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The standard of care for non-metastatic muscle invasive bladder cancer is either radical cystectomy or bladder preservation therapy, which consists of maximal transurethral bladder resection of the tumor followed by concurrent chemoradiation with a cisplatin-based regimen. However, for older cancer patients who are too frail for surgical resection or have decreased renal function, radiotherapy alone may offer palliation. Recently, immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising treatment when combined with radiotherapy due to the synergy of those two modalities. Transitional carcinoma of the bladder is traditionally a model for immunotherapy with an excellent response to Bacille Calmette-Guerin (BCG) in early disease stages, and with avelumab and atezolizumab for metastatic disease. Thus, we propose an algorithm combining immunotherapy and radiotherapy for older patients with locally advanced muscle-invasive bladder cancer who are not candidates for cisplatin-based chemotherapy and surgery.

Background/Objectives: The management of early breast cancer (BC) includes surgery, followed by adjuvant radiotherapy, chemotherapy, hormone therapy, or immunotherapy. However, the influence of these interventions in metabolic reprogramming remains unknown. This study explored alterations in the plasma metabolome of BC patients following distinct treatments to deepen our understanding of BC pathophysiology, outcomes, and the identification of potential biomarkers. Methods: We included 52 women diagnosed with BC and candidates for surgery as primary oncological treatment. Blood samples were collected at diagnosis, two weeks post-surgery, and one month post-radiotherapy. Plasma samples from 49 healthy women served as controls. Targeted metabolomics assessed 74 metabolites spanning carbohydrates, amino acids, lipids, nucleotide pathways, energy metabolism, and xenobiotic biodegradation. Results: Before treatment, the BC patients exhibited notable changes in carbohydrate, nucleotide, lipid, and amino acid metabolism. We noticed a gradual restoration of specific metabolite levels (hypoxanthine, 3-phosphoglyceric acid, xylonic acid, and maltose) throughout different treatments, suggesting a normalization of the nucleotide and carbohydrate metabolic pathways. Moreover, we observed increased dodecanoic acid concentrations, a metabolite associated with cancer protection. These variations distinguished patients from controls with high specificity and sensitivity. Conclusions: Our preliminary study suggests that oncological treatments modify the metabolism of patients towards a favorable profile with a decrease in the pathways that favor cell proliferation and an increase in the levels of anticancer molecules. These findings emphasize the pivotal role of metabolomics in recognizing the biological pathways influenced by each cancer treatment and the resulting metabolic consequences. Furthermore, it aids in identifying potential biomarkers for disease onset and progression.

The standard of care for non-metastatic renal cancer is surgical resection followed by adjuvant therapy for those at high risk for recurrences. However, for older patients, surgery may not be an option due to the high risk of complications which may result in death. In the past renal cancer was considered to be radio-resistant, and required a higher dose of radiation leading to excessive complications secondary to damage of the normal organs surrounding the cancer. Advances in radiotherapy technique such as stereotactic body radiotherapy (SBRT) has led to the delivery of a tumoricidal dose of radiation with minimal damage to the normal tissue. Excellent local control and survival have been reported for selective patients with small tumors following SBRT. However, for patients with poor prognostic factors such as large tumor size and aggressive histology, there was a higher rate of loco-regional recurrences and distant metastases. Those tumors frequently carry program death ligand 1 (PD-L1) which makes them an ideal target for immunotherapy with check point inhibitors (CPI). Given the synergy between radiotherapy and immunotherapy, we propose an algorithm combining CPI and SBRT for older patients with non-metastatic renal cancer who are not candidates for surgical resection or decline nephrectomy.

Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for over 85% of cases and poor prognosis in advanced stages. This study explored shifts in circulating metabolite levels in NSCLC patients versus healthy controls and examined the effects of conventionally fractionated radiation therapy (CFRT) and stereotactic body radiation therapy (SBRT). We enrolled 91 NSCLC patients (38 CFRT and 53 SBRT) and 40 healthy controls. Plasma metabolite levels were assessed using semi-targeted metabolomics, revealing 32 elevated and 18 reduced metabolites in patients. Key discriminatory metabolites included ethylmalonic acid, maltose, 3-phosphoglyceric acid, taurine, glutamic acid, glycocolic acid, and d-arabinose, with a combined Receiver Operating Characteristics curve indicating perfect discrimination between patients and controls. CFRT and SBRT affected different metabolites, but both changes suggested a partial normalization of energy and amino acid metabolism pathways. In conclusion, metabolomics identified distinct metabolic signatures in NSCLC patients with potential as diagnostic biomarkers. The differing metabolic responses to CFRT and SBRT reflect their unique therapeutic impacts, underscoring the utility of this technique in enhancing NSCLC diagnosis and treatment monitoring.

