| Part ⅠA multicenter study of using carbon nanoparticles to show sentinel lymph nodes in early gastric cancerBackground and purposeGastric cancer is one of the common malignant tumors in the digestive system. According to the latest information,1 million patients developed gastric cancer, while 800 thousands patients died of it every year in the world. The incidence and mortality of gastric cancer lie in the fourth and the second places respectively. In our country, the new cases of gastric cancer is about 400 thousands and 300 thousands persons die of it. Early gastric cancer (EGC) refers to the cancerous tissue limited to the mucosal or the submucosal, no matter how big the tumor is and lymph node status. Compared with advanced gastric cancers, the early ones have a better prognosis owing to low rates of lymph node metastasis and distant recurrence, and the 5-year survive is above 90%. Therefore, the early diagnosis and treatment of gastric cancer is very important.Recently, with the improvement of social economy, the emphasis on peoples’ health consciousness, the popularity of digestive endoscopy, and the perfection of tumor screening strategy, there is an upward trend in the discovery of early gastric cancer. Currently, surgical treatment for early gastric cancer includes laparoscopic or open total or subtotal gastrectomy with D1/D2 lymphadenectomy, full-thickness resection with basin lymphadenectomy, and endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). Gastrectomy with D1/D2 lymphadenectomy remains the cornerstone treatment for patients with early gastric cancer.It is reported that lymph node metastasis occurs in approximately 10% of early gastric cancer. What’s more, study by Sekiguchi et al in large cases founds that most of early gastric cancer were without lymph node metastasis. For these patients standard gastrectomy with D2 lymph node detection may increase the surgical trauma and postoperative complications, and affect patients with postoperative quality of life.Japanese gastric cancer association(JGCA) treatment guidelines clearly demonstrated the treatment of early gastric cancer:for patient with lymph node metastasis, standard gastrectomy is necessary; while for patient without lymph node metastasis, local resection or combined with D1 lymphadenectomy may be enough. Therapeutic endoscopies such as EMR and ESD have emerged as a treatment option in recent years.Knowledge of the lymph node status not only affects prognosis but also shapes treatment decisions. However, no single feature of the primary tumor convincingly and reliably predicts lymph nodes metastases at present. Existing imaging examination means, such as EUS, CT, MRI, even PET-CT, for lymph node status assessment is still lack of accuracy and sensitivity. Additionally, how to identify patient with or without lymph node metastasis intro-operation is very difficult. Therefore, exploring an accurate judgment method for regional lymph node status in gastric cancer is of significance, which has been the hot topic of gastric cancer study.The sentinel lymph node (SLNs) is the first regional lymph node to accept the primary tumor draining, also the first stop where tumor metastasis would occur. Hence, it could predict the regional lymph node metastasis status. Therefore, sentinel lymph nodes (SLNs) biopsy is necessary for early gastric cancer to make sure whether or not patient has lymph node metastasis. Unfortunately, in contrast to several other malignant tumors such as melanoma and breast cancer, the type of dye and procedure used to show sentinel lymph nodes in gastric cancer has not been well established.In recent years, with the development of nanotechnology, nano materials have been used more and more widely in medicine. Carbon nanoparticles suspension comprises nanosized carbon particles with an average diameter of 150 nm, which ensures that these particles pass through the lymphatic vessels rather than blood capillaries due to the molecular size and permeability. Submocosal injection into the tissues around the tumor, carbon nanoparticles are rapidly engulfed by macrophages. The particles then enter the lymphatic vessels and accumulate in the lymph nodes, thus staining them black. This technique has facilitated the vital staining of tumor-draining lymph nodes and has been applied in the detection of sentinel lymph nodes (SLNs) in breast and thyroid cancers.To date, treatment decisions for early gastric cancer vary based on lymph nodes status. How to identify whether or not early gastric cancer has lymph node metastasis is still a crucial problem in clinic, which prompts us to perform this multicenter study to investigate the feasibility of using carbon nanoparticles to show sentinel lymph nodes (SLNs) in early gastric cancer.Material and MethodsPatientsA multicenter study was performed between July 2012 and November 2014 by Nanfang Hospital Sourthem Medical University, Fujian Provincial Hospital, and Fujian Provincial Tumor Hospital. Inclusion criteria include 18-70 years of age, single gastric cancer confirmed by preoperative endoscopic biopsy, T1 stage evaluated by endoscopic ultrasonography, American Society of Anesthesiologists (ASA) class 1-3, with ECOG 0-1, without EMR or ESD, without history of abdominal surgery and planned radical resection. Exclusion criteria included multiple centricities, combined with other maliganants, emergency