Gut microbiota and its association with cancer development/treatment has been intensively studied during the past several years. Currently, there is a growing interest toward next-generation probiotics (NGPs) as therapeutic agents that alter gut microbiota and impact on cancer development. In the present review we focus on three emerging NGPs, namely Faecalibacterium prausnitzii, Akkermansia muciniphila, and Bacteroides fragilis as their presence in the digestive tract can have an impact on cancer incidence. These NGPs enhance gastrointestinal immunity, maintain intestinal barrier integrity, produce beneficial metabolites, act against pathogens, improve immunotherapy efficacy, and reduce complications associated with chemotherapy and radiotherapy. Notably, the use of NGPs in cancer patients does not have a long history and, although their safety remains relatively undefined, recently published data has shown that they are non-toxigenic. Notwithstanding, A. muciniphila may promote colitis whereas enterotoxigenic B. fragilis stimulates chronic inflammation and participates in colorectal carcinogenesis. Nevertheless, the majority of B. fragilis strains provide a beneficial effect to the host, are non-toxigenic and considered as the best current NGP candidate. Overall, emerging studies indicate a beneficial role of these NGPs in the prevention of carcinogenesis and open new promising therapeutic options for cancer patients.
Background Calcitriol (an active metabolite of vitamin D) modulates the expression of hundreds of human genes by activation of the vitamin D nuclear receptor (VDR). However, VDR-mediated transcriptional modulation does not fully explain various phenotypic effects of calcitriol. Recently a fast non-genomic response to vitamin D has been described, and it seems that mitochondria are one of the targets of calcitriol. These non-classical calcitriol targets open up a new area of research with potential clinical applications. The goal of our study was to ascertain whether calcitriol can modulate mitochondrial function through regulation of the potassium channels present in the inner mitochondrial membrane. Methods The effects of calcitriol on the potassium ion current were measured using the patch-clamp method modified for the inner mitochondrial membrane. Molecular docking experiments were conducted in the Autodock4 program. Additionally, changes in gene expression were investigated by qPCR, and transcription factor binding sites were analyzed in the CiiiDER program. Results For the first time, our results indicate that calcitriol directly affects the activity of the mitochondrial large-conductance Ca ²⁺ -regulated potassium channel (mitoBK Ca ) from the human astrocytoma (U-87 MG) cell line but not the mitochondrial calcium-independent two-pore domain potassium channel (mitoTASK-3) from human keratinocytes (HaCaT). The open probability of the mitoBK Ca channel in high calcium conditions decreased after calcitriol treatment and the opposite effect was observed in low calcium conditions. Moreover, using the AutoDock4 program we predicted the binding poses of calcitriol to the calcium-bound BK Ca channel and identified amino acids interacting with the calcitriol molecule. Additionally, we found that calcitriol influences the expression of genes encoding potassium channels. Such a dual, genomic and non-genomic action explains the pleiotropic activity of calcitriol. Conclusions Calcitriol can regulate the mitochondrial large-conductance calcium-regulated potassium channel. Our data open a new chapter in the study of non-genomic responses to vitamin D with potential implications for mitochondrial bioenergetics and cytoprotective mechanisms.
To achieve clinical impact in daily oncological practice, emerging AI-based cancer imaging research needs to have clearly defined medical focus, AI methods, and outcomes to be estimated. AI-supported cancer imaging should predict major relevant clinical endpoints, aiming to extract associations and draw inferences in a fair, robust, and trustworthy way. AI-assisted solutions as medical devices, developed using multicenter heterogeneous datasets, should be targeted to have an impact on the clinical care pathway. When designing an AI-based research study in oncologic imaging, ensuring clinical impact in AI solutions requires careful consideration of key aspects, including target population selection, sample size definition, standards, and common data elements utilization, balanced dataset splitting, appropriate validation methodology, adequate ground truth, and careful selection of clinical endpoints. Endpoints may be pathology hallmarks, disease behavior, treatment response, or patient prognosis. Ensuring ethical, safety, and privacy considerations are also mandatory before clinical validation is performed. The Artificial Intelligence for Health Imaging (AI4HI) Clinical Working Group has discussed and present in this paper some indicative Machine Learning (ML) enabled decision-support solutions currently under research in the AI4HI projects, as well as the main considerations and requirements that AI solutions should have from a clinical perspective, which can be adopted into clinical practice. If effectively designed, implemented, and validated, cancer imaging AI-supported tools will have the potential to revolutionize the field of precision medicine in oncology.
