Utility of ctDNA in predicting response to neoadjuvant chemoradiotherapy and prognosis assessment in locally advanced rectal cancer: A prospective cohort study.

BACKGROUND: For locally advanced rectal cancer (LARC) patients who receive neoadjuvant chemoradiotherapy (nCRT), there are no reliable indicators to accurately predict pathological complete response (pCR) before surgery. For patients with clinical complete response (cCR), a "Watch and Wait" (W&W) approach can be adopted to improve quality of life. However, W&W approach may increase the recurrence risk in patients who are judged to be cCR but have minimal residual disease (MRD). Magnetic resonance imaging (MRI) is a major tool to evaluate response to nCRT; however, its ability to predict pCR needs to be improved. In this prospective cohort study, we explored the value of circulating tumor DNA (ctDNA) in combination with MRI in the prediction of pCR before surgery and investigated the utility of ctDNA in risk stratification and prognostic prediction for patients undergoing nCRT and total mesorectal excision (TME). METHODS AND FINDINGS: We recruited 119 Chinese LARC patients (cT3-4/N0-2/M0; median age of 57; 85 males) who were treated with nCRT plus TME at Fudan University Shanghai Cancer Center (China) from February 7, 2016 to October 31, 2017. Plasma samples at baseline, during nCRT, and after surgery were collected. A total of 531 plasma samples were collected and subjected to deep targeted panel sequencing of 422 cancer-related genes. The association among ctDNA status, treatment response, and prognosis was analyzed. The performance of ctDNA alone, MRI alone, and combining ctDNA with MRI was evaluated for their ability to predict pCR/non-pCR. Ranging from complete tumor regression (pathological tumor regression grade 0; pTRG0) to poor regression (pTRG3), the ctDNA clearance rate during nCRT showed a significant decreasing trend (95.7%, 77.8%, 71.1%, and 66.7% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.008), while the detection rate of acquired mutations in ctDNA showed an increasing trend (3.8%, 8.3%, 19.2%, and 23.1% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.02). Univariable logistic regression showed that ctDNA clearance was associated with a low probability of non-pCR (odds ratio = 0.11, 95% confidence interval [95% CI] = 0.01 to 0.6, P = 0.04). A risk score predictive model, which incorporated both ctDNA (i.e., features of baseline ctDNA, ctDNA clearance, and acquired mutation status) and MRI tumor regression grade (mrTRG), was developed and demonstrated improved performance in predicting pCR/non-pCR (area under the curve [AUC] = 0.886, 95% CI = 0.810 to 0.962) compared with models derived from only ctDNA (AUC = 0.818, 95% CI = 0.725 to 0.912) or only mrTRG (AUC = 0.729, 95% CI = 0.641 to 0.816). The detection of potential colorectal cancer (CRC) driver genes in ctDNA after nCRT indicated a significantly worse recurrence-free survival (RFS) (hazard ratio [HR] = 9.29, 95% CI = 3.74 to 23.10, P < 0.001). Patients with detectable driver mutations and positive high-risk feature (HR_feature) after surgery had the highest recurrence risk (HR = 90.29, 95% CI = 17.01 to 479.26, P < 0.001). Limitations include relatively small sample size, lack of independent external validation, no serial ctDNA testing after surgery, and a relatively short follow-up period. CONCLUSIONS: The model combining ctDNA and MRI improved the predictive performance compared with the models derived from individual information, and combining ctDNA with HR_feature can stratify patients with a high risk of recurrence. Therefore, ctDNA can supplement MRI to better predict nCRT response, and it could potentially help patient selection for nonoperative management and guide the treatment strategy for those with different recurrence risks.

Intradural Neuroanatomy in the Cervical Spinal Canal: Importance of a New Anatomic Zone Division and Accurate Assessment of Neural Compression in Myeloradiculopathy Patients.

MINI: This study defined different anatomic zones within the cervical spinal canal and provides detailed anatomical quantitative data for an accurate diagnosis of cervical spondylosis and a safe and effective anterior decompression surgery.

