Real-Time Fluorescent Sentinel Lymph Node Mapping with Indocyanine Green in Women with Previous Conization Undergoing Laparoscopic Surgery for Early Invasive Cervical Cancer: Comparison with Radiotracer ± Blue Dye.

STUDY OBJECTIVE: To evaluate the added value of the fluorescence dye indocyanine green (ICG) for sentinel lymph node (SLN) mapping in women with cervical cancer who had undergone previous conization (stage 1A-1B1) by comparing ICG versus Tc99m radiotracer + blue dye (BD). DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Two European academic medical centers, San Gerardo Hospital, Italy and University of Berne, Switzerland. PATIENTS: Sixty-five women with early stage (IA-IB1) cervical cancer who had undergone previous conization and who underwent SLN mapping with Tc99m ± BD (n = 23) or ICG (n = 42) followed by pelvic lymphadenectomy and fertility-sparing surgery or hysterectomy were included in this analysis. INTERVENTION: Overall detection rate and bilateral SLN mapping rates of ICG were compared with those obtained using the standard Tc99m radiocolloid and BD. MEASUREMENT AND MAIN RESULTS: Overall, 220 SLNs were detected. The median number of SLNs per patient in the Tc99m ± BD group was 2 (range, 1-5) and in the ICG group, 3 (range, 2-15). The detection rate of SLNs was 95.7% in Tc99m ± BD group and 100% in the ICG group (p = .354). The women injected with ICG had a higher rate of bilateral mapping of the SLNs as compared with the Tc99m ± BD group (95.2% vs 69.6%, p = .016%). Only 12% of the patients (8/65) presented metastatic nodes, 2 in the Tc99m ± BD group and 6 in the ICG group. CONCLUSION: In early-stage cervical cancer patients conization had no significant impact on the SLN detection rate using both techniques (ICG and radiotracer ± BD). In this scenario a higher bilateral mapping rate was confirmed using the fluorescent dye ICG rather than the standard techniques.

Near-infrared Fluorescence-guided Sentinel Node Mapping of the Ovary With Indocyanine Green in a Minimally Invasive Setting: A Feasible Study.

Sentinel lymph node (SLN) mapping has increased its feasibility in both early-stage cervical and endometrial cancer. There are few SLN studies regarding the ovary because of the risk of tumor dissemination and perhaps because the ovary represents an inconvenient site for injection. In this preliminary study, we have shown the feasibility of SLN mapping of the ovary with indocyanine green during laparoscopic retroperitoneal aortic surgical staging. The 10 women who were included in this study underwent aortic with pelvic laparoscopic staging, which included SLN biopsy, extrafascial total hysterectomy, and bilateral salpingo-oophorectomy in case of an ovarian tumor. The fluorescent dye was injected on the dorsal and ventral side of the proper ovarian ligament and the suspensory ligament, close to the ovary and just underneath the peritoneum. In all cases except 1, SLNs were detected soon after the injection in the aortic compartment and in 3 cases also in the common iliac region. Only 1 intraoperative complication occurred: a superficial lesion of the vena cava that was recovered with a laparoscopic suture. Laparoscopic ovarian SLN mapping performed by means of an injection of indocyanine green fluorescent tracer in the ovarian ligaments seems feasible and promising. Further investigation are encouraged and necessary to evaluate the possible applications of this new technique for staging patients with early-stage ovarian cancer.

Indocyanine Green versus Radiotracer with or without Blue Dye for Sentinel Lymph Node Mapping in Stage >IB1 Cervical Cancer (>2 cm).

STUDY OBJECTIVE: To compare sentinel lymph node (SLN) mapping in women with cervical cancer stage >IB1 (tumor size >2 cm) using indocyanine green (ICG) versus the standard technique using radioisotope technetium 99m radiocolloid (Tc99m) radiotracer with or without blue dye. DESIGN: European multicenter, retrospective observational study (Canadian Task Force classification II-2). SETTING: Four academic medical centers. PATIENTS: Ninety-five women with stage IB1 cervical cancer (>2 cm) who underwent SLN mapping with Tc99m with or without blue dye or ICG and radical hysterectomy. INTERVENTION: The detection rate and bilateral mapping rate were compared between ICG and standard Tc99m radiotracer with or without blue dye. Lymphadenectomy was performed, and the false-negative rate was assessed. MEASUREMENTS AND MAIN RESULTS: Forty-seven patients underwent SLN mapping with Tc99m with or without blue dye, and 48 did so with ICG. All patients underwent radical hysterectomy with or without bilateral salpingo-oophorectomy between 2008 and 2016. The overall detection rate of SLN mapping was 91.5% for Tc99m with or without blue dye and 100% for ICG. A 91.7% rate of bilateral migration was achieved for ICG, significantly higher than the 66% obtained with Tc99m with or without blue dye (p = .025). Nine of the 23 SLN-positive patients (39.1%) were diagnosed exclusively as a result of the ultrastaging used to identify micrometastases or isolated tumor cells only. CONCLUSIONS: In advanced cervical cancer (stage IB1 >2 cm), the detection rate and bilateral migration rate on real-time fluorescent SLN mapping were higher with ICG than with Tc99m radiotracer with or without blue dye. SLN mapping and ultrastaging can provide additional information for nodal staging in advanced cervical cancer. In this setting, ICG is a promising tool for mapping, appearing less affected by higher disease stage compared with traditional methods.

