Longitudinal gut microbiome analyses and blooms of pathogenic strains during lupus disease flares.

OBJECTIVE: Whereas genetic susceptibility for systemic lupus erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between microbiota community resilience and disease activity, we performed the first longitudinal analyses of lupus gut-microbiota communities. METHODS: In an observational study, taxononomic analyses, including multivariate analysis of ß-diversity, assessed time-dependent alterations in faecal communities from patients and healthy controls. From gut blooms, strains were isolated, with genomes and associated glycans analysed. RESULTS: Multivariate analyses documented that, unlike healthy controls, significant temporal community-wide ecological microbiota instability was common in SLE patients, and transient intestinal growth spikes of several pathogenic species were documented. Expansions of only the anaerobic commensal, Ruminococcus (blautia) gnavus (RG) occurred at times of high-disease activity, and were detected in almost half of patients during lupus nephritis (LN) disease flares. Whole genome sequence analysis of RG strains isolated during these flares documented 34 genes postulated to aid adaptation and expansion within a host with an inflammatory condition. Yet, the most specific feature of strains found during lupus flares was the common expression of a novel type of cell membrane-associated lipoglycan. These lipoglycans share conserved structural features documented by mass spectroscopy, and highly immunogenic repetitive antigenic-determinants, recognised by high-level serum IgG2 antibodies, that spontaneously arose, concurrent with RG blooms and lupus flares. CONCLUSIONS: Our findings rationalise how blooms of the RG pathobiont may be common drivers of clinical flares of often remitting-relapsing lupus disease, and highlight the potential pathogenic properties of specific strains isolated from active LN patients.

Prognostic significance of the preoperative alkaline phosphatase­to­albumin ratio in patients with hepatocellular carcinoma after hepatic resection.

This study aimed to investigate the prognostic value of the preoperative alkaline phosphatase-to-albumin ratio (APAR) in patients with hepatocellular carcinoma (HCC) who underwent radical hepatectomy. The clinicopathological data from 330 patients was retrospectively analyzed. Receiver operating characteristic curves of APAR for diagnostic tumor recurrence were plotted with a cut-off value of 1.74. A high preoperative APAR value was significantly associated with hepatitis B surface antigen level, tumor diameter, and tumor-node-metastasis stage. The disease-free survival (DFS) and overall survival (OS) of patients with a high preoperative APAR were shorter than those with a low APAR. The independent risk factors for DFS were an APAR ≥1.74, and macrovascular invasion or tumor thrombus. The independent risk factors for OS were an APAR ≥1.74, existing clinical symptoms, α-fetoprotein level ≥20 ng/ml, macrovascular invasion or tumor thrombus, and family history of cancer. In conclusion, a preoperative APAR (≥1.74) is an independent risk factor influencing the poor prognosis of patients with HCC after curative hepatectomy, and patients with such a result should be closely monitored.

Remote Eradication of Bacteria on Orthopedic Implants via Delayed Delivery of Polycaprolactone Stabilized Polyvinylpyrrolidone Iodine.

Bacteria-associated late infection of the orthopedic devices would further lead to the failure of the implantation. However, present ordinary antimicrobial strategies usually deal with early infection but fail to combat the late infection of the implants due to the burst release of the antibiotics. Thus, to fabricate long-term antimicrobial (early antibacterial, late antibacterial) orthopedic implants is essential to address this issue. Herein, we developed a sophisticated MAO-I2-PCLx coating system incorporating an underlying iodine layer and an upper layer of polycaprolactone (PCL)-controlled coating, which could effectively eradicate the late bacterial infection throughout the implantation. Firstly, micro-arc oxidation was used to form a microarray tubular structure on the surface of the implants, laying the foundation for iodine loading and PCL bonding. Secondly, electrophoresis was applied to load iodine in the tubular structure as an efficient bactericidal agent. Finally, the surface-bonded PCL coating acts as a controller to regulate the release of iodine. The hybrid coatings displayed great stability and control release capacity. Excellent antibacterial ability was validated at 30 days post-implantation via in vitro experiments and in vivo rat osteomyelitis model. Expectedly, it can become a promising bench-to-bedside strategy for current infection challenges in the orthopedic field.

