A Holographic-Type Model in the Description of Polymer-Drug Delivery Processes.

A unitary model of drug release dynamics is proposed, assuming that the polymer-drug system can be assimilated into a multifractal mathematical object. Then, we made a description of drug release dynamics that implies, via Scale Relativity Theory, the functionality of continuous and undifferentiable curves (fractal or multifractal curves), possibly leading to holographic-like behaviors. At such a conjuncture, the Schrödinger and Madelung multifractal scenarios become compatible: in the Schrödinger multifractal scenario, various modes of drug release can be "mimicked" (via period doubling, damped oscillations, modulated and "chaotic" regimes), while the Madelung multifractal scenario involves multifractal diffusion laws (Fickian and non-Fickian diffusions). In conclusion, we propose a unitary model for describing release dynamics in polymer-drug systems. In the model proposed, the polymer-drug dynamics can be described by employing the Scale Relativity Theory in the monofractal case or also in the multifractal one.

A Prospective Study on the Progression, Recurrence, and Regression of Cervical Lesions: Assessing Various Screening Approaches.

(1) Background: The prediction of cervical lesion evolution is a challenge for clinicians. This prospective study aimed to determine and compare the predictive accuracy of cytology, HPV genotyping, and p16/Ki67 dual staining alone or in combination with personal risk factors in the prediction of progression, regression, or persistence of cervical lesions in human papillomavirus (HPV)-infected patients; (2) Methods: This prospective study included HPV-positive patients with or without cervical lesions who underwent follow-up in a private clinic. We calculated the predictive performance of individual tests (cervical cytology, HPV genotyping, CINtecPlus results, and clinical risk factors) or their combination in the prediction of cervical lesion progression, regression, and persistence; (3) Results: The highest predictive performance for the progression of cervical lesions was achieved by a model comprising a Pap smear suggestive of high-grade squamous intraepithelial lesion (HSIL), the presence of 16/18 HPV strains, a positive p16/Ki67 dual staining result along with the presence of at least three clinical risk factors, which had a sensitivity (Se) of 74.42%, a specificity of 97.92%, an area under the receiver operating curve (AUC) of 0.961, and an accuracy of 90.65%. The prediction of cervical lesion regression or persistence was modest when using individual or combined tests; (4) Conclusions: Multiple testing or new biomarkers should be used to improve HPV-positive patient surveillance, especially for cervical lesion regression or persistence prediction.

Digging in real-word electronic database for assessing CDK 4/6 inhibitors adherence in breast cancer patients from Romania.

Introduction: It is imperative for patients to respect the prescribed treatments to achieve the anticipated clinical outcomes, including the outpatients receiving oral anti-cancer drugs such as selective cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). With the introduction of three CDK 4/6i drugs in the Romanian pharmaceutical market in 2018, our study aimed to evaluate medication adherence and the influencing factors among patients undergoing treatment with palbociclib, ribociclib, or abemaciclib for advanced or metastatic breast cancer. Methods: Medication adherence was assessed using the Proportion of Days Covered (PDC) method, and Spearman correlation analysis was conducted to explore the relationships between adherence, age, gender, and follow-up duration. Results: The study enrolled 330 breast cancer patients, with an average follow-up period of 14.6 ± 12.5 months for palbociclib, 10.6 ± 7.1 months for ribociclib, and 8.6 ± 6.4 months for abemaciclib-treated patients. A small proportion of patients demonstrated non-adherence: 12.8% for palbociclib, 14.6% for ribociclib, and 14.7% for abemaciclib. Among patients receiving palbociclib, there was no significant correlation between adherence, age (rho = 0.07, p = 0.35), or gender (rho = -0.144, p = 0.054). However, a significant correlation was found with the duration of follow-up (rho = -0.304, p < 0.0001). Similar results were observed for patients receiving ribociclib or abemaciclib. Most patients received combination therapy with letrozole (46%) and exemestane (13%) for palbociclib, letrozole (48%) and fulvestrant (19%) for ribociclib, and fulvestrant (39%) and letrozole (27%) for abemaciclib, Discussion: High adherence rates were observed among patients treated with CDK 4/6i drugs, with no significant differences noted among the three drugs in this class. However, the collected patient data was limited, lacking information on adverse reactions that could potentially lead to treatment discontinuation, as determined by the oncologist's decision not to prescribe. Consequently, a comprehensive understanding of all factors contributing to the low adherence levels is hindered.