Quality of Care for Cervical and Endometrial Cancer Patients: The Impact of Different Techniques of Sentinel Lymph Node Mapping on Patient Satisfaction.

OBJECTIVES: The purpose of this study was to assess the quality of care in patients who underwent sentinel lymph node (SLN) mapping for endometrial and cervical cancer staging, and evaluate the impact of different techniques on patient satisfaction, i.e. radiotracer Tc99m versus indocyanine green (ICG) or methylene blue injection. METHOD: Women with preoperative stage I endometrial cancer or stage I (1A2-1B1) cervical cancer who underwent surgical staging, including SLN mapping, were considered for this study. Patient satisfaction was assessed using the European Organisation for Research and Treatment of Cancer IN-PATSAT32 questionnaire. Women were classified into two groups according to the different nodal mapping techniques: intracervical preoperative injection of Tc99m nanocolloid + intraoperative blue dye (Group 1) versus intraoperative cervical injection of ICG or blue dye (Group 2). Differences in patient satisfaction scores between the groups were analyzed. RESULTS: Of the 178 eligible women, 143 were included in the study (endometrial cancer n = 106, cervical cancer n = 37): 57 underwent SLN mapping with Tc99m and blue dye (Group 1), and 86 women were mapped intraoperatively with blue dye alone or ICG (Group 2). Analysis of IN-PATSAT32 questionnaire scores showed a higher patient satisfaction score for patients in Group 2 (p = 0.001), which was independent of the physician and surgical outcomes evaluated. The scores were statistically better for Group 2, and also in rating doctors (p = 0.0001), nurses (p = 0.006), and care and services organizations (p = 0.001). CONCLUSIONS: Cervical and endometrial cancer patients who underwent SLN mapping by ICG or blue dye perceived a better quality of care when compared with those patients who underwent the combined radiocolloid and blue dye technique.

From Conventional Radiotracer Tc-99(m) with Blue Dye to Indocyanine Green Fluorescence: A Comparison of Methods Towards Optimization of Sentinel Lymph Node Mapping in Early Stage Cervical Cancer for a Laparoscopic Approach.

BACKGROUND: The credibility of sentinel lymph node (SLN) mapping is becoming increasingly more established in cervical cancer. We aimed to assess the sensitivity of SLN biopsy in terms of detection rate and bilateral mapping in women with cervical cancer by comparing technetium-99 radiocolloid (Tc-99(m)) and blue dye (BD) versus fluorescence mapping with indocyanine green (ICG). METHODS: Data of patients with cervical cancer stage 1A2 to 1B1 from 5 European institutions were retrospectively reviewed. All centers used a laparoscopic approach with the same intracervical dye injection. Detection rate and bilateral mapping of ICG were compared, respectively, with results obtained by standard Tc-99(m) with BD. RESULTS: Overall, 76 (53 %) of 144 of women underwent preoperative SLN mapping with radiotracer and intraoperative BD, whereas 68 of (47 %) 144 patients underwent mapping using intraoperative ICG. The detection rate of SLN mapping was 96 % and 100 % for Tc-99(m) with BD and ICG, respectively. Bilateral mapping was achieved in 98.5 % for ICG and 76.3 % for Tc-99(m) with BD; this difference was statistically significant (p < 0.0001). CONCLUSIONS: The fluorescence SLN mapping with ICG achieved a significantly higher detection rate and bilateral mapping compared to standard radiocolloid and BD technique in women with early stage cervical cancer. Nodal staging with an intracervical injection of ICG is accurate, safe, and reproducible in patients with cervical cancer. Before replacing lymphadenectomy completely, the additional value of fluorescence SLN mapping on both perioperative morbidity and survival should be explored and confirmed by ongoing controlled trials.