Prognostic risk factors and survival models for T3 locally advanced rectal cancer: what can we learn from the baseline MRI?

OBJECTIVES: To evaluate the baseline MRI characteristics for predicting survival outcomes and construct survival models for risk stratification to facilitate personalized treatment and follow-up strategies in patients with MRI-defined T3 (mrT3) locally advanced rectal cancer (LARC). METHODS: We retrospectively reviewed 256 mrT3 LARC patients evaluated between 2008 and 2012 in our institution, with an average follow-up period of 6.8 ± 1.2 years. The baseline MRI characteristics, clinical data, and follow-up information were evaluated. The patients were randomized into a training cohort (TC, 186 patients) and validation cohort (VC, 70 patients). The TC dataset was used to develop multivariate nomograms for disease-free survival (DFS) and overall survival (OS), while the VC dataset was used for independent validation of the models. Harrell concordance (C) indices and Hosmer-Lemeshow calibration were used to evaluate the performances of the models. RESULTS: Baseline mrT3 substage, extramural venous invasion (EMVI) grading, mucinous adenocarcinoma, mesorectal fascia involvement, elevated pretreatment carcinoembryonic antigen level, and neoadjuvant chemoradiotherapy (NCRT) were independent predictors of DFS. T3 substage, EMVI grading, and NCRT were also independent predictors of OS. The nomograms constructed permitted the individualized prediction of 3-year and 5-year DFS and 5-year OS with high discrimination (C-index range, 0.833-0.892) and good calibration in the TC and VC. CONCLUSIONS: We have identified baseline MRI characteristics that help independently predict survival outcomes in patients with mrT3 LARC. The survival models based on these characteristics allow for the individualized pretreatment risk stratification in patients with mrT3 LARC. KEY POINTS: • Baseline MRI characteristics can independently stratify risk and predict survival outcomes in patients with mrT3 LARC. • The nomograms built using selected baseline MRI characteristics facilitate the individualized pretreatment risk stratification and help with clinical decision-making in patients with mrT3 LARC. • MR-defined risk factors should, therefore, be carefully reported in the baseline MRI evaluation.

A trilogy antimicrobial strategy for multiple infections of orthopedic implants throughout their life cycle.

Bacteria-associated infection represents one of the major threats for orthopedic implants failure during their life cycles. However, ordinary antimicrobial treatments usually failed to combat multiple waves of infections during arthroplasty and prosthesis revisions etc. As these incidents could easily introduce new microbial pathogens in/onto the implants. Herein, we demonstrate that an antimicrobial trilogy strategy incorporating a sophisticated multilayered coating system leveraging multiple ion exchange mechanisms and fine nanotopography tuning, could effectively eradicate bacterial infection at various stages of implantation. Early stage bacteriostatic effect was realized via nano-topological structure of top mineral coating. Antibacterial effect at intermediate stage was mediated by sustained release of zinc ions from doped CaP coating. Strong antibacterial potency was validated at 4 weeks post implantation via an implanted model in vivo. Finally, the underlying zinc titanate fiber network enabled a long-term contact and release effect of residual zinc, which maintained a strong antibacterial ability against both Staphylococcus aureus and Escherichia coli even after the removal of top layer coating. Moreover, sustained release of Sr2+ and Zn2+ during CaP coating degradation substantially promoted implant osseointegration even under an infectious environment by showing more peri-implant new bone formation and substantially improved bone-implant bonding strength.

The Predictive Value of Pre-/Postneoadjuvant Chemoradiotherapy MRI Characteristics for Patient Outcomes in Locally Advanced Rectal Cancer.

