Recent updates and current issues of sentinel node navigation surgery for early gastric cancer

With the increase in the incidence of early gastric cancer(EGC),several endoscopic and laparoscopic approaches,such as endoscopic submucosal dissection and function-preserving gastrectomy,have been accepted as standard treatments.Sentinel node navigation surgery(SNNS)is an ideal surgical option for preservation of most parts of the stomach and consequent maintenance of normal gastric function to improve quality of life in patients with EGC.Although many previous studies and clinical trials have demonstrated the safety and feasibility of the sentinel node concept in gastric cancer,the clinical application of SNNS is debatable.Several issues regarding technical standardization and oncological safety need to be resolved.Recently several studies to resolve these problems are being actively performed,and SNNS might be an important surgical option in the treatment of gastric cancer in the future.

Current status and challenges in sentinel node navigation surgery for early gastric cancer

Although a number of feasibility studies for sentinel node （SN） concepts in gastric cancer have been conducted since 2000, there remains a debate regarding detailed detection techniques and oncological safety. Two important multicenter phase II clinical trials were performed in Japan that used different methods and reached different conclusions; one confirmed acceptable results with a false-negative rate of 7%, and the other showed an unacceptably high false-negative rate of 46.4%. The Sentinel Node Oriented Tailored Approach （SENORITA） trial is a multicenter randomized controlled phase 1/I trial being performed in Korea. Patient enrollment is now complete and the long-term results are currently awaited. Recently, an image-guided SN mapping technique using infrared ray/fluorescence was introduced. This method might be a promising technology because it allows the clear visualization of SNs. With regard to the primary tumor, the non-exposed endoscopic wall-inversion surgery technique and non-exposure endolaparoscopic full-thickness resection with simple suturing technique have been reported. These methods prevent abdominal infection and tumor seeding and can be good alternatives to conventional laparoscopic gastric wedge resection. For indications, SN navigation surgery can be extended to patients who underwent non-curative endoscopic resection. Although a few studies have been performed on these patients, sentinel concepts may be beneficial to patients as they omit the need for additional gastrectomy. SN navigation surgery can lead to actual organ-preserving surgery and plays a key role in improving the quality of life of patients with early gastric cancer in the future.

Life prognosis of sentinel node navigation surgery for early-stage gastric cancer:Outcome of lymphatic basin dissection

BACKGROUND Lymphatic basin dissection is a sentinel node biopsy method that is specific for gastric cancer.In this method,the dyed lymphatic system is dissected en bloc,and sentinel nodes are identified at the back table(ex vivo).Even with lymphatic basin dissection,blood flow to the residual stomach can be preserved,and functionpreserving curative gastrectomy can be performed.The oncological safety of function-preserving curative gastrectomy combined with lymphatic basin dissection has not yet been fully investigated.We hypothesized that the oncological safety of sentinel node navigation surgery(SNNS)is not inferior to that of the guidelines.AIM To investigate the life prognosis of SNNS for gastric cancer in comparison with guidelines surgery.METHODS This was a retrospective cohort study.Patients were selected from gastric cancer patients who underwent sentinel node biopsy from April 1999 to March 2016.Patients from April 1999 to August 2008 were from the Department of Surgery II,Kanazawa University Hospital,and patients from August 2009 to March 2016 were from the Department of Surgical Oncology,Kanazawa Medical University Hospital.Patients who were diagnosed with gastric cancer,which was preoperatively diagnosed as superficial type(type 0),5 cm or less in length,clinical T1-2 and node negative,and underwent various gastrectomies guided by sentinel node navigation were retrospectively collected.The overall survival(OS)and relapsefree survival(RFS)of these patients(SNNS group)were investigated.Patients with gastric cancer of the same stage and who underwent guidelines gastrectomy with standard nodal dissection were also selected as the control group.RESULTS A total of 239 patients in the SNNS group and 423 patients in the control group were included.Pathological nodal metastasis was observed in 10.5%and 10.4%of the SNNS and control groups,respectively.The diagnostic abilities of sentinel node biopsy were 84%and 98.6%for sensitivity and accuracy,respectively.In the SNNS group,81.6%of patients underwent modified gastrectomy or functionpreserving curative gastrectomy with lymphatic basin dissection,in which the extent of nodal dissection was further reduced compared to the guidelines.The OS rate in the SNNS group was 96.8%at 5 years and was significantly better than 91.3%in the control group(P=0.0014).The RFS rates were equal in both groups.After propensity score matching,there were 231 patients in both groups,and the cumulative recurrence rate was 0.43%at 5 years in the SNNS group and 1.30%in the control group,which was not statistically different.CONCLUSION The oncological safety of patients who undergo gastrectomy guided by sentinel node navigation is not inferior to that of the guidelines surgery.

