Search Results (154)

Background/Objectives: Relapsed or refractory follicular lymphoma (rrFL) remains difficult to treat in elderly or frail patients who cannot tolerate standard-dose immuno-chemotherapy as well as novel therapies. Metronomic chemotherapy (mCHEMO) may offer sustained antitumor activity with reduced toxicity. This study assessed the clinical activity and safety of R-DEVEC or R-DEVEC-light in rrFL patients following lenalidomide discontinuation or ineligibility. Methods: Data from the ReLLi Lymphoma Registry (2013–2025) were retrospectively analyzed. Eligible patients had rrFL after ≥1 prior therapy and initiated mCHEMO at least six months before data cutoff. Thirteen patients received DEVEC or the etoposide-free DEVEC-light regimen; all but one also received rituximab. Responders received maintenance vinorelbine, low-dose prednisone, and rituximab, followed by vinorelbine-only maintenance until progression or intolerance. Responses were assessed by CT after cycle two and PET/CT at completion of six induction cycles. Results: median age was 77 years (range 58–92); most patients were frail and had advanced disease. At the end of induction, 84% achieved remission (46% CR, 38% PR), with three PR converting to CR during maintenance. After a median follow-up of 27 months, the PFS was 42% (95CI 15–69%) and the OS 73% (95CI 47–100%). A transformation occurred in one patient; the main toxicity was grade 3 neutropenia (31%). DEVEC-light showed improved tolerability versus full DEVEC, with manageable infections and rare discontinuations. Conclusions: Metronomic R-DEVEC-light is a feasible and effective disease-controlling strategy for frail, heavily pretreated rrFL patients who do not tolerate lenalidomide and are excluded from modern therapies. This schedule warrants further prospective evaluation and exploration in combination with targeted agents. Full article

Triple Negative Breast Cancers (TNBCs) are heterogeneous and aggressive tumors with a median overall survival of less than two years. Despite the availability of new drugs, the prognosis remains poor, implicating a more aggressive clinical course in the metastatic setting. This study investigated the effects of metronomic treatment (mCHT) with 5-fluorouracil (5-FU) plus vinorelbine (VNR) on spheroids derived from two different TNBC cell lines (BT-549 and MDA-MB-231) and a patient-derived primary cell line (MS-186). mCHT significantly reduced spheroid growth and altered spheroid architecture, with a pronounced effect in second-generation spheroids, enriched in self-renewing cancer stem cells (CSCs). Expression of CSC-related markers (CD44, CD133, NOTCH-1, and MYC) was more significantly altered—both at the mRNA and protein levels—by mCHT than by standard treatment (STD). In MS-186-derived spheroids, mCHT downregulated EZH2 and STAT3, key regulators of CSC maintenance, and reduced H3K27ac, suggesting a global epigenetic reprogramming. Unlike STD, which partially and transiently reduced stemness markers, mCHT achieved sustained suppression, indicating preferential targeting of therapy-resistant CSCs. These results indicate mCHT as a promising strategy for specifically aiming at the CSC-like compartment in TNBC, underscoring a therapeutic approach that reprograms key epigenetic networks and overcomes resistance to treatment. Full article

This retrospective case series describes 21 dogs with stage II splenic haemangiosarcoma (HSA) and spontaneous haemoabdomen treated with splenectomy followed by a doxorubicin–cyclophosphamide protocol. Median overall survival was 92 days, with longer survival observed in dogs completing three or more chemotherapy cycles. The regimen was well tolerated, with low haematological and gastrointestinal toxicity. Maintenance metronomic chemotherapy was administered in a small subset, and it was associated with prolonged survival. While the sample size is modest, the homogeneous and clinically specific cohort provides hypothesis-generating observations on feasibility, tolerability, and time-aware associations that warrant cautious interpretation and prospective confirmation. No clinical or laboratory variable at diagnosis was independently associated with outcome. While limited by retrospective design and small sample size, this study provides focused data on a specific clinical presentation and supports the feasibility of structured adjuvant treatment in dogs with splenic HSA and haemoabdomen. Full article

Background: Heart rate variability (HRV) is a well-established marker of autonomic nervous system (ANS) activity. It is also an important tool for investigating cardiovascular and neurological health. Changes in HRV have been associated with epilepsy and sudden unexpected death in epilepsy (SUDEP), conditions in which autonomic dysregulation is believed to play a significant role. HRV is traditionally measured using electrocardiography (ECG) under standardized laboratory conditions. Recently, however, wearable devices such as the Empatica E4 wristband have emerged as promising tools for continuous, noninvasive HRV monitoring in real-life, ambulatory, and clinical settings where laboratory infrastructure may be lacking. Methods: We evaluated the validity and clinical utility of the Empatica E4 wristband in two cohorts. In the first cohort of healthy controls (n = 29), we compared HRV measures obtained with the E4 against those obtained with a gold-standard laboratory ECG device under seated rest and metronomic breathing conditions. In persons with epilepsy (PWE, n = 42), we assessed HRV across wake and sleep states, as well as during exposure to sodium channel blockers. This was done to determine whether the device could detect physiologically and clinically meaningful changes in autonomic nervous system (ANS) function. Results: In healthy participants, the Empatica E4 provided heart rate (HR), root mean square of successive R-R intervals (RMSSD), and standard deviation of all interbeat intervals (SDNN) values that were strongly correlated with laboratory measurements. Both devices detected the expected increase in RMSSD during metronomic breathing; however, the E4 consistently reported higher absolute values than the ECG. In patients with epilepsy (PWE), the E4 reliably captured parasympathetic activation during sleep and detected a significant reduction in heart rate variability (HRV) in patients taking sodium channel blockers, demonstrating its sensitivity to clinically relevant autonomic changes. Conclusions: The Empatica E4 wristband is valid for measuring HRV in research and clinical contexts. It can detect modulations of ANS activity that are physiologically meaningful. While HRV metrics were robust, other signals, such as electrodermal activity and temperature, were less reliable. These results highlight the potential of wearable devices as practical alternatives to laboratory-based autonomic testing, especially in emergency and resource-limited settings, and emphasize their importance in epilepsy care risk assessment. Full article

