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Sentinel-lymph-node mapping has been advocated as an alternative staging technique for endometrial cancer. The aim of this study was to measure the sensitivity and negative predictive value of sentinel-lymph-node mapping compared with the gold standard of complete lymphadenectomy in detecting metastatic disease for endometrial cancer. In the FIRES multicentre, prospective, cohort study patients with clinical stage 1 endometrial cancer of all histologies and grades undergoing robotic staging were eligible for study inclusion. Patients received a standardised cervical injection of indocyanine green and sentinel-lymph-node mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. 18 surgeons from ten centres (tertiary academic and community non-academic) in the USA participated in the trial. Negative sentinel lymph nodes (by haematoxylin and eosin staining on sections) were ultra-staged with immunohistochemistry for cytokeratin. The primary endpoint, sensitivity of the sentinel-lymph-node-based detection of metastatic disease, was defined as the proportion of patients with node-positive disease with successful sentinel-lymph-node mapping who had metastatic disease correctly identified in the sentinel lymph node. Patients who had mapping of at least one sentinel lymph node were included in the primary analysis (per protocol). All patients who received study intervention (injection of dye), regardless of mapping result, were included as part of the assessment of mapping and in the safety analysis in an intention-to-treat manner. The trial was registered with ClinicalTrials.gov, number NCT01673022 and is completed and closed. Between Aug 1, 2012, and Oct 20, 2015, 385 patients were enrolled. Sentinel-lymph-node mapping with complete pelvic lymphadenectomy was done in 340 patients and para-aortic lymphadenectomy was done in 196 (58%) of these patients. 293 (86%) patients had successful mapping of at least one sentinel lymph node. 41 (12%) patients had positive nodes, 36 of whom had at least one mapped sentinel lymph node. Nodal metastases were identified in the sentinel lymph nodes of 35 (97%) of these 36 patients, yielding a sensitivity to detect node-positive disease of 97·2% (95% CI 85·0–100), and a negative predictive value of 99·6% (97·9–100). The most common grade 3–4 adverse events or serious adverse events were postoperative neurological disorders (4 patients) and postoperative respiratory distress or failure (4 patients). 22 patients had serious adverse events, with one related to the study intervention: a ureteral injury incurred during sentinel-lymph-node dissection. Sentinel lymph nodes identified with indocyanine green have a high degree of diagnostic accuracy in detecting endometrial cancer metastases and can safely replace lymphadenectomy in the staging of endometrial cancer. Sentinel lymph node biopsy will not identify metastases in 3% of patients with node-positive disease, but has the potential to expose fewer patients to the morbidity of a complete lymphadenectomy. Indiana University Health, Indiana University Health Simon Cancer Center, and the Indiana University Department of Obstetrics and Gynecology.

Background This prospective cohort study aimed to assess sentinel lymph node (SLN) mapping using isosulfan blue (ISB) compared with ISB plus indocyanine green (ICG) and near-infrared imaging (NIR) for patients with endometrial cancer. Methods In this study, 200 patients with endometrial cancer underwent SLN assessments and were randomized to ISB + ICG ( n  = 180) or ISB alone ( n  = 20). Blue dye determinations were recorded for all 200 cases followed by NIR imaging of ICG for 180 randomized subjects. All the patients underwent robotically assisted hysterectomy with pelvic ± aortic lymphadenectomy. Results The mean age of the patients was 64.5 ± 8.4 years, and the mean body mass index (BMI) was 33 ± 7.6 kg/m 2 . The histologies were endometrioid G1 (43%), G2 (30%), G3 (7%), and type 2 (20%). The mean time from dye injection to initiation of mapping was 13.4 ± 6.2 min, and the time to removal of SLN was 17.4 ± 11.2 min. Detection of SLN for the 20 ISB control cases did not differ from that for the 180 ISB + ICG cases ( p  > 0.05). The rates of SLN detection for ISB + ICG/NIR ( n  = 180) versus ISB ( n  = 200) were as follows: bilateral (83.9 vs. 40%), unilateral (12.2 vs. 36%), and none (3.9 vs. 24%) ( p  < 0.001). The median SLN per case was 2 (range 0–4). Positive SLNs were found in 21.1% ( n  = 38) of the ISB + ICG cases compared with 13.5% ( n  = 27) of the ISB cases ( p  = 0.056). The false-negative rate for SLN biopsy was 2.5% (95% confidence interval, 0.1–14.7%). In 61% (25/41) of the node-positive cases, SLN was the only positive lymph node (LN). Isolated tumor cells were found in 39.5% (15/38) of the SLN metastasis cases compared with 26.7% (4/15) of the non-SLN metastasis cases ( p  = 0.528). Conclusions In this prospective study, ISB + ICG and NIR detected more SLNs and more LN metastases than ISB alone. Assessment of SLN with ICG + ISB/NIR imaging had excellent sensitivity for detection of metastasis and no safety issues.

