TILs in ER+/HER2- breast cancer

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Treatment selection for patients with equivocal HER2 status and in luminal versus HER2-enriched disease

Equivocal HER2 status has been variably defined in the past, and its clinical implications have long been debated. In the 2018 focused update, ASCO/CAP guidelines recommended that tumours with double-equivocal (by immunohistochemistry and in situ hybridization assays) HER2 status should be considered HER2-negative due to the lack of evidence for any benefit of HER2-targeted therapy. The biology and the response to systemic therapies of tumours co-expressing HR and HER2 is quite complex. There is an extensive bi-directional cross-talk between these 2 pathways, that may result in both intrinsic and acquired resistance to endocrine agents, as well as in lower sensitivity to HER2-targeted therapies. In fact, neoadjuvant studies indicate that pCR rates are significantly lower in HER2-positive/ER-positive than ER-negative tumours, regardless the type of HER2 targeted treatment. The recent identification of different subtypes of HER2-positive breast cancer, according to the co-expression of HR and/or the molecular (intrinsic) subtyping, has prompted a renewed interest for clinical studies aimed at better tailoring the systemic therapy for these patients. A subgroup of them might not need chemotherapy if treated with dual HER2 blockade, and this option has been tested in a number of neo-adjuvant trials. In addition, triple targeting of HR, HER2, and CDK4/6 pathways simultaneously may be an effective treatment and overcome the drug resistance mechanisms that are typical of the disease. Finally, HER2-positive breast cancer may well benefit from immunotherapeutic interventions with anti-programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) agents

New Axioms in Set Theory

In this article we review the present situation in the foundations of set theory, discussing two programs meant to overcome the phenomenon of independence centered, respectively, on forcing axioms and Woodin’s V = Ultimate-L conjecture. While doing so, we briefly introduce the key notions of set theory

A clinical perspective on escalating or de-escalating adjuvant therapy in HER2+ breast cancer

Introduction: Patients with early HER2-positive breast cancer (BC) benefit from HER2-targeted systemic therapy. The endorsed standard adjuvant treatment for patients with early HER2-positive breast cancer is chemotherapy plus trastuzumab administered for 1 year. Areas covered: Several trials have investigated modifications of the standard treatment in terms of de-escalation by either shortening the duration or giving less resource-demanding regimens and in terms of escalation by either adding a second anti-HER2 agent or extending the duration of HER2-targeted treatment for more than 12\ua0months. In this perspective, we would offer a comprehensive view of these trials and discuss their findings. Expert commentary: At the current state of knowledge, there are still open questions regarding the management of HER2+ BC patients, such as the most adequate duration of trastuzumab therapy, the optimal chemotherapy regimen that should be combined with trastuzumab, and the addition of a second anti-HER2 agent. Growing evidences suggest that some HER2+ BC patients may not need chemotherapy. If these patients could be recognized upfront, optimal response could potentially be reached with HER2-targeted therapy alone

Dispersion and uncertainty in multislit matter wave diffraction

We show that single and multislit experiments involving matter waves may be constructed to assess correlations between the position and momentum of a single free particle. These correlations give rise to position dependent phases which develop dynamically and may play an important role in the interference patterns. For large enough transverse coherence lenght such interference patterns are noticeably different from those of a classical dispersion free wave.Comment: 7 pages, 5 figures, revised manuscrip

Tips and tricks in triple-negative breast cancer: how to manage patients in real-life practice?

Journal ArticleSCOPUS: cp.jinfo:eu-repo/semantics/publishe

An evidence-based multidisciplinary approach focused at creating algorithms for targeted therapy of bsis, cutis, and ciais caused by enterobacterales in critically ill adult patients