RATIONALE AND OBJECTIVES: This study aimed to investigate the predictive value of pre-/postneoadjuvant chemoradiotherapy (nCRT) magnetic resonance imaging (MRI) characteristics for the long-term survival outcomes in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: We retrospectively evaluated pre- and post-nCRT MRI and clinicopathologic characteristics of LARC patients. The 3-year disease-free survival (DFS) was estimated using the Kaplan-Meier product-limit method. Associations between MRI variabilities and survival outcomes were assessed using Cox proportional hazards model. RESULTS: In total, 171 LARC patients (112 men and 59 women) with a median age of 55 years (range, 27-82 years) treated with nCRT were evaluated. The median follow-up was 47.6 months, and the 3-, 4-, and 5-year DFS in the overall cohort was 76.6%, 74.5%, and 73.7%, respectively. MRI assessment of extramural venous invasion (mrEMVI) positivity was a significant independent adverse factor of long-term survival (hazard ratio [HR] = 2.589, 95% confidence interval [CI] = 1.398-4.794, p = 0.002) on multivariate analysis. Patients with positive mrEMVI had significantly lower 3-year DFS than those with negative mrEMVI (52.6 months vs 65.1 months; p = 0.003). Moreover, the tumor regression grade on MRI (mrTRG) also significantly correlated with survival outcomes in patients with LARC. Patients with partial response on post-nCRT MRI (mrPR) showed short DFS than those with complete response (mrCR; HR = 4.914, 95% CI = 1.176-20.533, p = 0.029). The 3-year DFS of mrCR and mrPR patients were 74.3 months and 58.9 months, respectively (p = 0.011). CONCLUSION: The pre-/post-nCRT MRI characteristics may be used to long-term survival stratification in LARC patients. mrEMVI positivity was an independent adverse prognostic indicator for 3-year DFS. Further, mrTRG may also be a predictive factor for the prognosis of LARC patients. The pre-/post-nCRT MR imaging may offer more information for providing individualized treatment.

Developing a prediction model based on MRI for pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: The aim of this study was to build an appropriate diagnostic model for predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC), by combining magnetic resonance imaging (MRI) parameters with clinical factors. METHODS: Eighty-four patients with LARC who underwent MR examination before and after nCRT were enrolled in this study. MRI parameters including cylindrical approximated tumor volume (CATV) and relative signal intensity of tumor (rT2wSI) were measured; corresponding reduction rates (RR) were calculated; and MR tumor regression grade (mrTRG) and other conventional MRI parameters were assessed. Logistic regression with lasso regularization was performed and the appropriate prediction model for pCR was built up. An external cohort of thirty-six patients was used as the validation group for testing the model. Receiver-operating characteristic (ROC) analysis was used to assess the diagnostic performance. RESULTS: In the development and the validation group, 17 patients (20.2%) and 11 patients (30.6%), respectively, achieved pCR. Two CATV-related parameters (CATVpost, which is the CATV measured after nCRT and CATVRR), one rT2wSI-related parameter (rT2wSIRR), and mrTRG were the most important parameters for predicting pCR and were retained in the diagnostic model. In the development group, the area under the receiver-operating characteristic curve (AUC) for predicting pCR is 0.88 [95% confidence interval (CI) 0.78-0.97, p < 0.001], with a sensitivity of 82.4% and a specificity of 83.6%. In the validation group, the AUC is 0.84 (95% CI 0.70-0.98, p = 0.001), with a sensitivity of 81.8% and a specificity of 76.0%. CONCLUSION: A diagnostic model including CATVpost, CATVRR, rT2wSIRR, and mrTRG was useful for predicting pCR after nCRT in patients with LARC and may be used as an effective organ-preservation strategy.

MRI morphologic and clinicopathologic characteristics for predicting outcomes in patients with locally advanced rectal cancer.

