Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study.

BACKGROUND: The current standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by radical surgery, but this approach can lead to multiple complications. We aimed to investigate the clinical activity and safety of neoadjuvant therapy with sintilimab, a single-agent PD-1 antibody, in patients with mismatch-repair deficient locally advanced rectal cancer. METHODS: This open-label, single-arm, phase 2 study was done at the Sun Yat-sen University Cancer Center, Guangzhou, China. Patients aged 18-75 years with mismatch-repair deficient or microsatellite instability-high locally advanced rectal cancer were enrolled and received neoadjuvant sintilimab monotherapy (200 mg by intravenous infusion) every 21 days. After an initial four cycles of treatment, patients and clinicians could choose one of the following options: total mesorectal excision surgery, followed by four cycles of adjuvant sintilimab with or without CapeOX chemotherapy (capecitabine 1000 mg/m2, orally administered twice daily on days 1-14; oxaliplatin 130 mg/m2, intravenously administered on day 1 every 3 weeks), determined by clinicians; or another four cycles of sintilimab followed by radical surgery or observation (only for patients with a clinical complete response; also known as the watch and wait strategy). The primary endpoint was the complete response rate, which included both a pathological complete response after surgery and a clinical complete response after completion of sintilimab treatment. Clinical response was evaluated by digital rectal examination, MRI, and endoscopy. Response was assessed in all patients who received treatment at least until the first tumour response assessment, after the first two cycles of sintilimab. Safety was analysed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04304209). FINDINGS: Between Oct 19, 2019, and June 18, 2022, 17 patients were enrolled and received at least one dose of sintilimab. The median age was 50 years (IQR 35-59) and 11 (65%) of 17 patients were male. One patient was excluded from efficacy analyses because they were lost to follow-up after the first sintilimab cycle. Of the remaining 16 patients, six underwent surgery, of whom three had a pathological complete response. Nine other patients had a clinical complete response and chose the watch and wait strategy. One patient had a serious adverse event and discontinued treatment; this patient did not have a complete clinical response and refused to undergo surgery. A complete response was thus noted for 12 (75%; 95% CI 47-92) of 16 patients. One of the three patients who underwent surgery but did not have a pathological complete response showed an increase in tumour volume after the initial four cycles of sintilimab (at which point they underwent surgery); this patient was deemed to have primary resistance to immune checkpoint inhibitors. After a median follow-up of 17·2 (IQR 8·2-28·5) months, all patients were alive and none had disease recurrence. Only one (6%) patient had a grade 3-4 adverse event, which was deemed a serious adverse event (grade 3 encephalitis). INTERPRETATION: The preliminary results of this study suggest that anti-PD-1 monotherapy is effective and tolerable for patients with mismatch-repair deficient locally advanced rectal cancer and could potentially spare some patients from radical surgery. Longer treatment courses might be needed to achieve maximum effects in some patients. Longer follow-up is also needed to observe the duration of response. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, Science and Technology Program of Guangzhou, and Innovent Biologics.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

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.

The analysis of the characteristics of imported COVID-19 cases from January to April in 2020: a cross-sectional study.

Background: Since the first case reported in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an outbreak of coronavirus disease 2019 (COVID-19) worldwide. The global case count continued to rise and the WHO declared a Public Health Emergency of International Concern (PHEIC), causing a growing risk of imported COVID-19 infection. This study aimed to provide descriptive and quantitative epidemiological characteristics of imported COVID-19 cases in China. Methods: This cross-sectional study examined all imported COVID-19 cases in Mainland China from 22 January to 21 April 2020. Ratios, Median and percentile were used for descriptive analysis. Spearman's correlation analysis was performed between daily new imported cases in Mainland China and the country of origin. The chi-square test was used to evaluate the difference between home quarantine and compulsory centralized quarantine on native transmission. Results: A total of 1,610 cases of COVID-19 were imported from 49 countries to 27 provincial administrative regions in China; 79.8% were from European countries and the United States of America (the USA). Before 29 March 2020, the imported cases were mainly from the USA (27.7%) and United Kingdom (UK; 42.6%). After 29 March 2020, the daily newly imported cases from Russia rapidly grew. After 12 April 2020, the number of daily newly imported cases gradually decreased and remained at a low level (12±7 cases per day). Airport entry was encouraged, and ground border crossing was limited. Among the 1,610 cases, 54.0% were in the asymptomatic incubation period on arrival in Mainland China. Conclusions: The transmissions by imported COVID-19 were gradually and effectively curbed in Mainland China, despite a disproportionally high number of cases worldwide. Entry screening measures must be implemented universally to all inbound travelers at a point of entry or targeted to specific travel routes or to specific travelers. Compulsory centralized quarantine should be recommended in the prevention of the imported COVID-19 epidemic.

