS, DFS, and DMFS (all P > .05). The administration of neoadjuvant radiotherapy for LARC patients might be determined by baseline risk classification, the high-risk individuals could be delivered while low-risk patients might be omitted.

Association between adjuvant chemotherapy and survival in patients with rectal cancer and pathological complete response after neoadjuvant chemoradiotherapy and resection.

BACKGROUND: For patients with locally advanced rectal cancer (LARC), it is unclear whether neoadjuvant chemoradiotherapy-induced pathologic complete response (pCR) individuals would further benefit from adjuvant chemotherapy (ACT). METHODS: The pCR individuals who received different ACT cycles were paired by propensity score matching. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan-Meier and log-rank test. RESULTS: In total, 1041 pCR individuals were identified from 5567 LARC cases. Specifically, 303 pCR cases had no ACT treatment, and 738 pCR patients received fluoropyrimidine-based ACT (median, 4 cycles) treatment. After 1:3 propensity score matching, 297 cases without ACT treatment were matched to 712 cases who received ACT treatment. Kaplan-Meier analysis showed that pCR individuals treated with or without ACT had the similar 3-year outcome (OS, DFS, LRFS and DMFS) (all P > 0.05). Moreover, the pCR patients received different ACT cycle(s) (0 vs. 1-4 cycles, 0 vs. ≥5 cycles) had comparable 3-year OS, DFS, LRFS and DMFS (all P > 0.05). In stratified analysis, ACT treatment did not improve 3-year survival (OS, DFS, LRFS and DMFS) for the baseline high-risk (cT3-4/cN1-2) subgroup patients (all P > 0.05). CONCLUSION: ACT, which did not improve survival, is unnecessary to neoadjuvant treatment-induced pCR LARC patients. TRIAL REGISTRATION: 2019ZSLYEC-136 (24-6-2019).

Distant Metastasis Risk Definition by Tumor Biomarkers Integrated Nomogram Approach for Locally Advanced Nasopharyngeal Carcinoma.

Identifying metastasis remains a challenge for death control and tailored therapy for nasopharyngeal carcinoma (NPC). Here, we addressed this by designing a nomogram-based Cox proportional regression model through integrating a panel of tumor biomarkers. A total of 147 locally patients with advanced NPC, derived from a randomized phase III clinical trial, were enrolled. We constructed the model by selecting the variables from 31 tumor biomarkers, including 6 pathological signaling pathway molecules and 3 Epstein-Barr virus-related serological variables. Through the least absolute shrinkage and selection operator (LASSO) Cox proportional regression analysis, a nomogram was designed to refine the metastasis risk of each NPC individuals. Using the LASSO Cox regression model, we constructed a 9 biomarkers-based prognostic nomogram: Beclin 1, Aurora-A, Cyclin D1, Ki-67, P27, Bcl-2, MMP-9, 14-3-3σ, and VCA-IgA. The time-dependence receiver operating characteristic analysis at 1, 3, and 5 years showed an appealing prognostic accuracy with the area under the curve of 0.830, 0.827, and 0.817, respectively. In the validation subset, the concordance index of this nomogram reached to 0.64 to identify the individual metastasis pattern. Supporting by this nomogram algorithm, the individual metastasis risk might be refined personally and potentially guiding the treatment decisions and target therapy against the related signaling pathways for patients with locally advanced NPC.

Effects of abhydrolase domain containing 5 gene (ABHD5) expression and variations on chicken fat metabolism.

Abhydrolase domain containing 5 gene (ABHD5), also known as comparative gene identification 58 (CGI-58), is a member of the α/ß-hydrolase family as a protein cofactor of ATGL stimulating its triacylglycerol hydrolase activity. In this study, we aim to characterize the expression and variations of ABHD5 and to study their functions in chicken fat metabolism. We compared the ABHD5 expression level in various tissues and under different nutrition conditions, identified the variations of ABHD5, and associated them with production traits in an F2 resource population of chickens. Overexpression analysis with two different genotypes and siRNA interfering analysis of ABHD5 were performed in chicken preadipocytes. Chicken ABDH5 was expressed widely and most predominantly in adipose tissue. Five SNPs of the ABHD5 gene were identified and genotyped in the F2 resource population. The c.490C > T SNP was associated with subcutaneous fat thickness (P < 0.01), carcass weight (P < 0.05), body weight (P < 0.05), shank diameter (P < 0.05), and shank length (P < 0.05). The c.423T > C SNP was also associated with chicken body weight (P < 0.05) and shank diameter (P < 0.05). In chicken preadipocytes, overexpression of wild type ABDH5 did not affect the mRNA level of ATGL (adipose triglyceride lipase) but markedly decreased (P < 0.05) the TG (triglyceride) content of the cell, whereas overexpression of mutation type ABHD5 did not affect either ATGL expression or TG content of the cell. The expression of ATGL and TG content of the cell were decreased (P < 0.05) after ABHD5 knockdown in preadipocytes. The mRNA level of ABHD5 was regulated by both feeding and fasting, and by consumption of a high fat diet. It was increased greatly by fasting (P < 0.05) and was returned to control levels after re-feeding in the adipose tissues, and down-regulated in abdominal fat (P < 0.05) and the liver (P < 0.01) of chickens with a high fat diet. These results suggest that expression and variations of ABHD5 may affect fat metabolism through regulating the activity of ATGL in chickens.

