Modulation of Rb phosphorylation and antiproliferative response to palbociclib: the preoperative-palbociclib (POP) randomized clinical trial.

Background: The cyclin-dependent kinase 4 (CDK4)/6 inhibitor Palbociclib is a new standard treatment in hormone-receptor positive breast cancer patients. No predictive biomarkers have been identified and no pharmacodynamics has properly been described so far. Patients and methods: Patients with early-breast cancer were randomized 3 : 1 to oral palbociclib 125 mg daily for 14 days until the day before the surgery versus no treatment. Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 below 1. Secondary end points were subgroups analyses and safety. Exploratory analyses included search for predictive biomarkers. Immunostainings (Ki67, RB, pRB, p16, pAKT, pER, pCDK2, CyclinD1), FISH (CCND1) and gene expression (GE) arrays were carried out at baseline and at surgery. In addition, activating PIK3CA and AKT1 mutations were assessed at baseline. Results: 74 patients were allocated to palbociclib and 26 to control. Most patients (93%) were hormone-receptor (HR)-positive, whereas 8% were HER2-positive. Palbociclib led to significantly more antiproliferative responses when compared with control (58% versus 12%, P < 0.001), and to a significantly higher Ki67 decrease (P < 0.001). In the HR-positive/HER2-negative subgroup, this antiproliferative effect was even more marked in the palbociclib arm when compared with control (70% versus 9%, P < 0.001). Palbociclib treatment led also to a significantly higher decrease from baseline in phospho-Rb when compared with control (P < 0.001). Among treated patients, changes in Ki67 correlated with changes in phospho-Rb (Spearman rank r = 0.41, P < 0.0001). GE analyses confirmed a major effect on proliferation and cell cycle genes. Among treated patients, CCNE2 expression was significantly more decreased in antiproliferative responders versus nonresponders (P = 0.006). Conclusion: Short-term preoperative palbociclib decreases Ki67 in early-breast cancer patients. Early decrease of Rb phosphorylation correlates with drug's effect on cell proliferation and could potentially identify patients with primary resistance. Clinical trial registration: NCT02008734.

Preoperative imaging prior to breast reconstruction surgery: benchmarking bringing together radiologists and plastic surgeons. Proposed guidelines.

BACKGROUND: Prescription of preoperatory imaging assessment prior to planned breast reconstruction surgery (reduction or augmentation mastoplasty, correction of congenital breast asymmetry) is poorly codified. The objective of this study was to analyze the attitudes of French radiologists and plastic surgeons with regard to prescription of preoperative imaging in the framework of non-oncologic breast surgery. MATERIAL AND METHODS: This is a descriptive and comparative observational study involving two groups, one consisting of 50 plastic surgeons (P) and the other of 50 radiologists (R) specialized in breast imaging. A questionnaire was handed out to radiologists during a conference on breast imaging at the Institut Gustave-Roussy in Paris (France) held on 17th December 2012. The same questionnaire was handed out to plastic surgeons at the National Congress of the French Society of Plastic and Reconstructive Surgery (SOFCPRE) held on 19th, 20th and 21st November 2012, also in Paris (France). The questionnaire focused on prescription of preoperative and postoperative imaging evaluation for non-oncologic breast surgery in patients with no risk factors for breast cancer or clinically identified indications. RESULTS: Forty-six percent of the plastic surgeons considered an imaging exam to be recent when it had been carried out over the previous 6 months, while 40% of the radiologists set the figure at 1 year. Clinical breast density exerted no influence on 92% of the plastic surgeons and 98% of the radiologists. A majority of the plastic surgeons would prescribe a preoperative exam regardless of age (57% for breast reduction, 61% for breast implant placement and 61% for surgical correction of asymmetry) while the radiologists would prescribe exams mainly for patients over 40 years (50% for reduction, 44% for augmentation, 49% for asymmetry correction). The plastic surgeons would prescribe either ultrasound or mammograms (59% for reduction, 72% for augmentation, 66% for asymmetry correction) while radiologists would usually prescribe mammograms (64%, 57%, 64%). Most of the radiologists, along with the plastic surgeons, did not think that postoperative examination is justified (58% of P and 62% of R for reduction, 56% P and 68% of R for augmentation, 52% of P and 64% of R for asymmetry correction). CONCLUSION: In 2012, there existed no French consensus on prescription of a preoperative imaging assessment in the framework of non-oncologic breast surgery in patients without risk factors for breast cancer. Active cooperation bringing together radiologists and plastic surgeons is likely to facilitate the harmonizing of their respective practices. In this paper, we propose guidelines that could help them to synchronize their efforts.