High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer.

BACKGROUND: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long-term survival and functional outcomes have been rarely investigated. METHODS: Patients with non-metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan-Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. RESULTS: A total of 57 patients were included, with a median age of 59.0 (range, 29-84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil-based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60-86) Gy. All kinds of grade 3-4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow-up of 43.5 (range 14.9-163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3-year local recurrence-free survival and distant metastasis-free survival were 77.3% (95% CI, 65.7-88.8%) and 79.2% (95% CI, 68.2-90.2%), while the 3-year progression-free survival, cancer-specific survival, overall survival were 61.9% (95% CI, 48.8-75.0%), 93.1% (95% CI, 85.8-100.0%) and 91.4% (95% CI, 83.6-99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow-up. Long-term adverse events mainly were anal blood loss. 21 patients completed the quality-of-life questionnaire and had a score of the global health status of 78.57 ± 17.59. Of them, 95.2% reported no urinary incontinence and 85.7% reported no fecal incontinence. CONCLUSIONS: High dose chemoradiation demonstrated promising survival outcomes with acceptable short-term and long-term side effects, and satisfying long-term functional outcomes and quality of life. It could be considered as a non-invasive alternative for rectal cancer patients who refuse surgery.

Comprehensive treatment experience of anal squamous cell carcinoma from a tertiary cancer center in South China.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is a rare malignant tumor with increasing incidence. The goal of our study was to analyze the treatment outcome and prognostic factors of ASCC in South China in the past half-century. METHODS: This study retrospectively included 59 patients with ASCC admitted from 1975 to 2018 in Sun Yat-sen University cancer center. The clinical records and follow-up information of all patients were collected. Survival analysis and univariate and multivariate regression analyses were performed using the "survival" and "survminer" packages of R software. RESULTS: In 59 patients, 5 patients had distant metastasis at diagnosis. Among 54 M0 stage patients, 33 patients received chemoradiotherapy (CRT), 19 patients received local surgery, and 2 patients refused curative treatment and received the best supportive treatment (BST). The most common grade 3-4 acute toxicities during treatment were myelosuppression and radiation dermatitis. The median follow-up time was 32 months. For the whole group, the 3-year and 5-year overall survival (OS) rates and disease-free survival (DFS) were 71.1% and 63.6%, and 73.4% and 69.0%, respectively. Multivariate regression analysis showed that the T3-4 stage was an independent prognostic risk factor for OS, progression-free survival (PFS), and DFS. And M1 was an independent prognostic risk factor for PFS and DFS. Patients in stage M0 mainly treated with CRT had better local control than those mainly treated with surgery (p = 0.027). For M0 patients, induction chemotherapy combined with CRT tends to prolong OS compared with CRT alone (p = 0.26). The 3-year colostomy-free survival for the whole group was 81.1%. CONCLUSIONS: CRT is recommended as the first choice for the treatment of M0 stage ASCC. Induction chemotherapy may bring better survival benefits for some patients. Patients with ASCC in China seem to have a better local control rate, which suggested different treatment strategies may be needed in China.

A Deep-Learning Pipeline for TSS Coverage Imputation From Shallow Cell-Free DNA Sequencing.

Cell-free DNA (cfDNA) serves as a footprint of the nucleosome occupancy status of transcription start sites (TSSs), and has been subject to wide development for use in noninvasive health monitoring and disease detection. However, the requirement for high sequencing depth limits its clinical use. Here, we introduce a deep-learning pipeline designed for TSS coverage profiles generated from shallow cfDNA sequencing called the Autoencoder of cfDNA TSS (AECT) coverage profile. AECT outperformed existing single-cell sequencing imputation algorithms in terms of improvements to TSS coverage accuracy and the capture of latent biological features that distinguish sex or tumor status. We built classifiers for the detection of breast and rectal cancer using AECT-imputed shallow sequencing data, and their performance was close to that achieved by high-depth sequencing, suggesting that AECT could provide a broadly applicable noninvasive screening approach with high accuracy and at a moderate cost.

Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer.

This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis-free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch-and-wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19-9 were selected to establish the RPA-based risk stratification, categorizing LARC patients into low-risk (n = 139; CA19-9 < 35 U/mL and CEA < 5 ng/mL) and high-risk (n = 73; CA19-9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5-y DMFS was observed in the low-risk group vs. the high-risk group (92.9% vs. 76.2%, P = .002). Low-risk LARC patients who underwent TME had significantly improved 5-y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high-risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19-9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.

Oncologic and survival outcomes in elderly patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy and total mesorectal excision.

BACKGROUND: The efficacy of the addition of neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer in elderly patients has not been established. METHODS: A total of 3096 locally advanced rectal cancer patients who received neoadjuvant chemotherapy, along with neoadjuvant chemoradiotherapy and total mesorectal excision, with or without adjuvant chemotherapy, between January 2010 and December 2018, were studied retrospectively. Patients were divided into elderly (>75 years) and younger (≤75 years) groups, and propensity score matching was used to balance a potentially confounding clinical bias. Overall survival, cancer-specific survival, disease-free survival, distant metastasis-free survival and local recurrence-free survival rates for the two groups were compared. Hazard ratios (HR) with 95% confidence intervals (CI) for different clinicopathological variables were calculated to determine predictors of 3-year overall survival. RESULTS: Mean follow-up was 39.0 (range, 5-140) months. The overall 3-year overall survival, cancer-specific survival, disease-free survival, distant metastasis-free survival and locoregional relapse-free survival rates were 86.1, 87.6, 80.0, 82.4 and 95.4%, respectively. Only 3-year overall survival rates differed significantly between the elderly (77.2%) and younger (88.9%) groups (P = 0.01). Cancer-specific survival, disease-free survival, distant metastasis-free survival and locoregional relapse-free survival rates did not differ significantly between the two groups. Significant negative independent prognostic factors for 3-year overall survival were age >75 years (HR = 2.016, 95% CI 1.157-23.511, P = 0.01) and high pathologic TNM stage (yp stage III, P < 0.001). CONCLUSION: For elderly locally advanced rectal cancer patients who have good health and performance status, the addition of neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy and total mesorectal excision can result in disease-related survival rates and oncological outcomes similar to those experienced by younger patients. The decision to use this treatment approach in elderly patients should not be based solely on chronological age.

Neoadjuvant chemoradiotherapy in patients with unresectable locally advanced sigmoid colon cancer: clinical feasibility and outcome.

BACKGROUND: Patients with locally advanced sigmoid colon cancer (LASCC) have limited treatment options and a dismal prognosis with poor quality of life. This retrospective study aimed to further evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by surgery as treatment for select patients with unresectable LASCC. METHODS: We studied patients with unresectable LASCC who received NACRT between November 2010 and April 2019. The NACRT regimen consisted of intensity modulated radiotherapy (IMRT) of 50 Gy to the gross tumor and positive lymphoma node and 45 Gy to the clinical target volume. Capecitabine­based chemotherapy was administered every 2 (mFOLFOX6) or 3 weeks (CAPEOX). Surgery was scheduled 6-8 weeks after radiotherapy. RESULTS: Seventy­two patients were enrolled in this study. Patients had a regular follow-up (median, 41.1 months; range, 8.3-116.5 months). Seventy­one patients completed NACRT, and sixty-five completed surgery. Resection with microscopically negative margins (R0 resection) was achieved in 64 patients (88.9%). Pathologic complete response was observed in 15 patients (23.1%), and multivisceral resection was necessary in 38 patients (58.3%). The cumulative probability of 3-year overall survival (OS) and progression-free survival (PFS) were 75.8 and 70.7%, respectively. CONCLUSIONS: For patients with unresectable LASCC, neoadjuvant chemoradiotherapy is feasible, surgery can be performed safely and may result in increased survival and organ preservation rates.

Prognostic value of ubiquitin E2 UBE2W and its correlation with tumor-infiltrating immune cells in breast cancer.