Elevated postoperative carcinoembryonic antigen guides adjuvant chemotherapy for stage II colon cancer: a multicentre cohort retrospective study.

Most clinical doctors rely on high-risk factors recommended by guidelines to decide whether to undergo adjuvant chemotherapy for stage II colon cancer. However, these high-risk factors do not include postoperative carcinoembryonic antigen (CEA). This study aims to explore the elevation of postoperative CEA as a risk factor, in addition to other high-risk factors, to guide adjuvant chemotherapy for patients with stage II colon cancer. A retrospective analysis was conducted on stage II colon cancer patients who underwent curative surgery at Yunnan Cancer Hospital and The Sixth Affiliated Hospital of Sun Yat-Sen University from April 2008 to January 2019. Patients were classified into three groups based on high-risk factors recommended by guidelines and postoperative CEA levels: low-risk with normal postoperative CEA, low-risk with elevated postoperative CEA and high-risk. COX regression analysis was used to identify independent prognostic factors affecting patients' recurrence free survival (RFS). The Kaplan-Meier method was used to create the patients' RFS curve. The restricted cubic spline (RCS) curve was used to assess the correlation between postoperative CEA and RFS on a continuous scale. Among 761 patients, there were 444 males (62.01%), with a median [IQR] age of 58.0 (18.0-88.0) years. A group of 425 high-risk patients had a 3-year RFS of 82.2% (95% CI 78.5-86.1%), while a group of 291 low-risk patients had a 3-year RFS of 89.7% (95% CI 86.1-93.5%). There was a statistically significant difference between the two groups (HR 1.83; 95% CI 1.22-2.74; P = 0.0067). Among them, the 3-year RFS of 261 low-risk patients with normal postoperative CEA was 93.6% (95% CI 90.5-96.8%), while the 3-year RFS of 30 low-risk patients with elevated postoperative CEA was 57.3% (95% CI 41.8-71.4%). There was a significant difference compared to the 3-year RFS of 425 high-risk patients (overall log-rank P < 0.0001). The multivariate analysis adjusted by the COX proportional hazards model showed that low-risk patients with elevated postoperative CEA patients (HR 14.95, 95% CI 4.51-49.63, P < 0.0001) was independently associated with a 3-year RFS. The restricted cubic spline model showed that in stage II colon cancer patients with tumor diameter > 1.955 ng/mL, the risk of postoperative recurrence increased with increasing postoperative CEA levels. Patients with elevated postoperative CEA levels have a significantly increased risk of recurrence. They should be included as high-risk factors to guide adjuvant chemotherapy for stage II colon cancer.

The Prognostic Significance of Postoperative Adjuvant Chemotherapy in the Population Aged 75 Years and Older with Stage II-III Colorectal Cancer: A Retrospective Multi-Center Cohort Study.

