Alternative Treatment Research Articles

Tumor Hyperprogression in Squamous Cell Carcinomas of Head and Neck after Immunotherapy: Our Perspective

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. Although there have been some advances in multimodality therapy, the overall 5-year survival rate remains poor approximately at 40%-50%. Currently, Immune Checkpoint Inhibitor (ICI) based Immunotherapies are being evaluated as an alternate treatment modality for recurrent/metastatic HNSCCs in clinical trials.

Intra-articular knee injections in patients with primary osteoarthritis in a tertiary clinical setting: a best practice implementation project.

This project aimed to improve physicians' adherence to evidence-based practices regarding the selection and administration of intra-articular knee injections for patients with osteoarthritis. The project also aimed to empower patients by increasing their awareness of these evidence-based practices. In the management of knee osteoarthritis, intra-articular injections are commonly used when initial treatments prove inadequate. However, issues such as patients' demand for rapid relief and variability in physicians' familiarity with optimal practices often lead to suboptimal treatment decisions and potential adverse outcomes. This project followed the JBI Evidence Implementation Framework, which is grounded in an audit, feedback, and re-audit process. Initially, physicians were surveyed on the topic under consideration, and hospital records were reviewed. Subsequently, targeted interventions were implemented, including briefings and the distribution of informative flyers. The baseline audit indicated low adherence with all audit criteria. Various parameters, such as adherence to best clinical practices, informed decision-making by patients, and the recommendation of alternative treatment modalities, were significantly lacking. Following the interventions, substantial improvements were observed, including higher rates of adherence to best clinical practices by physicians for multiple criteria, such as stepwise referral to conservative therapy options and the content of intra-articular injections. Adherence to best clinical practices can be improved through educational briefings for physicians on the most current evidence-based treatment practices for injectable substances in knee osteoarthritis. The active engagement of patients, facilitated by informative flyers and physician assistance, contributed to better involvement in their treatment choices. However, the participation of health care institutions and providers as well as lifelong education practices may be necessary for more comprehensive and sustainable changes. http://links.lww.com/IJEBH/A277.

Double arch technique - a novel surgical procedure for the hypoplastic aortic arch syndrome

Abstract Background The hypoplastic aortic arch syndrome was defined as a combination of hypoplastic aortic arch and complex proximal descending aortic anomalies (such as aortic aneurysm, aortic coarctation, aortic tortuosity, or aortic dissection). In this study, we proposed a novel 'double arch' technique as a simple surgical procedure to treat the hypoplastic aortic arch syndrome, which could eliminate the requirement for cardiopulmonary bypass. Purpose This study aimed to investigate the surgical outcomes of patients who underwent the 'double arch' technique, and further evaluate the effectiveness and safety of this novel technique. Methods Briefly, J-shaped mini-sternotomy and left posterolateral thoracotomy were both performed in this technique. The ascending aorta, aortic arch, and proximal descending aorta were dissociated. After that, the ascending aorta was occluded using a side-biting clamp, followed by an end-to-side anastomosis between the proximal end of vascular graft and the ascending aorta. Similarly, the thoracic descending aorta was occluded with two aortic clamps beyond the opening of the left subclavian artery, and was then transected between the clamps, followed by an end-to-end anastomosis between the distal end of vascular graft and the distal descending aorta, while the proximal descending aorta was closed with sutures. The transection site of the aorta could be adjusted according to the extent of the lesions, and the vascular graft was placed in the left thoracic cavity. The operation was performed at room temperature. The primary endpoint was early mortality, which referred to in-hospital death and/or death within 30 days after surgery (including intraoperative death), whichever is longer. Critical secondary endpoints included aortic reoperation, newly developed aneurysms, and the blood pressure difference between the upper and lower extremities. Results Twelve patients with hypoplastic aortic arch syndrome were enrolled from December 2015 to February 2022. Patients were diagnosed using computed tomography. The median age (interquartile range, IQR) was 26.5 (17.0, 39.0) years (ranging from 12.0 to 55.0), and 8 patients were female (66.7%). The median operation time (IQR) was 4.7 (3.8, 5.5) hours (ranging from 2.8 to 7.3). All patients survived to discharge and completed the follow-up. The median follow-up time (IQR) was 5.42 (3.25, 5.97) years (ranging from 0.02 to 6.25). During the follow-up, no patient died or was required for reoperation. In addition, no newly developed aneurysm was found, and no severe adverse event was recorded. The median blood pressure difference (IQR) between the upper and lower extremities was 9 (4, 17) mmHg (ranging from 3 to 27). Conclusions The 'double arch' technique is a viable alternative surgical treatment for the hypoplastic aortic arch syndrome. This technique is expected to significantly simplify the surgical procedure and improve the long-term prognosis of patients.Diagram of the 'double arch' techniqueCT scans of pre- and post-operation