BACKGROUND: Ubiquitin-conjugating enzyme E2W (UBE2W) is a protein-coding gene that has an important role in ubiquitination and may be vital in the repair of DNA damage. However, studies on the prognostic value of UBE2W and its correlation with tumor-infiltrating immune cells in multiple cancers have not been addressed. METHODS: We investigated UBE2W expression in the Oncomine database, the Tumor Immune Estimation Resource (TIMER), TNMplot database. Then, the clinical prognostic value of UBE2W was analyzed via online public databases. Meanwhile, we explored the correlation between UBE2W and DNA repair associate genes expression and DNA methyltransferase expression by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). By using the same method, the correlation between UBE2W and tumor-infiltrating immune cells was explored. Genomic Profiles of UBE2W in breast cancer (BRCA) were accessed in cBioPortal (v3.5.0). Functional proteins associated network was analyzed by STRING database (v11.0). RESULTS: UBE2W was abnormally expressed and significantly correlated with mismatch repair (MMR) gene mutation levels, DNA methyltransferase, and BRCA1/2 expression in breast cancer. High expression of UBE2W may promote the tumor immunosuppression and metastasis, induce endocrine therapy resistance and deteriorate outcomes of patients with breast cancer. These findings suggest that UBE2W could be a potential biomarker of prognosis and tumor-infiltrating immune cells. Besides, RBX1 may be a new E3 that was regulated by UBE2W. CONCLUSIONS: Ubiquitin E2 UBE2W is a potential prognostic biomarker and is correlated with immune infiltration in BRCA.

Neoadjuvant chemoradiotherapy for patients with unresectable radically locally advanced colon cancer: a potential improvement to overall survival and decrease to multivisceral resection.

BACKGROUND: The management of unresectable locally advanced colon cancer (LACC) remains controversial, as resection is not feasible. The goal of this study was to evaluate the treatment outcomes and toxicity of neoadjuvant chemoradiotherapy (NACRT) followed with surgery and adjuvant chemotherapy in patients with unresectable radically LACC. METHODS: We included patients who were diagnosed at our institution, 2010-2018. The neoadjuvant regimen consisted of radiotherapy and capecitabine/ 5-fluorouracil-based chemotherapy. RESULTS: One hundred patients were identified. The median follow-up time was 32 months. The R0 resection rate, adjusted nonmultivisceral resection rate and bladder preservation rate were 83.0, 43.0 and 83.3%, respectively. The pCR and clinical-downstaging rates were 18, and 81.0%%, respectively. The 3-year PFS and OS rates for all patients were 68.6 and 82.1%, respectively. Seventeen patients developed grade 3-4 myelosuppression, which was the most common adverse event observed after NACRT. Tumor perforation occurred in 3 patients during NACRT. The incidence of grade 3-4 surgery-related complications was 7.0%. Postoperative anastomotic leakage was observed in 3 patients. CONCLUSIONS: NACRT followed by surgery was feasible and safe for selected patients with LACC, and can be used as a conversion treatment to achieve satisfactory downstaging, long-term survival and quality of life, with acceptable toxicities.

A Genotype Signature for Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer.

PURPOSE: To construct and validate a predicting genotype signature for pathologic complete response (pCR) in locally advanced rectal cancer (PGS-LARC) after neoadjuvant chemoradiation. METHODS AND MATERIALS: Whole exome sequencing was performed in 15 LARC tissues. Mutation sites were selected according to the whole exome sequencing data and literature. Target sequencing was performed in a training cohort (n = 202) to build the PGS-LARC model using regression analysis, and internal (n = 76) and external validation cohorts (n = 69) were used for validating the results. Predictive performance of the PGS-LARC model was compared with clinical factors and between subgroups. The PGS-LARC model comprised 15 genes. RESULTS: The area under the curve (AUC) of the PGS model in the training, internal, and external validation cohorts was 0.776 (0.697-0.849), 0.760 (0.644-0.867), and 0.812 (0.690-0.915), respectively, and demonstrated higher AUC, accuracy, sensitivity, and specificity than cT stage, cN stage, carcinoembryonic antigen level, and CA19-9 level for pCR prediction. The predictive performance of the model was superior to clinical factors in all subgroups. For patients with clinical complete response (cCR), the positive prediction value was 94.7%. CONCLUSIONS: The PGS-LARC is a reliable predictive tool for pCR in patients with LARC and might be helpful to enable nonoperative management strategy in those patients who refuse surgery. It has the potential to guide treatment decisions for patients with different probability of tumor regression after neoadjuvant therapy, especially when combining cCR criteria and PGS-LARC.