case with obstruction or o bleeding or perforation, patient received chemotherapy, radiotherapy or both prior to surgery, and distant metastasisCarbon nanoparticles injectionOne milliliter carbon nanoparticles suspension was endoscopically injected into the submucosal layer at four points around the site of the primary tumor 6-8 hours before surgery.Surgery and lymph node detectionLaparoscopic radical gastrectomy with D2 or D2- lymphadenectomy was performed for all patients. Lymph nodes were detected as detailed as possible after surgery. SLNs were defined as nodes that were black-dyed by carbon nanoparticles in greater omentum and lesser omentum near gastric cancer.Main outcome measuresLymph node status and SLNs accuracy were confirmed by pathological analysis.Results1. Sentinel lymph node traced by carbon nanoparticles were successful in all the 91 patients with early gastric cancer. During the operation, SLNs were easily found under Laparoscopy.2. There were 394 SLNs harvested in total. The mean number of SLNs was 4 (range 1-9).3. After pathological analysis,10 patients (10.99%) had lymph node metastasis in 91 patients with early gastric cancer, among which SLNs were positive in 9 cases. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of black-dyed SLNs in early gastric cancers were 90%,100%,98.9%, 100%, and 98.78%, respectively.ConclusionsSentinel lymph node traced by carbon nanoparticles could accurately predict the status of regional lymph node metastasis and may be helpful for lymphadenectomy and individualized treatment for early gastric cancer.Part ⅡA multicenter study of using carbon nanoparticles to track lymph nodes metastasis in T1-2 colorectal cancerBackground and purposeColorectal cancer is one of the common malignant tumors in the digestive system. In the whole world, colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, with the highest incidence in 40-50 years people. It seriously threatens human health. Recently, the incidence of CRC presents an increasing tendency in our country. According to some statistic, the new cases of gastric cancer are about 250 thousands and 140 thousands persons die of it. The new cases and the death ones respectively account for about 20% of the cases happening in the world at the same period. And it occurs more often in younger patients.Surgery is still the main treatment for colorectal cancer, and lymphadenectomy is one important part of radical resection for colorectal cancer. Additionally, lymph node metastasis is considered to be the most important factor influencing the prognosis of colorectal cancer. However, there still have different points of view on the extent and indication of lymph node detection. Recently, with the popularity of endoscopy and the development of endoscopic technique, there is an upward trend in the discovery of early colorectal cancer. The rate of lymph node metastasis is relatively low and the prognosis is good, so how to choose the suitable treatment still be a clinician concern. With the development of endoscopic treatment and surgical technique, individualized treatment, such as endoscopic mucosal or submucosal resection, local excision etc., has gradually become a new treatment choice for the patients with early colorectal cancer. Many scholars believe that local excision may achieve the effect of radical surgery for early colorectal cancer patients without lymph node metastasis, which reduces trauma incidence of postoperative complications and the treatment cost, and improve the life quality of the patients.Lymph nodes metastases are not as common in early colorectal cancers, occurring in 8.0-14.5% of T1 tumors and 18.4-23.9% of T2 tumors. However, only local resection inevitably leads to tumor recurrence and distant metastasis postoperatively for these patients with lymph node metastasis; Contrast, blindly expanding the scope of the operation for a radical cure may be appropriate to increase the surgical trauma, postoperative complications, and perioperative mortality.Ideally, patients with tumors at high risk for associated lymph nodes metastases would undergo radical resection, while the remainder could be treated with local excision and diligent clinical follow-up. Knowledge of the lymph node status not only affects prognosis but also shapes treatment decisions. However, no single feature of the primary tumor convincingly and reliably predicts lymph nodes metastases at present. Existing imaging examination means, such as EUS, CT, MRI, even PET-CT for lymph node status assessment is still lack of accuracy and sensitivity. Therefore, sentinel lymph nodes biopsy is necessary for T1-2 colorectal cancer to make sure whether or not patient has lymph node metastasis. Unfortunately, in contrast to several other malignant tumors such as melanoma and breast cancer, the type of dye and procedure used to show sentinel lymph nodes in gastric cancer has not been well established.In recent years, with the development of nanotechnology, nano materials have been used more and more widely in medicine. Carbon nanoparticles suspension comprises nanosized carbon particles with an average diameter of 150 nm, which ensures that these particles pass through the lymphatic vessels rather than blood capillaries due to the molecular size and permeability. Submocosal injection into the tissues around the tumor, carbon nanoparticles are rapidly