In Situ Albumin-Hitchhiking NIR-II Probes for Accurate Detection of Micrometastases.

Tumor metastasis remains the primary cause of treatment failure in cancer patients, and the high-sensitivity preoperative and intraoperative detection of occult micrometastases continues to pose a notorious challenge. Therefore, we have designed an in situ albumin-hitchhiking near-infrared window II (NIR-II) fluorescence probe, IR1080, for the precise detection of micrometastases and subsequent fluorescence image-guided surgery. IR1080 rapidly covalently conjugates with albumin in plasma, resulting in a stronger fluorescence brightness upon binding. Moreover, the albumin-hitchhiked IR1080 has a high affinity for secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein that is overexpressed in micrometastases. The interaction between SPARC and IR1080-hitchhiked albumin enhances IR1080's capacity to track and anchor micrometastases, leading to a high detection rate and margin delineation ability, as well as a high tumor-to-normal tissue ratio. Therefore, IR1080 represents a highly efficient strategy for the diagnosis and image-guided resection surgery of micrometastases.

Evaluation of the one-step nucleic acid amplification method for rapid detection of lymph node metastases in endometrial cancer: prospective, multicenter, comparative study.

OBJECTIVE: To evaluate the diagnostic performance of the one-step nucleic acid amplification (OSNA) method for the detection of sentinel lymph node (SLN) metastases in women with apparent early-stage endometrial cancer compared with standard ultrastaging. METHODS: Prospective, multicentric, interventional study. Patients with apparent early-stage endometrial cancer who underwent primary surgical staging with SLN mapping were included. SLNs were serially sectioned with 2 mm slices perpendicular to the longest axis of the node: the odd slices were submitted to ultrastaging, whereas the even slices were submitted to the OSNA analysis. Diagnostic performance was calculated taking ultrastaging as referral standard. RESULTS: Three-hundred and sixteen patients with 668 SLNs were included. OSNA assay detected 22 (3.3%) positive SLNs, of which 17 (2.5%) were micrometastases and 5 (0.7%) macrometastases, whereas ultrastaging detected 24 (3.6%) positive SLNs, of which 15 (2.2%) were micrometastases and 9 (1.3%) macrometastases (p=0.48). Regarding negative SLNs, OSNA detected 646 (96.7%) negative nodes, including 8 (1.2%) isolated tumor cells, while ultrastaging detected 644 (96.4%) negative nodes with 26 (3.9%) isolated tumor cells. Specificity of OSNA was 98.4% (95% CI 97.5 to 99.4), accuracy was 96.7% (95% CI 95.4 to 98.1), sensitivity was 50% (95% CI 30.0 to 70.0), while negative predictive value was 98.1% (95% CI 97.1 to 99.2). Discordant results were found in 22 SLNs (3.3%) corresponding to 20 patients (6.3%). These were 10 (1.5%) false-positive SLNs (all micrometastases): one (0.1%) of these was a benign epithelial inclusion at ultrastaging. There were 12 (1.8%) false-negative SLNs of OSNA, of which 9 (1.3%) were micrometastases and 3 (0.5%) macrometastases. Overall, 17/668 (2.5%) benign epithelial inclusions were detected at ultrastaging. CONCLUSION: The OSNA method had high specificity and high accuracy in detecting SLN metastasis in apparent early-stage endometrial cancer. The advantage of the OSNA method could be represented as the possibility to analyze the entire lymph node thus eliminating sampling bias.

Prognostic Value of Mesorectal Lymph Node Micrometastases in ypN0 Rectal Cancer After Chemoradiation.