Background: It is common for elderly patients to be underrepresented in clinical trials for cancer, which can result in a lack of efficacy data and unclear criteria to guide treatment decisions for clinical doctors. Therefore, one of the common challenges in oncology treatment is determining the extent to which patients aged 75 and older have benefited from postoperative chemotherapy. Purpose: The study aimed to explore the effect of adjuvant chemotherapy (AC) on 3-year recurrence-free survival (RFS) after curative resection in patients aged 75 years and older with stage II-III colorectal cancer (CRC). Methods: The retrospective cohort analysis was performed on patients with stage II-III CRC who received curative resection at three cancer centers in China between 2008 and 2017. Kaplan-Meier curves and Multivariable Cox regression models were used to analyze the impact of AC on RFS in patients. Finally, propensity-score matching was used to reduce selection bias and confounding factors in patients aged 75 years and older with stage II-III CRC. Results: A total of 2885 patients were included (1729 (59.9%) male; 1312 (61.5%) received AC). The pre-matching cohort was comprised of 151 patients aged 75 years and older (median age (IQR)77.00 (76.00, 79.00); 97 (64.2%) male, 51 (72.9%) received AC). Age (P=0.001), postoperative carcinoembryonic antigen (CEA)(P=0.02) level were associated with prognosis. But AC was not associated with 3-year RFS (HR, 1.27; 95% CI, 0.80-2.0; log-rank P=0.37). After a predisposition 1: 1 match (with or without AC, n = 42), AC remains uncorrelated with 3-year RFS (HR, 1.39; 95% CI, 0.52-3.70; log-rank P=0.66). Conclusion: Patients over the age of 75 with stage II-III CRC who receive AC or do not face the same risk of postoperative recurrence. As a result, patients with stage II-III postoperative adjuvant chemotherapy can make an informed decision regarding whether they want to undergo chemotherapy based on their age and reduce the unnecessary side effects of chemotherapy.

Ozone preconditioning protects rabbit heart against global ischemia-reperfusion injury in vitro by up-regulating HIF-1α.

Myocardial ischemia-reperfusion injury (MIRI) is a major factor that leads to cardiac dysfunction in cardiovascular surgery during extracorporeal circulation. Recent studies have found that ozone (O3) has protective effect on MIRI caused by the anterior descending branch of the ligated left coronary artery. However, whether O3 preconditioning has the same protective effect on global MIRI and the mechanism underlying this clinical treatment remains elusive. Here, we hypothesized that O3 preconditioning (O3P) could protect rabbit heart against global MIRI in vitro by up-regulating HIF-1α. Rabbits were treated intraperitoneally with O2/O3 mixture with different concentrations and then injected with YC-1 (inhibitor of HIF-1α) before the establishment of the global MIRI model using the Langendorff isolated heart perfusion apparatus. We investigated the effects of O3 preconditioning on cardiac systolic function, myocardial infarction, inflammatory response, mitochondrial function, myocardial pathological changes and arrhythmias. We found that the heart with O3 preconditioning significantly increased HR, LVDP and IL-10 expression, and decreased IL-6 expression, CK-MB, cTnT and cTnI concentration, myocardial infarction area, myocardial pathological injury and the occurrence of ventricular tachycardia and ventricular fibrillation. Meanwhile, the level of HIF-1α was significantly increased. However, after treatment of specific inhibitor of HIF-1α, the protective effect of O3 preconditioning was reversed completely. Our data indicates that O3 preconditioning has protective effect on MIRI and this protective effect is positively associated with dosage of O3. Energy metabolism disorder is the initial stage of MIRI and up-regulation of HIF-1α plays an important role in reducing mitochondrial dysfunction.

Platelet-rich plasma combined with ozone prevents cartilage destruction and improves weight-bearing asymmetry in a surgery-induced osteoarthritis rabbit model.

BACKGROUND: Osteoarthritis (OA) is the most common degenerative disease in older adults and its treatment remains unsatisfactory. This study aimed to evaluate the effectiveness and explore the therapeutic mechanisms of the combination of platelet-rich plasma (PRP) and ozone (O3) for knee OA. METHODS: Thirty male rabbits were randomly divided into five groups (Control group, OA group, PRP group, O3 group, and PRP + O3 group). Rabbit model of OA were induced by improved Hulth surgery. Gross articular observation, histopathological examination and cartilage scoring system were used to assess the articular cartilage destruction. The bone morphogenetic protein-2 (BMP-2) mRNA expression in joint fluid was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression of type II collagen, matrix metalloproteinase-1 (MMP-1) of cartilage was detected via Immunohistochemistry. Pain behavior was observed by percent ipsilateral weight-bearing (PIW) asymmetry. RESULTS: The content of platelet in PRP was increased by 6.2-times that in whole blood. Among induced OA groups (the OA, PRP, O3 and PRP + O3 group), PRP + O3 significantly inhibited the surgically induced increase in gross articular alterations, histopathological damage of cartilage and Mankin score when compared to the OA, PRP and O3 groups (P<0.05). Observed pain behavior by weight-bearing asymmetry, in the PRP + O3 group was reversed at 3 and 6 weeks after the administration of PRP + O3 (PIW asymmetry: -10.66%±1.172%). In addition, surgery-induced BMP-2 mRNA expression was significantly downregulated after the treatment of PRP, O3 and PRP + O3 (P<0.01). PRP + O3 group significantly increased the expression of type II collagen but decreased MMP-1 of cartilage in comparison to OA, PRP and O3 groups (P<0.05) by immunohistochemical analysis. CONCLUSIONS: PRP combined with O3 may prevent cartilage destruction and improve weight-bearing asymmetry by restoring homeostasis between anabolism and catabolism of extracellular matrix in progressive OA. Furthermore, a combination of PRP and O3 might achieve even better results than the two agents alone.

