Regional and intratumoral adoptive T-cell therapy.

Adoptive T-cell therapies (ACTs) including tumor-infiltrating lymphocytes and engineered T cells (transgenic T-cell receptor and chimeric antigen receptor T cells), have made an important impact in the field of cancer treatment over the past years. Most of these therapies are typically administered systemically in approaches that facilitate the elimination of hematologic malignancies. Therapeutical efficacy against solid tumors, however, with the exception of tumor-infiltrating lymphocytes against melanoma, remains limited due to several barriers preventing lymphocyte access to the tumor bed. Building upon the experience of regional administration in other immunotherapies, the regional administration of adoptive cell therapies is being assessed to overcome this challenge, granting a first round of access of the transferred T cells to the tumor niche and thereby ensuring their activation and expansion. Intralesional and intracavitary routes of delivery have been tested with promising antitumor objective responses in preclinical and clinical studies. Additionally, several strategies are being developed to further improve T-cell activity after reinfusing them back to the patient such as combinations with other immunotherapy agents or direct engineering of the transferred T cells, achieving long-term immune memory. Clinical trials testing different regional adoptive T-cell therapies are ongoing but some issues related to methodology of administration and correct selection of the target antigen to avoid on-target/off-tumor side-effects need to be further evaluated and improved. Herein, we discuss the current preclinical and clinical landscape of intratumoral and locoregional delivery of adoptive T-cell therapies.

Metabolic characterization of structural lung changes in patients with findings suggestive of incidental COVID-19 pneumonia on 18F-FDG PET/CT. Pathophysiological insights from multimodal images obtained during the pandemic.

PURPOSE: To evaluate the metabolic uptake of different tomographic signs observed in patients with incidental structural findings suggestive of COVID-19 pneumonia through 18F-FDG PET/CT. MATERIALS AND METHODS: We retrospectively analyzed 596 PET/CT studies performed from February 21, 2020 to April 17, 2020. After excluding 37 scans (non-18F-FDG PET tracers and brain studies), we analyzed the metabolic activity of several structural changes integrated in the CO-RADS score using the SUVmax of multimodal studies with 18F-FDG. RESULTS: Forty-three patients with 18F-FDG PET/CT findings suggestive of COVID-19 pneumonia were included (mean age: 68±12.3 years, 22 male). SUVmax values were higher in patients with CO-RADS categories 5-6 than in those with lower CO-RADS categories (6.1±3.0 vs. 3.6±2.1, p=0.004). In patients with CO-RADS 5-6, ground-glass opacities, bilaterality and consolidations exhibited higher SUVmax values (p-values of 0.01, 0.02 and 0.01, respectively). Patchy distribution and crazy paving pattern were also associated with higher SUVmax (p-values of 0.002 and 0.01). After multivariate analysis, SUVmax was significantly associated with a positive structural diagnosis of COVID-19 pneumonia (odds ratio=0.63, 95% confidence interval=0.41-0.90; p=0.02). The ROC curve of the regression model intended to confirm or rule out the structural diagnosis of COVID-19 pneumonia showed an AUC of 0.77 (standard error=0.072, p=0.003). CONCLUSIONS: In those patients referred for standard oncologic and non-oncologic indications (43/559; 7.7%) during pandemic, imaging with 18F-FDG PET/CT is a useful tool during incidental detection of COVID-19 pneumonia. Several CT findings characteristic of COVID-19 pneumonia, specifically those included in diagnostic CO-RADS scores (5-6), were associated with higher SUVmax values.

Impact of acetaminophen on the efficacy of immunotherapy in cancer patients.

BACKGROUND: Acetaminophen (APAP) use has been associated with blunted vaccine immune responses. This study aimed to assess APAP impact on immunotherapy efficacy in patients with cancer. PATIENTS AND METHODS: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICBs). The immunomodulatory effects of APAP were evaluated on a preclinical tumor model and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. RESULTS: Detectable plasma APAP levels at treatment onset were associated with a significantly worse clinical outcome in ICB-treated cancer patients, independently of other prognostic factors. APAP significantly reduced ICB efficacy in the preclinical MC38 model, as well as the production of PD-1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly up-regulated upon treatment with ICB in cancer patients taking APAP. CONCLUSIONS: This study provides strong preclinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.

Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort.

Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7-59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7-49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6-16.5) and 2.4% (95% CI, 0.1-12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients' selection for pembrolizumab treatment.

CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications.

Background: Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1. Methods: We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy. Cell proliferation, cell death and cell cycle analysis were evaluated with high throughput assay. In vivo experiments were carried out by using TP53-mutated and TP53 wild-type patient-derived xenograft models of STS. Clinical activity of GDC-0575 combined with chemotherapy in patients with TP53-mutated and TP53 wild-type STS was also assessed. Results: We found that GDC-0575 abrogated DNA damage-induced S and G2-M checkpoints, exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. In a phase I study of GDC-0575 in combination with gemcitabine, two patients with metastatic TP53-mutated STS had an exceptional, long-lasting response despite administration of a very low dose of gemcitabine whereas one patient with wild-type TP53 STS had no clinical benefit. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2. Conclusion: We provide the first preclinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase II setting.

Molecular identification of Vermamoeba vermiformis from freshwater fish in lake Taal, Philippines.

Free Living Amoebae (FLA) are considered ubiquitous. FLAs may infect various biological organisms which act as reservoir hosts. Infected freshwater fishes can pose a public health concern due to possible human consumption. This study aims to identify possible pathogenic FLAs present in freshwater fishes. Seventy five (75) Oreochromis niloticus were studied for the presence of FLAs. Fish organs were suspended in physiologic saline pelleted and cultured in non-nutrient agar (NNA) lawned with Escherichia coli and were incubated in 33 °C for 14 days. Eighteen (18) fish gills and nineteen (19) fish intestine samples presented with positive growth. Trophozoites and cystic stages of FLAs were subcultured until homogenous growth was achieved. Cells were harvested from cultured plates and DNA was extracted using Chelex resin. DNA was subjected to polymerase chain reaction using universal forward primer EukA and reverse primer EukB targeting the 18s RNA. Of the 37 plates that presented with positive amoebic growth, 9 samples showed the presence of DNAs and were sent for further purification and sequencing. Basic Local Alignment Search Tool (BLAST) results showed that protists isolated from fish organs in Lake Taal include: Eocercomonas (HM536152), Colpoda steinii (KJ607915) and Vermamoeba vermiformis (KC161965). The results showed that fresh-water fishes can harbour FLAs in the gut. It is proposed that freshwater reservoirs utilized for aquaculture be monitored for the presence of FLAs and extensive study be conducted on the pathogenicity of bacterial endosymbionts and infecting viruses to its mammalian and non-mammalian host.

Acute bleeding from pseudoaneurysms following liver and pancreatobiliary surgery.

PURPOSE: We report 12 patients with visceral PA following pancreato-biliary and hepatic surgery. RESULTS: Seven patients (7/11, 63 %) had developed postoperative complications from their original procedure; that information was missing in one patient. Bleeding occurred in eight (three with hemoperitoneum two with haemobilia, and three with GI bleeding through a biliary-enteric anastomosis), three were asymptomatic, and the other one presented with abdominal pain. Eleven patients had an interventional radiology procedure performed (Five underwent angioembolization, a stent was placed in four, and two patients underwent both procedures). Complications related to the procedure developed in 6 (54.5 %) patients, and surgery was required in four of them. CONCLUSION: Postoperative pseudoaneurysms (PA) of visceral arteries are rare and usually secondary to vascular injury after pancreato-biliary and liver surgery. They usually present with bleeding and nowadays most are amenable to initial control by interventional radiology.

Prognostic value of metabolic tumour volume and total lesion glycolysis in 18F-FDG PET/CT scans in locally advanced breast cancer staging. / Papel pronóstico del volumen metabólico tumoral y de la glucólisis tumoral total en los estudios 18F-FDG PET/TC de estadificación del cáncer localmente avanzado de mama.