Different treatments in chronic thromboembolic pulmonary hypertension: comparison of strategies in the Italian centre real-world experience

Abstract Rationale Pulmonary endarterectomy (PEA) has been the most effective therapy for chronic thromboembolic pulmonary hypertension (CTEPH). However, there is a substantial proportion of patients declared not operable in whom other treatment strategies are available: medical therapy and balloon pulmonary angioplasty (BPA). We aimed to compare different CTEPH treatment strategies effect in real-world setting. Methods All CTEPH referred to our Centre were included. We compare the short-term clinical, functional, exercise and haemodynamic effect of medical therapy (irrespective of subsequent treatment strategies), PEA and BPA (irrespective of previous/subsequent treatment strategies); we also describe the long-term outcome of the different patient groups. Results We included 467 patients (39% were treated only with medical therapy, 43% underwent PEA, 13% underwent BPA and 5% were not treated with any therapy). Patients treated only with medical therapy were the oldest; compared to patients undergoing PEA, they had a lower exercise capacity, a higher risk profile and gained a lower haemodynamic, functional and survival benefit from the treatment. Patients undergoing BPA had a lower haemodynamic improvement but a comparable functional, exercise and risk improvement and a similar survival compared to patients undergoing PEA; their survival is anyway better than patients undergoing only medical treatment. Untreated historical control patients had the worst survival. Conclusions We confirm the superiority of PEA compared to any alternative treatment in CTEPH and we observe that BPA, in patients declared not operable or with persistent/recurrent PH after PEA, leads to a better outcome than medical therapy alone.

Application of Artificial Intelligence Models to Predict the Onset or Recurrence of Neovascular Age-Related Macular Degeneration

Neovascular age-related macular degeneration (nAMD) is one of the major causes of vision impairment that affect millions of people worldwide. Early detection of nAMD is crucial because, if untreated, it can lead to blindness. Software and algorithms that utilize artificial intelligence (AI) have become valuable tools for early detection, assisting doctors in diagnosing and facilitating differential diagnosis. AI is particularly important for remote or isolated communities, as it allows patients to endure tests and receive rapid initial diagnoses without the necessity of extensive travel and long wait times for medical consultations. Similarly, AI is notable also in big hubs because cutting-edge technologies and networking help and speed processes such as detection, diagnosis, and follow-up times. The automatic detection of retinal changes might be optimized by AI, allowing one to choose the most effective treatment for nAMD. The complex retinal tissue is well-suited for scanning and easily accessible by modern AI-assisted multi-imaging techniques. AI enables us to enhance patient management by effectively evaluating extensive data, facilitating timely diagnosis and long-term prognosis. Novel applications of AI to nAMD have focused on image analysis, specifically for the automated segmentation, extraction, and quantification of imaging-based features included within optical coherence tomography (OCT) pictures. To date, we cannot state that AI could accurately forecast the therapy that would be necessary for a single patient to achieve the best visual outcome. A small number of large datasets with high-quality OCT, lack of data about alternative treatment strategies, and absence of OCT standards are the challenges for the development of AI models for nAMD.