Sentinel Lymph Node Mapping With Near-Infrared Fluorescent Imaging Using Indocyanine Green: A New Tool for Laparoscopic Platform in Patients With Endometrial and Cervical Cancer.

Indocyanine green (ICG) represents a feasible alternative to the more traditional methods of sentinel lymph node (SLN) mapping, and interest in this promising tracer is growing. This report outlines our experience with ICG in a minimally invasive laparoscopic approach in women with endometrial cancer and cervical cancer using the Storz SPIES ICG near-infrared fluorescence imaging technology. A total of 49 patients with clinical stage I endometrial cancer (n = 40) or stage I cervical cancer (n = 9) were retrospectively reviewed. All patients had undergone simple or radical laparoscopic hysterectomy with pelvic and/or aortic lymphadenectomy and SLN mapping by means of an intracervical injection of ICG dye at the 3 o'clock and 9 o'clock locations after the induction of general anesthesia. The detection rate of ICG was 100% (49 of 49). The rate of bilateral SLN detection was 86% (42 of 49). Positive lymph nodes were found in 6 patients (12%), with at least 1 positive SLN. The sensitivity and negative predictive value of SLN detection were 100%. All procedures were successfully completed without conversion to open laparotomy, and no intraoperative or postoperative complications occurred. In our preliminary experience, ICG showed a high overall detection rate, and bilateral mapping appears to be a feasible alternative to the more traditional methods of SLN mapping in patients with endometrial cancer and cervical cancer. Laparoscopic SLN mapping with ICG appears to be safe, easy, and reproducible, with a positive impact on patient management.

Dacomitinib (PF-00299804), a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro.

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that carries an extremely poor prognosis. Up to 35 % of USC may overexpress the epidermal growth factor receptor-2 (HER2/neu) at strong (i.e., 3+) level by immunohistochemistry (IHC) or harbor HER2/neu gene amplification by fluorescence in situ hybridization (FISH). In this study, we assessed the sensitivity of a panel of USC cell lines with and without HER2/neu gene amplification to dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor tyrosine kinase inhibitor. Eight primary cell lines (i.e., four harboring HER2/neu gene amplification by FISH and four FISH- cell lines), all demonstrating similar in vitro growth rates, were evaluated in viability/proliferation assays. The effect of dacomitinib on cell growth, cell cycle distribution, and signaling was determined using flow cytometry-based assays. Dacomitinib caused a significantly stronger growth inhibition in HER2/neu FISH+ USC cell lines when compared to FISH- USC (dacomitinib half maximal inhibitory concentration (IC50) mean ± SEM = 0.02803 ± 0.003355 µM in FISH+ versus 1.498 ± 0.2209 µM in FISH- tumors, P < 0.0001). Dacomitinib growth inhibition was associated with a significant and dose-dependent decline in phosphorylated HER2/neu and S6 transcription factor and a dose-dependent and time-dependent cell cycle arrest in G0/G1 in FISH+ USC. Dacomitinib is remarkably effective against chemotherapy-resistant HER2/neu gene-amplified USC. Clinical studies with dacomitinib in HER2/neu FISH+ USC patients resistant to standard salvage chemotherapy are warranted.

Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo.

OBJECTIVE: Carcinosarcoma is a deadly gynecologic malignancy with few effective treatment options. The study of new therapies is difficult because of its rarity. The objective of this study was to determine the efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma. METHODS: The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Data regarding IC50, cell cycle distribution, and cell signaling changes were assessed by flow cytometry. The efficacy of neratinib was determined in treating mice harboring HER2 amplified carcinosarcoma xenografts. RESULTS: Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50:0.014µM±0.004vs.0.164µM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Neratinib inhibited tumor growth (p=0.012) and prolonged survival in mice harboring HER2 amplified carcinosarcoma xenografts (p=0.0039). CONCLUSIONS: Neratinib inhibits HER2 amplified carcinosarcoma proliferation, signaling, cell cycle progression and tumor growth in vitro. Neratinib inhibits HER2/neu amplified xenograft growth and improves overall survival. Clinical trials are warranted.

Optimizing Strategies for Sentinel Lymph Node Mapping in Early-Stage Cervical and Endometrial Cancer: Comparison of Real-Time Fluorescence With Indocyanine Green and Methylene Blue.

