Impact of preoperative brachytherapy followed by radical hysterectomy in stage IB2 (FIGO 2018) cervical cancer: An analysis of SENTICOL I-II trials.

INTRODUCTION: The goal of this study was to compare the outcomes of preoperative brachytherapy followed by radical surgery versus radical surgery alone in cervical cancer with tumor between 2 and 4 cm (FIGO 2018 IB2). MATERIAL AND METHODS: SENTICOL I and SENTICOL II were two French prospective multicentric trials evaluating sentinel node biopsy in early-stage cervical cancer between 2005 and 2012. Preoperative brachytherapy (low-dose rate or pulse-dose rate at the dose of 60Gy) could be performed 6 to 8 weeks prior to the radical hysterectomy, at the discretion of each center. SENTICOL I and SENTICOL II cohorts were retrospectively analysed to compare the outcomes of preoperative brachytherapy or upfront surgery in patients with IB2 cervical tumor. RESULTS: A total of 104 patients were included: 55 underwent upfront radical hysterectomy and 49 underwent preoperative brachytherapy followed by radical hysterectomy. Patients with preoperative brachytherapy were more likely to have no residual disease (71.4% vs. 25.5%, p < 0.0001) and to be defined as low risk according to Sedlis criteria (83.3% vs. 51.2%, p < 0.0001). Adjuvant treatments were required less frequently in case of preoperative brachytherapy (14.3% vs. 54.5%, p < 0.0001). Patients with preoperative brachytherapy experienced more postoperative complications grade ≥ 3 (24.5% vs. 9.1%, p = 0.03). Patients with preoperative brachytherapy had better 5-year disease-free survival compared to patients who underwent surgery alone, 93.6% and 74.4% respectively (p = 0.04). CONCLUSION: Although preoperative brachytherapy was significantly associated with more severe postoperative complications, better pathologic features were obtained on surgical specimens and led to a better 5-year disease-free survival in IB2 cervical cancer.

Diagnostic value of frozen section examination of sentinel lymph nodes in early-stage cervical cancer at the time of ultrastaging.

OBJECTIVES: We aimed to assess the diagnostic value of frozen-section pathologic examination (FSE) of sentinel lymph nodes (SLN) in patients with early-stage cervical cancer. METHODS: Two French prospective multicentric database on SLN biopsy for cervical cancer (SENTICOL I and II) were analysed. Patients with IA to IIA1 2018 FIGO stage, who underwent SLN biopsy with both FSE and ultrastaging examination were included. RESULTS AND DISCUSSION: Between 2005 and 2012, 313 patients from 25 centers fulfilled the inclusion criteria. Metastatic involvement of SLN was diagnosed in 52 patients (16.6%). Macrometastases, micrometastases and isolated tumor cells (ITCs) were found in 27, 12 and 13 patients respectively. Among the 928 SLNs analysed, FSE identified 23 SLNs with macrometastases in 20 patients and 5 SLNs with micrometastases in 2 patients whereas no ITCs were identified. Ultrastaging of negative SLNs by FSE found macrometastases, micrometastases and ITCs in additional 7, 11 and 17 SLNs. Ultrastaging increased significantly the rate of patients with positive SLN from 7% to 16.6% (p < 0.0001). The sensitivity and the negative predictive value of FSE were 42.3% and 89.7% respectively or 56.4% and 94.1% if ITCs were excluded. False-negative cases were more frequent with tumor size ≥ 20 mm (OR = 4.46, 95%IC = [1.45-13.66], p = 0.01) and preoperative brachytherapy (OR = 4.47, 95%IC = [1.37-14.63], p = 0.01) and less frequent with patients included in higher volume center (>5 patients/year) (OR = 0.09, 95%IC = [0.02-0.51], p = 0.01). CONCLUSIONS: FSE of SLN had a low sensitivity for detecting micrometastases and ITCs and a high negative predictive value for SLN status. Clinical impact of false-negative cases has to be assessed by further studies.

Risk factors for failure of bilateral sentinel lymph node mapping in early-stage cervical cancer.

BACKGROUND: The objective of this study was to determine clinical, tumoral and surgical factors associated with successful bilateral sentinel lymph node mapping (SBM) in early-stage cervical cancer. METHODS: We performed an ancillary work on the data of two prospective trials on SLN biopsy for FIGO IA-IIA cervical cancer (SENTICOL I & II). Patients having Sentinel lymph node (SLN) mapping for early-stage cervical cancer were included between 2005 and 2012 from 28 French oncologic centers. SLN was detected by a combined labeling technique (blue and isotopic). RESULTS: 405 patients were included for analysis: SLNs were identified on at least one side of the pelvis in 381 patients (94.1%) and bilaterally in 326 patients (80.5%). The mean age was 45.4 years [22-85 years]. Most patients had IB1 pathologic FIGO 2018 stage (81.3%) and squamous cell carcinoma (71%). Surgeries were mainly performed by minimally invasive approach (368 patients - 90.9%). By multivariate analysis, lower SBM rate was significantly associated with Age ≥70 years (ORa = 0.02, 95%CI = [0.001-0.28], p = 0.004), tumor size larger than 20 mm (ORa = 0.46,95%CI = [0.21-0.99], p = 0.048) and Body-mass index higher than 30 kg/m2 (ORa = 0.28, 95%CI = [0.12-0.65], p = 0.003). SBM rate was significantly higher in high skills centers (>5patients/year) (ORa = 8.05, 95%CI = [2.06-31.50], p = 0.003) and in SENTICOL II (2009-2012) compared to SENTICOL I (2005-2007) (ORa = 2.6, 95%CI = [1.23-5.51], p = 0.01). CONCLUSIONS: In early-stage cervical cancer, bilateral SLN detection rates is lower in patients aged more than 70years, patients with BMI≥30 kg/m2 and larger tumor ≥20 mm whereas stronger experience of SLN biopsy technique improves bilateral SLN detection.

