Endocrine therapy in advanced high-grade ovarian cancer: real-life data from a multicenter study and a review of the literature.

BACKGROUND: In women, ovarian cancer is the eighth most frequent cancer in incidence and mortality. It is often diagnosed at advanced stages; relapses are frequent, with a poor prognosis. When platinum resistant, subsequent lines of chemotherapy are of limited effect and often poorly tolerated, leading to quality of life deterioration. Various studies suggest a hormonal role in ovarian carcinogenesis, with a rationale for endocrine therapy in these cancers. PATIENTS AND METHODS: This multicenter, retrospective study assessed the use of endocrine treatment for high-grade ovarian epithelial carcinomas treated between 2010 and 2020. RESULTS: Eighty-one patients with ovarian cancers were included. The median duration of platinum sensitivity was 29 months. We observed a 35% disease control rate with endocrine therapy, and 10% reported symptom improvement. For 19 patients (23.5%), the disease was stabilized for more than 6 months. Median overall survival from diagnosis was 62.6 months. Regarding endocrine therapy predictive factors of response, in a multivariate analysis, 3 factors were statistically significant in favoring progression-free survival: platinum sensitivity (P = .021), an R0 surgical resection (P = .020), and the indication for hormone therapy being maintenance therapy (P = .002). CONCLUSION: This study shows real-life data on endocrine therapy in ovarian cancer. As it is a low-cost treatment with many advantages such as its oral administration and its safety, it may be an option to consider. A perspective lies in the search for cofactors to aim as future therapeutic targets to improve the effectiveness of hormone treatment by means of combination therapy.

Biosimilars in an era of rising oncology treatment options.

New diagnostic technologies, including molecular profiling, have enabled advances in treatments of various cancers; this has significantly improved clinical outcomes, including overall survival. However, the high cost of biologic drugs may prevent patients from having access to optimal treatment. Introduction of lower priced biosimilar agents into the therapeutic armamentarium brings the potential to ease the burden on healthcare expenditure and facilitate better access to effective cancer treatments. Oncology biosimilars have shown comparable efficacy and safety based on clinical evidence and physicochemical quality data as well as in real-world settings. This paper aims to review changes in the management of oncology treatment and their implication with respect to biosimilars.

Defibrotide in Severe Sinusoidal Obstruction Syndrome: Medicine and Economic Issues.

In Europe, Defitelio (defibrotide) has a Market Authorization in curative treatment of severe sinusoidal obstruction syndrome (SOS) but not in prophylaxis (2013). In France, defibrotide has had a compassionate-use program since 2009. Today, the high cost of defibrotide remains a major hurdle for hospital budgets. Medicine and economic issues were evaluated for the 39 hospitals of the French Public Assistance-Hospitals of Paris (AP-HP). We analyzed literature reviews, consumption, and expenditures through AP-HP data in 2014 and patient profiles with defibrotide in the corresponding diagnostic-related groups (DRGs) and consulted a board of hematologists. Finally, 18 publications were selected. Between 2011 and 2014 consumption increased to €5.2M. In 2014, 80 patients receiving defibrotide were mainly ascribed to the DRG "hematopoietic stem cell transplantation" levels 3 or 4. The tariffs attributed to drugs (€3544 to 4084) cover a small part of treatment costs (€97,524 for an adult). French experts thus recommended a harmonization of indications in prophylaxis (off-label use), improvement of pretransplant care, and optimization of the number of vials used. The economic impact led experts to change their practices. They recommended the restriction of defibrotide use to SOS curative treatment and to high-risk situations in prophylaxis.

How to Balance Prognostic Factors in Controlled Phase II Trials: Stratified Permuted Block Randomization or Minimization? An Analysis of Clinical Trials in Digestive Oncology.