Background ANCHOVY was a global, multicenter, chart-review study that aimed to describe the natural history of Type 1 spinal muscular atrophy (SMA) from a broad geographical area and provide further contextualization of results from the FIREFISH (NCT02913482) interventional study of risdiplam treatment in Type 1 SMA. Methods Data were extracted from medical records of patients with first symptoms attributable to Type 1 SMA between 28 days and 3 months of age, genetic confirmation of SMA, and confirmed survival of motor neuron 2 copy number of two or unknown. The study period started on 1 January 2008 for all sites; study end dates were site-specific due to local treatment availabilities. Primary endpoints were time to death and/or permanent ventilation and proportion of patients achieving motor milestones. Secondary endpoints included time to initiation of respiratory and feeding support. Results Data for 60 patients from nine countries across Asia, Europe and North and South America were analyzed. The median age (interquartile range [IQR]) for reaching death or permanent ventilation was ~ 7.3 (5.9–10.5) months. The median age (IQR) at permanent ventilation was ~ 12.7 (6.9–16.4) months and at death was ~ 41.2 (7.3–not applicable) months. No patients were able to sit without support or achieved any level of crawling, standing or walking. Interpretation Findings from ANCHOVY were consistent with published natural history data on Type 1 SMA demonstrating the disease’s devastating course, which markedly differed from risdiplam-treated infants (FIREFISH Part 2). The results provide meaningful additions to the literature, including a broader geographical representation.
Background and aims Elevated concentration of CRP has been associated with the risk of diabetes as well as cardiovascular events and microvascular complications in T1D patients. We hypothesize that the +1846 C > T CRP gene polymorphism may have impact on the risk of T1D and/or its complications. Methods We have examined 400 young patients with T1D and 250 healthy age-matched controls. The +1846 C > T CRP gene polymorphism was genotyped by ARMS–PCR method. The analysis covers microvascular complications, concentrations of serum pro- and anti-inflammatory markers, adhesion molecules, proangiogenic factor as well as blood pressure. Results CT genotype (OR = 1.799) and T allele (OR = 1.733) are associated with increased risk of T1D, while CC genotype decreases the risk of this condition (OR = 0.458). Moreover, increased risk of hypertension corresponds with TT and T variant (OR = 3.116 and OR = 1.830, resp.) while CC genotype is decreasing the risk (OR = 0.547). Furthermore, CT variant is connected with lower risk of retinopathy (OR = 0.512) whereas TT variant decreases the risk of this complication (OR = 2.228). Our data also implies various effects of CRP +1846 C > T polymorphism on the inflammatory status of T1D patients. Conclusions Although further studies are required, the +1846 C > T CRP gene polymorphism could be considered a genetic marker to predict susceptibility to retinopathy and hypertension in T1D adolescents.
Background Primary lung carcinoma is an exceptionally rare childhood tumour, as per definition of the European Cooperative Study Group on Paediatric Rare Tumours (EXPeRT), with an incidence of 0.1–0.2/1,000,000 per year. Little is known about the clinical characteristics of children with primary lung carcinoma, a gap which this joint analysis of the EXPeRT group aimed to fill. Patients and methods We performed a retrospective case series of children (aged 0–18 years) with primary lung carcinoma, as collected through the EXPeRT databases between 2000 and 2021. We recorded relevant clinical characteristics including treatment and outcome. Results Thirty-eight patients were identified with a median age of 12.8 years at diagnosis (range: 0–17). Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 20), followed by adenocarcinoma (n = 12), squamous cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and small-cell lung cancer (n = 1). Patients with MEC presented rarely with lymph node metastases (2/20 cases). Overall, 19/20 patients achieved long-lasting remission by surgical resection only. Patients with other histologies often presented in advanced stages (14/18 TNM stage IV). With multimodal treatment, 3-year overall survival was 52% ± 13%. While all patients with squamous cell carcinoma died, the 12 patients with adenocarcinoma had a 3-year overall survival of 64% ± 15%. Conclusions Primary lung carcinomas rarely occur in children. While the outcome of children with MEC is favourable with surgery alone, patients with other histotypes have a poor prognosis, despite aggressive treatment, highlighting the need to develop new strategies for these children, such as mutation-guided treatment.