Cardiac motion in patients with ventricular tachycardia: potential implications for the treatment of patients candidates to stereotactic arrhythmia radio-ablation (STAR)

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has proven to be a valid alternative treatment for refractory ventricular tachycardia (VT) in patients who are unsuitable to undergo standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. There is increased research activity on better understanding the complex and fast motion of the heart and on reducing radiation toxicity. Purpose In the context of an in silico study to evaluate the feasibility of STAR with protons in patients with VT, the initial findings related to cardiac motion on the first 10 patients are here presented. Methods Prior to CA, each patient underwent ECG gated CT scans in expiratory breath-hold, with and without contrast and reconstructed at 30% (systole) and 80% (diastole) of the cardiac R-R cycle. Contouring of the ablation target as a clinical target volume (CTV) for proton treatment planning was performed based on a standard electrophysiological study with 3D eletroanatomical mapping. Two different treatment plans were created: the first with only the diastolic CTV as target (gated treatment), the second including both diastolic and systolic CTVs to create an Internal Target Volume (ITV) in the hypothesis of non-gated treatment. Robust optimization was used to create the Planning Target Volume (PTV). Results The target volumes used for treatment planning are given in Table 1. The median CTV was 10.90 (2.93-36.94) cm3 for diastole and 14.26 (1.73-36.31) cm3 for systole. These volumes are somewhat smaller than those reported in patients treated previously with STAR: this difference may be due to the fact that no respiratory motion was included in the target contour and that the study population includes many patients referred for ventricular ectopic beats without structural heart disease, where the ablation target is expected to be smaller as compared to patients with VT in structural heart disease. Despite a small median difference between the diastolic and systolic CTV of 0.53 (0.03-9.61) cm3, the ITV approach resulted in a median increase in volume compared to the largest of the two CTVs of 29 % (1%-44%). When considering the proton range uncertainty and potential errors in patient positioning (PTV), the target is this time enlarged by a factor 2.9 (1.9-3.9). This data indicates that both cardiac motion and uncertainties in patient positioning before treatment will have a large impact on the treatment volume thus affecting the amount of surrounding tissue exposed to radiation. Conclusion The ablation target contour at systole and diastole are of similar magnitude but their non-overlap results in a large increase in treated volume when radiation delivery is not gated for cardiac motion. Further analysis shall investigate on a case-by-case basis the potential reduction in risk of healthy tissue toxicity with cardiac-gated proton delivery.Table 1

Selective Cytotoxicity and Gene Expression Profiles in Response to Methanolic Extract of Phyllanthus amarus Extract against MCF-7 Breast Cancer Cells

Background Breast cancer, a malignant tumor, is the most common cancer type among women worldwide. Conventional chemotherapy treatments for breast cancer often cause adverse side effects in normal tissues and can lead to treatment failure. Plant-derived natural compounds offer an effective alternative with fewer side effects for cancer patients. Phyllanthus amarus is a medicinal plant widely distributed in China, India, and Brazil and reported to be used for the treatment of various types of cancer. Purpose This study was aimed to investigate the anticancer efficacy of methanolic extract of P. amarus against MCF-7 breast cancer cells. Methods We probed the anticancer activity in MCF-7 breast cancer cells by isolating the methanolic extract of P. amarus leaf extract (MEPA). The standard chemotherapy drug docetaxel is combined with MEPA to increase the drug efficacy. Moreover, the intracellular reactive oxygen species (ROS), alterations in mitochondrial membrane potential (MMP), nuclear condensation, and apoptotic activation were investigated in MCF-7 cells. Additionally, the customized PCR array comprising of cell cycle, apoptosis, mTOR, and JAK-STAT-related genes was studied during different MEPA treatments. Results In the MCF-7 breast cancer cells, the MEPA and docetaxel combination demonstrated strong cytotoxicity, with IC50 values of 45 and 2.6 µg/mL, respectively. MEPA and docetaxel together exhibited enhanced alterations in MMP and increased generation of ROS in MCF-7 cells. Furthermore, the combination of docetaxel with MEPA induces nuclear condensation and apoptotic cell death. During MEPA treatment, the gene expression profiles in MCF-7 cells were accessed. The JAK-STAT, mTOR signaling pathway, apoptosis, and cell growth-related genes were strongly affected by the dose-dependent administration of MEPA. Conclusion This study suggests that MEPA could be a useful alternative treatment for breast cancer. When combined with traditional chemotherapy, MEPA might offer better results with fewer side effects. More in vivo studies are needed to confirm MEPA’s effectiveness in animal models.