In controlled phase II trials, major prognostic factors need to be well balanced between arms. The main procedures used are SPBR (Stratified Permuted Block Randomization) and minimization. First, we provide a systematic review of the treatment allocation procedure used in gastrointestinal oncology controlled phase II trials published in 2019. Second, we performed simulations using data from six phase II studies to measure the impacts of imbalances and bias on the efficacy estimations. From the 40 articles analyzed, all mentioned randomization in both the title and abstract, the median number of patients included was 109, and 77.5% were multicenter. Of the 27 studies that reported at least one stratification variable, 10 included the center as a stratification variable, 10 used minimization, 9 used SBR, and 8 were unspecified. In real data studies, the imbalance increased with the number of centers. The total and marginal imbalances were higher with SBR than with minimization, and the difference increased with the number of centers. The efficiency estimates per arm were close to the original trial estimate in both procedures. Minimization is often used in cases of numerous centers and guarantees better similarity between arms for stratification variables for total and marginal imbalances in phase II trials.

Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer.

Importance: Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC). Objective: To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan. Design, Setting, and Participants: This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022. Exposure: Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose. Main Outcomes and Measures: Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR). Results: A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months. Conclusions and Relevance: In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

Consore: A Powerful Federated Data Mining Tool Driving a French Research Network to Accelerate Cancer Research.

BACKGROUND: Real-world data (RWD) related to the health status and care of cancer patients reflect the ongoing medical practice, and their analysis yields essential real-world evidence. Advanced information technologies are vital for their collection, qualification, and reuse in research projects. METHODS: UNICANCER, the French federation of comprehensive cancer centres, has innovated a unique research network: Consore. This potent federated tool enables the analysis of data from millions of cancer patients across eleven French hospitals. RESULTS: Currently operational within eleven French cancer centres, Consore employs natural language processing to structure the therapeutic management data of approximately 1.3 million cancer patients. These data originate from their electronic medical records, encompassing about 65 million medical records. Thanks to the structured data, which are harmonized within a common data model, and its federated search tool, Consore can create patient cohorts based on patient or tumor characteristics, and treatment modalities. This ability to derive larger cohorts is particularly attractive when studying rare cancers. CONCLUSIONS: Consore serves as a tremendous data mining instrument that propels French cancer centres into the big data era. With its federated technical architecture and unique shared data model, Consore facilitates compliance with regulations and acceleration of cancer research projects.

Opportunities and Obstacles to the Development of Health Data Warehouses in Hospitals in France: The Recent Experience of Comprehensive Cancer Centers.

Big Data and Artificial Intelligence can profoundly transform medical practices, particularly in oncology. Comprehensive Cancer Centers have a major role to play in this revolution. With the purpose of advancing our knowledge and accelerating cancer research, it is urgent to make this pool of data usable through the development of robust and effective data warehouses. Through the recent experience of Comprehensive Cancer Centers in France, this article shows that, while the use of hospital data warehouses can be a source of progress by taking into account multisource, multidomain and multiscale data for the benefit of knowledge and patients, it nevertheless raises technical, organizational and legal issues that still need to be addressed. The objectives of this article are threefold: 1. to provide insight on public health stakes of development in Comprehensive Cancer Centers to manage cancer patients comprehensively; 2. to set out a challenge of structuring the data from within them; 3. to outline the legal issues of implementation to carry out real-world evidence studies. To meet objective 1, this article firstly proposed a discussion on the relevance of an integrated approach to manage cancer and the formidable tool that data warehouses represent to achieve this. To address objective 2, we carried out a literature review to screen the articles published in PubMed and Google Scholar through the end of 2022 on the use of data warehouses in French Comprehensive Cancer Centers. Seven publications dealing specifically with the issue of data structuring were selected. To achieve objective 3, we presented and commented on the main aspects of French and European legislation and regulations in the field of health data, hospital data warehouses and real-world evidence.

A novel high-current, high-resolution, low-kinetic-energy electron source for inverse photoemission spectroscopy.

A high-current electron source for inverse photoemission spectroscopy is described. The source comprises a thermal cathode electron emission system, an electrostatic deflector-monochromator, and a lens system for variable kinetic energy (1.6-20 eV) at the target. When scaled to the energy resolution, the electron current is an order of magnitude higher than that of previously described electron sources developed in the context of electron energy loss spectroscopy. Surprisingly, the experimentally measured energy resolution turned out to be significantly better than calculated by standard programs, which include the electron-electron repulsion in the continuum approximation. The achieved currents are also significantly higher than predicted. We attribute this "inverse Boersch-effect" to a mechanism of velocity selection in the forward direction by binary electron-electron collisions.