The standard of care for locally advanced rectal cancer is total neoadjuvant therapy followed by surgical resection. Current evidence suggests that selected patients may be able to delay or avoid surgery without affecting survival rates if they achieve a complete clinical response (CCR). However, for older cancer patients who are too frail for surgery or decline the surgical procedure, local recurrence may lead to a deterioration of patient quality of life. Thus, for clinicians, a treatment algorithm which is well tolerated and may improve CCR in older and frail patients with rectal cancer may improve the potential for prolonged remission and potential cure. Recently, immunotherapy with check point inhibitors (CPI) is a promising treatment in selected patients with high expression of program death ligands receptor 1 (PD- L1). Radiotherapy may enhance PD-L1 expression in rectal cancer and may improve response rate to immunotherapy. We propose an algorithm combining immunotherapy and radiotherapy for older patients with locally advanced rectal cancer who are too frail for surgery or who decline surgery.

Background: Triple-negative breast cancer stands out as the most aggressive subtype of breast malignancy and is characterized by an unfavourable prognosis. Objective: This systematic review summarizes the insights gleaned from metabolomic analyses of individuals afflicted with this cancer variant. The overarching goal was to delineate the molecular alterations associated with triple-negative breast cancer, pinpointing potential therapeutic targets and novel biomarkers. Methods: We systematically searched for evidence using the PubMed database and followed the PRISMA and STARLITE guidelines. The search parameters were delimited to articles published within the last 13 years. Results: From an initial pool of 148 scrutinized articles, 17 studies involving 1686 participants were deemed eligible for inclusion. The current body of research shows a paucity of studies, and the available evidence presents conflicting outcomes. Notwithstanding, Pathway Enrichment Analysis identified the urea and glucose-alanine cycles as the most affected metabolic pathways, followed by arginine, proline, and aspartate metabolism. Conclusion: Future investigations need to focus on elucidating which of those metabolites and/or pathways might be reliable candidates for novel therapeutic interventions or reliable biomarkers for diagnosis and prognosis of this subtype of breast cancer.

Paraoxonase-1 (PON1) is an antioxidant enzyme associated with high-density lipoproteins (HDL). Reduced serum PON1 activity is found in diseases marked by oxidative stress and inflammation, but its role in obesity remains unclear. This study investigated PON1 activities and concentrations in morbidly obese individuals and explored the impacts of the genetic polymorphism PON1 rs662 and non-alcoholic fatty liver disease on enzymatic properties. We recruited 1349 morbidly obese patients undergoing bariatric surgery and 823 non-obese volunteers. PON1-related variables, including arylesterase, paraoxonase, and lactonase activities and PON1 concentrations, were examined. Our results showed that morbidly obese individuals exhibited higher PON1 concentrations but lower enzymatic activities than non-obese individuals. We observed inverse associations of arylesterase and paraoxonase activities with waist circumference (rho = −0.24, p < 0.001, and rho = −0.30, p < 0.001, respectively) and body mass index (rho = −0.15, p = 0.001, and rho = −0.23, p < 0.001), as well as direct associations of arylesterase, paraoxonase, and lactonase activities with HDL cholesterol (rho = 0.11, p = 0.005, rho = 0.20, p < 0.001, and rho = 0.20, p < 0.001). No significant differences were observed regarding metabolic syndrome, type 2 diabetes mellitus, hypertension, dyslipidemia, rs662 polymorphism allele frequencies, or the diagnosis of non-alcoholic steatohepatitis. Nevertheless, correlations were found between certain PON1-related variables, steatosis, and ballooning. In conclusion, changes in PON1-related variables in morbidly obese patients are dependent on the disease itself and HDL levels. The relationships between these variables and specific liver histological changes raise intriguing questions for consideration in future studies.