INTRODUCTION: More than 25% of patients with node-negative colorectal cancer experience a recurrent disease even after curative surgery. This suggests the existence and oncologic influence of micrometastasis in regional lymph nodes or in distant organs. The objective of this study was to identify mesorectal lymph node micrometastases using an immunohistochemical analysis and to determine its prognostic value in node-negative rectal cancer after neoadjuvant chemoradiation. MATERIALS AND METHODS: A total of 91 patients who received preoperative chemoradiation and radical resection for rectal cancer were included. Based on conventional hematoxylin and eosin staining, all patients had a node-negative disease. Mesorectal lymph nodes from resected specimens were re-evaluated to detect micrometastases by immunohistochemistry using anticytokeratin antibody AE1/AE3. The clinicopathologic data were collected from a prospectively maintained database of colorectal cancer patients and analyzed retrospectively. RESULTS: Micrometastases of mesorectal lymph nodes were detected in nine patients (9.9%). The three-year overall survival was similar regardless of micrometastasis (88.9% in the positive group versus 90.7% in the negative group, P = 0.681); however, the three-year disease-free survival was significantly poorer in the patients with micrometastases (40.0% versus 84.2%, P = 0.001). In the multivariate analysis, the advanced pT category (ypT3/T4 versus ypT0: hazard ratio [HR] 10.477, 95% confidence interval [CI] 1.102-99.594, P = 0.041) and micrometastases in mesorectal lymph nodes (HR 5.655, 95% CI 1.837-17.409, P = 0.003) were independent prognostic factors for disease-free survival. CONCLUSIONS: In node-negative rectal cancer after preoperative chemoradiation, immunohistochemically detected micrometastases of mesorectal lymph nodes were significantly correlated with poor disease-free survival.

Septin 9 methylation analysis of lymph node micrometastases for predicting relapse of colorectal cancer.

BACKGROUND: Molecular markers for the detection of lymph node micrometastases of malignant tumors have been extensively investigated. However, epigenetic signatures have rarely been reported for identification of metastatic lymph nodes and disease relapse. Septin 9 is the most frequently reported hypermethylated gene in colorectal cancer (CRC). This study aimed to assess the clinical relevance of Septin 9 methylation in regional lymph nodes in recurrence/metastases of CRC. METHODS: We analyzed Septin 9 methylation of DNA from resected lymph nodes in 75 CRC patients with or without tumor recurrence using quantitative methylation-sensitive PCR (qMS-PCR). RESULTS: Of the 30 histologically negative lymph node CRC patients without recurrence (group 1), methylated Septin 9 was detected in 3 (10 %) cases. The positivity rate of methylated Septin 9 in group 2 containing 30 histologically node-negative CRC patients with recurrence was 30 % (9/30). For group 3, lymphatic invasion as well as tumor recurrence, 11 (73 %) out of 15 subjects had Septin 9 methylation-positive lymph nodes. Moreover, patients in group 3 had a higher level of methylated Septin 9 compared to subjects in group 1 and group 2 (p < 0.05). In addition, CRC patients with Septin 9 methylation in lymph nodes had significantly reduced survival (Log-rank P < 0.0001). CONCLUSION: Our data support the predictive role of Septin 9 methylation analysis of lymph node micrometastases for tumor relapse after surgery.

Can risk groups accurately predict non-sentinel lymph node metastasis in sentinel lymph node-positive endometrial cancer patients? A Turkish Gynecologic Oncology Group Study (TRSGO-SLN-004).

BACKGROUND AND OBJECTIVES: The purpose of this study was to find out the risk factors associated with non-sentinel lymph node metastasis and determine the incidence of non-sentinel lymph node metastasis according to risk groups in sentinel lymph node (SLN)-positive endometrial cancer patients. METHODS: Patients who underwent at least bilateral pelvic lymphadenectomy after SLN mapping were retrospectively analyzed. Patients were categorized into low, intermediate, high-intermediate, and high-risk groups defined by ESMO-ESGO-ESTRO. RESULTS: Out of 395 eligible patients, 42 patients had SLN metastasis and 16 (38.1%) of them also had non-SLN metastasis. Size of SLN metastasis was the only factor associated with non-SLN metastasis (p = .012) as 13/22 patients with macrometastasis, 2/10 with micrometastasis and 1/10 with isolated tumor cells (ITCs) had non-SLN metastasis. Although all 4 metastases (1.8%) among the low-risk group were limited to SLNs, the non-SLN involvement rate in the high-risk group was 42.9% and all of these were seen in patients with macrometastatic SLNs. CONCLUSIONS: Non-SLN metastasis was more frequent in higher-risk groups and the risk of non-SLN metastasis increased with the size of SLN metastasis. Proceeding to complete lymphadenectomy when SLN is metastatic should further be studied as the effect of leaving metastatic non-SLNs in-situ is not known.