engulfed by macrophages. The particles then enter the lymphatic vessels and accumulate in the lymph nodes, thus staining them black. This technique has facilitated the vital staining of tumor-draining lymph nodes, and has been applied in the detection of sentinel lymph nodes (SLNs) in breast and thyroid cancers.Based on these, the purpose of this study is to investigate the feasibility of using carbon nanoparticles to show sentinel lymph nodes in T1-2 colorectal cancer and its clinical value.Material and MethodsPatientsA multi-center study was performed between July 2012 and January 2014 by Nanfang Hospital Sourthern Medical University, Fujian Provincial Hospital, and Fujian Provincial Tumor Hospital. Inclusion criteria include 18-70 years of age, single colorectal cancer confirmed by colonoscopy biopsy, T1-2 cancer evaluated by EUS, American Society of Anesthesiologists (ASA) class 1-3, with ECOG 0-1, without EMR or ESD, without significant history of abdominal surgery, and planned radical resection. Exclusion criteria included multiple centricities, combined with other malignant, emergency case with obstruction or o bleeding or perforation, patient received chemotherapy, radiotherapy or both prior to surgery, and distant metastasisCarbon nanoparticles injectionOne milliliter carbon nanoparticles suspension was endoscopically injected into the submucosal layer at four points around the site of the primary tumor 6-8 hours before surgery (usually in the morning of the surgery day).Surgery and lymph node detectionLaparoscopic radical resection with D3 lymphadenectomy was performed. Carbon nanoparticles-dyed lymph nodes were identified from all dissected lymph nodes. SLNs were defined as nodes that were black-stained by carbon nanoparticles. Histologic analysis of all resected nodes was performed on hematoxylin and eosin stained sections.Main outcome measuresPathology confirmed whether lymph nodes have cancer metastases and the accuracy of SLNs dyed by carbon nanoparticles in T1-2 colorectal cancers.Results1. Sentinel lymph node traced by carbon nanoparticles were successful in all the 73 patients with T1-2 colorectal cancer. During the operation, SLNs were easily found under Laparoscopy. The mean number of SLNs was 3 (range 1-5).2. After pathological analysis,2 patients (9.52%) had lymph node metastasis in 21 patients with EUS T1 cancers, and 10 patients (19.23%) had lymph node metastasis in 52 patients with EUS T2 cancers.3. In two T1 cases with lymph node metastasis, SLNs were positive with 100% accuracy. In ten T2 cases with lymph node metastasis, SLNs were positive in nine cases. The sensitivity, specificity, and accuracy of SLNs in T2 colorectal cancers were 90%,100%, and 98%, respectively.4. Taken together, the overall sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of SLNs in T1-2 colorectal cancers were 91.67%,100%,98.63%,100%,98.39%, respectively.ConclusionsSentinel lymph node black-dyed by carbon nanoparticles could accurately predict the metastatic status of regional lymph node, which may be valuable for lymphadenectomy and individual treatment for T1-2 colorectal cancer.Part Ⅲ Preoperative submucosal injection of carbon nanoparticles improves small lymph node harvest and staging accuracy in colorectal cancerBackground and purposeLymph node status of colorectal is an important factor in its positive adjuvant treatment and prognosis. Lymph node metastasis affects patients with postoperative treatment options and prognosis, especially for patients with stage Ⅱ and stage Ⅲ tumors.Related studies demonstrated that survival would be improved by 17% for patients with lymph node metastasis received positive adjuvant treatment than those only underwent radical surgery. In addition, some study found that 15%-25% patients diagnosed with stage Ⅰ or stage Ⅱ colorectal occurred recurrence or distant metastasis in the following 5 years after radical surgery.At present, how many number of lymph node should be harvested from the colorectal cancer specimen is still controversial. To achieve appropriate node staging, the AJCC recommend that at least 12 lymph nodes should be obtained from a colorectal cancer specimen with some studies suggesting that obtaining even more nodes may be beneficial. However, population-based data suggest that lymph node evaluation is not adequate in the majority of patients with colorectal cancer, even some patients with lymph nodes harvested less than 12. The number of lymph node detection from the specimen may be affected by many factors, such as gender, age, degree of obesity, tumor site, tumor differentiation, the picking of lymph node, preoperative neoadjuvant therapy, etc. Of the above factors, the picking of lymph node is considered to be the most important one. Now there is no unified specification on the lymph node detection from the tumor specimen. Most still adopts the traditional method of macroscopic observation and hand touching to detect lymph node, of which the sensitivity is relatively low. And many small lymph nodes are often hidden in the fat or mesangial, which often cannot be touched. So the may be some residual small lymph node. Unfortunately, these small nodes have an opportunity to occur metastasis, which may cause residual of cancer cell and result inaccurate tumor staging and affect the subsequent treatment.To investigate the metastatic status of the small lymph node, some