Machine Learning-Based Algorithms for Enhanced Prediction of Local Recurrence and Metastasis in Low Rectal Adenocarcinoma Using Imaging, Surgical, and Pathological Data.

(1) Background: Numerous variables could influence the risk of rectal cancer recurrence or metastasis, and machine learning (ML)-based algorithms can help us refine the risk stratification process of these patients and choose the best therapeutic approach. The aim of this study was to assess the predictive performance of 4 ML-based models for the prediction of local recurrence or distant metastasis in patients with locally advanced low rectal adenocarcinomas who underwent neoadjuvant chemoradiotherapy and surgical treatment; (2) Methods: Patients who were admitted at the first Oncologic Surgical Clinic from the Regional Institute of Oncology, Iasi, Romania were retrospectively included in this study between November 2019 and July 2023. Decision tree (DT), naïve Bayes (NB), support vector machine (SVM), and random forest (RF) were used to analyze imagistic, surgical, and pathological data retrieved from the medical files, and their predictive performance was assessed; (3) Results: The best predictive performance was achieved by RF when used to predict disease recurrence (accuracy: 90.85%) or distant metastasis (accuracy: 89.63%). RF was closely followed by SVM (accuracy for recurrence 87.8%; accuracy for metastasis: 87.2%) in terms of predictive performance. NB and DT achieved moderate predictive power for the evaluated outcomes; (4) Conclusions: Complex algorithms such as RF and SVM could be useful for improving the prediction of adverse oncological outcomes in patients with low rectal adenocarcinoma.

Predicting the Feasibility of Curative Resection in Low Rectal Cancer: Insights from a Prospective Observational Study on Preoperative Magnetic Resonance Imaging Accuracy.

Background and Objectives: A positive pathological circumferential resection margin is a key prognostic factor in rectal cancer surgery. The point of this prospective study was to see how well different MRI parameters could predict a positive pathological circumferential resection margin (pCRM) in people who had been diagnosed with rectal adenocarcinoma, either on their own or when used together. Materials and Methods: Between November 2019 and February 2023, a total of 112 patients were enrolled in this prospective study and followed up for a 36-month period. MRI predictors such as circumferential resection margin (mCRM), presence of extramural venous invasion (mrEMVI), tumor location, and the distance between the tumor and anal verge, taken individually or combined, were evaluated with univariate and sensitivity analyses. Survival estimates in relation to a pCRM status were also determined using Kaplan-Meier analysis. Results: When individually evaluated, the best MRI predictor for the detection of a pCRM in the postsurgical histopathological examination is mrEMVI, which achieved a sensitivity (Se) of 77.78%, a specificity (Sp) of 87.38%, a negative predictive value (NPV) of 97.83%, and an accuracy of 86.61%. Also, the best predictive performance was achieved by a model that comprised all MRI predictors (mCRM+ mrEMVI+ anterior location+ < 4 cm from the anal verge), with an Se of 66.67%, an Sp of 88.46%, an NPV of 96.84%, and an accuracy of 86.73%. The survival rates were significantly higher in the pCRM-negative group (p < 0.001). Conclusions: The use of selective individual imaging predictors or combined models could be useful for the prediction of positive pCRM and risk stratification for local recurrence or distant metastasis.

Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy.

Oncolytic viruses (OVs) are emerging as potential treatment options for cancer. Natural and genetically engineered viruses exhibit various antitumor mechanisms. OVs act by direct cytolysis, the potentiation of the immune system through antigen release, and the activation of inflammatory responses or indirectly by interference with different types of elements in the tumor microenvironment, modification of energy metabolism in tumor cells, and antiangiogenic action. The action of OVs is pleiotropic, and they show varied interactions with the host and tumor cells. An important impediment in oncolytic virotherapy is the journey of the virus into the tumor cells and the possibility of its binding to different biological and nonbiological vectors. OVs have been demonstrated to eliminate cancer cells that are resistant to standard treatments in many clinical trials for various cancers (melanoma, lung, and hepatic); however, there are several elements of resistance to the action of viruses per se. Therefore, it is necessary to evaluate the combination of OVs with other standard treatment modalities, such as chemotherapy, immunotherapy, targeted therapies, and cellular therapies, to increase the response rate. This review provides a comprehensive update on OVs, their use in oncolytic virotherapy, and the future prospects of this therapy alongside the standard therapies currently used in cancer treatment.