Accelerated innervation of biofabricated skeletal muscle implants containing a neurotrophic factor delivery system

IntroductionVolumetric muscle loss (VML) is one of the most severe and debilitating conditions in orthopedic and regenerative medicine. Current treatment modalities often fail to restore the normal structure and function of the damaged skeletal muscle. Bioengineered tissue constructs using the patient’s own cells have emerged as a promising alternative treatment option, showing positive outcomes in fostering new muscle tissue formation. However, achieving timely and proper innervation of the implanted muscle constructs remains a significant challenge. In this study, we present a clinically relevant strategy aimed at enhancing and sustaining the natural regenerative response of peripheral nerves to accelerate the innervation of biofabricated skeletal muscle implants.MethodsWe previously developed a controlled-release neurotrophic factor delivery system using poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF). Here, we incorporate this neurotrophic factor delivery system into bioprinted muscle constructs to facilitate innervation in vivo.ResultsOur results demonstrate that the neurotrophic factors released from the microspheres provide a chemical cue, significantly enhancing the neurite sprouting and functional innervation of the muscle cells in the biofabricated muscle construct within 12 weeks post-implantation.DiscussionOur approach provides a clinically applicable treatment option for VML through accelerated innervation of biomanufactured muscle implants and subsequent improvements in functionality.

Ethical Dilemmas in Home Palliative Care

Abstract Background In the past two decades, there has been a noticeable shift towards home-based care, reflecting the broader trend among OECD countries to prioritize a comprehensive approach to health and well-being. This approach emphasizes preventive and proactive measures, often relying on home-based care delivered by multidisciplinary teams providing both curative and palliative care. However, the unique nature of providing care in a home environment raises ethical questions among healthcare providers, necessitating high levels of attentiveness and sensitivity from the caregiving team to address them effectively. Research Objectives This study aims to identify ethical challenges encountered by a multidisciplinary team, as perceived by managers of an organization offering home palliative services in Israel. Methods A qualitative study was conducted, involving interviews with nine key managers to explore prevalent ethical issues in delivering home-based care. Findings Thematic analysis unveiled common ethical dilemmas in providing Home Palliative Care. These dilemmas include balancing patient preferences with professional obligations, addressing the needs of both patients and their families, navigating caregiver-patient relationships, understanding patients’ cultural backgrounds, and advocating for home care as the preferred option while considering alternative treatment approaches. Conclusions Home palliative care poses ethical dilemmas for caregiving teams. It’s imperative for organizations in the home care sector to devise strategies aimed at assisting teams in navigating these challenges while upholding the autonomy and dignity of patients within their home environment. Key messages • Home-based care faces ethical challenges, requiring strategies to balance patient preferences and professional duties. • Ethical home hospice care needs strategies that respect patient autonomy and dignity.

Preliminary results of the non-invasive cardiac radioablation for ventricular tachycardia study; an in silico dosimetric comparison of photon vs proton radiotherapy for ventricular arrhythmias

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has been proposed as an alternative treatment for refractory ventricular arrhythmias (VA) in patients who are unsuitable or refractory to standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. Most of the STAR treatments performed so far used photon radiotherapy. As compared to photons, particle therapy with protons, based on its finite penetration depth in tissue, might have the potential to reduce the dose to surrounding healthy tissues thus lowering the risk of side effects. Purpose The purpose of this in silico simulation study was to evaluate the feasibility of STAR with protons in patients with VA and to compare the doses of the organs at risk (OARs) in photon and proton treatment plans. Methods 14 patients (11 males) candidates to standard CA for VA were enrolled. ECG gated CT scans in expiratory breath-hold, and standard electroanatomical mapping were performed in each patients to reconstruct a 3D bipolar voltage map and identify the ablation target. Based on the information obtained by the contouring of the ablation target three treatment plans were simulated: one with photons, and two with protons - with and without cardiac gating- to assess the doses at the OARs. Results The median age was 68.5 (63.25-71.5), all patients had a history of recurrent VA and the indication for treatment with CA. 7 patients had an ischemic cardiomyopathy, 4 an idiopathic cardiomyopathy and 3 ventricular ectopic beats without structural heart disease. The mean left ventricular ejection fraction was 40±11% and 8 out of 14 patients were ICD carriers. Both photons and protons treatment plans reached the goals for target coverage (25 Gy on 98% of the target volume). A statistically significant reduction in the mean maximum dose (Dmax) to some OARs was observed in proton compared to photon plans (see table 1). Specifically, the Dmax delivered to the mitral valve, vena cava, descending aorta, esophagus and to the lungs have been largely reduced with the proton plans. However, in some specific cases, a higher maximum dose was observed for protons in structures close or overlapping with the target, mainly due to the need of an additional margin in the treatment plan to account for proton range uncertainty. The use of cardiac gating did not show a significant dose reduction to OARs compared to the non-gated proton plan. Conclusion The preliminary results of our in silico simulation study suggest that STAR therapy with the use of protons might be associated with a significant dose reduction to the surrounding organs. Nevertheless, the choice of the best treatment should be evaluated on a case by-case strategy since some specific cases may be better suitable for photon treatment.Table 1