Pure and mixed mucinous carcinoma of the breast: fine needle aspiration cytology findings and review of the literature.

OBJECTIVE: Mucinous (colloid) breast carcinoma accounts for 1-6% of all breast cancer. It comprises pure mucinous tumours and mixed infiltrating ductal carcinomas with a mucinous component. As this latter mixed form has a worse prognosis than pure colloid carcinoma, making this diagnosis on fine needle aspiration cytology (FNAC) might influence the choice of treatment. METHODS: We report a consecutive series of 22 cases consisting of 17 mixed and five pure mucinous carcinomas diagnosed by cytology and verified on histopathology. Patients underwent FNAC at the one-stop clinic of our institution during a 7-year period of time. Cytological findings were evaluated by a semi-quantitative method and included percentage of smear surface occupied by mucin, shape of cell groupings, size and outline of tumour nuclei as well as presence or absence of nucleolus. RESULTS: Three of five pure mucinous carcinomas displayed at least two of the following features: abundant mucin, small nuclei and/or regular nuclear outlines. Sparse mucin, large nuclei, irregular nuclear outlines or the presence of nucleoli were found in 7 out of 17 mixed mucinous carcinomas but not in pure tumours. CONCLUSION: Cytopathological identification of patients with pure mucinous carcinomas may be performed in a limited number of cases.

[Fertility preservation in cervical cancer, analysis of 30 years of practice and immersion in future developments]. / La préservation de fertilité en cas de cancer du col, analyse de 30 ans de pratique et immersion dans les évolutions à venir.

OBJECTIVES: The strategy of fertility preservation (FP) in cervical cancer has been challenged for several years and a therapeutic de-escalation seems to be necessary. In this context, we evaluated the oncological, fertility and obstetric outcomes of surgical techniques performed in our centre for FP. METHODS: This retrospective uni centric trial included 75 patients, managed at the Gustave Roussy Institute between 1995 and 2020, for cervical cancer (stage IB1 FIGO 2018) and having conducted a fertility preservation project after a complete pre-therapy work-up. The objective of this study was to understand our results on fertility and obstetrical outcomes and to correlate them with oncological data and finally to evaluate the evolution of our surgical practices. RESULTS: 54 patients benefited from an extended trachelectomy and no lymph node involvement was found. 1 patient received a complementary treatment postoperatively which did not allow to preserve her fertility. The recurrence rate was 4.8% (4/75) with one death described. 31 pregnancies were obtained, representing a pregnancy rate of 50%. 74% of pregnancies were obtained spontaneously and 60% of pregnancies were carried to term. CONCLUSION: Our results are similar to those in the literature. Despite a fertility preservation project, only half of the patients were able to achieve a pregnancy.

Impact of adjuvant treatment modalities on the management of patients with stages I-II endometrial stromal sarcoma.

PURPOSE: To explore whether adjuvant treatment options may impact on the prognosis in localized endometrial stromal sarcomas (ESSs; stages I and II). The historical options usually discussed in addition to hysterectomy and bilateral salpingoophorectomy (BSO) are active surveillance, pelvic radiotherapy, chemotherapy and hormonal therapy, alone or in combination. PATIENTS AND METHODS: Among 84 consecutive patients treated for ESS at a single referral center, 54 with localized stage disease were identified. Recurrence-free survival and overall survival were estimated and patterns of recurrences described. Univariate and multivariate analyses were carried out. RESULTS: With a median follow-up of 58 months, only one patient had died. None of the 23 patients who had received adjuvant therapy relapsed compared with 13 of 31 patients who had not received any adjuvant therapy. Adjuvant treatments were hormonal therapy (n = 10) and brachytherapy with/without pelvic radiotherapy (n = 13). Almost the majority of relapses were local (92%) and extra-pelvic metastasis was observed in nearly half of the patients (46%). In the multivariate analysis, the major determinants of relapse-free survival were adjuvant treatment, myometrial invasion (P = 0.005) and no BSO (P = 0.005). CONCLUSIONS: In this series, adjuvant treatment of localized ESSs was associated with the absence of recurrence.

Inter- and intraobserver consistency in assessing eligibility for bevacizumab (BVZ) in non-small-cell lung cancer (NSCLC) patients with centrally located tumors.