Purpose The recently introduced tethered DROP-IN gamma probe has revolutionized the way robotic radioguided surgery is performed, fully exploiting the nature of steerable robotic instruments. Given this success, the current first-in-human study investigates if the DROP-IN can also provide benefit in combination with steerable non-robotic instruments during conventional laparoscopic surgery, showing equivalence or even benefit over a traditional rigid gamma probe. Methods The evaluation was performed in ten patients during laparoscopic cervical ( n  = 4) and endometrial ( n  = 6) cancer sentinel lymph node (SLN) procedures. Surgical guidance was provided using the hybrid, or bi-modal, SLN tracer ICG- 99m Tc-nanocolloid. SLN detection was compared between the traditional rigid laparoscopic gamma probe, the combination of a DROP-IN gamma probe and a steerable laparoscopic instrument (LaproFlex), and fluorescence imaging. Results The gynecologists experienced an enlarged freedom of movement when using the DROP-IN + LaproFlex combination compared to the rigid laparoscopic probe, making it possible to better isolate the SLN signal from background signals. This did not translate into a change in the SLN find rate yet. In both cervical and endometrial cancer combined, the rigid probe and DROP-IN + LaproFlex combination provided an equivalent detection rate of 96%, while fluorescence provided 85%. Conclusion We have successfully demonstrated the in-human use of steerable DROP-IN radioguidance during laparoscopic cervical and endometrial cancer SLN procedures, expanding the utility beyond robotic procedures. Indicating an improved surgical experience, these findings encourage further investigation and consideration on a path towards routine clinical practice and improved patient outcome. Trial registration HCB/2021/0777 and NCT04492995; https://clinicaltrials.gov/study/NCT04492995

ObjectiveTo evaluate the relationship between pelvic/para-aortic sentinel lymph node status and two different injection sites of 99m-technetium (99mTc)-labeled phytate in patients with endometrial cancer.MethodsThis was a randomized controlled trial involving 81 patients with endometrial cancer. In the cervical group (n=40), injections of 99mTc were performed at the 3 and 9 o’clock positions of the uterine cervix. In the endometrial group (n=41), 99mTc was injected into the fundal endometrium using a transcervical catheter. Sentinel lymph nodes were detected through pre-operative lymphoscintigraphy and intra-operatively using a handheld gamma probe. All patients underwent complete pelvic and para-aortic lymphadenectomy procedures. Pathologic ultra-staging was performed with immunostaining for cytokeratin in sentinel lymph nodes after routine hematoxylin and eosin histological examinations. The primary endpoint was the estimation of detection rates, sensitivity, false-negative rates, negative predictive value, and analysis of the distribution of pelvic and para-aortic sentinel lymph nodes.ResultsThe rate of detection of at least one sentinel lymph node, sensitivity, and the negative predictive value was 80%, 66.6%, 96.6% for the cervical group and 85%, 66.6%, 96.9% for the endometrial group, respectively. False-negative sentinel lymph nodes were detected in one patient from each group . There was no significant difference between the groups in terms of total sentinel lymph node count, sentinel pelvic lymph node count, and pelvic bilaterality, but the para-aortic sentinel lymph node count was significantly higher in the endometrial group (p<0.001). Ultra-staging examination of the pelvic sentinel lymph nodes revealed isolated tumor cells in one patient from each group.ConclusionTranscervical endometrial tracer injection in endometrial cancer revealed similar pelvic but significantly higher para-aortic sentinel lymph node detection.