OBJECTIVE: To determine whether metabolic tumour volume (MTV) and total lesion glycolysis (TLG) are able to predict recurrence risk in locally advanced breast cancer (LABC) patients. MATERIAL AND METHODS: Retrospective study of LABC patients who undertook neoadjuvant, local and adjuvant treatment and follow up. A 18F-FDG PET/CT study for initial staging was performed analysing in this study different metabolic parameters (MTV, TLG, SUVmax and SUVmed) both in the primary tumour (T) as well as in axillary nodes (N) and whole-body (WB). RESULTS: Forty females were included between January 2010-2011; follow up until January 2015 was completed. The average follow-up was 46 months. Twenty percent presented recurrence: local disease (n=2) and distant metastasis (n=6); 3 patients died (38% of the patients which recurred and 7.5% from the total). SUVmax, MTV and TLG, in T, N and WB, were higher in those patients with recurrence. The MTV and TLG parameters in the tumour (T) were related to the recurrence rate (P=.020 and P=.028, respectively); whereas SUVmax in the lymph nodes (N) was significantly related (P=.008) to the recurrence rate. The best cut-off points to predict recurrence where: MTV T ≥19.3cm3, TLG T≥74.4g and SUVmax N≥13.8, being 10-12 times more likely to recidivate when these thresholds where exceeded. Tumour grade was the only clinical-pathological variable which was related to recurrence probability (p=.035). CONCLUSIONS: In this study of LABC patients the metabolic parameters which have a better relationship with recurrence rate are: MTV and TLG in the primary tumour, SUVmax in the regional lymph node disease and whole-body PET data.

Resolvin D1 and E1 promote resolution of inflammation in microglial cells in vitro.

Sustained inflammation in the brain together with microglia activation can lead to neuronal damage. Hence limiting brain inflammation and activation of microglia is a real therapeutic strategy for inflammatory disease. Resolvin D1 (RvD1) and resolvin E1 (RvE1) derived from n-3 long chain polyunsaturated fatty acids are promising therapeutic compounds since they actively turn off the systemic inflammatory response. We thus evaluated the anti-inflammatory activities of RvD1 and RvE1 in microglia cells in vitro. BV2 cells were pre-incubated with RvD1 or RvE1 before lipopolysaccharide (LPS) treatment. RvD1 and RvE1 both decreased LPS-induced proinflammatory cytokines (TNF-α, IL-6 and IL-1ß) gene expression, suggesting their proresolutive activity in microglia. However, the mechanisms involved are distinct as RvE1 regulates NFκB signaling pathway and RvD1 regulates miRNAs expression. Overall, our findings support that pro-resolving lipids are involved in the resolution of brain inflammation and can be considered as promising therapeutic agents for brain inflammation.

[Unexplicated neuropsychiatric disorders: Do not ignore dysimmune encephalitis. A case report of a dysimmune encephalitis with anti-leucine rich glioma inactivated 1 (LGI-1) antibodies]. / Troubles neuropsychiatriques inexpliqués : penser aux encéphalites dysimmunitaires. À propos d'une observation d'encéphalite à anticorps anti-leucine rich glioma inactivated 1 (LGI-1).

INTRODUCTION: Anti-leucine rich glioma inactivated 1 encephalitis is a common and a treatable etiology of autoimmune encephalitis. Its diagnosis is a challenge because the initial diagnostic work-up is often normal. CASE REPORT: A 48-year-old man experienced cognitive and behavioral troubles, facio-brachial dystonic seizures and a syndrome of inappropriate antidiuretic hormone secretion. First line tests excluded infectious, neoplastic, systemic inflammatory, endrocrine or toxic etiologies. Cerebral (18)Fluoro-desoxy-glucose (FDG) position emission tomography and research of specific antibodies in cerebro-spinal fluid and serum led to diagnose an anti-leucine rich glioma inactivated 1 encephalitis. Intravenous immunoglobulins and corticosteroids were partially effective. Cyclophosphamid permitted a good recovery. CONCLUSION: In the presence of acute neuropsychiatric disorders with a negative etiologic research, physician should think about dysimmune encephalitis. Facio-brachial dystonic seizures and syndrome of inappropriate antidiuretic hormone secretion are highly evocative of anti-leucine rich glioma inactivated 1 encephalitis. The diagnosis needs specific diagnostic tests (cerebral (18)FDG position emission tomography and antibodies research in cerebro-spinal fluid and in serum), after the exclusion of alternative diagnoses. Extensive and repeated diagnostic work-up for neoplasia is required. Immunosupressive therapies are effective in most cases.