The watch-and-wait strategy versus surgical resection for rectal cancer patients with a clinical complete response after neoadjuvant chemoradiotherapy.

BACKGROUND: The watch-and-wait strategy offers a non-invasive therapeutic alternative for rectal cancer patients who have achieved a clinical complete response (cCR) after chemoradiotherapy. This study aimed to investigate the long-term clinical outcomes of this strategy in comparation to surgical resection. METHODS: Stage II/III rectal adenocarcinoma patients who received neoadjuvant chemoradiotherapy and achieved a cCR were selected from the databases of three centers. cCR was evaluated by findings from digital rectal examination, colonoscopy, and radiographic images. Patients in whom the watch-and-wait strategy was adopted were matched with patients who underwent radical resection through 1:1 propensity score matching analyses. Survival was calculated and compared in the two groups using the Kaplan-Meier method with the log rank test. RESULTS: A total of 117 patients in whom the watch-and-wait strategy was adopted were matched with 354 patients who underwent radical resection. After matching, there were 94 patients in each group, and no significant differences in term of age, sex, T stage, N stage or tumor location were observed between the two groups. The median follow-up time was 38.2 months. Patients in whom the watch-and-wait strategy was adopted exhibited a higher rate of local recurrences (14.9% vs. 1.1%), but most (85.7%) were salvageable. Three-year non-regrowth local recurrence-free survival was comparable between the two groups (98% vs. 98%, P = 0.506), but the watch-and-wait group presented an obvious advantage in terms of sphincter preservation, especially in patients with a tumor located within 3 cm of the anal verge (89.7% vs. 41.2%, P < 0.001). Three-year distant metastasis-free survival (88% in the watch-and-wait group vs. 89% in the surgical group, P = 0.874), 3-year disease-specific survival (99% vs. 96%, P = 0.643) and overall survival (99% vs. 96%, P = 0.905) were also comparable between the two groups, although a higher rate (35.7%) of distant metastases was observed in patients who exhibited local regrowth in the watch-and-wait group. CONCLUSION: The watch-and-wait strategy was safe, with similar survival outcomes but a superior sphincter preservation rate as compared to surgery in rectal cancer patients achieving a cCR after neoadjuvant chemoradiotherapy, and could be offered as a promising conservative alternative to invasive radical surgery.

Rapid isolation and determination of bisphenol A in complicated matrices by magnetic molecularly imprinted electrochemical sensing.

Because of its widespread distribution in the environment, bisphenol A (BPA) has become a global concern as an endocrine disruptor and a threat to human health through the food chain. Thus an efficient determination method is urgently needed for monitoring the levels of BPA. Herein, a novel electrochemical technique for the detection of BPA was performed by synchronous extraction and pre-concentration of BPA onto magnetic molecularly imprinted polymer (BMMIP), with subsequent readout on a magneto-actuated glassy carbon electrode (MGCE) by differential pulse voltammetry. Compared to the current methods of BPA determination, this BMMIP-based electrochemical sensor (BMMIPs@MGCE) not only simplifies the sample handling procedures substantially, without filtration, centrifugation, or other complex operations, but also can be easily renewed by a controllable magnetic field. As a sensor component, the core-shell BMMIPs exhibited excellent binding capacity (Qe = 82.5 mg g-1), short adsorption equilibrium time (30 s), and outstanding selectivity (k' = 7.239) towards BPA, as well as stability and recyclability. Importantly, the BMMIPs@MGCE sensor was successfully applied for the on-site monitoring and rapid detection of BPA in complicated real-world specimens, with good recoveries (81.31-119.77%) and a low limit of detection (0.133 µmol L-1). Therefore, the stable and low-cost BMMIPs@MGCE sensor provides a new approach for the rapid determination of BPA in the field of environmental control and food safety. Graphical abstract.

Enzyme-treated soy protein supplementation in low protein diet enhanced immune function of immune organs in on-growing grass carp.