Theoretical-Experimental Approach of Chitosan/Quaternized Chitosan Nanofibers' Behavior in Wound Exudate Media.

This study aimed to investigate the behavior of chitosan/quaternized chitosan fibers in media mimicking wound exudates to understand their capacities as wound dressing. Fiber analysis of the fibers using dynamic vapor sorption proved their ability to adsorb moisture up to 60% and then to desorb it as a function of humidity, indicating their outstanding breathability. Dissolution analyses showed that quaternized chitosan leached from the fibers in water and PBS, whereas only small portions of chitosan were solubilized in water. In media containing lysozyme, the fibers degraded with a rate determined by their composition and pH, reaching a mass loss of up to 47% in media of physiologic pH. Notably, in media mimicking the wound exudate during healing, they adsorbed moisture even when their mass loss due to biodegradation was high, whereas they were completely degraded in the media of normal tissues, indicating bioabsorbable dressing capacities. A mathematical model was constructed, which characterized the degradation rate and morphology changes of chitosan/quaternized chitosan fibers through analyses of dynamics in scale space, using the Theory of Scale Relativity. The model was validated using experimental data, making it possible to generalize it to the degradation of other biopolymeric systems that address wound healing.

Unfolding the role of the PI3K/AKT/MTOR pathway in male breast cancer: A pragmatic appraisal.

Breast cancer in men is rare, but a relevant public health issue, yielding a 25% higher risk of mortality comparing to female counterparts. The representation of males in clinical trials has been scarce and treatment decisions are based mainly on extrapolations from data in females. In the setting of estrogen-dependent metastatic disease, the use of everolimus has been seldom reported, although the PI3K/AKT/mTOR pathway seems to be a critical oncogenic driver. This paper dissects hallmark biological features of ER+/HER2-advanced male breast cancer, setting a comprehensive basis to promote personalized care, focusing on the potential of targeting the PI3K/AKT/mTOR pathway.

Clinical and morphofunctional identity of the nasal SMAS.

The fascial system of the face (superficial musculo-aponeurotic system, SMAS) in the nasal part is a sustained layer that connects the nearby regions. In this paper, we aimed to emphasize the presence of SMAS in different areas of the nasal region: ala nasi, nasolabial fold, nasal dorsum and radix. We performed three studies (anatomical, histological, and radiological) to demonstrate the existence of nasal SMAS. The study group consisted of cadaveric analyses and retrospective analysis of the patient radiological data. The nasal SMAS was identified as a superficial fascia and a subcutaneous adipose layer. The anatomical dissection study together with histological and radiological evaluations demonstrated the presence of SMAS in the nasal region. We identified peculiarities of the nasal SMAS in two areas: in the ala nasi where it is thinner, and the deep part of the dermis does not adhere to the underlying structures and at the radix and dorsum nasi, where the adipose layer is very thin. The results of our research define nasal SMAS as a unit of great value in facial surgeries, such as facial rejuvenation, the resolution of malformations, or tumor removal.

Theoretical and Experimental Aspects of Sodium Diclofenac Salt Release from Chitosan-Based Hydrogels and Possible Applications.

Two formulations based on diclofenac sodium salt encapsulated into a chitosan hydrogel were designed and prepared, and their drug release was investigated by combining in vitro results with mathematical modeling. To understand how the pattern of drug encapsulation impacted its release, the formulations were supramolecularly and morphologically characterized by scanning electron microscopy and polarized light microscopy, respectively. The mechanism of diclofenac release was assessed by using a mathematical model based on the multifractal theory of motion. Various drug-delivery mechanisms, such as Fickian- and non-Fickian-type diffusion, were shown to be fundamental mechanisms. More precisely, in a case of multifractal one-dimensional drug diffusion in a controlled-release polymer-drug system (i.e., in the form of a plane with a certain thickness), a solution that allowed the model's validation through the obtained experimental data was established. The present research reveals possible new perspectives, for example in the prevention of intrauterine adhesions occurring through endometrial inflammation and other pathologies with an inflammatory mechanism background, such as periodontal diseases, and also therapeutic potential beyond the anti-inflammatory action of diclofenac as an anticancer agent, with a role in cell cycle regulation and apoptosis, using this type of drug-delivery system.