PURPOSE: The aim of this study was to investigate the value of MRI morphologic and clinicopathologic factors for predicting 3-year disease-free survival (DFS) in patients with locally advanced rectal cancer (LARC). METHOD: In this retrospective study, pre- and post-neoadjuvant chemoradiotherapy (nCRT) MRI morphologic (e.g., pre-nCRT MRI-detected extramural venous invasion) and clinicopathologic variabilities (e.g., pathological complete response) were evaluated in all patients. Three-year DFS was estimated using Kaplan-Meier product-limit method, and Cox proportional hazards models were used to determine associations between morphologic or clinicopathologic variabilities and survival outcomes. RESULTS: A total of 115 patients (39 females and 76 males; median age, 54 years; age range, 28-82 years) with LARC treated with nCRT were enrolled. With a median follow-up of 48.0 months, the 3-year DFS was 79.0% for all patients. During follow-up, 18 patients died, 28 patients experienced relapse (26 distant, one local, and one both), and 69 patients were censored. MRI-detected extramural venous invasion (mrEMVI) was the only significantly independent factor of long-term survival, while HR was 2.308 (95% CI 1.151-4.629, P = 0.018) on univariate and 2.495 (95% CI 1.243-5.012, P = 0.010) on multivariate analysis. The 3-year cumulative survival rate in patients with mrEMVI negativity compared with positivity were 86.6% versus 65.0% (P = 0.015), respectively. CONCLUSION: In conclusion, pre-nCRT mrEMVI status was the independent significant risk factor for long-term outcomes in LARC patients treated with nCRT, while the other morphologic and clinicopathologic characteristics were not related to the patient survival.

MRI texture analysis in predicting treatment response to neoadjuvant chemoradiotherapy in rectal cancer.

To evaluate the importance of MRI texture analysis in prediction and early assessment of treatment response before and early neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). This retrospective study comprised of 59 patients. The tumoral texture parameters were compared between pre- and early nCRT. Area Under receiver operating characteristic (ROC) Curves [AUCs] were used to compare the diagnostic performance of statistically significant difference parameters and logistic regression analysis predicted probabilities for discriminating responders and nonresponders. The Standard Deviation (SD), kurtosis and uniformity were statistically significantly difference between pre- and early nCRT (p = 0.0012, 0.0001, and < 0.0001, respectively). In pathological complete response (pCR) group, pre-uniformity and pre-Energy were significantly higher than that of nonresponders (p = 0.03 and p < 0.01, respectively), while the pre-entropy in nonresponder was reverse (p = 0.01). The diagnostic performance of pre-kurtosis and pre-Energy were higher in tumor regression grade (TRG) and pCR group (AUC = 0.67, 0.73, respectively). Logistic regression analysis showed that diagnostic performance for prediction responder and nonresponder did not significantly improve compared with to pre-uniformity, energy and entropy in pCR group (AUC = 0.76, p = 0.2794, 0.4222 and 0.3512, respectively). Texture parameters as imaging biomarkers have the potential to prediction and early assessment of tumoral treatment response to neoadjuvant chemoradiotherapy in patients with LARC.

Morphologic predictors of pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: To evaluate the value of morphological parameters that can be obtained conveniently by MRI for predicting pathologically complete response (pCR) in patients with rectal cancer. MATERIALS AND METHODS: A cohort of 101 patients was examined using MRI before and after Neoadjuvant chemoradiotherapy (nCRT). Morphological parameters including maximum tumor area (MTA), maximum tumor length (MTL) and maximum tumor thickness (MTT), as well as cylindrical approximated tumor volume (CATV), distance to anal verge (DTA), and the reduction rates were evaluated by two experienced readers independently. RESULTS: Post-nCRT MTA and MTL, reduction rates and pre-nCRT DTA were proved to be significantly different between pCR and non-pCR with the AUCs of 0.672-0.853. The sensitivity and specificity for assessing pCR were 61.1-89.9% and 59.0-80.7% respectively. No significant correlation between pre-nCRT size measurements and pCR was obtained. CONCLUSION: The convenient morphological measurements may be useful for predicting pCR with moderate sensitivity and specificity. Combining these predictors with the aim of building diagnostic model should be explored.