BACKGROUND: Bevacizumab (BVZ) combined with platinum-based therapy is registered for first-line treatment of nonsquamous non-small-cell lung cancer (NSCLC). Patients with centrally located tumors are stated ineligible for BVZ treatment. The goal of this study was to assess the consistency in evaluating eligibility of patients with central tumors for BVZ treatment. MATERIALS AND METHODS: The study group was composed of 150 NSCLC patients with centrally located tumors. Eligibility for BVZ was assessed by chest computed tomography (CT) scan. Eligibility was assessed independently using CT images reviewed on workstations. Inter- and intraobserver variations on 50 randomly extracted patients were estimated through a statistical modeling (multiple correspondence analysis). RESULTS: Discordance in eligibility was found for 82 patients (55%). The interobserver strength of agreement was fair to moderate (average kappa = 0.40). Contrarily, the intraobserver strength of agreement was good to very good (average kappa = 0.74). At multivariate analysis, the risk of discrepancy was essentially related to the assessment of the contact between the tumor and the vessels (odds ratio = 13.3, 95% confidence interval 2.8-62.6, P = 0.001). CONCLUSIONS: The consistency in evaluating eligibility of patients with central tumors for BVZ treatment is weak. The study group indicated more stringent criteria to help physicians in taking the best treatment choice that need however to be prospectively validated.

[MR imaging patterns of bone marrow]. / Approche didactique de la moelle osseuse en IRM.

The marrow contains a variable amount of yellow or fatty marrow and red or cellular marrow creating the signal intensity observed on MRI. Marrow replacement (by cells not normally present in bone marrow) typically is T1W hypointense. Marrow proliferation (by cells normally present in bone marrow) may be T1W hypointense (pseudo marrow replacement) or show intermediate T1W signal intensity due to red marrow redistribution. Marrow edema (reaction to an external process) show intermediate T1W hypointensity (mixture of water and marrow). Location will allow correct diagnosis. Bone marrow ischemia usually results in a necrotic fragment surrounded by a thin T1W hypointense rim.

Sequential sorafenib and sunitinib for renal cell carcinoma.

PURPOSE: Sorafenib and sunitinib are 2 tyrosine kinase inhibitors that were recently approved for renal cell carcinoma. In many patients sequential administration of the 2 drugs occurs because of the lack of sustained efficacy of the first agent. We determined the efficacy and safety of sequential administration. MATERIALS AND METHODS: To determine whether cross-resistance occurs between these 2 drugs we analyzed the outcome in 90 consecutive patients with renal cell carcinoma from 4 sites in France who had received the 2 drugs sequentially. All patients received sorafenib followed by sunitinib or vice versa. From 2003 to 2006, 68 patients received sorafenib, while 22 received sunitinib first. RESULTS: In the sorafenib-sunitinib group median progression-free survival was 26 weeks with sorafenib and 28 with sunitinib. In the sunitinib-sorafenib group median progression-free survival was 22 weeks with sunitinib and 17 with sorafenib. Median overall survival was 135 weeks in the sorafenib-sunitinib group and 82 weeks in the sunitinib-sorafenib group (HR 0.49, 95% CI 0.16 to 0.96, p = 0.04). The average duration of sequential administration was 61 and 49 weeks, respectively, in the sorafenib-sunitinib and sunitinib-sorafenib groups. Each sequence was well tolerated and no increase in grade 3-4 toxicity was observed. CONCLUSIONS: Overall this retrospective study supports the conclusion of the lack of absolute cross-resistance between tyrosine kinase inhibitors. In this renal cell carcinoma population sorafenib followed by sunitinib was associated with longer survival than sunitinib followed by sorafenib. However, this observation needs further confirmation.

Staging of endometrial cancer with MRI: guidelines of the European Society of Urogenital Imaging.

The purpose of this study was to define guidelines for endometrial cancer staging with MRI. The technique included critical review and expert consensus of MRI protocols by the female imaging subcommittee of the European Society of Urogenital Radiology, from ten European institutions, and published literature between 1999 and 2008. The results indicated that high field MRI should include at least two T2-weighted sequences in sagittal, axial oblique or coronal oblique orientation (short and long axis of the uterine body) of the pelvic content. High-resolution post-contrast images acquired at 2 min +/- 30 s after intravenous contrast injection are suggested to be optimal for the diagnosis of myometrial invasion. If cervical invasion is suspected, additional slice orientation perpendicular to the axis of the endocervical channel is recommended. Due to the limited sensitivity of MRI to detect lymph node metastasis without lymph node-specific contrast agents, retroperitoneal lymph node screening with pre-contrast sequences up to the level of the kidneys is optional. The likelihood of lymph node invasion and the need for staging lymphadenectomy are also indicated by high-grade histology at endometrial tissue sampling and by deep myometrial or cervical invasion detected by MRI. In conclusion, expert consensus and literature review lead to an optimized MRI protocol to stage endometrial cancer.