Ovarian Real-World International Consortium (ORWIC): A multicentre, real-world analysis of epithelial ovarian cancer treatment and outcomes.

Introduction: Much drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium; ORWIC). Methods: 3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved. Results: Median age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L); up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice: trial compounds and unspecified combinations of other agents were common. Discussion: Specific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites.

The Challenges of Implementing Comprehensive Clinical Data Warehouses in Hospitals.

Digital health, e-health, telemedicine-this abundance of terms illustrates the scientific and technical revolution at work, made possible by high-speed processing of health data, artificial intelligence (AI), and the profound upheavals currently taking place and yet to come in health systems [...].

Optimizing the Retrieval of the Vital Status of Cancer Patients for Health Data Warehouses by Using Open Government Data in France.

Electronic Medical Records (EMR) and Electronic Health Records (EHR) are often missing critical information about the death of a patient, although it is an essential metric for medical research in oncology to assess survival outcomes, particularly for evaluating the efficacy of new therapeutic approaches. We used open government data in France from 1970 to September 2021 to identify deceased patients and match them with patient data collected from the Institut de Cancérologie de l'Ouest (ICO) data warehouse (Integrated Center of Oncology-the third largest cancer center in France) between January 2015 and November 2021. To meet our objective, we evaluated algorithms to perform a deterministic record linkage: an exact matching algorithm and a fuzzy matching algorithm. Because we lacked reference data, we needed to assess the algorithms by estimating the number of homonyms that could lead to false links, using the same open dataset of deceased persons in France. The exact matching algorithm allowed us to double the number of dates of death in the ICO data warehouse, and the fuzzy matching algorithm tripled it. Studying homonyms assured us that there was a low risk of misidentification, with precision values of 99.96% for the exact matching and 99.68% for the fuzzy matching. However, estimating the number of false negatives proved more difficult than anticipated. Nevertheless, using open government data can be a highly interesting way to improve the completeness of the date of death variable for oncology patients in data warehouses.

Momentum space imaging of σ orbitals for chemical analysis.

Tracing the modifications of molecules in surface chemical reactions benefits from the possibility to image their orbitals. While delocalized frontier orbitals with π character are imaged routinely with photoemission orbital tomography, they are not always sensitive to local chemical modifications, particularly the making and breaking of bonds at the molecular periphery. For such bonds, σ orbitals would be far more revealing. Here, we show that these orbitals can indeed be imaged in a remarkably broad energy range and that the plane wave approximation, an important ingredient of photoemission orbital tomography, is also well fulfilled for these orbitals. This makes photoemission orbital tomography a unique tool for the detailed analysis of surface chemical reactions. We demonstrate this by identifying the reaction product of a dehalogenation and cyclodehydrogenation reaction.

Large Distortion of Fused Aromatics on Dielectric Interlayers Quantified by Photoemission Orbital Tomography.

Polycyclic aromatic compounds with fused benzene rings offer an extraordinary versatility as next-generation organic semiconducting materials for nanoelectronics and optoelectronics due to their tunable characteristics, including charge-carrier mobility and optical absorption. Nonplanarity can be an additional parameter to customize their electronic and optical properties without changing the aromatic core. In this work, we report a combined experimental and theoretical study in which we directly observe large, geometry-induced modifications in the frontier orbitals of a prototypical dye molecule when adsorbed on an atomically thin dielectric interlayer on a metallic substrate. Experimentally, we employ angle-resolved photoemission experiments, interpreted in the framework of the photoemission orbital tomography technique. We demonstrate its sensitivity to detect geometrical bends in adsorbed molecules and highlight the role of the photon energy used in experiment for detecting such geometrical distortions. Theoretically, we conduct density functional calculations to determine the geometric and electronic structure of the adsorbed molecule and simulate the photoemission angular distribution patterns. While we found an overall good agreement between experimental and theoretical data, our results also unveil limitations in current van der Waals corrected density functional approaches for such organic/dielectric interfaces. Hence, photoemission orbital tomography provides a vital experimental benchmark for such systems. By comparison with the state of the same molecule on a metallic substrate, we also offer an explanation why the adsorption on the dielectric induces such large bends in the molecule.