Cisplatin and AKI: an ongoing battle with new perspectives-a narrative review.

Acute kidney injury (AKI) is a growing global health problem with increased mortality and morbidity. Cisplatin is achemotherapy drug first introduced in 1978, and since then, it became one of the most widely used and successful anti-cancer medication. However, there are risks associated with cisplatin administration, such as nephrotoxicity. Mechanisms of nephrotoxicity include proximal tubular injury, DNA damage, apoptosis, inflammation, oxidative stress, and vascular injury. Although various protocols are being used in clinical practice in nephrotoxicity prevention due to cisplatin, there are no clear guidelines regarding this approach. Most recommendations include hydration and avoiding additional nephrotoxic drugs. To prevent nephrotoxicity, future perspectives could rely on natural products, such as flavonoids or saponins or pharmacological products, such as aprepitant, but data are scarce in this direction. Repetitive administration of cisplatin could cause subclinical kidney injury, which over time, leads to chronic kidney disease (CKD). Therefore, more studies are needed to determine possible ways to prevent nephrotoxicity and avoid the burden of CKD worldwide.

Use of Personalized Biomarkers in Metastatic Colorectal Cancer and the Impact of AI.

Colorectal cancer is a major cause of cancer-related death worldwide and is correlated with genetic and epigenetic alterations in the colonic epithelium. Genetic changes play a major role in the pathophysiology of colorectal cancer through the development of gene mutations, but recent research has shown an important role for epigenetic alterations. In this review, we try to describe the current knowledge about epigenetic alterations, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators and the prognostic and predictive biomarkers in metastatic colorectal disease that can allow increases in the effectiveness of treatments. Additionally, the intestinal microbiota's composition can be an important biomarker for the response to strategies based on the immunotherapy of CRC. The identification of biomarkers in mCRC can be enhanced by developing artificial intelligence programs. We present the actual models that implement AI technology as a bridge connecting ncRNAs with tumors and conducted some experiments to improve the quality of the model used as well as the speed of the model that provides answers to users. In order to carry out this task, we implemented six algorithms: the naive Bayes classifier, the random forest classifier, the decision tree classifier, gradient boosted trees, logistic regression and SVM.

Multi-fractal modeling of curcumin release mechanism from polymeric nanomicelles.

The physicochemical properties of "smart" or stimuli-sensitive amphiphilic copolymers can be modeled as a function of their environment. In special, pH-sensitive copolymers have practical applications in the biomedical field as drug delivery systems. Interactions between the structural units of any polymer-drug system imply mutual constraints at various scale resolutions and the nonlinearity is accepted as one of the most fundamental properties. The release kinetics, as a function of pH, of a model active principle, i.e., Curcumin, from nanomicelles obtained from amphiphilic pH-sensitive poly(2-vinylpyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) tailor-made diblock copolymers was firstly studied by using the Rietger-Peppas equation. The value of the exponential coefficient, n, is around 0.5, generally suggesting a diffusion process, slightly disturbed in some cases. Moreover, the evaluation of the polymer-drug system's nonstationary dynamics was caried out through harmonic mapping from the usual space to the hyperbolic one. The kinetic model we developed, based on fractal theory, fits very well with the experimental data obtained for the release of Curcumin from the amphiphilic copolymer micelles in which it was encapsulated. This model is a variant of the classical kinetic models based on the formal kinetics of the process.

Endoglin (CD105) as a putative prognostic biomarker for colorectal cancer: a systematic review.

