Breast carcinoma detection in ex vivo fresh human breast surgical specimens using a fast slide-free confocal microscopy scanner: HIBISCUSS project.

BACKGROUND: New generation ultra-fast fluorescence confocal microscopy allows the ex vivo intraoperative analysis of fresh tissue. The High resolution Imaging for Breast carcInoma detection in ex vivo Specimens after breast Conserving sUrgery by hiStolog Scanner (HIBISCUSS) project aimed to develop an online learning program to recognize the main breast tissue features on ultra-fast fluorescence confocal microscopy images and to evaluate the performance of surgeons and pathologists in diagnosing cancerous and non-cancerous breast tissue in ultra-fast fluorescence confocal microscopy images. METHODS: Patients who underwent conservative surgery or mastectomy for breast carcinoma (invasive or in situ lesions) were included. The fresh specimens were stained with a fluorescent dye and imaged using a large field-of-view (20 cm2) ultra-fast fluorescence confocal microscope. RESULTS: One hundred and eighty-one patients were included. The images from 55 patients were annotated to generate learning sheets and images from 126 patients were blindly interpreted by seven surgeons and two pathologists. The time for tissue processing and ultra-fast fluorescence confocal microscopy imaging was between 8 and 10 min. The training program was composed of 110 images divided into nine learning sessions. The final database for blind performance assessment comprised 300 images. The mean duration for one training session and one performance round was 17 and 27 min respectively. The performance of pathologists was almost perfect with 99.6 per cent (standard deviation (s.d.) 5.4 per cent) accuracy. Surgeons' accuracy significantly increased (P = 0.001) from 83 per cent (s.d. 8.4 per cent) in round 1 to 98 per cent (s.d. 4.1 per cent) in round 7 as well as the sensitivity (P = 0.004). Specificity increased without significance from 84 per cent (s.d. 16.7 per cent) in round 1 to 87 per cent (s.d. 16.4 per cent) in round 7 (P = 0.060). CONCLUSION: Pathologists and surgeons showed a short learning curve in differentiating breast cancer from non-cancerous tissue in ultra-fast fluorescence confocal microscopy images. Performance assessment for both specialties supports ultra-fast fluorescence confocal microscopy evaluation for intraoperative management. REGISTRATION NUMBER: NCT04976556 (http://www.clinicaltrials.gov).

Robotic Prophylactic Nipple-Sparing Mastectomy with Immediate Prosthetic Breast Reconstruction: A prospective Study of 138 Procedures.

Bachground: Robotic breast surgery is an emergent procedure with encouraging preliminary results. The aim of this study is to assess the feasibility and the safety of robotic nipple sparing mastectomy (RNSM) with immediate prosthetic breast reconstruction (IPBR). Methods: This is a prospective study including from December 2015 to January 2020 all RNSM surgeries with IPBR, in patients with moderate ptosis and A B or C cup. The primary endpoint was the rate of major necrosis. Secondary endpoints were conversion rate, postoperative complications (infections, hematoma, implant exposure), aesthetic results and quality of life. Results: 79 patients underwent 138 RNSM with IPBR. The average follow-up was 28 months. 2 procedures required conversion. Two cases of major necrosis occurred (1.4%). 9 surgical site infections were observed (6.5%), 4 infections could be treated with implant replacement. Unfortunately, 5 others resulted in implant loss. 4 other implant losses occurred: 2 due to major necrosis, and 2 due to periprosthetic capsula. In total, 9 implants were lost (6.5%). Esthetical results were mostly very satisfying and quality of life was not affected by the mastectomy. Conclusions: RSNM with IPBR was associated with low rates of major necrosis. It is a safe and reproducible procedure that allows breast reconstruction without visible scar.

Transumbilical Single-port Robotically Assisted Nipple-sparing Mastectomy: A Cadaveric Study.

The authors performed a transumbilical, single-port robotically assisted, nipple-sparing mastectomy on a cadaveric model to assess technical feasibility. Surgeon-controlled, robotic-wristed instrumentation, as well as 3-dimensional high definition (HD) vision allowed the entire dissection to be performed through a single incision placed in the umbilicus. The technique warrants further exploration and development before any application in clinical applied research.