Prompt implementation of appropriate targeted antibiotic therapy represents a valuable approach in improving clinical and ecological outcome in critically septic patients. This multidisciplinary opinion article focused at developing evidence-based algorithms for targeted antibiotic therapy of bloodstream (BSIs), complicated urinary tract (cUTIs), and complicated intrabdominal infections (cIAIs) caused by Enterobacterales. The aim was to provide a guidance for intensive care physicians either in appropriately placing novel antibiotics or in considering strategies for sparing the broadest-spectrum antibiotics. A multidisciplinary team of experts (one intensive care physician, one infectious disease consultant, one clinical microbiologist and one MD clinical pharmacologist), performed several rounds of assessment to reach agreement in developing six different algorithms according to the susceptibility pattern (one each for multi-susceptible, extended-spectrum beta-lactamase-producing, AmpC beta-lactamase-producing, Klebsiella pneumoniae carba-penemase (KPC)-producing, OXA-48-producing, and Metallo-beta-lactamase (MBL)-produ-cing Enterobacterales). Whenever multiple therapeutic options were feasible, a hierarchical scale was established. Recommendations on antibiotic dosing optimization were also pro-vided. In order to retrieve evidence-based support for the therapeutic choices proposed in the algorithms, a comprehensive literature search was performed by a researcher on PubMed-MEDLINE from inception until March 2021. Quality and strength of evidence was established according to a hierarchical scale of the study design. Only articles published in English were included. It is expected that these algorithms, by allowing prompt revision of antibiotic regimens whenever feasible, appropriate place in therapy of novel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and pharmacoki-netic/pharmacodynamic optimization of antibiotic dosing regimens, may be helpful either in improving clinical outcome or in containing the spread of antimicrobial resistance

What can the pathologist offer for optimal treatment choice?

The choice of the most appropriate systemic treatment of patients with metastatic breast carcinoma is a multifaceted decision-making process. The role for the pathologist is to provide a definite diagnosis of metastatic breast carcinoma, whenever needed, and especially to assess the biological parameters with prognostic and predictive value. Although the vast majority of breast carcinomas maintain the same biological features both in the primary and in the metastases, some undergo changes that may indicate that a targeted systemic treatment should be stopped or started, be it endocrine or anti-HER2. Unfortunately these tumours cannot be easily identified clinically, and it may be useful to biopsy the metastatic sites for reassessment of the biological characteristic of the tumours. Intra-tumoural heterogeneity and clonal selection due to the therapy could explain changes in biological features during tumour progression, but it should also be taken into account that the available assays for evaluating hormone receptor and HER2 status are not 100% accurate, even in the hands of expert pathologists. To minimize the risk of inducing inappropriate changes in systemic treatments due to false-positive or false-negative results, the pathologists should make all efforts to improve accuracy and reproducibility of the assay procedures

Recent advances in triple negative breast cancer: the immunotherapy era

Background: Several accomplishments have been achieved in triple-negative breast cancer (TNBC) research over the last year. The phase III IMpassion130 trial comparing chemotherapy plus atezolizumab versus chemotherapy plus placebo brought breast cancer into the immunotherapy era. Nevertheless, despite encouraging results being obtained in this trial, many open questions remain. Main body: A positive overall survival outcome was achieved only in PD-L1 + TNBC patients, suggesting a need to enrich the patient population more likely to benefit from an immunotherapeutic approach. Moreover, it remains unknown whether single-agent immunotherapy might be a good option for some patients. In this context, the discovery and implementation of novel and appropriate biomarkers are required. Focusing on the early onset of TNBC, neoadjuvant trials could represent excellent in vivo platforms to test immunotherapy agents and their potential combinations, allowing the performance of translational studies for biomarker implementation and improved patient selection. Conclusion: The aim of our review is to present recent advances in TNBC treatment and to discuss open issues in order to better define potential future directions for immunotherapy in TNBC

Mismatch Repair Deficiency as a Predictive Biomarker for Immunotherapy Efficacy

Immunotherapy has revolutionized cancer treatment. Immune-checkpoint inhibitors, on balance, showed a favorable efficacy/toxicity profile with durable response in different cancer types. No predictive biomarker has been validated thus far to select patients who would benefit from therapy. Among the candidate predictive biomarkers, mismatch repair status of the tumor is currently one of the most promising. Indeed, tumors displaying mismatch repair deficiency or microsatellite instability showed remarkable response to immunotherapy in clinical trials. This correlation has been first reported in colorectal cancers, but similar results have been observed also in other cancer types. The possible mechanism behind this correlation may be the higher mutational load observed in mismatch repair deficient tumors, leading to neoantigens formation, recruitment of immune cells, and release of proinflammatory factors in the microenvironment. These results support an approach to treatment based on assessment of the genomic stability of the tumor besides its biologic characteristics and may change our therapeutic decision making process. However, due to the small percentage of patients with tumors displaying mismatch repair deficiency, data from clinical trials should not be considered definitive and need further confirmation