Mitrofanovite Pt3Te4: A Topological Metal with Termination-Dependent Surface Band Structure and Strong Spin Polarization.

Due to their peculiar quasiparticle excitations, topological metals have high potential for applications in the fields of spintronics, catalysis, and superconductivity. Here, by combining spin- and angle-resolved photoemission spectroscopy, scanning tunneling microscopy/spectroscopy, and density functional theory, we discover surface-termination-dependent topological electronic states in the recently discovered mitrofanovite Pt3Te4. Mitrofanovite crystal is formed by alternating, van der Waals bound layers of Pt2Te2 and PtTe2. Our results demonstrate that mitrofanovite is a topological metal with termination-dependent (i) electronic band structure and (ii) spin texture. Despite their distinct electronic character, both surface terminations are characterized by electronic states exhibiting strong spin polarization with a node at the Γ point and sign reversal across the Γ point, indicating their topological nature and the possibility of realizing two distinct electronic configurations (both of them with topological features) on the surface of the same material.

Going beyond Pentacene: Photoemission Tomography of a Heptacene Monolayer on Ag(110).

Longer acenes such as heptacene are promising candidates for optoelectronic applications but are unstable in their bulk structure as they tend to dimerize. This makes the growth of well-defined monolayers and films problematic. In this article, we report the successful preparation of a highly oriented monolayer of heptacene on Ag(110) by thermal cycloreversion of diheptacenes. In a combined effort of angle-resolved photoemission spectroscopy and density functional theory (DFT) calculations, we characterize the electronic and structural properties of the molecule on the surface in detail. Our investigations allow us to unambiguously confirm the successful fabrication of a highly oriented complete monolayer of heptacene and to describe its electronic structure. By comparing experimental momentum maps of photoemission from frontier orbitals of heptacene and pentacene, we shed light on differences between these two acenes regarding their molecular orientation and energy-level alignment on the metal surfaces.

Unveiling the Mechanisms Ruling the Efficient Hydrogen Evolution Reaction with Mitrofanovite Pt3Te4.

By means of electrocatalytic tests, surface-science techniques and density functional theory, we unveil the physicochemical mechanisms ruling the electrocatalytic activity of recently discovered mitrofanovite (Pt3Te4) mineral. Mitrofanovite represents a very promising electrocatalyst candidate for energy-related applications, with a reduction of costs by 47% compared to pure Pt and superior robustness to CO poisoning. We show that Pt3Te4 is a weak topological metal with the Z2 invariant, exhibiting electrical conductivity (∼4 × 106 S/m) comparable with pure Pt. In hydrogen evolution reaction (HER), the electrode based on bulk Pt3Te4 shows a very small overpotential of 46 mV at 10 mA cm-2 and a Tafel slope of 36-49 mV dec-1 associated with the Volmer-Heyrovsky mechanism. The outstanding ambient stability of Pt3Te4 also provides durability of the electrode and long-term stability of its efficient catalytic performances.

Systematic Literature Review of Economic Evaluations of Biological Treatment Sequences for Patients with Moderate to Severe Rheumatoid Arthritis Previously Treated with Disease-Modifying Anti-rheumatic Drugs.