Bi2O2CO3/red phosphorus S-scheme heterojunction for H2 evolution and Cr(VI) reduction.

Red phosphorus (RP) has a suitable energy band structure and excellent photocatalytic properties. However, there are some problems, such as low quantum efficiency and serious photogenerated electron-hole recombination. The S-scheme heterostructure shows great potential in facilitating the separation and transfer of photogenerated carriers and obtaining strong photo-redox ability. Herein, hydrothermally treated red phosphorus (HRP) was combined with Bi2O2CO3 to construct Bi2O2CO3/HRP S-scheme heterojunction composite. The Bi2O2CO3 content was optimized, and the 5 %Bi2O2CO3/HRP composite obtained at 5 %Bi2O2CO3 mass fraction exhibited the strongest photoreduction ability. The Cr(VI) photoreduction and photolytic hydrogen production rates were as high as 0.22 min-1 and 157.2 µmol •h-1, which were 7.3 and 3.0 times higher than those of HRP, respectively. The promoted photocatalytic activity could be attributed to the formation of S-scheme heterojunctions, which accelerated the separation and transfer of useful photogenerated electron-hole pairs, while enhancing the recombination of relatively useless photogenerated electron-hole pairs, thereby resulting in the highest photocurrent density (17.3 µA/cm2) of the 5 %Bi2O2CO3/HRP composite, which was 1.6 and 4.3 times higher than pure Bi2O2CO3 (10.5 µA/cm2) and pure HRP (4.0 µA/cm2), respectively. This work would provide an advanced approach to enhance the photocatalytic activity of RP.

MRNIP condensates promote DNA double-strand break sensing and end resection.

The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.

Development and validation of a radiopathomics model to predict pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a multicentre observational study.

BACKGROUND: Accurate prediction of tumour response to neoadjuvant chemoradiotherapy enables personalised perioperative therapy for locally advanced rectal cancer. We aimed to develop and validate an artificial intelligence radiopathomics integrated model to predict pathological complete response in patients with locally advanced rectal cancer using pretreatment MRI and haematoxylin and eosin (H&E)-stained biopsy slides. METHODS: In this multicentre observational study, eligible participants who had undergone neoadjuvant chemoradiotherapy followed by radical surgery were recruited, with their pretreatment pelvic MRI (T2-weighted imaging, contrast-enhanced T1-weighted imaging, and diffusion-weighted imaging) and whole slide images of H&E-stained biopsy sections collected for annotation and feature extraction. The RAdioPathomics Integrated preDiction System (RAPIDS) was constructed by machine learning on the basis of three feature sets associated with pathological complete response: radiomics MRI features, pathomics nucleus features, and pathomics microenvironment features from a retrospective training cohort. The accuracy of RAPIDS for the prediction of pathological complete response in locally advanced rectal cancer was verified in two retrospective external validation cohorts and further validated in a multicentre, prospective observational study (ClinicalTrials.gov, NCT04271657). Model performances were evaluated using area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). FINDINGS: Between Sept 25, 2009, and Nov 3, 2017, 303 patients were retrospectively recruited in the training cohort, 480 in validation cohort 1, and 150 in validation cohort 2; 100 eligible patients were enrolled in the prospective study between Jan 10 and June 10, 2020. RAPIDS had favourable accuracy for the prediction of pathological complete response in the training cohort (AUC 0·868 [95% CI 0·825-0·912]), and in validation cohort 1 (0·860 [0·828-0·892]) and validation cohort 2 (0·872 [0·810-0·934]). In the prospective validation study, RAPIDS had an AUC of 0·812 (95% CI 0·717-0·907), sensitivity of 0·888 (0·728-0·999), specificity of 0·740 (0·593-0·886), NPV of 0·929 (0·862-0·995), and PPV of 0·512 (0·313-0·710). RAPIDS also significantly outperformed single-modality prediction models (AUC 0·630 [0·507-0·754] for the pathomics microenvironment model, 0·716 [0·580-0·852] for the radiomics MRI model, and 0·733 [0·620-0·845] for the pathomics nucleus model; all p<0·0001). INTERPRETATION: RAPIDS was able to predict pathological complete response to neoadjuvant chemoradiotherapy based on pretreatment radiopathomics images with high accuracy and robustness and could therefore provide a novel tool to assist in individualised management of locally advanced rectal cancer. FUNDING: National Natural Science Foundation of China; Youth Innovation Promotion Association of the Chinese Academy of Sciences.