Detection of Lung Cancer Lymph Node Metastases from Whole-Slide Histopathologic Images Using a Two-Step Deep Learning Approach.

The application of deep learning for the detection of lymph node metastases on histologic slides has attracted worldwide attention due to its potentially important role in patient treatment and prognosis. Despite this attention, false-positive predictions remain problematic, particularly in the case of reactive lymphoid follicles. In this study, a novel two-step deep learning algorithm was developed to address the issue of false-positive prediction while maintaining accurate cancer detection. Three-hundred and forty-nine whole-slide lung cancer lymph node images, including 233 slides for algorithm training, 10 slides for validation, and 106 slides for evaluation, were collected. In the first step, a deep learning algorithm was used to eliminate frequently misclassified noncancerous regions (lymphoid follicles). In the second step, a deep learning classifier was developed to detect cancer cells. Using this two-step approach, errors were reduced by 36.4% on average and up to 89% in slides with reactive lymphoid follicles. Furthermore, 100% sensitivity was reached in cases of macrometastases, micrometastases, and isolated tumor cells. To reduce the small number of remaining false positives, a receiver-operating characteristic curve was created using foci size thresholds of 0.6 mm and 0.7 mm, achieving sensitivity and specificity of 79.6% and 96.5%, and 75.5% and 98.2%, respectively. A two-step approach can be used to detect lung cancer metastases in lymph node tissue effectively and with few false positives.

Disparities of Management of the Axilla in Women With Clinically Node Negative Breast Cancer.

BACKGROUND: In women with clinically node-negative breast cancer, sentinel lymph node biopsy is the first step in axillary staging. A randomized trial published in 2013 concluded that patients with sentinel lymph node micrometastases (N1mi) do not benefit from axillary lymph node dissection (ALND). We hypothesized that disparities exist in management of the axilla in node-negative patients. METHODS: We included women aged >40 years with nonmetastatic, clinically node-negative breast cancer from 2014 to 2016 in the National Cancer Database. Women treated neoadjuvantly, with large tumors (cT4), or no tumor (cT0) were excluded. Multivariable logistic regression identified patient and facility characteristics associated with undergoing ALND as first axillary surgery and completion ALND in the setting of N1mi disease. RESULTS: Of 273,951 patients, 22,898 (8%) underwent ALND first. These patients were more likely to be Hispanic (OR: 1.21, 95% CI: 1.10, 1.32), have Medicare (OR: 1.13, 95% CI: 1.03, 1.24), be uninsured (OR: 1.28, 95% CI: 1.08, 1.53), have lower educational attainment (OR: 1.24, 95% CI: 1.17, 1.32), be treated at a community hospital (OR: 1.62, 95% CI: 1.52, 1.74), or reside in the South (OR: 1.19, 95% CI: 1.12, 1.26). In the sentinel lymph node biopsy first group, 8,882 (4%) were classified as N1mi and 1,872 (21%) underwent subsequent ALND. These patients were more likely to be Hispanic (OR: 1.70, 95% CI: 1.19, 2.42) and have the lowest income (OR: 1.62, 95% CI: 1.15, 2.27). CONCLUSION: Disparities persist in implementation of evidence-based management of the axilla in women with clinically node-negative breast cancer.

Prospective clinical trial of robotic sentinel lymph node assessment with isosulfane blue (ISB) and indocyanine green (ICG) in endometrial cancer and the impact of ultrastaging (NCT01818739).