Phaleria macrocarpa Fruit Protein Aqueous Extract Affects Viral Entry, Virucidal Activity, and Progeny Release

Presence of acyclovir (ACV) resistant virus posed a major problem in treating virus infection. Alternative treatment with the ability to encounter infection of acyclovir-resistant virus is thus needed and possibly with a different mode of action from ACV. Hence, this study evaluates the antiviral effect of Phaleria macrocarpa (Scheff.) Boerl fruit protein aqueous extract (PMFPAE) against three different strains of human herpesvirus type-1 (HHV-1) including a clinical strain, a less pathogenic strain (KOS-1), and acyclovir (ACV) resistant mutant (UKM-1). PMFPAE displayed antiviral activity towards all the HHV-1 strains when post-treated with high selective indices (SIs) of 80.6, 50, and 35, respectively. Plaque reduction percentages were reduced in attachment and penetration assays following treatment with PMFPAE indicating the ability to deactivate the early phases of the HHV-1 replication cycle. The virucidal activity was also noted following treatment of the virus with PMFPAE and this is supported by damages to the virus envelope as observed by transmission electron microscopy (TEM). Incubation of virus-treated cells with PMFPAE for 24 hr, reduced progeny release in a dose-dependent manner. The study confirms the antiviral mode of action of P. macrocarpa fruit against HHV-1 strains and the ACV-mutant strain includes inhibition during virus entry represented as the early stages of viral replication, virucidal activity, and interfering with progeny release. PMFPAE mode of action is hence different from ACV and worthy for the development of future antiviral drugs.

The LTAR Croplands Common Experiment at the Gulf Atlantic Coastal Plain.

The Gulf Atlantic Coastal Plain (GACP) Long-Term Agroecosystem Research (LTAR) Network site is characterized by hot and humid summers with low gradient stream channels surrounded by wetland forests and croplands. Beneath its sandy soils, a confining layer stifles recharge to the deeper aquifer system, so a substantial proportion of streamflow is driven by shallow subsurface baseflow. Agricultural practices in the area consist of forage and livestock production, forestry, and rotational cropping systems dominated by cotton (Gossypium hirsutum) and peanut (Arachis hypogaea). Certain factors impose challenges to the viability of GACP agricultural systems, like changing economics and demographics, as well as pest and disease pressures. The GACP communicates with stakeholders from various backgrounds, who provide their perspectives as agricultural research service scientists execute their research plans. The GACP LTAR common experiment (CE) is carried out via plot- and field-scale studies. The plot-scale CE compares prevailing practices, determined from regional data, with an alternative treatment including winter covers, such as the biofuel feedstock carinata (Brassica carinata, A. Braun), to provide both economic and environmental benefits. The field-scale CE is observational; key variables are monitored for two farms where management practices largely emulate the prevailing treatment. Data collection efforts quantify vegetation, hydrology, soils, and climate data to produce datasets for modeling and statistical analysis. Research teams quantify relationships between land management, environment, and socioeconomic benefits. Ultimately, the GACP LTAR site works to facilitate agricultural system health and wellbeing at local, regional, and national scales by providing long-term science-based solutions.

Novel Perspectives in the Management of Colorectal Cancer: Mechanistic Investigations Into the Reversal of Drug Resistance via Active Constituents Derived From Herbal Medicine.