A Pipeline for Predicting the Treatment Response of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer Using Single MRI Modality: Combining Deep Segmentation Network and Radiomics Analysis Based on "Suspicious Region".

Patients with locally advanced rectal cancer (LARC) who achieve a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) typically have a good prognosis. An early and accurate prediction of the treatment response, i.e., whether a patient achieves pCR, could significantly help doctors make tailored plans for LARC patients. This study proposes a pipeline of pCR prediction using a combination of deep learning and radiomics analysis. Taking into consideration missing pre-nCRT magnetic resonance imaging (MRI), as well as aiming to improve the efficiency for clinical application, the pipeline only included a post-nCRT T2-weighted (T2-w) MRI. Unlike other studies that attempted to carefully find the region of interest (ROI) using a pre-nCRT MRI as a reference, we placed the ROI on a "suspicious region", which is a continuous area that has a high possibility to contain a tumor or fibrosis as assessed by radiologists. A deep segmentation network, termed the two-stage rectum-aware U-Net (tsraU-Net), is designed to segment the ROI to substitute for a time-consuming manual delineation. This is followed by a radiomics analysis model based on the ROI to extract the hidden information and predict the pCR status. The data from a total of 275 patients were collected from two hospitals and partitioned into four datasets: Seg-T (N = 88) for training the tsraUNet, Rad-T (N = 107) for building the radiomics model, In-V (N = 46) for internal validation, and Ex-V (N = 34) for external validation. The proposed method achieved an area under the curve (AUC) of 0.829 (95% confidence interval [CI]: 0.821, 0.837) on In-V and 0.815 (95% CI, 0.801, 0.830) on Ex-V. The performance of the method was considerable and stable in two validation sets, indicating that the well-designed pipeline has the potential to be used in real clinical procedures.

Associations between clinical characteristics and tumor response to neoadjuvant chemoradiotherapy in rectal cancer.

Following standard neoadjuvant chemoradiotherapy and total mesorectal excision, some patients with locally advanced rectal cancer achieve good response (pathological T0-2N0), while others show nonresponse (pathological T3-4N0 or node-positive). To date, the clinicopathological predictors of good response and the necessity of adjuvant chemotherapy treatment (ACT) in good responders remain unclear. In this retrospective study, clinicopathological characteristics were surveyed to investigate the correlation with good response; furthermore, a propensity score matching (PSM) model was designed to balance the confounding factors between good responders treated with ACT or observation. A total of 2255 patients were enrolled, including 1069 good responders and 1186 nonresponders. The results of the survival analysis showed a good response predicted a better 3-year prognosis (p < 0.001). The logistic regression analysis showed less advanced T and N stages (T3 vs. T4; N0 vs. N1-2), more neoadjuvant chemotherapy (nCT) cycles (≥4 vs. 1-3), and delayed surgery (≥8 weeks vs. <8 weeks) were independent predictors of a good response (p < 0.05). Especially, patients treated with both more nCT cycles and a delay in surgery included the greatest number of good responders (p < 0.001). For good responders, after PSM (1:3), 235 observation cases were matched to 705 ACT cases. As compared with observation, ACT had no greater impact on prognosis analysis (p > 0.05). In conclusion, more cycles of nCT and a delay in surgery predicted a better response, and the delivery of ACT might be omitted in good responders.

Association Between Serum Carcinoembryonic Antigen Levels at Different Perioperative Time Points and Colorectal Cancer Outcomes.