Radiotherapy (RT) is part of the standard treatment of breast cancer (BC) because of its effects on relapse reduction and survival. However, response to treatment is highly variable, and some patients may develop disease progression (DP), a second primary cancer, or may succumb to the disease. Antioxidant systems and inflammatory processes are associated with the onset and development of BC and play a role in resistance to treatment. Here, we report our investigation into the clinical evolution of BC patients, and the impact of RT on the circulating levels of the antioxidant enzyme paraoxonase-1 (PON1), cytokines, and other standard biochemical and hematological variables. Gradient Boosting Machine (GBM) algorithm was used to identify predictive variables. This was a retrospective study in 237 patients with BC. Blood samples were obtained pre- and post-RT, with samples of healthy women used as control subjects. Results showed that 24 patients had DP eight years post-RT, and eight patients developed a second primary tumor. The algorithm identified interleukin-4 and total lymphocyte counts as the most relevant indices discriminating between BC patients and control subjects, while neutrophils, total leukocytes, eosinophils, very low-density lipoprotein cholesterol, and PON1 activity were potential predictors of fatal outcome.

The aim of our study was to investigate the changes produced by low-dose radiotherapy (LDRT) in the circulating levels of the antioxidant enzyme paraoxonase-1 (PON1) and inflammatory markers in patients with COVID-19 pneumonia treated with LDRT and their interactions with clinical and radiological changes. Data were collected from the IPACOVID prospective clinical trial (NCT04380818). The study included 30 patients treated with a whole-lung dose of 0.5 Gy. Clinical follow-up, as well as PON1-related variables, cytokines, and radiological parameters were analyzed before LDRT, at 24 h, and 1 week after treatment. Twenty-five patients (83.3%) survived 1 week after LDRT. Respiratory function and radiological images improved in survivors. Twenty-four hours after LDRT, PON1 concentration significantly decreased, while transforming growth factor beta 1 (TGF-β1) increased with respect to baseline. One week after LDRT, patients had increased PON1 activities and lower PON1 and TGF-β1 concentrations compared with 24 h after LDRT, PON1 specific activity increased, lactate dehydrogenase (LDH), and C-reactive protein (CRP) decreased, and CD4+ and CD8+ cells increased after one week. Our results highlight the benefit of LDRT in patients with COVID-19 pneumonia and it might be mediated, at least in part, by an increase in serum PON1 activity at one week and an increase in TGF-β1 concentrations at 24 h.

We report a pilot study on the feasibility of determinations of circulating levels of paraoxonase-1 (PON1) and compounds related to energy metabolism as biomarkers for the evaluation of patients with rectal cancer (RC), and the effects produced by neoadjuvant radiochemotherapy (NRCT). We studied 32 patients treated with radiotherapy plus capecitabine concomitant chemotherapy and 48 control subjects. We identified pre-NRCT PON1 and α-ketoglutarate as the parameters that best discriminated between RC patients and the control group. Receiver operating characteristics analysis of the combination of the two parameters showed an area under the curve (AUC) of 0.918. Moreover, patients who presented a pathological complete response (pCR) to treatment had lower plasma pre-NRCT valine concentrations (AUC of 0.826). Patients who had a relapse had lower concentrations of succinate (AUC of 0.833). The results of the present study illustrate the usefulness of investigating alterations in oxidative stress and metabolism in RC. Due to the small number of patients studied, our results must be considered preliminary, but they suggest that the determination of circulating levels of PON1 and α-ketoglutarate might be a valuable tool for the early diagnosis of RC, while the determination of valine and succinate might effectively predict pCR and the appearance of relapse.

Infectious and many non-infectious diseases share common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors produce an imbalance between the production of free radicals and endogenous antioxidant systems; the consequence being the oxidation of lipids, proteins, and nucleic acids. Oxidation and inflammation are closely related, and whether oxidative stress and inflammation represent the causes or consequences of cellular pathology, both produce metabolic alterations that influence the pathogenesis of the disease. In this review, we highlight two key molecules in the regulation of these processes: Paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2). PON1 is an enzyme bound to high-density lipoproteins. It breaks down lipid peroxides in lipoproteins and cells, participates in the protection conferred by HDL against different infectious agents, and is considered part of the innate immune system. With PON1 deficiency, CCL2 production increases, inducing migration and infiltration of immune cells in target tissues and disturbing normal metabolic function. This disruption involves pathways controlling cellular homeostasis as well as metabolically-driven chronic inflammatory states. Hence, an understanding of these relationships would help improve treatments and, as well, identify new therapeutic targets.