Predictive factors of unexpected lymphatic drainage pathways in early-stage cervical cancer.

OBJECTIVES: The purpose of this study was to describe sentinel lymph nodes (SLN) topography in patients with early-stage cervical cancer and to determine factors associated with atypical lymphatic drainage pathway (LDP). METHODS: We analyzed the data of two prospective multicentric trials on SLN biopsy for cervical cancer (SENTICOL I and II) in women undergoing surgery for early-stage cervical cancer. SLN detection was realized with a combined labeling technique (Patent blue and radioactive tracer). Patients having bilateral SLN detection were included. Univariate and Multivariate analysis were performed by patients and by side to assess clinical and pathologic factors that may predict atypical LDP. RESULTS: Between January 2005 and July 2012, 326 patients with 1104 intraoperative detected SLNs fulfilled the inclusion criteria. The SLNs were mainly located in the interiliac or external iliac area in 83.2%. The other localizations were: 9.2% in the common iliac area, 3.9% in the parametrium, 1.6% in the promontory area, 1.5% in the paraaortic area and 0.5% in other areas. Thirty-five patients (10.7%) had atypical SLN without SLN in typical area on one or both sides. In multivariate analysis, tumor size ≥20 mm appeared as an independent factor of having at least one exclusive atypical LDP (ORa = 3.95 95%CI = [1.60-9.78], p = 0.003). Multiparity decreased significantly the probability of having at least one exclusive atypical LDP (ORa = 0.16 95%CI = [0.07-0.39], p < 0.0001). CONCLUSIONS: Tumor size larger than 20 mm and nulliparity increase the risk of having exclusive atypical LDP in early-stage cervical cancer.

Induced superconductivity in graphene grown on rhenium.

We report a new way to strongly couple graphene to a superconductor. The graphene monolayer has been grown directly on top of a superconducting Re(0001) thin film and characterized by scanning tunneling microscopy and spectroscopy. We observed a moiré pattern due to the mismatch between Re and graphene lattice parameters that we have simulated with ab initio calculations. The density of states around the Fermi energy appears to be position dependent on this moiré pattern. Tunneling spectroscopy performed at 50 mK shows that the superconducting behavior of graphene on Re is well described by the Bardeen-Cooper-Schrieffer theory and stands for a very good interface between the graphene and its metallic substrate.

Unraveling the intrinsic and robust nature of van Hove singularities in twisted bilayer graphene by scanning tunneling microscopy and theoretical analysis.

Extensive scanning tunneling microscopy and spectroscopy experiments complemented by first-principles and parametrized tight binding calculations provide a clear answer to the existence, origin, and robustness of van Hove singularities (vHs) in twisted graphene layers. Our results are conclusive: vHs due to interlayer coupling are ubiquitously present in a broad range (from 1° to 10°) of rotation angles in our graphene on 6H-SiC(000-1) samples. From the variation of the energy separation of the vHs with the rotation angle we are able to recover the Fermi velocity of a graphene monolayer as well as the strength of the interlayer interaction. The robustness of the vHs is assessed both by experiments, which show that they survive in the presence of a third graphene layer, and by calculations, which test the role of the periodic modulation and absolute value of the interlayer distance. Finally, we clarify the role of the layer topographic corrugation and of electronic effects in the apparent moiré contrast measured on the STM images.

Localization of dirac electrons in rotated graphene bilayers.

For Dirac electrons the Klein paradox implies that the confinement is difficult to achieve with an electrostatic potential although it can be of great importance for graphene-based devices. Here, ab initio and tight-binding approaches are combined and show that the wave function of Dirac electrons can be localized in rotated graphene bilayers due to the Moire pattern. This localization of wave function is maximum in the limit of the small rotation angle between the two layers.

Predictive factors of severe perioperative morbidity of radical hysterectomy with lymphadenectomy in early-stage cervical cancer: A French prospective multicentric cohort of 248 patients.