The MAP3K ZAK, a novel modulator of ERK-dependent migration, is upregulated in colorectal cancer.

Often described as a mediator of cell cycle arrest or as a pro-apoptotic factor in stressful conditions, the MAP3K ZAK (Sterile alpha motif and leucine zipper-containing kinase) has also been proven to positively regulate epidermal growth factor receptor (EGFR) and WNT signaling pathways, cancer cell proliferation and cellular neoplastic transformation. Here, we show that both isoforms of ZAK, ZAK-α and ZAK-ß are key factors in cancer cell migration. While ZAK depletion reduced cell motility of HeLa and HCT116 cells, its overexpression triggered the activation of all three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38, as well as an increase in cell motion. On the contrary, the kinase-dead mutants, ZAK-α K45M and ZAK-ß K45M, were not able to provoke such events, and instead exerted a dominant-negative effect on MAPK activation and cell migration. Pharmacological inhibition of ZAK by nilotinib, preventing ZAK-autophosphorylation and thereby auto-activation, led to the same results. Activated by epidermal growth factor (EGF), we further showed that ZAK constitutes an essential element of the EGF/ERK-dependent cell migration pathway. Using public transcriptomic databases and tissue microarrays, we finally established that, as strong factors of the EGFR signaling pathway, ZAK-α and/or ZAK-ß transcripts and protein(s) are frequently upregulated in colorectal adenoma and carcinoma patients. Notably, gene set enrichment analysis disclosed a significant correlation between ZAK+ colorectal premalignant lesions and gene sets belonging to the MAPK/ERK and motility-related signaling pathways of the reactome database, strongly suggesting that ZAK induces such pro-tumoral reaction cascades in human cancers.

Breslow thickness and (18)F-FDG PET-CT result in initial staging of cutaneous melanoma: Can a cut-off point be established?

AIM: To establish a Breslow Thickness (BT) cut-off point for indication of PET-CT of cutaneous melanoma in early stages and evaluate its prognostic value. MATERIAL AND METHODS: Retrospective analysis of 347 PET-CT studies with diagnosis of melanoma, of which 108 were performed for initial staging. Thirty-one patients were excluded, and a final sample of 77 patients remained. A ROC curve analysis was performed to establish an optimal cut-off point. A survival analysis was performed, considering death assignable to melanoma as the main event, for the evaluation of its prognostic value. RESULTS: Forty-seven (61.04%) of all 77 patients selected were men, and 11 (14.29%) had a positive PET-CT result. Mean age was 65.17±15.00 years. The median BT in patients with a negative PET-CT result was 2.75 mm (IQR 1.83-4.50) and in the positive group 6.25 mm (IQR 5.40-7.50) (P=.0013). In the ROC curve analysis (AUC 0.804, SE 0.054), an optimal value of 5 mm BT with the following values was obtained: sensitivity 90.91%, specificity 78.79%, negative predictive value (NPV) 98.1%, positive predictive value (PPV) 41.7%, diagnostic OR 37.1, and accuracy 80.52%. Mean follow-up was 18.66±14,35 months, detecting 2/53 (3.77%) deaths in the BT<5 mm group, and 7/24 (29.17%) in the BT≥5 mm group. Survival curves between both groups were significantly different (P=.0013). CONCLUSIONS: A 5 mm cut-off point correctly distinguishes those patients with positive PET-CT from those with negative results in the early stages of cutaneous melanoma; therefore it could be included in initial staging of this subgroup of patients.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

18F-FDG PET-CT imaging in the neoadjuvant setting for stages II-III breast cancer: association of loco­regional SUVmax with classical prognostic factors.