A dissection-based study of 10 embalmed human cadavers. To provide an anatomic basis to examine the underlying mechanisms of cervical spondylosis. Detailed anatomical quantitative data of cervical spine is limited in current literature. Ten cervical spines from C2 to T1 were obtained. We defined three zones from midline to lateral part (zone I, II, and III) and two zones from cranial to caudal (zone P and zone IP) on the coronal plane within the cervical spinal canal. Quantitative anatomy of the zones at different cervical segments were measured including: (1) horizontal widths of zone I, II, and III; (2) length of the cervical spinal cord segment at the ventral rootlets (LV); (3) the pedicle height (PH, zone P) and the inter-pedicle height (IPH, zone IP); (4) the distance between the superior margin of pedicle and the exit of the uppermost ventral nerve rootlet (PN). The value of zone II at C4 was significantly less than that at other levels. The value of zone III increases from C4 to C8, and the values at C7 and C8 were significantly higher than those at C4, C5, and C6. PHs and IPHs were not significantly different between different levels. The values of LV at C4 and C8 were smaller than those of C5, C6, and C7. The value of PN showed an increasing trend. At C4, the uppermost ventral rootlet was at about the same height as C3 pedicle, while C8 uppermost ventral rootlet was at the same level as the inferior part of C6 pedicle. Ventral intradural intersegmental connections were found in three intersegments out of 20 intersegments. The current definition of anatomic zones may be useful for an accurate diagnosis of cervical spondylosis and a safe and effective anterior decompression surgery. Level of Evidence: N/A.

Changes in diffusion tensor imaging indices of the lumbosacral enlargement correlate with cervical spinal cord changes and clinical assessment in patients with cervical spondylotic myelopathy.

OBJECTIVES: We examined whether changes in diffusion tensor imaging (DTI) indices of the lumbosacral enlargement are similar to those at the cervical level, and correlate with clinical assessments in patients with cervical spondylotic myelopathy (CSM). PATIENTS AND METHODS: Patients with CSM and healthy volunteers (40-42/group) received DTI scans at both lumbosacral enlargement and cervical spinal cord. Modified Japanese Orthopedic Association (mJOA) score was also recorded for those with CSM. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of DTI in the two groups were compared. We also examined the correlation between DTI indices (ADC and FA) of the lumbosacral enlargement and those of the cervical spinal cord, and between DTI indices and mJOA in the CSM group. RESULTS: Compared with the values of healthy subjects, the ADC values of patients with CSM were significantly increased, and FA values were significantly decreased at both cervical spinal cord and lumbosacral enlargement. Changes in FA value of the cervical cord showed a positive correlation to those of the lumbosacral enlargement in the CSM group. Importantly, a linear correlation was detected between mJOA score and DTI indices (ADC and FA) of the cervical cord, as well as FA value of the lumbosacral enlargement in the CSM group. CONCLUSION: DTI indices, especially FA, of the lumbosacral enlargement correlate with clinical assessments of patients with CSM, and hence may be useful for evaluating the severity of cervical cord injury.

[Speciation Distribution and Risk Assessment of Heavy Metals in Typical Material Roof Dusts].

With the modified BCR sequential extraction procedure, the chemical speciation and risk for 10 heavy metals (Ba, Co, Cr, Cu, Mn, Ni, Pb, Sb, Sr and Zn) in roof dusts were investigated. The subjects of this study were collected from four typical material paved roofs (i. e., ceramic tile, concrete, metal and asphalt) in southeast China. The results indicated that the average contents of heavy metals in roof dust significantly exceeded road dust. The analysis of chemical fraction showed that the acid soluble/exchangeable fraction of Zn was much higher than other elements, the existence of Pb and Cu was mainly in oxidization fraction, while other heavy metals dominated by the residual fraction. The mobility sequence percentages for all roof dust samples decreased in the order of Pb > Zn > Cu >>Mn > Co >>Sr > Sb > Ni > Ba > Cr, and it should be noted that Pb, Zn, Cu, Mn and Co all have more than 50% proportion in mobility sequence. Based on environmental risk assessment, the highest values of contamination factors (Cf) and risk assessment code (RAC) consistently was observed in Zn, which indicated that Zn had relatively high ecological risk. Health risk assessment showed that the non-carcinogenic hazard indexes (HI) of heavy metals decreased in the order of Pb > Cr > Sb > Zn > Mn > Cu > Ba > Ni > Co > Sr, the HI of heavy metals for adults were lower than safe value while the HI of Pb for children was higher than safe value, suggesting that they will not harm the adult's health except Pb for children. The carcinogenic risk for Cr, Co and Ni were all below the threshold values, which indicated that there was no carcinogenic risk.