Lung cancer is the leading cause of cancer-related deaths in Europe. Europe's Beating Cancer Plan calls for a comprehensive approach to the disease in general but not specifically to lung cancer. Such a comprehensive approach, integrating efforts to strengthen anti-tobacco policies, early detection and underlying models of care, is sorely needed for lung cancer – particularly considering disruptions to care during the COVID-19 pandemic. In a recently published think piece, a multidisciplinary group of experts proposed four key policy priority areas. First, to reduce stigma and improve awareness of potential symptoms, there is a need to foster a better understanding of lung cancer – among the public and healthcare professionals. Second, opportunities for early detection should be enhanced, and the implementation of targeted screening through low-dose computed tomography should be encouraged as a complement to smoking cessation services. This complementarity should be recognised and built into joint policy proposals, with development and better integration of screening and smoking cessation programmes on the ground. Third, the socioeconomic inequalities underpinning disparities in outcomes in people with lung cancer must be addressed, with targeted approaches to overcome barriers to access Finally, the overall quality of lung cancer care must be improved, making multidisciplinary care available to all and ensuring survivorship is given due attention.
The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.
Background The effect of age on the incidence of late sequelae that occur after anticancer treatment in childhood is still not fully elucidated. In this multicenter study of long-term survivors diagnosed before age of three, we investigated the prevalence of late effects many years after treatment. Methods The study group (n = 561) was selected from the Polish National Childhood Cancer Survivors Registry (n = 1761) created in 2007. A survivor was defined as an individual who has survived at least 5 years after completion of anticancer treatment. All children were diagnosed between 1991 and 2016, mean age at diagnosis was 1.82 years (range 0.03–2.99) and median follow up time - 9.85 years (range 5.0–23.6). They were treated in accordance with international protocols approved by the Polish Pediatric Leukemia and Lymphoma Group and Polish Solid Tumor Group. Chemotherapy alone was used in 192 (34.2%), chemotherapy and radiotherapy – 56 (10%), chemotherapy and surgery – 176 (31.4%), chemotherapy, radiotherapy, and surgery – 79 (14.1%), and surgery alone in 58 patients (10.3%). Results Of all patients enrolled to the study, only 94 (16.8%) had normal function of all organs. Seventy-six (13.5%) children developed dysfunction in one organ, another 83 (14.8%) had symptoms or complaints suggestive of dysfunction in two organs or systems, 88 (15.7%) had abnormalities in three organs, and 220 (39.2%) had at least four or more dysfunctions. In the entire study group, dysfunctions most frequently (> 20% of cases) involved the following organs/systems: circulatory – 21.8%, urinary – 30.8%, gastrointestinal – 20.8%, immune – 23.5%, vision – 20.7%, hearing – 21.8%, and oral and masticatory dysfunction – 26.9%. We did not find any significant differences in organ dysfunction between children diagnosed under the age of 1 and those diagnosed at the age of 1–3, except for a lower incidence of thyroid abnormalities (p = 0.007) and the higher prevalence of liver dysfunction in youngest patients. In the subset with longer follow-up period (> 10 years) more frequent thyroid abnormalities (p = 0.019), male (p = 0.002) and female (p = 0.026) gonads dysfunction, as well as musculoskeletal problems (p < 0.001) were observed. Among subjects who received radiotherapy compared to those who did not, short stature (p = 0.001), and dysfunction of the following systems/organs – circulatory (p = 0.049), urinary (p = 0.012), thyroid gland (p < 0.0001), nervous (p = 0.007), immunological (p = 0.002), liver (p = 0.03), dental or chewing difficulties (p = 0.001), hearing (p = 0.001) and musculoskeletal (p = 0.026) were more frequently reported. When multimodal therapy was applied (chemotherapy, radiotherapy, and surgery) a higher incidence of short stature (p = 0.007), urinary system disorders (p < 0.0001), thyroid dysfunction (p < 0.0001), hearing loss (p < 0.0001), and skin problems (p = 0.031) were observed. Conclusion This study confirms that radiotherapy and some specific toxicity of cytostatics are the most important factors affecting organ function. Apart from a higher incidence of liver dysfunction in the youngest patients, there were no significant differences in organ and system toxicities between children diagnosed under the age of 1 and those diagnosed at the age of 1–3. We have shown that this group requires systematic, careful and long-term follow-up.
