| Valid pathologic assessment of lymph node involvement is a crucial component of staging because it provides the most relevant indication of prognosis and is a determinant of further treatment strategies for patients with colorectal cancer.To achieve appropriate node staging,current guidelines recommend that at least 12 to 14 lymph nodes should be obtained from a colorectal cancer specimen,with certain studies suggesting that obtaining even more nodes may be beneficial.Neoadjuvant chemoradiotherapy(NCRT)followed by total mesorectal excision is the current standard of treatment for patients with locallyadvanced rectal cancer,improving local tumor control and allowing sphincter-preserving surgery.However,recent reports have identified a significant decrease in the number of lymph nodes detected in surgical specimens from patients with rectal cancer after NCRT.Although the influence of this reduction in lymph node detection on node staging accuracy is still controversial,certain studies have shown a significantly higher number of nodes harvested from node-positive patients compared with node-negative patients.Accurate positive nodal status was recently shown to be associated with prognosis and to help to guide adjuvant chemotherapy in patients with rectal cancer after NCRT.Therefore,improving lymph node detection is beneficial to patient outcomes.In a previous study,we found that submucosal carbon nanoparticle(CNP)staining can improve lymph node retrieval from gastrointestinal carcinoma specimens,without additional operative or pathologic time requirements.To further investigate the relationship between the number of nodes retrieved and the rate of node positivity,and to evaluate the effect of submucosal CNP staining on improvements in lymph node detection and staging accuracy,we have used this technique since August 2013 in patients who have received NCRT followed by curative resection.Carbon nanoparticles(CNPs),a type of dye widely used in the clinic to map LNs,can improve LN retrieval in carcinoma cases.[12]In a previous study,CNPs were injected into the tumor submucosal or subserosal layer 1 day before surgery,and the particles then quickly entered into the lymphatic vessels instead of the bloodstream because of their diameter limits(100?200 nm).The CNPs gathered together in LNs,thereby dying the nodes black to clearly map regional LNs.Even though CNPs have a high degree of lymphatic targeting,they are similar to other dyes that have no tumor specificity,and most of the time,CNPs can only be used to improve the rate of LN detection and shorten detection time.[4]Therefore,we chose to synthesize modifiable polymeric nanoparticles that not only possess a high degree of lymphatic targeting but can also carry fluorescent material for intraoperative metastatic LN mapping.To address these issues,in this research,we first designed a dextran-coated iron oxide nanocluster(DION),which mainly consists of Fe3+/Fe2+ and dextran.The diameter of the DIONs was limited to 100?200 nm,similar to CNPs,so that the DIONs will specifically gather together within LNs.Furthermore,because the modifiable dextran contains a large number of hydroxyl groups,which can be conjugated to drugs or fluorescent material either by direct attachment or through a linker,there exists a potential application in the specific diagnosis and treatment of metastatic LNs.[13-16]Therefore,the main purpose of this study is to evaluate the effectiveness of DIONs in regional LN mapping and the biosafety of these nanoparticles after injection,thereby laying a foundation for further clinical use and functionalized modifications.Part ?Preoperative Submucosal Injection of Carbon Nanoparticles Improves Lymph Node Staging Accuracy in Rectal Cancer after Neoadjuvant ChemoradiotherapyAIM:The aim of this study was to evaluate the association between the number of nodes harvested and the rate of node positivity,and to evaluate the effect of carbon nanoparticles(CNPs)in improving lymph node detection and staging accuracy in patients who received neoadjuvant chemoradiotherapy(NCRT)followed by curative resection.STUDY DESIGN:Between September 2008 and June 2014,152 consecutive rectal cancer patients treated with NCRT and curative resection were included.Forty-five patients underwent preoperative submucosal injection of CNPs(CNP group);the other patients underwent surgery only(control group).The relationship between the number of lymph nodes harvested and the rate of node positivity was investigated.A comparison of the number of harvested lymph nodes and the node positivity rate between the 2 groups was also performed.The lymph nodes in the CNP group were analyzed in detail.RESULTS:The rate of node positivity increased gradually from 8.6%in patients with 1 to 5 nodes assessed to 37.8%in patients with 17 to 44 nodes assessed.The number of lymph nodes harvested was an independent risk factor for node positivity(p 1/4 0.036).The mean number of lymph nodes retrieved in the CNP group was more than in the control group(21.1 vs 8.0,p 1/4 0.000).The percentage of patients with positive lymph nodes was lower than in the control group(19.6%vs 35.6%,p 1/40.037).In the CNP group,of 58 metastatic lymph nodes,45(77.6%)were dyed.Of 37 metastatic lymph nodes smaller than 5 mm,33(89.2%)were dyed.CONCLUSIONS:More precise oncologic prognosis assessment was provided for patients with rectal cancer after NCRT by increasing the number of lymph nodes counted using a dye-tracing method,indicating that the use of CNPs is beneficial.Part ?One-Pot Synthesis of Dextran-coated Iron Oxide Nanoclusters for Real-time Regional Lymph Node MappingAim:The intraoperative precision cleaning of lymph nodes(LNs)is an essential component of treating neoplastic disease.The aim of this study was to develop efficient probes for the targeted detection of LNs and that could act as carriers for the specific diagnosis and treatment of metastatic lymph nodes in the futurnMethods:In this study,dextran-coated iron oxide nanoclusters(DIONs)were synthesized using a one-pot co-precipitation procedure.The cytotoxicity was evaluated using lymphatic endothelial cells(LECs)to predict biosafety and biocompatibility.Most importantly,the effectiveness of DIONs in mapping perigastric lymph nodes in Sprague-Dawley mice following injection into the gastric submucosal layer was demonstrated.Results:These modified DIONs have good water dispersibility,cytocompatibility,an optimum size and a stable,dark brown color for LN imaging.In addition,a long-term tracing in vivo(from 4 days to 3 months)indicated that the DIONs had good biosafety and biocompatibility according to an evaluation of the behavior and blood biochemistry of the mice and a histopathological examination of the important organs.Conclusions:In conclusion,we have successfully developed newly modifiable DIONs with an optimum diameter to realize intraoperative visual guidance for LN mapping similar to CNPs.Furthermore,the results from both in vitro and in vivo evaluations indicated that DIONs would not enter the blood circulation to develop biological toxicity.All of these current results support the possibility that DIONs could be used for specific,sensitive and safe LN mapping.In addition,our recent preliminary studies further demonstrated that DIONs could also serve as a safe and effective material carrier for tumor-specific tracers and targeted chemotherapy. |
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