OBJECTIVES: To assess the performance sentinel lymph node (SLN) biopsy and effect of ultrastaging in clinically early stage endometrial cancer. METHODS: Patients with endometrial cancer prospectively enrolled after informed consent was obtained. The cervix was injected superficially with 1 mL of ISB and 1 mL of ICG (diluted 1:25) at 3 and 9 o'clock each. SLN biopsy was followed by complete pelvic lymphadenectomy (aortic lymphadenectomy at the discretion of the surgeon). Lymph nodes (LNs) were analyzed by standard sectioning with H&E; ultrastaging of SLN was done retrospectively and blinded to treating physicians. RESULTS: 204 patients received dye injections. In 184 (90.2%) patients at least one SLN was identified. Of all patients, 138 (68%) had bilateral mapping. In the patients with successful mapping of a hemipelvis, ICG detected SLNs in 83% and ISB in 64% of cases (p < 0.0001). Median BMI (kg/m2) for patients with successful mapping was 35.7 compared to 40.1 for those who did not map (p = 0.01). Twenty-three (11.3%) patients had positive LNs. Applying the SLN algorithm, positive nodes were detected in 21/23 (91.3%). The negative predictive value (NPV) was 98.9% (95% CI: 96.01% to 99.71%). Eleven patients had positive SLN with isolated tumor cells (ITCs) or micrometastases detected on ultrastaging. Including these patients, 34 (17%) had positive LNs, increasing the NPV to 99% and sensitivity to 94%. There were no recurrences in patients with ITCs only. CONCLUSIONS: SLN assessment in endometrial cancer is feasible and safe with high NPV (99%). ICG was more effective in detecting SLN compared to ISB. Although ultrastaging detected additional positive LNs, treatment based on standard sectioning appears reasonable but further research is needed.

Sentinel Lymph Node Biopsy in Early Breast Cancer: Magnetic Tracer as the Only Localizing Agent.

BACKGROUND: The combined use of radioisotope and blue dye is the gold standard in sentinel lymph node (SLN) localization in early breast cancer. Superparamagnetic iron oxide (SPIO) has recently emerged as a non-inferior new tracer in sentinel lymph node mapping with fewer disadvantages. This study represents the first and the largest cohort of superparamagnetic iron oxide application in Asian population. METHODS: Retrospective analysis of a prospectively maintained database was performed from August 2016 to December 2017. All patients with SLN localization by SPIO were included in this study. RESULTS: A total of 328 breast cancer patients with 333 SLNB procedures were included in this study. Median age was 54 years (range 32-86). Median tumor size was 1.9 cm (range 0.1-12 cm).There were 138 breast-conserving surgeries and 195 mastectomies. All patients received injection of SPIO 1 day prior to operation. A total of 329 successful sentinel lymph node biopsy (SLNB) procedures were undertaken with 1514 sentinel lymph nodes (SLNs) identified. One hundred and fifty-three (10.1%) of the SLNs were positive for malignancy. There were 54 patients with macrometastases, 26 with micrometastases and 24 with isolated tumor cells. Sixty-seven patients underwent subsequent axillary dissection. Four patients failed sentinel lymph node identification with SPIO. The success rate of SPIO in sentinel lymph node localization was 98.8%. CONCLUSION: SPIO represents a feasible alternative in sentinel lymph node mapping with comparably high nodal detection rate.

Detection of micro-metastases by flow cytometry in lymph nodes from patients with penile cancer.

BACKGROUND: The tumor draining lymph node concept was first described in penile cancer for staging. Immunohistochemistry and histopathology evaluations are routinely used in clinical practice to examine lymph nodes for metastasis. However, these methods are time-consuming with low diagnostic accuracy and micro-metastases might be missed. In this study, we aim to evaluate detection of metastatic cells in draining lymph nodes by flow cytometry. METHODS: To assess the sensitivity of micro-metastasis detection by FACS (Fluorescence-activated cell sorting), HeLa cells were titrated into Peripheral blood mononuclear cells (PBMCs) and expression of pan-cytokeratin AE1/AE3 was analyzed. Single cell suspensions were separately prepared from 10 regional lymph nodes obtained from 5 patients with invasive penile cancer undergoing radical surgery and lymph node dissection. Lymph node dereived cells were examined for cell surface expression of EpCAM, E-cadherin and intracellular expression of pan-cytokeratin AE1/AE3 by FACS. RESULTS: Ten lymph nodes from 5 penile cancer patients were investigated in a head-to-head comparison between FACS and pathology examination of sections. All metastatic lymph nodes verified by pathology examination were also identified by FACS. Two additional lymph nodes with micro-metastases were diagnosed by FACS only. CONCLUSIONS: FACS analyses of pan-cytokeratin AE1/AE3 stained single cells from tumor draining lymph nodes can be used to detect micro-metastases in patients with penile cancer patients.