Prospective, multicenter French study evaluating the clinical impact of the Breast Cancer Intrinsic Subtype-Prosigna® Test in the management of early-stage breast cancers.

PURPOSE: The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna's assay information on physicians' adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results. METHODS: Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians' opinion on the test results and the patients' degree of anxiety, difficulties with therapy and quality of life. RESULTS: Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p<0.001, Fisher's exact test). Prosigna test results also decreased patients' anxiety about the chosen adjuvant therapy, and improved emotional well-being and measures of personal perceptions of uncertainty. CONCLUSIONS: The results of this prospective decision impact study are consistent with 2 previous, identically designed studies carried out in Spain and Germany. The availability of Prosigna test results increased the confidence of treating physicians in their adjuvant treatment decisions, and led to an 18% change in chemotherapy treatment plan (from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa). Prosigna testing decreased anxiety and improved measures of health-related quality of life in patients facing adjuvant therapy. The 25% discordance between Prosigna test and IHC subtyping underlines the importance of molecular testing for optimal systemic therapy indications in early breast cancer.

Denaturing fixatives are compatible with the NanoString nCounter® platform and the Prosigna® assay.

The objective of this study was to establish that the denaturing fixative, formalin and acetic acid (AFA), is equivalent to neutral-buffered formalin (NBF) on the nCounter system using the Prosigna assay. Twenty-five previously resected tumors from breast cancer patients were apportioned and fixed with either NBF or AFA prior to embedding in paraffin. Differentially fixed and paraffin embedded tissue pairs were sectioned and pathological review was performed according to the Prosigna assay protocol. RNA was isolated using the Prosigna assay kit and analyzed using the NanoString nCounter Dx Analysis system. 47 of the 50 blocks (94%) passed RNA quality control (QC) criteria and were collectively designated as the analysis set. We found that RNA yield and purity (A260/A280) were not significantly different between the fixatives within the analysis set. In the analysis of ROR score, the tissue pairs had a Pearson Correlation Coefficient of 0.91, similar to the correlation observed between paired tissue blocks using a single fixative in previous studies. Subtype concordance between differentially fixed tissue pairs was high (K=0.80). No significant bias or variability in risk of recurrence (ROR) score attributable to fixative was detected in this study. Further analysis revealed that sample pairs with larger differences in ROR score were limited to nearly-depleted tissue blocks containing large amounts of normal tissue due to proximity of the tumor margin. The results of this study demonstrate that the fixative, AFA, does not contribute significantly to bias and variability of assay results.

Colpoplasty by laparoscopic modified Davydov's procedure.

OBJECTIVE: To show laparoscopic surgery to treat vaginal shortening, with functional sequelae (sexual disorders), after radiotherapy and brachytherapy for vaginal carcinoma. METHODS: Davydov's procedure was initially described to treat vaginal aplasia (Davydov & Zhvitiashvili, 1974). This surgery was then improved for the upper part of the vagina, performed by laparoscopy (Leblanc, 2010; Adamyan, 1995) [2-3]. We used surgical technique, based on Davydov's procedure, by laparoscopy, to cover the upper neovagina, with two large peritoneal flaps, one anterior with the pre-vesical peritoneum and a second one posterior with the peritoneum of Douglas pouch. This surgery can be performed with no use of intestinal gesture, skin grafting, flap or any foreign material. Leblanc et al. (2016) [4] reported promising results about eight patients with this technique. RESULTS: A 36-years old patient had been treated by chemotherapy, radiotherapy and brachytherapy for a vagina cancer with a para-rectal extension. After four years of remission, she was worried about an important vaginal atrophy related to a significant vaginal shortening (about 5cm), causing major dyspareunia. This situation had caused sexual disorders with a real impact on the quality of life. All non-invasive techniques (dilatators, lubricants…) had led to failures. A colpoplasty by laparoscopic modified Davydov's procedure was performed. The post-operative follow-up was simple without complication. The vaginal mandrel was removed after 12days. The clinical examination after 4months demonstrates that size and elasticity of the neovaginal cavity was rewarding. CONCLUSION: This surgical technique requires training and experienced team, but seems to be promising way to restore a normal vaginal length.

Tumoral heterogeneity of breast cancer.