Current status and challenges in sentinel node navigation surgery for early gastric cancer

As an optimal surgical procedure to accurately evaluate lymph node(LN)metastasis during surgery with minimal surgical resection,we have been developing sentinel node(SN)biopsy for early gastric cancer since the 1990s.Twelve institutions from the Japanese Society of Sentinel Node Navigation Surgery(SNNS),including Keio University Hospital,conducted a multicenter prospective trial to validate the SN concept using the dual-tracer method with blue dye and a radioisotope.According to the results,397 patients were included in the final analysis,and the overall accuracy in detecting LN metastasis using SN biopsy was 99%(383 of 387).Based on the validation study,we are targeting cT1N0 with a primary tumor of≤4 cm in diameter as an indication for SN biopsy for gastric cancer.We are currently running a multicenter nonrandomized phaseⅢtrial to assess the safety and efficacy of SN navigation surgery.The Korean group has reported the result of a multicenter randomized phaseⅢtrial.Since meticulous gastric cancer in the remnant stomach was rescued by subsequent gastrectomy,the disease-specific survival was comparable between the two techniques,implying that SN navigation surgery can be an alternative to standard gastrectomy.With the development of SN biopsy procedure and treatment modalities,the application of SN biopsy will be expanded to achieve an individualized minimally invasive surgery.

SENTINEL NODE BIOPSY BY TWO KINDS OF BLUE DYES IN PATIENTS WITH BREAST CANCER

Objective To evaluate the identification successful rate of sentinel lymph node with breast cancer and the accuracy to predict axillary lymph node status in different vital blue dyes.Methods 94 patients with breast cancer were recruited for the study between Oct. 1999 and Apr. 2001, of whom 32 and 62, respectively, were injected 0.028mmol·L -1 Methylene blue and 0.018mmol·L -1 Patent blue violet in breast parenchyma surrounding the primary tumor to identify SLN.All 94 patients underwent the axillary lymph node dissection.Results For Methylene blue group and Patent blue violet group, SLN identification successful rates were 65.6% and 88.7% and accuracy rate to predict axillary lymph node status were 90.5% and 98.2% , respectively.Conclusion In identifying SLN,Patent blue violet is more ideal vital blue dye than Methylene blue, whereas the accuracy rate to predict axillary lymph node status had no significant difference.

Axillary Recurrences after Sentinel Node Surgery—Results over Ten Years in a University Hospital

Background: Sentinel node biopsy (SNB) was introduced at Ullevaal University Hospital in 2000. This article presents results from the first ten years use of the method. Material and Methods: A prospective registration of 2762 patients was made from 2000 through 2009. Results: The median follow-up time was 51 months. The overall detection rate was 93%. 36% of the patients with positive SNs had non-sentinel metastases. These were significantly associated with a macrometastatic SN and a primary tumour>20 mm. 18% of patients with sentinel metastasis≤2 mm had non-sentinel metastases. 14 patients with negative SN (0.7%) developed axillary recurrence. 32% with a preoperative diagnosis of ductal carcinoma in situ (DCIS) were upstaged to infiltrating carcinoma on final histology. None of the patients with pure DCIS had positive SNs. Conclusion: Few late events (0.7%) in SN negative axillas demonstrate the safety of the technique.