Objective The aim of this study is to prospectively evaluate and compare the accuracy of high-frequency TVS and of two type of MRI (dynamic contrast-enhanced MRI or diffusion-weighted MRI), in association with HE4 in preoperative endometrial cancer (EC) staging. Study design Starting from January 2012 to February 2015, all patients with EC at prior endometrial biopsy, referred to the Division of Gynaecologic Oncology of the University Campus Bio-Medico of Rome, were prospectively included in the study. All of them underwent complete surgical staging hysterectomy and bilateral oophorectomy, pelvic and lumboaortic lymphadenectomy, according to 2011 NCCN guidelines. The day before surgery, patients underwent to transvaginal ultrasonography (TVS), HE4 serum dosage, and using a computer-based random procedure, to dynamic contrast-enhanced MRI (Group A) or to diffusion-weighted MRI (Group B), to assess myometrial invasion and cervical involvement. Results Starting from January 2012 to February 2015, a total of 79 patients were considered for the analysis and randomly divided into Group A ( n  = 38) and Group B ( n  = 41). Regarding myometrial invasion, MRI and TVS resulted comparable in terms of preoperative detection. Concerning the cervical infiltration, the association between TVS and HE4 is characterized by a better preoperative diagnostic validity (TVS + HE4 96.3 vs. 91 % for MRI and 85 % for the TVS). Conclusion Our results, even the low number of enrolled patients, are promising and may lead to a greater efficiency and lower health care costs in identifying those women who require radical surgery and pelvic lymphadenectomy and should be addressed, in specialized centers.

Purpose The aim of this study is to analyze the correct staging of primary endometrial cancer (EC) using clinical examination and 3 Tesla (T) magnetic resonance imaging (MRI) results compared to histopathology. Methods In this prospective, non-randomized, single-center study, 26 women with biopsy-proven EC were evaluated. All women underwent clinical examination including transvaginal ultrasound (CE/US) and 3T MRI (T2-weighted, diffusion-weighted and dynamic contrast-enhanced sequences) prior to surgery. Spearman’s correlation coefficient was employed to analyze the correlation between both staging methods and histopathology and generalized estimation equation analysis to compare their staging results. Main outcome measures are determinations of local tumor extent for EC on CE/US and 3T MRI compared to histopathology (gold standard). Results Sixteen women had an early-stage pT1a tumor, 10 a locally advanced ≥ pT1b tumor. The early stage was correctly diagnosed at CE/US in 100%, by MRI in 81%. Spearman’s correlation coefficient was r  = 1.0 ( p  < 0.001) for correlation of CE/US and histopathology, r  = 0.93 ( p  < 0.001) for correlation of MRI and pathology. A locally advanced tumor stage was exactly diagnosed by MRI in 70% and at CE/US in 50%. Conclusions CE/US is sufficient for staging T1a endometrial cancer, while MRI provides higher sensitivity in detecting locally advanced tumors. Based on our results, combining CE/US and 3T MRI in patients with at least suspected deep myometrial invasion offers a more reliable workflow for individual treatment planning.

Background This study was designed to evaluate detection rate and anatomical location of sentinel lymph node (SLN) at lymphoscintigraphy, to compare short and long lymphoscintigraphy protocols, and to correlate lymphoscintigraphic and surgical mapping of SLN in patients with early-stage endometrial cancer (EC). Methods Subanalysis of the prospective multicenter study Senti-endo performed from July 2007 to August 2009. Patients with stage I and II EC received four cervical injections of 0–2 mL of unfiltered technetium sulphur colloid the day before (long protocol) or the morning (short protocol) before surgery. SLN detection used a combined technetium/patent blue labeling technique, and all patients had a systematic bilateral pelvic lymphadenectomy. Results A total of 133 patients were enrolled in the study and 118 (94.5 %) underwent a lymphoscintigraphy. Of these 118 patients, 44 (37 %) underwent a short protocol and 66 (56 %) a long protocol (data on lymphoscintigraphy were not available in eight patients). Lymphoscintigraphic detection rate was 74.6 % (34 % for short protocol and 60.2 % for long protocol). No difference in the detection rate was observed according to lymphoscintigraphy protocol ( p  = 0.22), but a higher number of SLN was noted for the long protocol ( p  = 0.02). Aberrant drainage was noted on lymphoscintigraphy in 30.5 % of the patients. Paraaortic SLNs were exclusively detected using the long protocol. A poor correlation was noted between short ( κ test = 0.24) or long lymphoscintigraphy ( κ test = 0.3) protocol and SLN surgical mapping. Conclusions Our study demonstrates that preoperative lymphoscintigraphy allowed a high SLN detection rate and that long lymphoscintigraphy protocol was associated with a higher detection of aberrant drainage especially in the paraaortic area.