The outcome of colorectal cancer (CRC) can be improved by the identification of prognostic biomarkers. This systematic review of observational cohort and case-control studies was conducted to investigate the role of Endoglin (CD105) in the prognosis of CRC. The databases PubMed, Web of Science, Scopus, and Cochrane CENTRAL were searched to identify the qualified studies using the relevant keywords. After the removal of duplicate articles, the screening was implemented on the titles, abstracts, and potential full-text articles. Afterward, the eligible cohort and case-control studies were identified, and the data were extracted into an Excel datasheet. In total, 11 observational cohort studies and 1 case-control study were identified to be eligible for this systematic review. The majority of the included studies achieved a moderate to high-degree quality according to the Newcastle-Ottawa Scale. Moreover, the eligible studies included a total of 1,400 patients with CRC and mean age of 60 years, the majority of whom were male. Endoglin was observed to be more upregulated in colorectal carcinomas and associated with poor survival outcomes, compared to healthy controls. The levels of Endoglin seem to reflect the degree of cancer invasiveness, therefore predicting dismal prognosis in patients with CRC. Larger and well-designed clinical studies with longer follow-up intervals are needed to investigate the role of Endoglin and its association with cancer metastasis.

Update on the Use of Nanocarriers and Drug Delivery Systems and Future Directions in Cervical Cancer.

Cervical cancer represents a major health problem among females due to its increased mortality rate. The conventional therapies are very aggressive and unsatisfactory when it comes to survival rate, especially in terminal stages, which requires the development of new treatment alternatives. With the use of nanotechnology, various chemotherapeutic drugs can be transported via nanocarriers directly to cervical cancerous cells, thus skipping the hepatic first-pass effect and decreasing the rate of chemotherapy side effects. This review comprises various drug delivery systems that were applied in cervical cancer, such as lipid-based nanocarriers, polymeric and dendrimeric nanoparticles, carbon-based nanoparticles, metallic nanoparticles, inorganic nanoparticles, micellar nanocarriers, and protein and polysaccharide nanoparticles. Nanoparticles have a great therapeutic potential by increasing the pharmacological activity, drug solubility, and bioavailability. Through their mechanisms, they highly increase the toxicity in the targeted cervical tumor cells or tissues by linking to specific ligands. In addition, a nondifferentiable model is proposed through holographic implementation in the dynamics of drug delivery dynamics. As any hologram functions as a deep learning process, the artificial intelligence can be proposed as a new analyzing method in cervical cancer.

Landscape of Immunotherapy Options for Colorectal Cancer: Current Knowledge and Future Perspectives beyond Immune Checkpoint Blockade.

Colorectal cancer is the third most prevalent malignancy in Western countries and a major cause of death despite recent improvements in screening programs and early detection methods. In the last decade, a growing effort has been put into better understanding how the immune system interacts with cancer cells. Even if treatments with immune checkpoint inhibitors (anti-PD1, anti-PD-L1, anti-CTLA4) were proven effective for several cancer types, the benefit for colorectal cancer patients is still limited. However, a subset of patients with deficient mismatch repair (dMMR)/microsatellite-instability-high (MSI-H) metastatic colorectal cancer has been observed to have a prolonged benefit to immune checkpoint inhibitors. As a result, pembrolizumab and nivolumab +/- ipilimumab recently obtained the Food and Drug Administration approval. This review aims to highlight the body of knowledge on immunotherapy in the colorectal cancer setting, discussing the potential mechanisms of resistance and future strategies to extend its use.

The Landscape of Nanovectors for Modulation in Cancer Immunotherapy.

Immunotherapy represents a promising strategy for the treatment of cancer, which functions via the reprogramming and activation of antitumor immunity. However, adverse events resulting from immunotherapy that are related to the low specificity of tumor cell-targeting represent a limitation of immunotherapy's efficacy. The potential of nanotechnologies is represented by the possibilities of immunotherapeutical agents being carried by nanoparticles with various material types, shapes, sizes, coated ligands, associated loading methods, hydrophilicities, elasticities, and biocompatibilities. In this review, the principal types of nanovectors (nanopharmaceutics and bioinspired nanoparticles) are summarized along with the shortcomings in nanoparticle delivery and the main factors that modulate efficacy (the EPR effect, protein coronas, and microbiota). The mechanisms by which nanovectors can target cancer cells, the tumor immune microenvironment (TIME), and the peripheral immune system are also presented. A possible mathematical model for the cellular communication mechanisms related to exosomes as nanocarriers is proposed.

A Comprehensive Review of the Use of Antioxidants and Natural Products in Cancer Patients Receiving Anticancer Therapy.