Context: Isocitrate dehydrogenase 1 (IDH1) mutations are oncogenic drivers in acute myeloid leukemia (AML), with 6-10% of AML patients harboring mutant IDH1 (mIDH1). Ivosidenib (IVO) is a small molecule mIDH1 inhibitor that silences the oncogenic pathways activated by this mutation. Objective: Assess efficacy/safety of IVO+azacitidine (AZA) as frontline therapy for AML patients ineligible for intensive chemotherapy (IC). Design: Randomized, placebo (PBO)-controlled, global phase 3 study. Patients: Patients with untreated AML, centrally confirmed mIDH1 status, ineligible for IC. Interventions: Once daily IVO 500 mg (or PBO) plus AZA 75 mg/m2 for 7 days in 28-day cycles. Main outcome measures: Event-free survival (EFS), overall survival (OS), response rates, blood counts, transfusion dependence, health-related quality of life (HRQoL), and adverse events (AEs). Results: 146 patients were randomized to IVO+AZA (n=72) and PBO+AZA (n=74). Median age was 76.0 and 75.5 years, respectively. EFS was significantly in favor of IVO+AZA (HR=0.33; 1-sided P=0.0011). Median OS was 24.0 vs 7.9 months for IVO+AZA vs PBO+AZA, respectively (HR=0.44; 1-sided P=0.0005). Complete response rates were 47.2% and 14.9% for IVO+AZA vs PBO+AZA, respectively (P<0.0001). During 2 weeks after treatment initiation, only the IVO+AZA treatment group showed an increase in absolute neutrophil count (from 0.99×109/L at baseline to 2.05×109/L at week 2). Significantly more patients in the IVO+AZA group became RBC and platelet transfusion independent (2-sided P=0.006). IVO+AZA preserved or improved HRQoL from treatment cycles 5 to 19, with few clinically meaningful improvements with PBO+AZA. Grade ≥3 AEs occurring in >20% of patients receiving IVO+AZA vs PBO+AZA included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), pneumonia (22.5% vs 28.8%), and infections (21.1% vs 30.1%). Conclusions: In patients with IC-ineligible, newly diagnosed mIDH1 AML, IVO+AZA significantly improved EFS, OS, and clinical response compared with PBO+AZA. Blood counts rapidly recovered in patients given IVO+AZA, patients were less dependent on RBC/platelet transfusion than those given PBO+AZA, with HRQoL improvements in the IVO+AZA group. The safety profile of IVO+AZA was favorable, with fewer febrile neutropenia and infection events with IVO+AZA vs PBO+AZA.
Context: Classic Hodgkin lymphoma (cHL) is a phenotypically heterogeneous disease with enigmatic biology and pathogenesis. By leveraging ctDNA analysis, here we identify molecular groups of cHL with phenotype- and outcome-associated signatures. Objective: Identification and biological characterization of novel cHL subgroups. Methods: We sequenced 202 cHL patients targeting ~344 kb of genomic space. The length of ctDNA mapped reads was extracted, and unsupervised clustering was performed. PET/CT scan and 71 plasma cytokines were obtained for clinical correlation. Single-cell RNA sequencing was performed for 8 patients. Results: To identify molecular subgroups within cHL, we focused on the fragmentation profile of cfDNA, a non-genetic way of detecting tumor-derived DNA in the cfDNA samples. We identified two distinct clusters, one with a fragmentation profile close to healthy (N=135), named mono-nucleosomal, and a submono-nucleosomal cluster characterized by a global shift toward shorter fragments, whose length was less than the typical wrap around the nucleosome (N=67). We explored whether cHL subtypes defined by the cfDNA fragmentation profile are clinically and biologically validated. Patients with the submono-nucleosomal fragmentome showed more frequent advanced-stage B symptoms and elevated ESR at the clinical level, higher tumor volume (TMTV and TLG) at the radiomic level, and lower PFS in terms of outcome. Tumor mutations and immune microenvironment are pathophysiologic features of cHL. The submono-nucleosomal cluster carried a higher tumor mutation burden because of heavier aberrant somatic hypermutation (ASHM). The submono-nucleosomal cluster had an immune-suppressive microenvironment enriched of T-regs and higher plasmatic levels of T-regs chemoattractants and inducers of PD1 expression (IL6, CCL2, CCL4). Conversely, mono-nucleosomal cHL had a microenvironment enriched of TFH cells and cytotoxic CD8 TEM cells and associated with cytokines and chemokines that are known for being attractants and activators of effector T cells (IL-1a, CCL21, CXCL12, IL-17A). Conclusions: Our observations indicate that cHL subgroups belonging to the submono-nucleosomal cluster have a more aggressive disease, a higher mutation load and more neoantigens likely due to denser ASHM, and an immune-suppressive microenvironment. Instead, cHL subgroups belonging to the mono-nucleosomal cluster have a less aggressive disease, a lower mutation load and lower neoantigens likely due to lighter ASHM, and a tumor-suppressive microenvironment.
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