Detection and characterization of MRI breast lesions using deep learning.

PURPOSE: The purpose of this study was to assess the potential of a deep learning model to discriminate between benign and malignant breast lesions using magnetic resonance imaging (MRI) and characterize different histological subtypes of breast lesions. MATERIALS AND METHODS: We developed a deep learning model that simultaneously learns to detect lesions and characterize them. We created a lesion-characterization model based on a single two-dimensional T1-weighted fat suppressed MR image obtained after intravenous administration of a gadolinium chelate selected by radiologists. The data included 335 MR images from 335 patients, representing 17 different histological subtypes of breast lesions grouped into four categories (mammary gland, benign lesions, invasive ductal carcinoma and other malignant lesions). Algorithm performance was evaluated on an independent test set of 168 MR images using weighted sums of the area under the curve (AUC) scores. RESULTS: We obtained a cross-validation score of 0.817 weighted average receiver operating characteristic (ROC)-AUC on the training set computed as the mean of three-shuffle three-fold cross-validation. Our model reached a weighted mean AUC of 0.816 on the independent challenge test set. CONCLUSION: This study shows good performance of a supervised-attention model with deep learning for breast MRI. This method should be validated on a larger and independent cohort.

Artificial intelligence and breast screening: French Radiology Community position paper.

The objective of this article was to evaluate the evidence currently available about the clinical value of artificial intelligence (AI) in breast imaging. Nine experts from the disciplines involved in breast disease management - including physicists and radiologists - convened a meeting on June 3, 2019 to discuss the evidence for the use of this technology in plenary and focused sessions. Prior to the meeting, the group performed a literature review on predefined topics. This paper presents the consensus reached by this working group on recommendations for the future use of AI in breast screening and related research topics.

Five simultaneous artificial intelligence data challenges on ultrasound, CT, and MRI.

PURPOSE: The goal of this data challenge was to create a structured dynamic with the following objectives: (1) teach radiologists the new rules of General Data Protection Regulation (GDPR), while building a large multicentric prospective database of ultrasound, computed tomography (CT) and MRI patient images; (2) build a network including radiologists, researchers, start-ups, large companies, and students from engineering schools, and; (3) provide all French stakeholders working together during 5 data challenges with a secured framework, offering a realistic picture of the benefits and concerns in October 2018. MATERIALS AND METHODS: Relevant clinical questions were chosen by the Société Francaise de Radiologie. The challenge was designed to respect all French ethical and data protection constraints. Multidisciplinary teams with at least one radiologist, one engineering student, and a company and/or research lab were gathered using different networks, and clinical databases were created accordingly. RESULTS: Five challenges were launched: detection of meniscal tears on MRI, segmentation of renal cortex on CT, detection and characterization of liver lesions on ultrasound, detection of breast lesions on MRI, and characterization of thyroid cartilage lesions on CT. A total of 5,170 images within 4 months were provided for the challenge by 46 radiology services. Twenty-six multidisciplinary teams with 181 contestants worked for one month on the challenges. Three challenges, meniscal tears, renal cortex, and liver lesions, resulted in an accuracy>90%. The fourth challenge (breast) reached 82% and the lastone (thyroid) 70%. CONCLUSION: Theses five challenges were able to gather a large community of radiologists, engineers, researchers, and companies in a very short period of time. The accurate results of three of the five modalities suggest that artificial intelligence is a promising tool in these radiology modalities.

Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: Comparison of RECIST 1.1, irRECIST and iRECIST criteria.