The objective of this literature review is to describe the types of tumor heterogeneity in breast cancer and their clinical implication. Two kinds of tumor heterogeneity are described: intertumor heterogeneity and intra-tumor heterogeneity. In breast cancer, inter-tumor heterogeneity was best characterized in the 2000s thanks to high throughput analyses. These analyzes resulted in a molecular classification of breast cancers distinguishing four subtypes: Luminal A, Luminal B, HER 2+ and basal like. This variability may be observed between the primary tumor and metastases, namely the temporal intratumor heterogeneity. The average discrepancy for the progesterone receptor, estrogen, and between HER2 status appears to be 33%, 20% and 8%, respectively. It is then interesting to study the heterogeneity within the primary tumor: this spatial intra-tumor heterogeneity is poorly known. Physiopathology of intra-tumor heterogeneity light be deciphered by studies on cancer stem cells and clonal evolution model. In addition, the tumor microenvironment seems to actively contribute to this heterogeneity. The major interest to study this heterogeneity is the clinical implication that could result. While precision medicine is emerging, it is important to capture the heterogeneity of each specific tumor type. These new biological knowledge will allow us to anticipate such heterogeneity and individualize the management of breast cancer.

Serum CA125 and HE4 levels as predictors for optimal interval surgery and platinum sensitivity after neoadjuvant platinum-based chemotherapy in patients with advanced epithelial ovarian cancer.

BACKGROUND: The aim of this study is to evaluate a new tumour marker, HE4, and to compare it with CA125 in predicting optimal cytoreduction and response to chemotherapy. Thirty patients with advanced epithelial ovarian cancer and multiple sera harvested during neoadjuvant chemotherapy (NAC) were included. RESULTS: Based on ROC curves analysis, CA125 ≤ 75 UI/ml and HE4 ≤ 252 pmol/L after the 3rd cycles of NAC, with a sensitivity of 93.7 % and a specificity of 92.3 % (PPV = 93.7 % and NPV = 92.3 %), offered the best combination for predicting optimal cytoreduction. In addition, the HE4 value of 115 pmol/L is the best cut-off level for identifying platinum-sensitive patients. CONCLUSIONS: The introduction of HE4 as a new tool for predicting platinum-sensitivity and interval optimal cytoreduction is promising.

The patient-breast cancer care pathway: how could it be optimized?

BACKGROUND: A care pathway is defined as patient-focused global care that addresses temporal (effective and coordinated management throughout the illness) and spatial issues (treatment is provided near the health territory in or around the patient's home). Heterogeneity of the care pathways in breast cancer (BC) is presumed but not well evaluated. The OPTISOINS01 study aims to assess every aspect of the care pathway for early BC patients using a temporal and spatial scope. METHODS/DESIGN: An observational, prospective, multicenter study in a regional health territory (Ile-de-France, France) in different types of structures: university or local hospitals and comprehensive cancer centers. We will include and follow during 1 year 1,000 patients. The study consists of 3 work-packages: - Cost of pathway The aim of this WP is to calculate the overall costs of the early BC pathway at 1 year from different perspectives (society, health insurance and patient) using a cost-of-illness analysis. Using a bottom-up method, we will assess direct costs, including medical direct costs and nonmedical direct costs (transportation, home modifications, home care services, and social services), and indirect costs (loss of production). - Patient satisfaction and work reintegration Three questionnaires will assess the patients' satisfaction and possible return to work: the occupational questionnaire for employed women; the questionnaire on the need for supportive care, SCNS-SF34 ('breast cancer' module, SCNS-BR8); and the OUTPASSAT-35 questionnaire. - Quality, coordination and access to innovation Quality will be evaluated based on visits and treatment within a set period, whether the setting offers a multidisciplinary consultative framework, the management by nurse coordinators, the use of a personalized care plan, the provision of information via documents about treatments and the provision of supportive care. The coordination between structures and caregivers will be evaluated at several levels. Day surgery, home hospitalization and one-stop breast clinic visits will be recorded to assess the patient's access to innovation. DISCUSSION: The assessment of care pathways encourages the implementation of new payment models. Our approach could help health care professionals and policymakers to establish other cost-of-illness studies and plan the allocation of resources on a patient basis rather than a visit basis.