BACKGROUND: Whether elevated postoperative serum carcinoembryonic antigen (CEA) levels are prognostic in patients with stage II colorectal cancer (CRC) remains controversial. PATIENTS AND METHODS: Primary and sensitivity analysis populations were obtained from a retrospective, multicenter longitudinal cohort including consecutive patients without neoadjuvant treatment undergoing curative resection for stage I-III CRC. Serum CEA levels before (CEApre-m1) and within 1 (CEApost-m1), 2-3 (CEApost-m2-3), and 4-6 months (CEApost-m4-6) after surgery were obtained, and their associations with recurrence-free survival (RFS) and overall survival (OS) were assessed using Cox regression. Sensitivity and subgroup analyses were performed. RESULTS: Primary and sensitivity analysis populations included 710 [415 men; age, 54.8 (11.6) years] and 1556 patients [941 men; age, 56.2 (11.8) years], respectively. Recurrence hazard ratios (HRs) in the elevated CEApre-m1, CEApost-m1, CEApost-m2-3, and CEApost-m4-6 groups were 1.30 (95% CI: 0.91-1.85), 1.53 (95% CI: 0.89-2.62), 1.88 (95% CI: 1.08-3.28), and 1.15 (95% CI: 0.91-1.85), respectively. The HRs of the elevated CEApre-m1, CEApost-m1, CEApost-m2-3, and CEApost-m4-6 groups for OS were 1.09 (95% CI: 0.60-1.97), 2.78 (95% CI: 1.34-5.79), 2.81 (95% CI: 1.25-6.30), and 3.30 (95% CI: 1.67-.536), respectively. Adjusted multivariate analyses showed that both in the primary and sensitivity analysis populations, elevated CEApost-m2-3, rather than CEApre-m1, CEApost-m1, and CEApost-m4-6, was an independent risk factor for recurrence, but not for OS. The RFS in the elevated and normal CEApost-m2-3 groups differed significantly among patients with stage II disease [n = 266; HR, 2.89; 95% CI, 1.02-8.24 (primary analysis); n = 612; HR, 2.69; 95% CI, 1.34-5.38 (sensitivity analysis)]. CONCLUSIONS: Elevated postoperative CEA levels are prognostic in patients with stage II CRC, with 2-3 months after surgery being the optimal timing for CEA measurement.

Trajectories of Perioperative Serum Tumor Markers and Colorectal Cancer Outcomes: A Retrospective, Multicenter Longitudinal Cohort Study.

BACKGROUND: The dynamic monitoring of perioperative carcinoembryonic antigen (CEA) is recommended by current colorectal cancer (CRC) guidelines, while the benefits of additional measurements of carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 125 (CA125) have remained controversial. METHODS: This retrospective longitudinal cohort included 3539 CRC patients who underwent curative resection. Distinct trajectory groups were identified by the latent class growth mixed model. Patients were grouped into subgroups jointly by CEA, CA19-9, and CA125 according to preoperative levels and longitudinal trajectories, respectively. The end points were overall survival (OS) and recurrence-free survival (RFS). FINDINGS: Three distinct trajectory groups were characterized for serum CEA, CA19-9, and CA125: low-stable, early-rising, and later-rising. Jointly, patients were grouped into six preoperative (trajectory) joint groups. Compared with the three-low group, the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) associated with death were 1.87 (1.29-2.70), 3.82 (2.37-6.17), 1.87 (0.97-3.61), 2.81 (1.93-4.11), and 4.99 (2.80-8.86) for the CEA-high, CA19-9-high, CA125-high, two-high, and three-high group, respectively. And compared with the three-stable trajectory group, the corresponding HRs (95% CIs) were 1.59 (1.10-2.30), 1.55 (0.77-3.10), 6.25 (4.02-9.70), 4.05 (2.73-6.02), and 12.40 (5.77-26.70) for the five rising trajectory groups, respectively. Similar associations between joint groups and RFS were observed. Notably, the trajectory joint group still had prognostic significance after adjusting for preoperative levels. The CA19-9-high group (HR: 3.82, 95% CI: 2.37-6.17) was associated with higher risk of death than the two-high group (HR: 2.81, 95% CI: 1.93-4.11). Likewise, for the CA125-rising trajectory group and two-rising trajectory group, the HRs (95% CIs) were 6.13 (3.75-10.00) and 3.99 (2.63-6.05) for death, and 3.08 (2.07-4.58) and 2.10 (1.52-2.90) for recurrence. INTERPRETATION: In addition to CEA, the dynamic measurements of CA19-9 and CA125 are recommended to monitor the prognosis of CRC patients. FUNDING: National Natural Science Foundation of China [81973147, 82001986, 81960592, 82073569, 81660545].