OBJECTIVE: The purpose of this study was to assess the postoperative morbidity after radical hysterectomy (RH) for early-stage cervical cancer and to determine risk factors of severe perioperative morbidity. METHODS: Data of two prospective trials on sentinel node biopsy for cervical cancer (SENTICOL I & II) were analysed. Patients having a radical hysterectomy were included between 2005 and 2012 from 25 French oncologic centers. Postoperative complications were prospectively recorded in a pre-specified analysis. RESULTS: 248 patients met the inclusion criteria. The median age was 44.5 years [25-85]. 88.7% of patients had a stage IB1 disease. There were 71.4% epidermoid carcinomas and 25% adenocarcinomas. 125 patients (50.4%) had a laparoscopic-assisted vaginal RH, 88 patients (35.5%) had a total laparoscopic RH, 26 patients (10.5%) had an open RH and 9 patients (3.6%) had a robotic-assisted RH. Sixteen patients (6.4%) had intraoperative complications. On a multivariate analysis, intraoperative complications were significantly associated with BMI >30 kg/m2. The urinary, lymphovascular and neurologic complications rates were respectively 34.3%, 20.6% and 19.8%. 31 patients (12.5%) had severe postoperative complications (Clavien-Dindo ≥ 3 or CTCAE ≥ 3). On multivariate analysis, severe postoperative complications were associated with parametrial involvement, preoperative brachytherapy and inclusion in low surgical skills center. CONCLUSIONS: This study based on prospective data showed that RH has low severe postoperative complications. The main complications were urinary infections and lower limb lymphedema. Patients with early-stage cervical cancer should be referred to expert center to ensure best surgical outcomes.

Universal classification of twisted, strained and sheared graphene moiré superlattices.

Moiré superlattices in graphene supported on various substrates have opened a new avenue to engineer graphene's electronic properties. Yet, the exact crystallographic structure on which their band structure depends remains highly debated. In this scanning tunneling microscopy and density functional theory study, we have analysed graphene samples grown on multilayer graphene prepared onto SiC and on the close-packed surfaces of Re and Ir with ultra-high precision. We resolve small-angle twists and shears in graphene, and identify large unit cells comprising more than 1,000 carbon atoms and exhibiting non-trivial nanopatterns for moiré superlattices, which are commensurate to the graphene lattice. Finally, a general formalism applicable to any hexagonal moiré is presented to classify all reported structures.

The formation of the smallest fullerene-like carbon cages on metal surfaces.

The nucleation and growth of carbon on catalytically active metal surfaces is one of the most important techniques to produce nanomaterials such as graphene or nanotubes. Here it is shown by in situ electron microscopy that fullerene-like spherical clusters with diameters down to 0.4 nm and thus much smaller than C60 grow in a polymerized state on Co, Fe, or Ru surfaces. The cages appear on the surface of metallic islands in contact with graphene under heating to at least 650 °C and successively cooling to less than 500 °C. The formation of the small cages is explained by the segregation of carbon on a supersaturated metal, driven by kinetics. First principles energy calculations show that the clusters polymerize and can be attached to defects in graphene. Under compression, the polymerized cages appear in a crystalline structure.

Quasiparticle chirality in epitaxial graphene probed at the nanometer scale.

Graphene exhibits unconventional two-dimensional electronic properties resulting from the symmetry of its quasiparticles, which leads to the concepts of pseudospin and electronic chirality. Here, we report that scanning tunneling microscopy can be used to probe these unique symmetry properties at the nanometer scale. They are reflected in the quantum interference pattern resulting from elastic scattering off impurities, and they can be directly read from its fast Fourier transform. Our data, complemented by theoretical calculations, demonstrate that the pseudospin and the electronic chirality in epitaxial graphene on SiC(0001) correspond to the ones predicted for ideal graphene.

Why multilayer graphene on 4H-SiC(0001[over ]) behaves like a single sheet of graphene.

We show experimentally that multilayer graphene grown on the carbon terminated SiC(0001[over ]) surface contains rotational stacking faults related to the epitaxial condition at the graphene-SiC interface. Via first-principles calculation, we demonstrate that such faults produce an electronic structure indistinguishable from an isolated single graphene sheet in the vicinity of the Dirac point. This explains prior experimental results that showed single-layer electronic properties, even for epitaxial graphene films tens of layers thick.

Electronic structure of epitaxial graphene layers on SiC: effect of the substrate.

A strong substrate-graphite bond is found in the first all-carbon layer by density functional theory calculations and x-ray diffraction for few graphene layers grown epitaxially on SiC. This first layer is devoid of graphene electronic properties and acts as a buffer layer. The graphene nature of the film is recovered by the second carbon layer grown on both the (0001) and (0001[over]) 4H-SiC surfaces. We also present evidence of a charge transfer that depends on the interface geometry. Hence the graphene is doped and a gap opens at the Dirac point after three Bernal stacked carbon layers are formed.

Electron transport via local polarons at interface atoms.

Electronic transport is profoundly modified in the presence of strong electron-vibration coupling. We show that in certain situations, the electron flow takes place only when vibrations are excited. By controlling the segregation of boron in semiconducting Si(111)-square root 3 x square root 3 R 30 degrees surfaces, we create a type of adatom with a dangling-bond state that is electronically decoupled from any other electronic state. However, probing this state with scanning tunnelling microscopy at 5 K yields high currents. These findings are rationalized by ab-initio calculations that show the formation of a local polaron in the transport process.