Purpose: To evaluate the effects of rectal enemas on rectal doses during radical high-dose-rate (HDR) intracavitary cervical brachytherapy (BT). Material and methods : Twenty patients suffering from cervical cancer and treated with external beam radiotherapy and HDR-BT were included in a prospective trial. The first brachytherapy fraction was considered the basal status, and patients were instructed to self-administer two rectal cleansing enemas before the second fraction. Dose-volume histogram (DVH) values were generated for the rectum and correlated with rectal volume variation. Brachytherapy was carried out with a Fletcher or Utrecht applicator. Results : No significant rectal volume differences were observed between fractions with or without rectal enemas (without, 52.64 ± 15.92 cc; with, 53.16 ± 19.28 cc). There was a significant correlation between both rectal volumes (r = 0.722, p = 0.001). No significant differences were observed in analyzed DVH parameters (median values: ΔD 0.1cc , 4.17 vs. 3.61 Gy; ΔD 1cc , 3.23 vs. 2.87 Gy; Δ D2cc , 2.9 vs. 2.54 Gy; ΔD 5cc , 2.35 vs. 2.05 Gy, for no enema and enema fraction, respectively). No significant rectal volume differences nor DVH parameter differences were observed according the applicator type. Conclusions : Our rectal enemas protocol prior to HDR-BT was ineffective in significantly modifying rectal DVH parameters. No differences were observed according to the type of applicator used.

Purpose: Skin cancer is the most common tumor in the population. There are different therapeutic modalities. Brachytherapy is one of the techniques used, in which it is necessary to build customized moulds for some patients. Currently, these moulds are made by hand using rudimentary techniques. We present a new procedure based on 3D printing and the analysis of the clinical workflow. Material and methods: Moulds can be made either by hand or by automated 3D printing. For making moulds by hand, a patient’s alginate negative is created and, from that, the gypsum cast and customized moulds are made by hand from the patient’s negative template. The new process is based on 3D printing. The first step is to take a 3D scan of the surface of the patient and then, 3D modelling software is used to obtain an accurate anatomical reconstruction of the treatment area. We present the clinical workflow using 3D scanning and printing technology, comparing its costs with the usual custom handmade mould protocol. Results: The time spent for the new process is 6.25 hours, in contrast to the time spent for the conventional process, which is 9.5 hours. We found a 34% reduction in time required to create a mould for brachytherapy treatment. The labor cost of the conventional process is 211.5 vs. 152.5 hours, so the reduction is 59 hours. There is also a 49.5% reduction in the financial costs, mostly due to lack of need of a computed tomography (CT) scan of the gypsum and the mould. 3D scanning and printing offers financial benefits and reduces the clinical workload. Conclusions : As the present project demonstrates, through the application of 3D printing technologies, the costs and time spent during the process in the clinical workload in brachytherapy treatment are reduced. Overall, 3D printing is a promising technique for brachytherapy that might be well received in the community.

Breast cancer (BC) is one of the most important neoplasias among women. Many patients receive radiotherapy (RT), which involves radiation exposure of the thoracic zone, including the heart and blood vessels, leading to the development of cardiovascular disease (CVD) as a long-term side effect. The severity of CVD-related pathologies leads research on assessing novel CVD biomarkers as diagnostic, prognostic or therapeutic agents. Currently, the possible candidates include blood microRNAs (miRNAs). Previous studies have supported a role for miRNA-146a, -155, -221, and -222 in the progression of CVD. Our purpose was to evaluate the RT-induced modulation of the expression of these miRNAs in the blood of women with BC. Pre-RT control and post-RT blood samples were collected, and after miRNA isolation and reverse transcription, the levels of the selected miRNAs were measured by real-time PCR. Our results showed that miRNA-155 exhibited the lowest expression, while miRNA-222 exhibited the highest expression, followed by miRNA-221. The expression of each individual miRNA was positively correlated with that of the others both pre-RT control and post-RT and inversely correlated with age before RT. Furthermore, RT promoted the overexpression of the selected miRNAs. Their levels were also affected by CVD-linked clinical parameters, treatment and BC side. Modulation of the expression of the selected miRNAs together with other risk factors might be associated with the development of future cardiovascular pathologies. Further confirmatory studies are needed to assess their potential as possible biomarkers in the progression of or as therapeutic targets for RT-induced CVD in BC patients.