[Sentinel Lymph Node Diagnosis for Lung Cancer].

Many researchers have reported that the sentinel node (SN) theory has been established for lung cancer. However, sentinel node navigation surgery (SNNS) has not yet become a routine medical procedure in lung cancer surgery. SN identification is important for efficient retrieval of micrometastases. Methods for identifying SNs include the dye method and the radioisotope (RI) method, but methods such as the indocyanine green (ICG) method, computed tomographic lymphography (CTLG), and the magnetic method are also being studied. More careful surgical adaptation is required for reduction surgery for early lung cancer, and rapid intraoperative diagnosis is frequently used. SN lymph nodes may be used as an indicator for selecting lymph nodes to be diagnosed intraoperatively. SN identification is considered an important method for ensuring that reduction surgery is curative. Furthermore, if overlooking lymph node metastases can be avoided by using intraoperative rapid diagnosis of micrometastases, we believe that the safety of reduction surgery will be enhanced. In addition, SN identification provides a theoretical basis to support the omission of lymph node dissection. Future developments of SN research and technology are expected.

Blinded review of archival radical prostatectomy specimens supports that contemporary Gleason score 6 prostate cancer lacks metastatic potential.

BACKGROUND: Retrospective identification of Gleason pattern 4 in metastatic Gleason score 3 + 3 = 6 (GS6) radical prostatectomy (RP) specimens has suggested true GS6 prostate cancer (CaP) lacks metastatic potential. However, pathologist awareness of study design and metastasis outcomes at the time of RP review might have introduced upgrading bias. We used pathologist-blinded methodology for unbiased characterization of metastasis rates for contemporarily defined pathologic GS6 (pGS6) CaP. METHODS: An institutional RP database was queried to identify pGS6 patients with metastasis or concern for micrometastasis based on: 1) biochemical failure (BF) despite negative surgical margins or 2) incomplete biochemical response to salvage/adjuvant radiation. RP specimens were regraded independently by two genitourinary pathologists blinded to study aims or clinical outcomes. Additional blinding was performed by random inclusion of pGS6 control specimens from BF-free patients. Only upgrading identified independently by both pathologists was considered. RESULTS: Among 451 pGS6 patients identified, none had synchronous lymph node metastases and 43/451 (10%) suffered BF. Two patients (0.4%) developed metachronous metastasis during a 110-month median follow-up for BF patients. Both metastatic cases had Gleason pattern 4 on blinded RP review, as did 88% of cases with concern for micrometastasis versus 38% of control cases (P = 0.02). All BF patients (29/29) undergoing postoperative radiation had a complete biochemical response or Gleason pattern 4 on blinded RP review. CONCLUSIONS: Unbiased pathologist review of archival RP specimens supports absent metastatic potential for contemporarily defined GS6 CaP. Reduced postoperative monitoring is appropriate for pGS6, but may require pathology review to confirm absent Gleason pattern 4.

Prognostic significance of VEGF-C in predicting micrometastasis and isolated tumour cells in N0 oral squamous cell carcinoma.