The high incidence and mortality rate of colorectal cancer have become a significant global health burden. Chemotherapy has been the traditional treatment for colorectal cancer and has demonstrated promising antitumor effects, leading to significant improvements in patient survival. However, the development of chemoresistance poses a major challenge during chemotherapy in colorectal cancer, significantly impeding treatment efficacy and affecting patient prognosis. Despite the development of a variety of novel anticolorectal cancer chemotherapy agents, their effectiveness and side effects vary, possibly due to the complex mechanisms of resistance in colorectal cancer. Abnormal drug metabolism or protein targets are the most direct causes of resistance. Further studies have revealed that these resistance mechanisms involve biochemical processes such as altered protein expression, autophagy, and epithelial-mesenchymal transitions. Herbal active ingredients offer an alternative treatment option and have shown promise in reversing colorectal cancer drug resistance. This paper aims to summarize the role of various biochemical processes and key protein targets in the occurrence and maintenance of resistance mechanisms in colorectal cancer. Additionally, it elaborates on the mechanisms of action of herbal active ingredients in reversing colorectal cancer drug resistance. The article also discusses the limitations and opportunities in developing novel anticolorectal cancer drugs based on herbal medicine.

Photobiomodulation as a Potential Treatment for Alzheimer’s Disease: A Review Paper

Background: Alzheimer’s disease (AD), the most prevalent form of dementia, is a leading neurodegenerative disorder currently affecting approximately 55 million individuals globally, a number projected to escalate to 139 million by 2050. Despite extensive research spanning several decades, the cure for AD remains at a developing stage. The only existing therapeutic options are limited to symptom management, and are often accompanied by adverse side effects. The pathological features of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, result in progressive neuronal death, synaptic loss, and brain atrophy, leading to significant cognitive decline and a marked reduction in quality of life. Objective: In light of the shortcomings of existing pharmacological interventions, this review explores the potential of photobiomodulation (PBM) as a non-invasive therapeutic option for AD. PBM employs infrared light to facilitate cellular repair and regeneration, focusing on addressing the disease’s underlying biomechanical mechanisms. Method: This paper presents a comprehensive introduction to the mechanisms of PBM and an analysis of preclinical studies evaluating its impact on cellular health, cognitive function, and disease progression in AD.The review provides a comprehensive overview of the various wavelengths and application methods, evaluating their efficacy in mitigating AD-related symptoms. Conclusions: The findings underscore the significant potential of PBM as a safe and effective alternative treatment for Alzheimer’s disease, emphasizing the necessity for further research and clinical trials to establish its therapeutic efficacy conclusively.

Toxicity and Dermatokinetic Analysis of Ibrutinib in Human Skin Models

Background/Objectives: Ibrutinib (IBR) is a tyrosine kinase inhibitor under investigation in preclinical and clinical settings as an alternative treatment for melanoma. Nevertheless, the limited oral bioavailability of IBR and the need for high doses of the drug to kill melanoma cells are major drawbacks for this purpose. Considering that melanoma is restricted to the skin at early stages, the topical application of IBR might constitute an effective and safer administration route. In this study, we determined IBR’s toxicity and dermatokinetics using human primary cells and human organotypic skin explant cultures (hOSECs). Methods: After demonstrating that human primary fibroblasts and keratinocytes present IBR target genes, the cytotoxicity of the drug was determined using the MTT and annexin V/PI staining assays. IBR toxicity in the skin was assessed using the TTC assay, and the irritation potential was established using histological assessment. Finally, IBR cutaneous permeation was assessed ex vivo to determine the drug dermatokinetics. Results: Our findings reveal that IBR exerts dose-dependent toxicity towards skin cells, presenting an IC50 in the same range as melanoma cells. The topical application of the drug successfully reduced irritation and toxicity in the skin, and the drug was shown to successfully permeate the stratum corneum and reach the viable skin layers in therapeutic concentrations. Conclusions: Overall, our data encourage the topical application of IBR to treat melanoma, paving the way for future studies in this theme.