ObjectivesSentinel lymph node biopsy (SLNB) can identify patients with nodal metastases who are eligible for tailored treatment. The aim of study was to compare the SLN detection rates using cervical and subserosal administration of 2 tracers.ResultsIn group 1 (82 patients), SLNB was performed using radiocolloid injected to the cervix and blue dye administered to the fundus. In group 2, blue dye was injected to cervix and fundus (106 patients). Only SLNB was performed in 128 (68.1%) women. In the remaining 60 (31.9%) patients, pelvic/para-aortic lymphadenectomy together with SLNB was performed. Groups 1 and 2 did not differ with regard to the frequencies of SLNB and lymphadenectomy. The detection rate for both groups was 90.9%. Bilateral detection was achieved in 72.5%. Para-aortic SLNs were found in 9.6%. Detection rates in groups 1 and 2 were 95.1% and 87.7% (P = 0.065). In comparison of cervical administration of radioisotope and subserosal injection of blue dye in group 1, we found a significant difference for total SLN detection (91.5% vs 74.4%, P < 0.05) and no significant difference for bilateral detection (73.3% vs 59.1%, P = 0.776). We did not find differences in the para-aortic SLN detection rates achieved after administration of a radiotracer and injection of a blue dye (4.9% vs 9.8%, P = 0.184). Eighteen patients (9.6%) presented with nodal disease, including 15 women with SLN involvement. The false-negative rate, calculated for patients subjected to lymphadenectomy, was 12.5% (1/8); using the SLNB surgical algorithm, it was 10% (1/10).ConclusionsCervical administration of a tracer, especially radioisotope, results in high SLN detection rates. In turn, the subserosal injection can be used only as an adjuvant method for SLNB. Low para-aortic SLN detection rates observed after cervical administration of a tracer do not seem to be a serious limitation of this technique.

Folate receptor α (FRα) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. Binding to FRα is one of several methods by which folate is taken up by cells; however, this receptor is an attractive anticancer drug target owing to the overexpression of FRα in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FRα to better localize effective anticancer therapies to their target tumours using platforms such as antibody–drug conjugates, small-molecule drug conjugates, radioimmunoconjugates and, more recently, chimeric antigen receptor T cells could further improve the outcomes of patients with FRα-overexpressing cancers. FRα can also be harnessed for predictive biomarker research. Moreover, imaging FRα radiologically or in real time during surgery can lead to improved functional imaging and surgical outcomes, respectively. In this Review, we describe the current status of research into FRα in cancer, including data from several late-phase clinical trials involving FRα-targeted therapies, and the use of new technologies to develop FRα-targeted agents with improved therapeutic indices.Cancer cells, like non-malignant cells, are dependent on folate uptake for growth. However, cancer cells are much more reliant on folate receptors (FRs) and particularly FRα for folate uptake than non-malignant cells. In this Review, the authors describe the available data on the role of FRα as a biomarker and as a target of imaging probes, and of targeted therapies in patients with solid tumours.

Objective To construct a MRI radiomics model and help radiologists to improve the assessments of pelvic lymph node metastasis (PLNM) in endometrial cancer (EC) preoperatively. Methods During January 2014 and May 2019, 622 EC patients (age 56.6 ± 8.8 years; range 27–85 years) from five different centers (A to E) were divided into training set, validation set 1 (351 cases from center A), and validation set 2 (271 cases from centers B–E). The radiomics features were extracted basing on T2WI, DWI, ADC, and CE-T1WI images, and most related radiomics features were selected using the random forest classifier to build a radiomics model. The ROC curve was used to evaluate the performance of training set and validation sets, radiologists based on MRI findings alone, and with the aid of the radiomics model. The clinical decisive curve (CDC), net reclassification index (NRI), and total integrated discrimination index (IDI) were used to assess the clinical benefit of using the radiomics model. Results The AUC values were 0.935 for the training set, 0.909 and 0.885 for validation sets 1 and 2, 0.623 and 0.643 for the radiologists 1 and 2 alone, and 0.814 and 0.842 for the radiomics-aided radiologists 1 and 2, respectively. The AUC, CDC, NRI, and IDI showed higher diagnostic performance and clinical net benefits for the radiomics-aided radiologists than for the radiologists alone. Conclusions The MRI-based radiomics model could be used to assess the status of pelvic lymph node and help radiologists improve their performance in predicting PLNM in EC. Key Points • A total of 358 radiomics features were extracted. The 37 most important features were selected using the random forest classifier. • The reclassification measures of discrimination confirmed that the radiomics-aided radiologists performed better than the radiologists alone, with an NRI of 1.26 and an IDI of 0.21 for radiologist 1 and an NRI of 1.37 and an IDI of 0.24 for radiologist 2.