OBJECTIVE: This retrospective study aimed to compare the sentinel lymph node (SLN) mapping results of methylene blue (MB) and indocyanine green (ICG) in women with early-stage endometrial or cervical cancer. METHODS: From August 2011 to March 2015, all consecutive patients with stage I endometrial or cervical cancer who underwent SLN mapping with intracervical injection of MB or ICG using a 22-gauge spinal needle were included in the study. Radical or simple hysterectomy with bilateral pelvic and/or aortic lymphadenectomy was performed after SLN mapping. RESULTS: Overall, 81 women (64 women with endometrial cancer and 17 women with cervical cancer) underwent surgery, including SLN mapping. Sixty-five patients (80%) underwent minimally invasive surgery. The overall detection rate was 84% (34 of 38) and 100% (43 of 43) for MB and ICG, respectively (P = 0.041). Bilateral SLN detection was higher in the ICG group than in the MB group (88% vs 50; P = 0.002). Eleven patients (13.5%) were found to have positive nodes with at least 1 positive SLN. The sensitivity and negative predictive value of SLN were 100%. CONCLUSIONS: Real-time florescence mapping with ICG shows better overall detection rate and bilateral mapping than MB alone. In our pilot study, the differences are statistically significant. The higher number of bilateral mapping of ICG may increase the quality of life and recovery of women by reducing the need for complete lymphadenectomy.

The impact of different doses of indocyanine green on the sentinel lymph-node mapping in early stage endometrial cancer.

INTRODUCTION: Aim of the study is to evaluate the impact of different doses of indocyanine green (ICG) on the sentinel lymph-node (SLN) mapping in endometrial cancer (EC). MATERIALS AND METHODS: A retrospective analysis of EC patients undergoing a laparoscopic SLN mapping at two institutions was performed. Two different injection protocols were used (protocol # 1: 5 mg/ml and a volume of 8 ml; protocol # 2: 1.25 mg/ml and a volume of 4 ml). In every case, the injection was intracervical. The laparoscopic equipment adopted was the same among both institutions. Overall and bilateral detection rates (DR) and median number of retrieved SLNs were calculated. At uni- and multivariate analysis factors (including ICG dose) associated with DR and number of detected SLNs were investigated. RESULTS: Overall, 168 patients were included. The overall and bilateral DR were 96.3 and 84.5%. Median number of removed SLNs was 3 (0-18). In 56% of the patients, a median number of 6 (1-93) non-SLNs (NSLNs) were removed. Seventeen (10.1%) patients had metastatic SLNs. At multivariate analysis, no factors were associated with bilateral DR. ICG dose was the only factor associated with number of removed SLNs at multivariate analysis. CONCLUSION: A larger dose of ICG is associated with a higher number of retrieved SLNs but not with an increased bilateral DR.

Correction to: The impact of different doses of indocyanine green on the sentinel lymph-node mapping in early stage endometrial cancer.

Unfortunately, the P value at multivariate analysis for ICG concentration in Table 3 was incorrectly published.

Sentinel lymph node mapping in patients with stage I endometrial carcinoma: a focus on bilateral mapping identification by comparing radiotracer Tc99m with blue dye versus indocyanine green fluorescent dye.

PURPOSE: The aim of this study was to compare technetium radiocolloid (Tc99m) + blue dye (BD) versus Indocyanine green (ICG) fluorescent dye in terms of the overall detection rate and bilateral sentinel lymph node (SLN) mapping in patients with endometrial carcinoma. METHODS: Patients from five European centers with apparently confined clinical stage I endometrial cancer were reviewed. A comparison was made between women who received SLN mapping with pelvic and/or aortic lymphadenectomy (LND), and women who underwent SLN algorithm (SA), was also performed between the two groups. RESULTS: Three hundred and forty-two (342) women were involved (147 in the Tc99m + BD group and 195 in the ICG group). The overall detection rate of SLN biopsy was 97.3% (143/147) for women in the Tc99m + BD group and 96.9% (189/195) for women in the ICG group (p = 0.547). The bilateral mapping rate for ICG was 84.1%-significantly higher with respect to the 73.5% obtained with Tc99m + BD (p = 0.007). No differences in overall sensitivity (OS) and overall false negative rate (FNR) were seen between LND and SA (p value = 0.311), whereas the negative predictive value (NPV) was in favor of SA group (p value = 0.030). CONCLUSIONS: In this study, fluorescent mapping using ICG resulted equivalent to the standard combined radiocolloid and BD, but real-time SLN mapping achieves a higher bilateral detection rate. The added value that this fast emerging technology promises to give certainly warrants future studies to further consolidate the advantages there are over the standard technique.