BACKGROUND: Immune checkpoint inhibitors are an important tool in the therapeutic strategy against metastatic non-small cell lung cancer (NSCLC); however, radiological evaluation is challenging due to the emergence of atypical patterns of responses. Several evaluation criteria have been proposed, such as the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, immune -related RECIST (irRECIST) and iRECIST, but have not been systematically compared in a homogeneous population. PATIENTS AND METHODS: We conducted a monocentric retrospective analysis of consecutive advanced NSCLC patients treated with an anti-programmed cell death-1 or anti-program death-ligand 1. Response patterns and the discordance between RECIST 1.1, irRECIST and iRECIST guidelines were described, and associations of response patterns and clinical outcome were explored. RESULTS: Overall, 160 patients treated between February 2013 and October 2016 were included. Atypical responses were observed in 20 patients (13%), including eight pseudoprogressions (PsPDs) (5%) and 12 dissociated responses (8%). Thirteen of the 20 patients demonstrated clinical benefit. Per the RECIST 1.1, 37 patients (23%) showed an objective response or stable disease, and 123 patients (77%) exhibited progression. Eighty progressive patients were assessable for irRECIST and iRECIST: 15 patients were assessed differently; however, only three (3.8%) mismatches with a theoretical impact on the therapeutic decision were identified. Patients with PsPD or dissociated response had higher overall survival than patients with true progression. CONCLUSION: Atypical responses (PsPD/dissociated response) occurred in 13% of NSCLC patients under immune checkpoint inhibitors. Based on survival analyses, the RECIST 1.1 evaluation underestimated the benefit of immune checkpoint inhibitors in 11% of the progressive patients. Immune-related RECIST and iRECIST identified these unconventional responses, with a 3.8% discrepancy rate.

Autologous fat transfer in reconstructive breast surgery: indications, technique and results.

AIMS: Reconstructive techniques using flaps to preserve the enveloping skin, and even the nipple areolar complex where there is no neoplastic infiltration, have led to vast improvements in the results of reconstructive breast surgery. To further improve the cosmetic outcome, we have applied the technique of autologous fat transfer or lipoinjection, which has proven very successful in cosmetic surgery, to reconstructive breast surgery, and to the treatment of certain cosmetic sequelae of conservative breast treatment. We report our findings. METHODS: From September 2001 to September 2005, 74 autologous fat transfers were undertaken in 69 patients, with 5 patients receiving injections in both breasts, to improve the cosmetic appearance through resurfacing and to repair certain sequelae of conservative breast treatment. Pre- and postoperative imaging, including MRI, were undertaken to monitor the viability of the fat grafts and detect any suspicious lesions; no suspect lesions were detected either pre- or postoperatively. RESULTS: We did not undertake overcorrection, which creates irregularities of surface or contour. Five cases of cytosteatonecrosis were reported among the 74 procedures. The mean follow-up period for the patients was 11.7 months, ranging from 1 month to 3.2 years. The panel judged improvement to be good to very good in 64 breasts (86.5%) and moderate in 10 breasts (13.5%) primarily due to lack of available adipose material for harvesting in these patients. CONCLUSION: Autologous fat transfer is now a routine procedure in our clinic due to its simplicity, safety, and reproducibility. It is systematically proposed to all of our patients as the final, perfecting procedure of breast reconstruction, irrespective of the technique used for the initial reconstructive procedure, but also to repair certain conservative treatments.

Breast inflammatory gigantomastia in a context of immune-mediated diseases.

CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.

Breast radiological cases: training with BIRADS classification.

The American College of Radiology has established guidelines for outcomes monitoring known as the Breast Imaging Reporting and Data System. The last edition of the BIRADS classification includes mammography, but also ultrasonography and MRI. Radiologists must be used to the BIRADS lexicon and the BIRADS assessment, in order to clarify mammography reports and to facilitate communication with the other physicians. This work is a training on 20 mammography cases to be familiar with the BIRADS classification.

[Understanding CAD (computer-aided diagnosis) in mammography]. / Comprendre et utiliser le CAD (Aide informatisée au diagnostic) en mammographie.

Generalization of breast screening programs requires efficient double reading of mammograms, which allows reduction of false negative interpretations, but it may be difficult to achieve. CAD (Computed Aided Detection) systems are dramatically improving and can now assist in the detection of suspicious mammographic lesions, either suspicious microcalcifications, masses or architectural distortion. Characterization of the lesions is improving as well. CAD mammography might complete or substitute to "human" double reading. The aim of this review is to present the main CAD systems commercially available, review the principles of CAD and discuss the results of CAD mammography. Specifically, the role of CAD within breast screening program, according to the results of recent prospective studies will be discussed.

Breast pain and imaging.

Breast pain is a common reason for consultation and a source of anxiety for patients. Cyclical breast pain can be distinguished from non-cyclical pain and breast pain with other symptoms. Many causes, usually benign are possible and the clinical enquiry and physical examination are essential to establish predisposing factors. Although imaging is not always needed for isolated breast pain, it is still useful for the diagnosis of specific causes such as tension cysts, giant adenofibromas or Mondor's thrombophlebitis. Ultrasound is the first line investigation before mammography, MRI or biopsy, which may be indicated for suspicious abnormalities. Some cancers may be associated with pain, which implies that radiologists and physicians should always take breast pain seriously.