A 56 days feeding trial was conducted to investigate the effects of enzyme-treated soy protein (ETSP) supplementation in low protein diets on immune function of immune organs (head kidney, spleen and skin) in on-growing grass carp. A total of 540 on-growing grass carp (initial average weight: 325.72 ± 0.60 g) were fed six diets, which included a normal protein diet (28% crude protein) and five low protein diets (26% crude protein) supplemented with graded levels of ETSP (0.0, 0.8, 1.2, 1.6 and 2.0%). At the end of feeding period, a challenge test was performed by infection with Aeromonas hydrophila for two weeks. The results indicated that (1) reducing dietary protein content from 28 to 26% decreased antibacterial substances and aggravated inflammatory responses of above three immune organs; (2) under the condition of reducing protein level in diet, 0.8-1.2% ETSP supplementation reversed these above adverse effects on immune function of above three immune organs; (3) suitable ETSP supplementation-decreased inflammatory responses were partly associated with [IκB kinase ß (IKKß)/inhibitor of κBα (IκBα)/nuclear factor kappa B (NF-κB) p65 and p52 or NF-κB p65] signaling and [target of rapamycin (TOR)/(S6K1, 4E-BP)] signaling in above three immune organs. (4) On the basis of C3 content (head kidney), C4 content (spleen) and skin hemorrhage and lesion, the optimal ETSP supplementation levels in low protein diets were estimated to be 1.48%, 1.61% and 1.03%, respectively. In summary, ETSP supplementation in low protein diets improved immune function of head kidney, spleen and skin in on-growing grass carp.

Regular aspirin intake and prognosis of TxN2-3M0 nasopharyngeal carcinoma: A cohort study based on propensity score matching.

OBJECTIVES: Distant metastasis is the leading cause of death in patients with N2-3 nasopharyngeal carcinoma (NPC). And aspirin is found to reduce metastasis and improve prognosis in some other malignancies, such as colorectal cancer. This study aimed to evaluate the clinical value of regular aspirin intake (RAI) in N2-3 NPC treated with standard chemoradiotherapy. MATERIALS AND METHODS: Totally 2064 patients diagnosed with TxN2-3M0 NPC from Jan. 2008 to Dec. 2015 and treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy were involved. According to RAI, these patients were divided into 2 groups between which a propensity score matching was made, with a ratio of 1:3 and a series of clinical characteristics (age, gender, T stage, N stage and EBV DNA) as covariates. Then survivals and acute toxicities were compared in the 464 matched patients. RESULTS: RAI appeared to bring better overall (87.7% vs. 79.6%, P = 0.031), metastasis-free (87.8% vs. 76.5%, P = 0.017) and disease-free (85.9% vs. 75.5%, P = 0.033) survivals. It simultaneously increased total incidences of myelosuppression (55.2% vs. 32.2%, P < 0.001), oral mucositis (60.3% vs. 38.2%, P < 0.001), cervical dermatitis (60.3% vs. 38.5%, P < 0.001) and xerostomia (49.1% vs. 33.3%, P = 0.002). But RAI failed to affect incidence of any grade 3/4 toxicity. CONCLUSIONS: Post-diagnosis RAI might be a tolerable approach to control distant metastasis and provide survival benefit for N2-3 NPC in combination with standard chemoradiotherapy.

Toxicological responses, bioaccumulation, and metabolic fate of triclosan in Chlamydomonas reinhardtii.

Triclosan (TCS) is a broad-spectrum antimicrobial agent that is broadly used in personal care products. It has been shown to cause the contamination of a variety of aquatic environments. Since algae has been the primary producers of aquatic ecosystems, understanding the toxicological mechanisms and the metabolic fate of TCS is vital for assessing its risk in an aquatic environment. In our study, 0.5-4 mg L-1 TCS treatments for 72 h in a culture of Chlamydomonas reinhardtii (C. reinhardtii) showed progressive inhibition of cell growth and reduced the chlorophyll content. The EC50 value of C. reinhardtii after 72 h was 1.637 mg L-1, which showed its higher level of resistance to TCS in comparison with other algal species. The exposure to TCS led to oxidative injuries of algae in relation to the increment of malonaldehyde content, cell membrane permeability, and H2O2 levels. Furthermore, the oxidative stress from TCS stimulated a series of antioxidant enzyme activities and their gene expressions. Simultaneously, the accumulated TCS in C. reinhardtii arouses the detoxification/degradation-related enzymes and related gene transcriptions. In the medium, approximately 82% of TCS was removed by C. reinhardtii. Importantly, eight TCS metabolites were identified by ultra-performance liquid chromatography-high-resolution mass spectrometry and their relative abundances were measured in a time-course experiment. Six of these metabolites are reported here for the first time. The metabolic pathways of triclosan via C. reinhardtii including reductive dechlorination, hydroxylation, sulfhydrylation, and binding with thiol/cysteine/GSH/glycosyl were manifested to broaden our understanding of the environmental fate of TCS. Graphical Abstract.