BACKGROUND: Lymph node metastasis in oral squamous cell carcinoma (OSCC) is a well-known independent prognostic factor. However, the identification of occult tumour cells within the lymph nodes has remained a challenge for the pathologist as well as the clinician. OBJECTIVE: The aim of this study was to determine the prevalence of micrometastasis and isolated tumour cells (ITCs) in pathologically staged N0 OSCC of the tongue and buccal mucosa and to assess its correlation with vascular endothelial growth factor C, (VEGF-C) expression in the primary tumour. METHODS: Thirty-four cases of N0 OSCC comprising of 17 cases each from the tongue and buccal mucosa were evaluated by immunohistochemistry for VEGF-C expression. The corresponding lymph nodes from levels I and II were pathologically examined and cross-detected for micrometastasis and ITCs with desmoglein 3 (DSG3). RESULTS: The prevalence of micrometastasis and ITCs in OSCC of the tongue and buccal mucosa was 23.5% and 17.6%, respectively. A total of 12 out of 151 lymph nodes contained micrometastatic tumour foci and ITCs. A higher expression of VEGF-C in the primary tumour was associated with a greater probability for the occurrence of micrometastasis and ITCs in the lymph nodes. CONCLUSION: High expression of VEGF-C in the primary tumour may be a good determinant for detection of occult tumour cells in the lymph nodes of OSCC cases.

Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates.

Drug-resistant micrometastases that escape standard therapies often go undetected until the emergence of lethal recurrent disease. Here, we show that it is possible to treat microscopic tumors selectively using an activatable immunoconjugate. The immunoconjugate is composed of self-quenching, near-infrared chromophores loaded onto a cancer cell-targeting antibody. Chromophore phototoxicity and fluorescence are activated by lysosomal proteolysis, and light, after cancer cell internalization, enabling tumor-confined photocytotoxicity and resolution of individual micrometastases. This unique approach not only introduces a therapeutic strategy to help destroy residual drug-resistant cells but also provides a sensitive imaging method to monitor micrometastatic disease in common sites of recurrence. Using fluorescence microendoscopy to monitor immunoconjugate activation and micrometastatic disease, we demonstrate these concepts of "tumor-targeted, activatable photoimmunotherapy" in a mouse model of peritoneal carcinomatosis. By introducing targeted activation to enhance tumor selectively in complex anatomical sites, this study offers prospects for catching early recurrent micrometastases and for treating occult disease.

Frequency of bilateral cervical metastases in hypopharyngeal squamous cell carcinoma: a retrospective analysis of 203 cases after bilateral neck dissection.

The decision whether to perform an elective neck dissection in patients with head and neck squamous cell carcinoma and clinically negative lymph nodes (cN0) is made based on the probability of micrometastases in the neck for the given subsite and size of the primary. A retrospective chart review was performed of 203 patients with hypopharyngeal SCC who received a bilateral neck dissection. The frequency of histologically unveiled bilateral neck metastases was determined. A high frequency of contralateral metastases above 20% was detected for all carcinomas affecting the midline and those involving the medial wall of the pyriform sinus except of T1-stages (13%) and a low frequency for laterally located primaries (3%). Ipsilateral nodal status predicted contralateral neck metastases. Bilateral neck dissection should be recommended for primaries affecting the midline and T2-4 tumors involving the medial wall of the pyriform sinus.

Establishment of a novel method to evaluate peritoneal microdissemination and therapeutic effect using luciferase assay.

Peritoneal dissemination is a major cause of recurrence in patients with malignant tumors in the peritoneal cavity. Effective anticancer agents and treatment protocols are necessary to improve outcomes in these patients. However, previous studies using mouse models of peritoneal dissemination have not detected any drug effect against peritoneal micrometastasis. Here we used the luciferase assay to evaluate peritoneal micrometastasis in living animals and established an accurate mouse model of early peritoneal microdissemination to evaluate tumorigenesis and drug efficacy. There was a positive correlation between luminescence intensity in in vivo luciferase assay and the extent of tumor dissemination evaluated by ex vivo luciferase assay and mesenteric weight. This model has advantages over previous models because optimal luciferin concentration without cell damage was validated and peritoneal microdissemination could be quantitatively evaluated. Therefore, it is a useful model to validate peritoneal micrometastasis formation and to evaluate drug efficacy without killing mice.

Detection of micrometastases by flow cytometry in sentinel lymph nodes from patients with renal tumours.