AIM: Classical prognostic and predictive factors serve to predict outcome and response to neoadjuvant treatment in stage II and III breast cancer. The purpose is to determine the relation between the SUVmax of the locoregional disease with these classical prognostic factors. METHODS: A prospective study including 43 stage II and III breast cancer patients was performed. In all the patients, two 18F-FDG PET-CT studies were performed before and after neoadjuvant chemotherapy. After this treatment, surgery and adjuvant treatment were carried out. To combine the information of the locoregional disease, the SUVmax of the lesion (tumor or abnormal lymphnodes) with the highest uptake was used. SUVmax and prognostic factors were studied with the Kruskal-Wallis non-parametric test and with the Mann-Whitney U. RESULTS: A statistically significant association between elevated SUVmax value and absence of estrogen receptors (ER) expression (16 vs.. 10; P<0.019) was found. Locorregional disease with positive HER2 phenotype had a statistically significant SUVmax value greater than Luminal A (estrogen and/or progesterone positive receptors with Ki67<15%) and B (estrogen and/or progesterone positive receptors with Ki67≥to 15%) (13.4 vs. 7.9 and 8.9; P<0.022 and P<0.024, respectively). Triple negative phenotype disease had higher SUVmax than Luminal A and B (15.4; P<0.030 and P<0.038). Positive correlation between the percentage of the Ki67 Proliferation Index and SUVmax (P<0.007) was demonstrated. High grade disease had a higher SUVmax than low grade (P<0.004). CONCLUSION: Locorregional SUVmax is associated to prognostic and predictive factors and reaffirms the utility of PET-CT as a tool in the common clinical practice.

Mapping radon-prone areas using γ-radiation dose rate and geological information.

Identifying radon-prone areas is key to policies on the control of this environmental carcinogen. In the current paper, we present the methodology followed to delineate radon-prone areas in Spain. It combines information from indoor radon measurements with γ-radiation and geological maps. The advantage of the proposed approach is that it lessens the requirement for a high density of measurements by making use of commonly available information. It can be applied for an initial definition of radon-prone areas in countries committed to introducing a national radon policy or to improving existing radon maps in low population regions.

[Favourable outcome after treatment with rituximab in a case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome]. / Efficacité du rituximab dans un cas de syndrome de Lambert-Eaton non paranéoplasique séronégatif.

INTRODUCTION: Lambert-Eaton myasthenic syndrome is a rare and autoimmune presynaptic disorder of the neuromuscular junction, due in 85% of cases to autoantibodies directed against voltage-gated calcium channels. It is a paraneoplastic disorder in 50 to 60% of cases. Diagnosis involves a proximal muscle weakness and areflexia, associated with a significant increment after post-exercise stimulation in electrophysiological study. Symptomatic treatment is based on 3,4-diaminopyridine. No etiological treatment has proven its efficacy in both paraneoplastic and non-paraneoplastic Lambert-Eaton myasthenic syndrome. CASE REPORT: We report a 41-year-old man who presented with a seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome in whom conventional immunosuppressive treatments (corticosteroids, azathioprine) failed, and who eventually improved after treatment with rituximab. CONCLUSION: Rituximab was an effective and well-tolerated treatment in this case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome. Its indication should be discussed when conventional immunosuppressive therapy fails in both seropositive and seronegative patients.

Interaction between a bisphosphonate, tiludronate and nanocrystalline apatite: in vitro viability and proliferation of HOP and HBMSC cells.

Nanocrystalline apatites (NCA) are the inorganic components of mineralized tissues and they have been recently proposed as biomaterials for drug delivery systems. Bisphosphonates (BPs) are currently the reference drugs used to treat diseases involving bone disorders such as osteoporosis. Nevertheless, the interaction phenomena between BP molecules and apatite nanocrystals of bone are not well understood. Therefore, the adsorption characteristics have been examined and cellular activity of tiludronate molecules on NCA as models of bone mineral has been investigated. Adsorption experiments of tiludronate onto NCA were carried out and revealed a Langmuir-type adsorption isotherm. The uptake of tiludronate molecules is associated with a release of phosphate ions, indicating that the main reaction is an ion exchange process involving surface anions. The results evidence the strong affinity of BP molecules for the apatitic surface. The interactions of NCA-tiludronate associations with human osteoprogenitor cells and human bone marrow stromal cells do not reveal any cytotoxicity and evidence the activity of adsorbed tiludronate molecules. Moreover, an evolution of the physico-chemical characteristics of the apatitic substrate during biological study was observed, highlighting the existence of dynamic interactions. This work contributes to clarifying the reaction mechanisms between BPs and biomimetic apatites.