Development of a Comorbidity-Based Nomogram to Predict Survival After Salvage Reirradiation of Locally Recurrent Nasopharyngeal Carcinoma in the Intensity-Modulated Radiotherapy Era.

PURPOSE: To assess the impact of comorbidity on treatment outcomes in patients with locally recurrent nasopharyngeal carcinoma (lrNPC) using intensity-modulated radiotherapy (IMRT) and to develop a nomogram that combines prognostic factors to predict clinical outcome and guide individual treatment. METHODS: This was a retrospective analysis of patients with lrNPC who were reirradiated with IMRT between 2003 and 2014. Comorbidity was evaluated by Adult Comorbidity Evaluation-27 grading (ACE-27). The significant prognostic factors (P < 0.05) by multivariate analysis using the Cox regression model were adopted into the nomogram model. Harrell concordance index (C-index) calibration curves were applied to assess this model. RESULTS: Between 2003 and 2014, 469 lrNPC patients treated in our institution were enrolled. Significant comorbidity (moderate or severe grade) was present in 17.1% of patients by ACE-27. Patients with no or mild comorbidity had a 5-year overall survival (OS) rate of 36.2 versus 20.0% among those with comorbidity of moderate or severe grade (P < 0.0001). The chemotherapy used was not significantly different in patients with lrNPC (P > 0.05). For the rT3-4 patients, the 5-year OS rate in the chemotherapy + radiation therapy (RT) group was 30.0 versus 16.7% for RT only (P = 0.005). The rT3-4 patients with no or mild comorbidity were associated with a higher 5-year OS rate in the chemotherapy + RT group than in the RT only group (32.1 and 17.1%, respectively; P=0.003). However, for the rT3-4 patients with a comorbidity (moderate or severe grade), the 5-year OS rate in the chemotherapy + RT group vs. RT alone was not significantly different (15.7 vs. 15.0%, respectively; p > 0.05). Eight independent prognostic factors identified from multivariable analysis were fitted into a nomogram, including comorbidity. The C-index of the nomogram was 0.715. The area under curves (AUCs) for the prediction of 1-, 3-, and 5-year overall survival were 0.770, 0.764, and 0.780, respectively. CONCLUSION: Comorbidity is among eight important prognostic factors for patients undergoing reirradiation. We developed a nomogram for lrNPC patients to predict the probability of death after reirradiation and guide individualized management.

Effect of enzymatic hydrolysate of cottonseed protein supplementation on growth performance and intestinal health of nursery pigs in Thailand.

This study investigated the effects of enzymatic hydrolysate of cottonseed protein (EHCP) supplementation on the growth performance and intestinal health of nursery pigs in Thailand. A total of 180 newly weaned piglets were randomly allocated to 3 groups with 6 replicates in each group and 10 piglets per replicate. Nursery pigs were fed three diets containing 0, 1%, and 1.5% EHCP for 28-63 days of age. The results indicated that 1% EHCP supplementation increased average daily feed intake (ADFI) and average daily gain (ADG) and decreased feed conversion rate (FCR) in the numerical, suggesting that appropriate EHCP supplementation could numerically improve growth performance of nursery pigs in Thailand. Moreover, 1% EHCP supplementation significantly decreased intestinal crypt depth and diarrhea incidence and increased intestinal villus height to crypt depth ratio and fecal consistency, suggesting that optimum EHCP supplementation could improve intestinal morphology and decreased diarrhea incidence of nursery pigs in Thailand. Furthermore, 1% EHCP supplementation significantly improved intestinal glutathione (GSH) level and superoxide dismutase (SOD) activity and indicated that optimal EHCP supplementation could improve intestinal antioxidant capacity of nursery pigs in Thailand. Optimum EHCP supplementation numerically increased growth, significantly decreased diarrhea incidence, significantly improved intestinal morphology and antioxidant capacity of nursery pig in Thailand.