Novel radiomic signature as a prognostic biomarker for locally advanced rectal cancer.

BACKGROUND: Locally advanced rectal cancer (LARC) patient stratification by clinicoradiologic factors may yield variable results. Therefore, more efficient prognostic biomarkers are needed for improved risk stratification of LARC patients, personalized treatment, and prognostication. PURPOSE/HYPOTHESIS: To compare the ability of a radiomic signature to predict disease-free survival (DFS) with that of a clinicoradiologic risk model in individual patients with LARC. STUDY TYPE: Retrospective study. POPULATION: In all, 108 consecutive patients (allocated to a training and validation set with a 1:1 ratio) with LARC treated with neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). FIELD STRENGTH/SEQUENCE: Axial 3D LAVA multienhanced MR sequence at 3T. ASSESSMENT: ITK-SNAP software was used for manual segmentation of 3D pre-nCRT MR images. All manual tumor segmentations were performed by a gastrointestinal tract radiologist, and validated by a senior radiologist. The clinicoradiologic risk factors with potential prognostic outcomes were identified in univariate analysis based on the Cox regression model for the whole set. The results showed that ypT, ypN, EMVI, and MRF were potential clinicoradiologic risk factors. Interestingly, only ypN and MRF were identified as independent predictors in multivariate analysis based on the Cox regression model. STATISTICAL TESTS: A radiomic signature based on 485 3D features was generated using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The association of the radiomic signature with DFS was investigated by Kaplan-Meier survival curves. Survival curves were compared by the log-rank test. Three models were built and assessed for their predictive values, using the Harrell concordance index and integrated time-dependent area under the curve. RESULTS: The novel radiomic signature stratified patients into low- and high-risk groups for DFS in the training set (hazard ratio [HR] = 6.83; P < 0.001), and was successfully validated in the validation set (HR = 2.92; P < 0.001). The model combining the radiomic signature and clinicoradiologic findings had the best performance (C index = 0.788, 95% confidence interval [CI] 0.72-0.86; integrated time-dependent area under the curve of 0.837 at 3 years). DATA CONCLUSION: The novel radiomic signature could be used to predict DFS in patients with LARC. Furthermore, combining this radiomic signature with clinicoradiologic features significantly improved the ability to estimate DFS (P = 0.001, 0.005 in training set and in validation set, respectively), and may help guide individualized treatment in such patients. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018.

Chemical shift effect predicting lymph node status in rectal cancer using high-resolution MR imaging with node-for-node matched histopathological validation.

OBJECTIVES: To evaluate the value of the chemical shift effect (CSE) as well as other criteria for the prediction of lymph node status. MATERIALS AND METHODS: Twenty-nine patients who underwent radical surgery of rectal cancers were studied with pre- and postoperative specimen MRI. Lymph nodes were harvested from transverse whole-mount specimens and compared with in vivo and ex vivo images to obtain a precise slice-for-section match. Preoperative MR characteristics including CSE, as well as other predictors, were evaluated by two readers independently between benign and metastatic nodes. RESULTS: A total of 255 benign and 35 metastatic nodes were obtained; 71.4% and 69.4% of benign nodes were detected with regular CSE for two readers, whereas 80.0% and 74.3% of metastatic nodes with absence of CSE. The CSE rendered areas under the ROC curve (AUC) of 0.879 and 0.845 for predicting nodal status for two readers. The criteria of nodal location, border, signal intensity and minimum distance to the rectal wall were also useful but with AUCs (0.629-0.743) lower than those of CSE. CONCLUSIONS: CSE is a reliable predictor for differentiating benign from metastatic nodes. Additional criteria should be taken into account when it is difficult to determine the nodal status by using only a single predictor. KEY POINTS: • CSE is good for predicting nodal status with high confidence. • Nodal border and signal intensity are useful for assessing nodal status. • Location of mesorectal nodes could facilitate the prediction of nodal status. • Primary tumour stage could be used as reference for nodal staging.