Cancer is the leading cause of mortality and morbidity worldwide. The side effects of cancer treatment affect the quality of life. Cancer patients search for antioxidant dietary supplements and natural products during or after conventional cancer treatment for the alleviation of side effects, improvement of the benefits of treatment, and promotion of well-being. However, the efficacy and safety of these products remain controversial; moreover, previous data do not support the standardized use of those alternative treatments in clinics. The current study reviewed the manuscripts reporting the administration of antioxidants and natural products during cancer treatment and revised preclinical and clinical studies on various types of cancer. Most of the positive results were obtained from experimental animal models; however, human clinical studies are discouraging in this regard. Therefore, further precise and distinguishable studies are required regarding antioxidant dietary supplementation. Future studies are also needed to clarify dietary supplements' mechanism of action and pharmacokinetics in a suitable cancer patient population that will benefit the therapeutic regimens. Despite the popularity of dietary supplements, clinicians and patients should always consider their potential benefits and risks. Patients should discuss with their physician before taking any dietary antioxidant supplements or natural products.

Improved Personalised Neuroendocrine Tumours' Diagnosis Predictive Power by New Receptor Somatostatin Image Processing Quantification.

Although neuroendocrine tumours (NETs) are intensively studied, their diagnosis and consequently personalised therapy management is still puzzling due to their tumoral heterogeneity. In their theragnosis algorithm, receptor somatostatin scintigraphy takes the central place, the diagnosis receptor somatostatin analogue (RSA) choice depending on laboratory experience and accessibility. However, in all cases, the results depend decisively on correct radiotracer tumoral uptake quantification, where unfortunately there are still unrevealed clues and lack of standardization. We propose an improved method to quantify the biodistribution of gamma-emitting RSA, using tissular corrected uptake indices. We conducted a bi-centric retrospective study on 101 patients with different types of NETs. Three uptake indices obtained after applying new corrections to areas of interest drawn for the tumour and for three reference organs (liver, spleen and lung) were statistically analysed. For the corrected pathological uptake indices, the results showed a significant decrease in the error of estimating the occurrence of errors and an increase in the diagnostic predictive power for NETs, especially in the case of lung-referring corrected index. In conclusion, these results support the importance of corrected uptake indices use in the analysis of 99mTcRSA biodistribution for a better personalised diagnostic accuracy of NETs patients.

An Insight into Deficient Mismatch Repair Colorectal Cancer Screening in a Romanian Population-A Bi-Institutional Pilot Study.

Background and Objectives: Colorectal cancer (CRC) can be classified as mismatch-repair-deficient (dMMR) with high levels of microsatellite instability (MSI-H), or mismatch-repair-proficient (pMMR) and microsatellite stable (MSS). Approximately 15% of patients have microsatellite instability (MSI). MSI-H tumors are associated with a high mutation burden. Monoclonal antibodies that block immune checkpoints can induce long-term durable responses in some patients. Pembrolizumab is the first checkpoint inhibitor approved in the EU to treat dMMR-MSI-H metastatic CRC. Materials and Methods: Our study assesses the regional variability of MSI-H colorectal cancer tumors in Romania. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks containing tumor samples from 90 patients diagnosed with colorectal cancer were collected from two tertiary referral Oncology Centers from Romania. Tissues were examined for the expression loss of MMR proteins (MLH1, PMS2, MSH2, MSH6) using immunohistochemistry or MSI status using polymerase chain reaction (PCR), respectively. Results: MSI-H was detected in 19 (21.1%) patients. MSI-H was located more in ascending colon (36.8% vs. 9.9%, p-value = 0.0039) and less in sigmoid (5.3% vs. 33.8%, p-value = 0.0136) than MSS patients. Most patients were stage II for MSI-H (42.1%) as well as for MSS (56.3%), with significant more G1 (40.9% vs. 15.8%, p-value = 0.0427) for MSS patients. Gender, N stage, and M stage were identified as significant prognostic factors in multivariate analysis. MSI status was not a statistically significant predictor neither in univariate analysis nor multivariate analysis. Conclusion: Considering the efficacy of PD-1 inhibitor in metastatic CRC with MSI-H or dMMR, and its recent approval in EU, it is increasingly important to understand the prevalence across tumor stage, histology, and demographics, since our study displayed higher regional MSI-H prevalence (21%) compared to the literature.