Enhanced Antitumor Efficacy of Oncolytic Vaccinia Virus Therapy Through Keratin-Mediated Delivery in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) represents an aggressive subtype characterized by high rates of recurrence and metastasis, necessitating the exploration of alternative treatment strategies. Oncolytic vaccinia virus (OVV) therapy has emerged as a promising approach, selectively infecting and destroying tumor cells. However, its efficacy is often hampered by inadequate viral distribution within the tumor microenvironment. Here, we investigate the potential of keratin (KTN) as a carrier for OVV delivery to enhance viral distribution and antitumor efficacy. In vitro assays revealed that KTN significantly improves OVV stability, leading to increased tumor cell apoptosis and necrosis. Furthermore, KTN effectively inhibits cancer cell migration by suppressing the epithelial–mesenchymal transition (EMT) process and downregulating metastasis-related proteins. These findings are corroborated in a syngeneic TNBC mouse model, where KTN-mediated OVV delivery enhances cytotoxic T cell-mediated antitumor immune responses without compromising the anti-angiogenic effects of the virus. Notably, KTN alone exhibits antitumor effects by suppressing tumor growth and metastasis, underscoring its potential as a standalone therapeutic agent. In conclusion, our study underscores the promise of KTN-mediated OVV delivery as a promising therapeutic strategy for TNBC. By improving viral distribution, suppressing EMT, and enhancing antitumor immunity, this approach holds significant potential for enhancing patient outcomes in TNBC treatment. Further investigation is warranted to explore the broader utility of KTN in various cancer therapy approaches.

Autologous Micrografts Containing Nanovesicles, Exosomes, and Follicle Stem Cells in Androgenetic Alopecia: In Vitro and In Vivo Analysis Through a Multicentric, Observational, Evaluator-Blinded Study.

The use of micrografts (MCGs) containing human follicle mesenchymal stem cells (HF-MSCs) is a hair loss (HL) treatment that needs to be standardized as seems to have promising effects on hair regrowth (HR-G) also thanks to the presence of extracellular vesicles (EVs). The study aims to report both the in vivo results, obtained in patients affected by androgenic alopecia (AGA) treated using MCGs, and in vitro analysis characterizing the EVs. A multicentric, retrospective, observational, evaluator-blinded study was conducted. Eighty-three AGA patients were initially enrolled [52 suffering from male pattern hair loss (MPHL) at stages I-III vertex by the Norwood-Hamilton scale and 31 suffering from female PHL (FPHL) at stages I-II by the Ludwig scale]. Sixty patients (20 females and 40 males) were treated and analyzed after exclusion and inclusion criteria assessment. The in vivo HR-G was evaluated through photography, physician's, and patient's global assessment scales, in addition to standardized photo-trichograms, during a follow-up for 1 year, while the in vitro analysis was performed through a quantitative, morphological, and dimensional characterization of the EVs population using transmission electron microscopy (TEM) and fluorescent microscopy. A hair density (HD) increase of 28 ± 4hairs/cm2 at T4 after 12 months in the targeted area (TA) of FPHL, compared with the baseline, was observed using computerized trichograms with a statistically significant difference (SSD) in hair regrowth (HR-G) (p = 0.0429). Regarding MPHL, an HD increase of 30 ± 5hairs/cm2 at T4 after 12 months in the TA was observed with an SSD in HR-G (p = 0.0012). The presence of EVs and their interaction with the surrounding cellular population were demonstrated. MCGs containing HF-MSCs and exosomes may fill in as a safe and viable alternative treatment against HL in mild and moderate degrees of AGA both in MPHL and in FPHL. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Gentamicin Pharmacokinetics in Neonates Undergoing Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy.

The purpose of this study was to review the pharmacokinetic profile of gentamicin among neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) treatment. This was a retrospective study of neonates with HIE undergoing TH in the neonatal intensive care unit who received gentamicin between 2009 and 2014. Demographic information, diagnoses, laboratory test results, and medication administration and monitoring information were collected, and data were analyzed using SciPy. A total of 57 neonates were analyzed. The median birth weight was 3.25 kg (interquartile range [IQR] 2.8-3.68), and median gestational age was 39 weeks (IQR 38-40). An elevated gentamicin trough level (defined as > 2 mg/L) was observed in 61% (35/57) of neonates. Half of the neonates (49%) had multiple gentamicin trough levels obtained, and 4% of the neonates were switched to an alternate agent. There was a significant difference in the number of dosing interval changes in neonates with elevated gentamicin trough levels compared with those with therapeutic gentamicin trough levels (P < 0.001). Of the neonates with elevated gentamicin trough levels, 14% (5/35) failed their hearing screen (P = 0.389). Neonates with HIE undergoing TH may have an altered pharmacokinetic profile, requiring multiple blood draws so medication levels can be monitored and doses adjusted.Traditional gentamicin dosing regimens may not be ideal for this patient population, and further guidance is required for alternative treatment regimens.