OBJECTIVE: This systematic literature review (SLR) had two objectives: to analyse published economic evaluations of biological disease-modifying anti-rheumatic drugs (bDMARDs) for patients with moderate to severe rheumatoid arthritis (RA) previously treated with DMARDs and to assess the quality of those that included sequences of treatments. METHODS: We performed an SLR on PubMed, Central, Cochrane, and French databases from January 2000 to December 2018. The search focused on cost-effectiveness/utility/benefit analyses. We extracted data on treatment sequences, outcomes (e.g. quality-adjusted life year) and choices of economic evaluation methods (e.g. model type, type of analysis, and method of utility estimation). We analysed the improvement of methods by comparing two sub-periods (2000-2009 and 2010-2018). The quality of reporting and the quality of the methods were assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and a set of eight key aspects for a reference case for economic evaluation of bDMARDs based on the Outcome Measures in Rheumatology (OMERACT) and Drummond checklists. Data extraction and study assessment were performed independently by two health economists. RESULTS: From the 824 records identified in the initial search, 51 publications were selected. Of these, 31 included sequences. Individual models such as discrete-event simulations were used in over two-fifths (22/51, 43%) of the selected studies. Few studies (7/51, 14%) used utility scores based on generic instruments (e.g. EQ-5D). Estimation of hospitalization costs was described in only approximately one-third of studies (19/51). Loss of quality of life (QoL) related to adverse events such as tuberculosis and pneumonia was included in one-tenth (5/51, 10%) of the studies. It was difficult to compare the results of the economic evaluations (i.e. incremental cost-effectiveness ratios) due to the high heterogeneity of studies in terms of disease stage, data sources, inputs, and methods of health outcome assessment used. For identified studies including sequences, the CHEERS assessment of reporting quality showed insufficient reporting of uncertainty analyses and utility weights in more than a third of the studies (11/31, 35%; 9/25, 36%). An in-depth assessment of the quality of the studies revealed that only seven, mostly conducted during the sub-period 2010-2018, addressed the majority of methodological quality assessment issues such as the simulation of patient sequence pathways, the use of systematic reviews and meta-analyses of comparative effectiveness, the choice of treatment sequence, and rules for switching. CONCLUSION: Our SLR identified a lack of high-quality evaluations assessing bDMARD sequences, although some improvements were made in the reporting and modelling of patients' pathways in studies published after 2010. In order to improve economic evaluations of RA, clear health technology assessment guidance on RA health-related QoL instruments must be provided, and data including long-term disease progression must be made available.

Public Health Impact of Using Biosimilars, Is Automated Follow up Relevant?

Biologic reference drugs and their copies, biosimilars, have a complex structure. Biosimilars need to demonstrate their biosimilarity during development but unpredictable variations can remain, such as micro-heterogeneity. The healthcare community may raise questions regarding the clinical outcomes induced by this micro-heterogeneity. Indeed, unwanted immune reactions may be induced for numerous reasons, including product variations. However, it is challenging to assess these unwanted immune reactions because of the multiplicity of causes and potential delays before any reaction. Moreover, safety assessments as part of preclinical studies and clinical trials may be of limited value with respect to immunogenicity assessments because they are performed on a standardised population during a limited period. Real-life data could therefore supplement the assessments of clinical trials by including data on the real-life use of biosimilars, such as switches. Furthermore, real-life data also include any economic incentives to prescribe or use biosimilars. This article raises the question of relevance of automating real life data processing regarding Biosimilars. The objective is to initiate a discussion about different approaches involving Machine Learning. So, the discussion is established regarding implementation of Neural Network model to ensure safety of biosimilars subject to economic incentives. Nevertheless, the application of Machine Learning in the healthcare field raises ethical, legal and technical issues that require further discussion.

Preconceived notions about biosimilars-a French experience.

Since the arrival of the first biosimilar monoclonal antibodies into the market, many information has been circulating, leading to preconceived notions for patients and healthcare professionals. In a pressing economic context and faced with a growing number of available biosimilars, we (clinician, patient association, biologist, pharmacists, health economists) propose to take stock by trying to distinguish facts from misconceptions.

Kekulene: On-Surface Synthesis, Orbital Structure, and Aromatic Stabilization.

We revisit the question of kekulene's aromaticity by focusing on the electronic structure of its frontier orbitals as determined by angle-resolved photoemission spectroscopy. To this end, we have developed a specially designed precursor, 1,4,7(2,7)-triphenanthrenacyclononaphane-2,5,8-triene, which allows us to prepare sufficient quantities of kekulene of high purity directly on a Cu(111) surface, as confirmed by scanning tunneling microscopy. Supported by density functional calculations, we determine the orbital structure of kekulene's highest occupied molecular orbital by photoemission tomography. In agreement with a recent aromaticity assessment of kekulene based solely on C-C bond lengths, we conclude that the π-conjugation of kekulene is better described by the Clar model rather than a superaromatic model. Thus, by exploiting the capabilities of photoemission tomography, we shed light on the question which consequences aromaticity holds for the frontier electronic structure of a π-conjugated molecule.