Prediction of lymph node metastasis and sentinel node navigation surgery for patients with early-stage gastric cancer

Accurate prediction of lymph node(LN) status is crucially important for appropriate treatment planning in patients with early gastric cancer(EGC). However,consensus on patient and tumor characteristics associated with LN metastasis are yet to be reached. Through systematic search,we identified several independent variables associated with LN metastasis in EGC,which should be included in future research to assess which of these variables remain as significant predictors of LN metastasis. On the other hand,even if we use these promising parameters,we should realize the limitation and the difficulty of predicting LN metastasis accurately. The sentinel LN(SLN) is defined as first possible site to receive cancer cells along the route of lymphatic drainage from the primary tumor. The absence of metastasis in SLN is believed to correlate with the absence of metastasis in downstream LNs. In this review,we have attempted to focus on several independent parameters which have close relationship between tumor and LN metastasis in EGC. In addition,we evaluated the history of sentinel node navigation surgery and the usefulness for EGC.

Sentinel node navigation surgery for gastric cancer: Overview and perspective

The sentinel node(SN) technique has been established for the treatment of some types of solid cancers to avoid unnecessary lymphadenectomy. If node disease were diagnosed before surgery, minimal surgery with omission of lymph node dissection would be an option for patients with early gastric cancer. Although SN biopsy has been well ascertained in the treatment of breast cancer and melanoma, SN navigation surgery(SNNS) in gastric cancer has not been yet universal due to the complicated lymphatic flow from the stomach. Satisfactory establishment of SNNS will result in the possible indication of minimally invasive surgery of gastric cancer. However, the results reported in the literature on SN biopsy in gastric cancer are widely divergent and many issues are still to be resolved, such as the collection method of SN, detection of micrometastasis in SN, and clinical benefit. The difference in the procedural technique and learning phase of surgeons is also varied the accuracy of SN mapping. In this review, we outline the current status of application for SNNS in gastric cancer.

Sentinel node navigation surgery in gastric cancer: Current status

The theory behind using sentinel node mapping and biopsy in gastric cancer surgery, the so-called sentinel node navigation surgery, is to limit the extent of surgi-cal tissue dissection around the affected organ and subsequently the accompanied morbidity. However, ob-stacles on the clinical correspondence of sentinel node navigation surgery in everyday practice have occasion-ally alleviated researchers' interest on the topic. Only recently with the widespread use of minimally invasive surgical techniques, i.e., laparoscopic gastric cancer resections, surgical community's interest on the topic have been unavoidably reflated. Double tracer methods appear superior compared to single tracer techniques. Ongoing research is now focused on the invention of new lymph node detection methods utilizing sophisti-cated technology such as infrared ray endoscopy, flo-rescence imaging and near-infrared technology. Despite its notable limitations, hematoxylin/eosin is still the mainstay staining for assessing the metastatic status of an identified lymph node. An intra-operatively verified metastatic sentinel lymph node will dictate the need for further conventional lymph node dissection. Thus, laparoscopic resection of the gastric primary tumor combined with the appropriate lymph node dissection as determined by the process of sentinel lymph node status characterization represents an option for early gastric cancer. Patients with T3 or more advanced dis-ease should still be managed conventionally with resec-tion plus standard lymph node dissection.

NOTES:The question for minimal resection and sentinel node in early gastric cancer