VENO-VENOUS EXTRACORPOREAL MEMBRANE OXYGENATION IMPROVES OUTCOMES IN TRAUMA PATIENTS SUFFERING RESPIRATORY FAILURE.

Veno-venous extracorporeal membrane oxygenation (VV ECMO) improves hypoxemia and carbon dioxide clearance in patients with severe respiratory derangements. A greater understanding of the potential benefits of VV ECMO in trauma patients could lead to broader adoption. We hypothesize that trauma patients who receive VV ECMO have improved mortality outcomes when compared to those receiving conventional ventilator management given the rapid stabilization VV ECMO promotes. We performed a single center, propensity score matched cohort study. All trauma patients from January 1, 2014, to October 30, 2023, who were placed on VV ECMO or who would have met institutional guidelines for VV ECMO but were managed with conventional ventilator strategies were matched 1:1. The primary outcome analysis was survival at hospital discharge. Significance was defined as p < 0.05. Eighty-one trauma VV ECMO patients and 128 patients who received conventional management met criteria for inclusion. After matching, VV ECMO and conventional treatment cohort characteristics were similar in age and MOI. Matched ISS, SI, lactate levels, and frequency of TBI were also similar. Finally, respiratory parameters including pre-intervention, pH, partial pressure of carbon dioxide (PaCO2), lactate levels, and oxygen saturation were similar between matched groups. VV ECMO patients had higher survival rates at discharge when compared to the matched conventional treatment group (70% v 41%, p < 0.001). Corresponding hazard ratio for VV ECMO use was 0.31 (95%CI 0.18-0.52; p < 0.001). The odds ratio of mortality in matched trauma patients who receive VV ECMO versus conventional treatment was 0.29 (95%CI 0.14-0.58; p < 0.001). VV ECMO may represent a safe, alternative treatment approach for appropriately screened trauma patients with acute respiratory failure, however further studies are warranted.

Neutrophil count predicts the complete response after transarterial chemoembolization related to favorable outcome in hepatocellular carcinoma.

Systemic inflammatory markers have emerged as novel prognostic biomarkers associated with prognosis for tumors. This study aims to investigate the predictive value of systemic inflammatory markers for complete response (CR) in patients with hepatocellular carcinoma (HCC) who underwent transarterial chemoembolization (TACE). This retrospective study enrolled 575 HCC patients undergoing TACE. Survival outcomes were evaluated based on tumor response, and the analysis was conducted using a Kaplan-Meier curve. Predictive factors for achieving a CR after the initial TACE were analyzed by univariate and multivariate analyses in a Cox regression model. After the initial TACE, 246 of 575 (42.8%) patients achieved a CR. During a median of 60 months follow-up, the CR group had better overall survival than non-CR group (median: 82.3 vs. 51.6 months, P < 0.001). Pre-TACE neutrophil count was associated with tumor response (P = 0.06). Multivariate analysis showed that hepatitis B virus infection [hazard ratio (HR) = 0.585, 95% confidence interval (CI) = 0.360-0.952, P = 0.031] and pre-TACE neutrophil count (HR = 2.854, 95% CI = 1.115-7.307, P = 0.029) were independent predictive factors for CR after the initial TACE. Additionally, a high pre-TACE neutrophil count was associated with male gender (P < 0.001), large tumor size (P < 0.001), advanced Barcelona Clinic Liver Cancer stage (P = 0.003), and high protein induced by vitamin K absence or antagonist-II level (P < 0.001). Patients who achieved CR after the initial TACE showed a favorable prognosis. Pre-TACE neutrophil count was found to be an independent predictor of CR. These findings offer valuable insights for identifying patients who would derive the greatest benefit from TACE and for distinguishing those who may require alternative treatment approaches for HCC.