Breast density estimation with visual evaluation is still challenging due to low contrast and significant fluctuations in the mammograms’ fatty tissue background. The primary key to breast density classification is to detect the dense tissues in the mammographic images correctly. Many methods have been proposed for breast density estimation; nevertheless, most of them are not fully automated. Besides, they have been badly affected by low signal-to-noise ratio and variability of density in appearance and texture. This study intends to develop a fully automated and digitalized breast tissue segmentation and classification using advanced deep learning techniques. The conditional Generative Adversarial Networks (cGAN) network is applied to segment the dense tissues in mammograms. To have a complete system for breast density classification, we propose a Convolutional Neural Network (CNN) to classify mammograms based on the standardization of Breast Imaging-Reporting and Data System (BI-RADS). The classification network is fed by the segmented masks of dense tissues generated by the cGAN network. For screening mammography, 410 images of 115 patients from the INbreast dataset were used. The proposed framework can segment the dense regions with an accuracy, Dice coefficient, Jaccard index of 98%, 88%, and 78%, respectively. Furthermore, we obtained precision, sensitivity, and specificity of 97.85%, 97.85%, and 99.28%, respectively, for breast density classification. This study’s findings are promising and show that the proposed deep learning-based techniques can produce a clinically useful computer-aided tool for breast density analysis by digital mammography.

The aims of this study were to investigate changes in energy balance-associated metabolites associated with radiotherapy in patients with breast cancer, and to relate these changes to the clinical and pathological response-to-treatment. We studied 151 women with breast cancer who received radiotherapy following surgical excision of the tumor. Blood was obtained before and after the irradiation procedure. The control group was composed of 44 healthy women with a similar age distribution to that of the patients. We analyzed the concentrations of metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted quantitative metabolomics. Post-surgery, pre-radiotherapy, patients had major alterations in the serum concentrations of products of glycolysis, citric acid cycle and amino acid metabolism. The strongest alterations were decreases in serine, leucine and isoleucine concentrations. Alterations in metabolite levels were partially, or totally, reversed after irradiation; the concentrations of serine, leucine and isoleucine approached equivalence to those of the control group. Estrogen receptor-positive patients were those with lower concentrations, while triple negative patients had higher concentrations of these amino acids. The normalization of the amino acids serine, leucine and isoleucine concentrations could be clinically relevant because the normalization of these energy-balance metabolites would suggest that residual micro-metastatic disease had been effectively diminished by the radiotherapy, and may be an indicator of its efficacy.

Paraoxonase-1 (PON1) is an intra-cellular antioxidant enzyme found also in the circulation associated with high-density lipoproteins. The activity of this enzyme has been shown to be decreased in breast cancer (BC) patients. The aims of our study were to investigate the changes produced by radiotherapy (RT) on activity and concentration of serum PON1 in BC patients, and to evaluate the observed variations in relation to clinical and pathological characteristics of patients and tumors, and the response to treatment. We studied 200 women with BC who were scheduled to receive RT following excision of the tumor. Blood for analyses was obtained before and after the irradiation procedure. The control group was composed of 200 healthy women. Relative to control, BC patients had significantly lower serum PON1 activities pre-RT, while PON1 concentrations were at similar levels. RT was associated with a significant increase in serum PON1 activities and concentrations. We observed significant differences in serum PON1 concentrations post-RT between patients with luminal A or luminal B tumors. Serum PON1 concentration post-RT was markedly lower in BC patients with metastases. We conclude that benefit from RT accrues to the BC patients not only through its direct effect on cancer cells but also indirectly by improving the organism's anti-oxidant defense mechanisms. In addition, our preliminary evidence suggests that the measurement of serum PON1 concentration post-RT could be an efficient prognostic biomarker, and may be used as an index of the efficacy of the RT.

We investigated alterations in the levels of the antioxidant paraoxonase-1 (PON1) and the lipoprotein profile (analyzed by nuclear magnetic resonance) in patients with lung cancer (LC) or head and neck cancer (HNC), and the effects produced thereon by radiotherapy (RT). We included 33 patients with LC and 28 patients with HNC. Before irradiation, and one month after completion of RT, blood samples were obtained. The control group was composed of 50 healthy subjects. Patients had significantly lower serum PON1 activity and concentration before RT than the control group. PON1-related variables were good predictors of the presence of LC or HNC, with analytical sensitivities and specificities greater than 80%. Patients showed a significant increase in the number of particles of all subclasses of very-low-density lipoproteins (large, medium and small). However, these changes were not maintained when adjusted for age, sex, and other clinical and demographic variables. Irradiation was associated with a significant increase in PON1 concentration and, only in patients with HNC, with an increase in high-density lipoprotein-cholesterol concentration. Our results suggest that determinations of the levels of PON1-related variables may constitute good biomarkers for the evaluation of these diseases. Studies with a larger number of patients are needed to fully confirm this hypothesis.