Surgical therapy for gastric cancer involves both removal of the cancer lesion and complete lymph node dissection.Natural orifice transluminal endoscopic surgery(NOTES) is considered to represent the next revolution in surgery.Many surgeons and endoscopists believe that NOTES may be a superior alternative for early gastric cancer treatment.Sentinel node(SN) navigation surgery for gastric cancer:Single institution results of SN mapping for early gastric cancer are increasingly being considered acceptable.Furthermore,a major large-scale clinical trial of SN mapping for gastric cancer has recently been completed by The Japan Society of SN Navigation Surgery study group.They reported false negative rate of 7.0 while the sensitivity of metastasis detection based on SN status was 93.Combination of SN biopsy and NOTES:This concept was first described by Cahill et al who proved the feasibility of lymphatic mapping and SN biopsy by NOTES.Lymphatic channel filling was immediately observable via the intraperitoneal optics.Partial resection of the stomach by hybrid NOTES:Several centers have already reported gastrectomy assisted by NOTES using the transvaginal route.However,the main problem of full-thickness resection of gastric wall remains endoscopic gastric closure.Establishing an endoscopic suturing method would be an important step toward expanding potential indications.NOTES is met with both enthusiasm and skepticism but will gain its own place as human creativity eventually provides solutions to its technical limitations.In the near future,NOTES can evolve the capacity to complement the existing armamentarium for gastric cancer surgery.

What's wrong with sentinel node mapping in colon cancer?

Despite near-universal embrace of the concept and clinical relevance of lymphatic mapping for sentinel node identification and analysis for cancers of the breast and integument,the same technique has struggled to a find a role in gastrointestinal cancers in general and,perhaps,in colon cancer in particular. Despite many studies demonstrating its feasibility in malignancies of the large bowel,concern is continually aroused by the variable and often unacceptably low sensitivity rates. Additionally,many confess uncertainty as to what benefit it could ever confer to patients even if it were proven sufficiently accurate given that standard surgical resection incorporates mesenteric resection anyway. However,the huge impact sentinel node mapping has had on clinical practice in certain cancers means that each of these aspects merit careful reconsideration,from very first principles.

Sentinel node biopsy in colorectal cancer:Must we believe it?

Lymph node metastasis predicts survival and recurrence in colon cancer(CC),so decisions regarding adjuvant therapy are largely based on nodal status.Chemotherapy is not a routine treatment for node-negative CC because its toxicity and expense exceed its limited benefit in patients without evidence of nodal involvement.The sentinel lymph node(SLN) procedure is a selective sampling technique that can be used to ultrastage regional nodes.The real problem of SLN biopsy in CC is the procedure sensitivity rate.In future,studies concerning SLNs will have to consider issues such as the role of laparoscopy in colorectal resection(which cause technical difficulties in identification of SLNs) and the risk of overstaging of illness as well as the need to exclude T4 CC and,probably,rectal cancer from the studies.Is this the future of correct staging of colorectal cancer? Lymphadenectomy is at the present an integral part of colorectal surgery and surgeons must perform it correctly to improve their results.Nevertheless,for the future another "staging system" is necessary in colorectal cancer which takes into account biologic aspects of the tumor to identify patients with aggresive illness in order to treat them with more effective and less toxic therapies.

Usefulness of Breast MRI for Safe Omission of Axillary Lymph Nodes Dissection in Sentinel Node-Positive Breast Cancer Patients

Background: Preoperative identification of patients with extensive lymph node metastasis (LNM) is important for safe omission of axillary lymph node dissection (ALND) in sentinel node (SN)-positive (SN+) breast cancer patients. Methods: We evaluated retrospectively the collected data of 758 breast cancer patients who underwent axillary surgery between 2008 and 2017, excluding those who received neoadjuvant chemotherapy. Results: Of the 758 patients, 607 were not suspicious to have LNM by axillary ultrasound (AUS-), but 38 suspicious cases were found by breast magnetic resonance imaging (MRI). Of 15 patients undergoing axillary fine needle biopsy (AFNA) due to second-look axillary ultrasound (AUS), 9 underwent ALND because of a positive AFNA (AFNA+). Among 81 (10.9%) patients undergoing ALND due to SN+ findings, 6 (7.4%) had extensive LNM (LNM ≥ 4). If MRI was not performed, among the 90 of 673 patients undergoing ALND who had SN+ findings, 12 (13.3%) had LNM ≥ 4. Conclusions: The proportion of cases with LNM ≥ 4 was reduced from 13.3% to 7.4% among patients undergoing SN biopsies combined with breast MRI. ALND might be omitted safely in SN+ cases according to detailed preoperative evaluations using additional breast MRI to ultrasound.