scholarship defined the nodes with diameter less than 5mm as small lymph node, and do some research on these small nodes. In a retrospective study, Rodriquez-Bigasa eta found that 45.4% metastatic lymph node were the nodes with diameter less than 5mm. The study of Jin Fu found that about 8% nodes with diameter less than 4mm occur metastasis. In terms of prognosis, related studies showed that small lymph node metastasis were obviously correlated with the prognosis of patients. The study of Scott etc. used fat-soluble method to detect lymph node. In this study, they analyzed the 5-year survival and found that 4 of 5 patients who upstaged from stage II to stage III due to the detection of positive small lymph node died of tumor recurrence in the 5 years follow-up after surgery. And Miguel etc. found that the effect of lymph node metastasis on the prognosis of colorectal cancer has nothing to do with lymph node size. The positive small lymph node also is an important factor in its prognosis. Therefore, the small lymph node should be considered into the lymph node staging.To improve lymph node harvest, many techniques haves been used, such as fat clearance, fat lucidification, immunochemistry staining etc. However, their widely use were limited due to the complexity of the technical program, time-consuming and needing some special equipment. In recent years, with the development of nanotechnology, carbon nanoparticles have been used as a lymph node tracer in breast and thyroid cancers. An injection of carbon nanoparticles suspension comprises nanosized carbon particles with an average diameter of 150 nm, which ensures that these particles pass through the lymphatic vessels rather than blood capillaries due to the molecular size and permeability. Upon injection into the tissues around the tumor, carbon nanoparticles are rapidly engulfed by macrophages. The particles then enter the lymphatic vessels and accumulate in the lymph nodes, thus staining them black. This technique has facilitated the vital staining of tumor-draining lymph nodes.Based on these, this study aim to explore the value of carbon nanoparticles on small lymph node detection and staging accuracy.Material and MethodsPatientsA prospective study was performed between September 2014 and August 2015.by Nanfang Hospital Sourthern Medical University, Fujian Provincial Hospital, and Fujian Provincial Tumor Hospital.Inclusion criteria include 18-70 years of age, colorectal cancer confirmed by preoperative colonoscopy biopsy, single colorectal cancer without other carcinoma, American Society of Anesthesiologists (ASA) class 1-3, ECOG 0-1, planned radical resection. Exclusion criteria included multiple centricities, combined with other malignant, emergency case with obstruction or perforation bleeding or, and patient received chemotherapy, radiotherapy or both prior to surgery, and distant metastasis.Preoperative management in the two group patientsIn the carbon nanoparticles group, one milliliter carbon nanoparticles suspension was endoscopically injected into the submucosal layer at four points around the site of the primary tumor one day before surgery, while in the control group, no treatment was performed.Surgery and lymph node detectionLaparoscopic radical resection was performed for the two group’s patients. For rectal cancer, total mesorectal excision (TME) was used with careful dissection in the plane between the embryologic mesorectal and parietal fascia. For colon cancer, complete mesocolic excision (CME) with central vascular ligation was performed.The number and the metastatic status were compared between the carbon nanoparticles group and the control group.Statistical AnalysisStatistical analyses were carried out using SPSS for Windows version 17.0.A p value of<0.05 was considered statistically significant.Results1. The mean number of lymph nodes harvested in carbon nanoparticles group (25.5±6.5) was higher than that in control group (16.8±4.6) (P<0.01). And the mean number of small lymph nodes harvested in carbon nanoparticles group (10.6±4.2) was higher than that in control group (2.7±1.8) (P<0.01). The percentage of patients with lymph node less than 12 in carbon nanoparticles group was lower than that in the control group (1.7% vs.133%, p=0.032).2. The number of positive lymph node harvested in carbon nanoparticles group was 429, higher than that in the control group 322. The number positive small nodes harvested in carbon nanoparticles group was52, higher than that in the control group 13. However, there were no significantly different in lymph node positive radio (P> 0.05). The rate of lymph node metastasis in carbon nanoparticles was higher than that in the control group, but without significance (1.7% vs.13.3%, p=0.032)3. In carbon nanoparticles group, the rates of dyed nodes were 78.2% for all lymph nodes,95.7% for lymph nodes with diameter less than 3 mm and 88.6% for lymph nodes with diameter 3-5mm. Among the 11 metastatic lymph nodes with diameter less than 3 mm,10 (90.9%) were dyed. Of the 41 metastatic lymph nodes with diameter 3-5mm,38 (92.7%) were dyed.ConclusionCarbon nanoparticles could effectively trace the lymph node of colorectal cancer and improve the harvest of lymph node, especially the detection of small lymph node, which may be helpful for accurate assessment of tumor staging. |
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