BACKGROUND: Stage is an important prognostic factor in renal tumours and dissemination to regional lymph nodes is associated with poor outcomes. Lymph nodes are routinely assessed by immunohistochemistry and microscopic evaluation, a time-consuming process where micrometastases might go undiagnosed. We evaluate an alternative method for detecting metastatic cells in sentinel nodes (SNs) by flow cytometry. METHODS: A total of 15 nodes from 5 patients diagnosed with renal tumours were analysed by flow cytometry. Staining for the intracellular marker cytokeratin 18 (CK18) with the surface markers carbonic anhydrase IX (CA9) and Cadherin 6 were used in flow cytometry analysis. Peripheral blood mononuclear cells (PBMCs) with the addition of known concentrations of cancer cell lines were analysed to investigate the sensitivity of micrometastasis detection. RESULTS: Stability of the assay was marked by low intra-assay variability (coefficient of variance ⩽16%) and low inter-assay variability (R2=0.9996-1). Eight nodes in four patients were positive for metastasis; six of them were considered being micrometastatic. These metastases were undetected by routine pathology and the patients were restaged from pN0 to pN1. CONCLUSIONS: Flow cytometry is able to detect micrometastases in lymph nodes of renal tumour patients that were undetected under H&E examination.

CXCR-4 Targeted, Short Wave Infrared (SWIR) Emitting Nanoprobes for Enhanced Deep Tissue Imaging and Micrometastatic Cancer Lesion Detection.

Realizing the promise of precision medicine in cancer therapy depends on identifying and tracking cancerous growths to maximize treatment options and improve patient outcomes. This goal of early detection remains unfulfilled by current clinical imaging techniques that fail to detect lesions due to their small size and suborgan localization. With proper probes, optical imaging techniques can overcome this by identifying the molecular phenotype of tumors at both macroscopic and microscopic scales. In this study, the first use of nanophotonic short wave infrared technology is proposed to molecularly phenotype small lesions for more sensitive detection. Here, human serum albumin encapsulated rare-earth nanoparticles (ReANCs) with ligands for targeted lesion imaging are designed. AMD3100, an antagonist to CXCR4 (a classic marker of cancer metastasis) is adsorbed onto ReANCs to form functionalized ReANCs (fReANCs). fReANCs are able to preferentially accumulate in receptor positive lesions when injected intraperitoneally in a subcutaneous tumor model. fReANCs can also target subtissue microlesions at a maximum depth of 10.5 mm in a lung metastatic model of breast cancer. Internal lesions identified with fReANCs are 2.25 times smaller than those detected with ReANCs. Thus, an integrated nanoprobe detection platform is presented, which allows target-specific identification of subtissue cancerous lesions.

Optical innovations in surgery.

BACKGROUND: In the past decade, there has been a major drive towards clinical translation of optical and, in particular, fluorescence imaging in surgery. In surgical oncology, radical surgery is characterized by the absence of positive resection margins, a critical factor in improving prognosis. Fluorescence imaging provides the surgeon with reliable and real-time intraoperative feedback to identify surgical targets, including positive tumour margins. It also may enable decisions on the possibility of intraoperative adjuvant treatment, such as brachytherapy, chemotherapy or emerging targeted photodynamic therapy (photoimmunotherapy). METHODS: This article reviews the use of optical imaging for intraoperative guidance and decision-making. RESULTS: Image-guided cancer surgery has the potential to be a powerful tool in guiding future surgical care. Photoimmunotherapy is a theranostic concept (simultaneous diagnosis and treatment) on the verge of clinical translation, and is highlighted as an effective combination of image-guided surgery and intraoperative treatment of residual disease. Multispectral optoacoustic tomography, a technique complementary to optical image-guided surgery, is currently being tested in humans and is anticipated to have great potential for perioperative and postoperative application in surgery. CONCLUSION: Significant advances have been achieved in real-time optical imaging strategies for intraoperative tumour detection and margin assessment. Optical imaging holds promise in achieving the highest percentage of negative surgical margins and in early detection of micrometastastic disease over the next decade.