Digestive cancer surgery in the era of sentinel node and epithelial-mesenchymal transition

Lymph node involvement is one of the most important prognostic indicators of carcinoma of the digestive tract.Although the therapeutic impact of lymphadenectomy has not been proven and the number of retrieved nodes cannot be considered a measure of successful cancer surgery,an adequate lymph node count should be guaranteed to accurately assess the N-stage through the number of involved nodes,lymph node ratio,number of negative nodes,ratio of negative to positive nodes,and log odds,i.e.,the log of the ratio between the number of positive lymph nodes and the number of negative lymph nodes in digestive carcinomas.As lymphadenectomy is not without complications,sentinel node mapping has been used as the rational procedure to select patients with early digestive carcinoma in whom nodal dissection may be omitted or a more limited nodal dissection may be preferred.However,due to anatomical and technical issues,sentinel node mapping and nodal basin dissection are not yet the standard of care in early digestive cancer.Moreover,in light of the biological,prognostic and therapeutic impact of tumor budding and tumor deposits,two epithelial-mesenchymal transition-related phenomena that are involved in tumor progression,the role of staging and surgical procedures in digestive carcinomas could be redefined.

Haemofiltration and Noradrenaline Corrects life-Threatening Cardiovascular Instability Following Delayed Anaphylactic Reaction to Patent Blue Dye in Sentinel Node Biopsy for Breast Cancer

The aim of this case report is to present a novel approach to the management of very severe anaphylactic reaction to Patent Blue Dye used in Sentinel Node Biopsy for breast cancer treatment. The severity and duration of cardiovascular effects has not been described previously in this setting. Comprehensive ICU support including heamofiltration resulted in the patients’ complete recovery and successful long-term well-being despite a change to our routine cancer care plan.

The size of Metastasis in the Sentinel Node Is a Predictor of Additional Non-Sentinel Node Positivity

Background: The need for axillary lymph node dissection (ALND) when sentinel lymph nodes (SLN) contain micrometastasis is controversial. The purpose of this study was to determine if the size of tumor in the SLN corresponds with additional positive non-sentinel lymph nodes (non-SLN) in pT1 breast cancer. Methods: This retrospective review of 483 patients with pT1 breast cancer identified 96 patients with tumor positive SLN biopsies between June 1999 and February 2010. The size of SLN metastasis and the number of tumor positive non-SLN were recorded using AJCC criteria. Receiver operating characteristic analysis was used to discriminate the SLN size with the optimal sensitivity, specificity and likelihood ratios (LR) for additional positive non-SLN. Results: Among 96 patients with a tumor positive SLN, 41% (n = 39) had micrometastasis, and 59% (n = 57) had macrometastasis. A positive non-SLN was identified after ALND among 18% (n = 7 of 39) with micrometastasis compared with 39% (n = 22 of 57) with macrometastasis (p = 0.04). The size of the SLN metastasis and presence of additional tumor positive non-SLNs corresponds to a positive likelihood ratio of 1.1 for micrometastasis and 1.6 for macrometastasis (95%CI: 0.56 - 0.74). Conclusions: Increased size of tumor in SLN is associated with greater likelihood of non-SLN positivity and should be considered for more aggressive follow-up and therapy.

Towards optimal management of the axilla in the context of a positive sentinel node biopsy in early breast cancer

The sentinel lymph node biopsy(SLNB) was initially pioneered for staging melanoma in 1994 and it has been subsequently validated by several trials, and has become the new standard of care for patients with clinically node negative invasive breast cancer. The focussed examination of fewer lymph nodes in addition to improvements in histopathological and molecular analysis has increased the rate at which micrometastases and isolated tumour cells are identified. In this article we review the literature regarding the optimal management of the axilla when the SLNB is positive for metastatic disease based on level 1 evidence derived from randomised clinical trials.

Sentinel Node in Cutaneous Squamous Cell Carcinoma of the Trunk and Extremities: Experience in a Latin American Reference Center

This paper aims to assess the use of the sentinel node technique in squamous cell carcinoma (SCC) of the trunk and extremities in a Latin American oncology reference center. The descriptive retrospective cohort study included 60 patients diagnosed with SCC of the trunk and extremities, submitted to surgical treatment of the primary tumor and sentinel node biopsy at the breast and soft tissue tumor services of the National Institute of Cancerology (Bogotá, Colombia) over a period of 6 years. The sentinel node was identified in 96.6% (58/60) of the patients. The sentinel node pathology report was negative in 81.7% (49), positive in 15% (9). There were no complications due to the procedure in 85% of the patients. The mean recurrence-free survival time was 8.3 months (CI 95% 5.0 to 11.5 months) in patients with positive sentinel node and 58.6 months (CI 95% 47.8 to 69.3 months) in patients with negative results. Only 4 of 49 patients (8.1%) with negative sentinel node had regional relapse. The study evidenced that the sentinel node technique in patients with high-risk SCC of the trunk and extremities is an adequate staging tool for the lymph node chain, with a low rate of associated complications. This opens an interesting opportunity for prospective cohort studies that can demonstrate statistically significant differences.

Current status of sentinel node biopsy in urological malignancies

Like in most other malignancies the lymph node status is of outstanding prognostic relevance and an important tool for the determination of adjuvant strategies for urological tumor entities, too. Even in the era of PET/CT and MRI with iron oxid nano-particles the radiological imaging technology is strongly limited in cases of metastases smaller than 5 mm. Therefore only the operative lymph node exploration is suitable for an exact lymph node staging. The dilemma, however, is that the extended lymphadenectomy techniques feature a high morbidity and that any limitation of the dissection area results in a reduced detection rate of metastases in penile and prostate cancer. In contrast the sentinel- guided lymphadenectomy (SLND) offers a short operation time and a low morbidity without the risk of a significantly reduced detection of lymph node positive patients. As a consequence of many published papers dealing with a few thousands of patients the European Association of Urology (EAU) guidelines recommend the SLND in penile cancer (tumor stages ≥ T1G2) and as an option in prostate cancer. The latest studies of bladder, renal cell and testicular cancer promise the feasibility for these tumor entities, too. Up to which extend these thera- peutic concepts are able to replace or at least complement the default therapeutic procedures has to be shown in further studies.

A Comparison of Breast Surgeon and Nomogram-Generated Risk Predictions of Sentinel and Non-Sentinel Node Metastases

Memorial Sloan-Kettering Cancer Center (MSKCC) has developed 2 nomograms: the Sentinel Lymph Node Nomogram (SLNN), which is used to predict the likelihood of sentinel lymph node (SLN) metastases in patients with invasive breast cancer, and the Non-Sentinel Lymph Node Nomogram (NSLNN), which is used to predict the likelihood of residual axillary disease after a positive SLN biopsy. Our purpose was to compare the accuracy of MSKCC nomogram predictions with those made by breast surgeons. Two questionnaires were built with characteristics of two sets of 33 randomly selected patients from the MSKCC Sentinel Node Database. The first included only patients with invasive breast cancer, and the second included only patients with invasive breast cancer and positive SLN biopsy. 26 randomly selected Brazilian breast surgeons were asked about the probability of each patient in the first set having SLN metastases and each patient in the second set having additional non-SLN metastases. The predictions of the nomograms and breast surgeons were compared. There was no correlation between nomogram risk predictions and breast surgeon risk prediction estimates for either the SLNN or the NSLNN. The area under the receiver operating characteristics curves (AUCs) were 0.871 and 0.657 for SLNN and breast surgeons, respectively (p 0.0001), and 0.889 and 0.575 for the NSLNN and breast surgeons, respectively (p 0.0001). The nomograms were significantly more accurate as prediction tools than the risk predictions of breast surgeons in Brazil. This study demonstrates the potential utility of both nomograms in the decision-making process for patients with invasive breast cancer.