Metronomic chemotherapy (MC) represents an emerging strategy in veterinary oncology which involves the continuous or regularly scheduled administration of low-dose chemotherapeutic agents. Unlike conventional protocols known as maximum tolerated dose chemotherapy (MTDC), MC aims to inhibit tumor angiogenesis, stimulate antitumor immune responses, and delay or prevent the emergence of drug resistance. This review is structured into three key sections: the mechanisms of action of MC; its clinical indications in dogs and cats, particularly for advanced or treatment-resistant cancers; and reported outcomes regarding efficacy, safety, and tolerability. Additionally, we explore the growing interest in combining MC with other therapies, as well as the challenges and future directions for optimizing its use. Current evidence suggests that MC is a promising and well-tolerated option for managing various malignancies—such as carcinomas, sarcomas, and hemangiosarcomas—especially in patients who are not candidates for MTDC. Full article

Background/Objectives: We aimed to test whether home-based low-intensity interval training (LIIT) could be equally or more effective than traditional continuous walking advice (TWA) in a population hospitalized and healed from severe COVID-19. Methods: This pragmatic nonrandomized controlled trial (NCT04615390) enrolled patients admitted to intensive care units due to COVID-19 who at discharge from the hospital were given a choice between either a home-based LIIT program or TWA. The former received a structured LIIT walking (1:1 walk:rest ratio per 10 times) to be performed at a prescribed progressively increasing speed maintained with a metronome. The latter received TWA according to the guidelines (30 min or moderate intensity activity, 5 days/week). Outcome measures, collected at baseline, at the end of the 3-month training and at the 6-month follow-up, included 6 min walking distance (primary), lower limb strength, quality of life, depression and cognitive status. Results: From a total of 85 enrolled patients, 69 of them (LIIT n = 32; TWA n = 37) completed the study. Home exercise was safely executed with an 82% adherence for the LIIT group and 64% adherence for TWA. After the 3-month program, both groups significantly improved the 6MWD (LIIT: +87 m vs. TWA +42 m; p < 0.001) with a significant difference that was also maintained at follow-up (LIIT: +138 m vs. TWA +69 m; p < 0.001). No other significant between-group differences were noted. However, patients in the LIIT group significantly improved in the majority of the outcomes, while patients of TWA improved in only the primary outcome and the physical component of quality of life. Conclusions: Compared with TWA, LIIT walking was feasible, safe and associated with more favorable multidimensional recovery in COVID-19 survivors after hospitalization for severe pneumonitis. Full article

Compound T1089—a novel nitrogen mustard based on an indole-3-carboxylic acid derivative (ICAD)—has been synthesized. The ICAD used as the basis for T1089 is a TLR agonist capable of activating an antitumor immune response. This study describes the synthesis method and presents the results of preliminary investigations of this compound. This research included an assessment of acute toxicity in mice, in vivo clastogenic activity evaluated via the bone marrow chromosome aberration (BMCA) test in mice, in vitro cytotoxicity determined by the MTT assay against human lung carcinoma A549 cells, and in vivo antitumor effects (ATEs) in models of conventional chemotherapy (CCT) of solid tumors in mice. The bifunctional alkylating agent cyclophosphamide (CPA) was used as a reference drug. Toxicological studies revealed that T1089 belongs to toxicity class III (moderately toxic), with acute toxicity values (LD₁₆ and LD₅₀) in mice following intraperitoneal (i.p.) administration being 191 and 202 mg/kg, respectively. The alkylating activity and clastogenic potential of T1089 were demonstrated by its effects in the BMCA test, which were comparable to those of CPA. A single i.p. administration of CPA and T1089 at a dose of 0.064 mmol/kg induced similar stimulation of structural mutagenesis associated with DNA strand breaks. The frequency of karyocytes with aberrations increased 20-fold compared to the control, primarily due to a rise in chromatid breaks and fragments, and to a lesser extent, due to an increase in exchange-type aberrations. In vitro cytotoxicity studies indicated differences in the mechanisms of alkylating activity between CPA and T1089. According to the MTT assay, the cytotoxic effects of CPA were observed only at concentrations exceeding 2 mM (IC₅₀ = 4.2 ± 0.3 mM), corresponding to lethal in vivo doses, which is expected since the formation of CPA’s alkylating metabolite requires hepatic microsomal enzymes. In contrast, significant cytotoxic effects of T1089 were observed at much lower concentrations (15–50 μM, IC₅₀ = 33.4 ± 1.3 μM), corresponding to safe in vivo doses. Differences were also observed in the in vivo ATEs of CPA and T1089 in the Ehrlich solid carcinoma (ESC) CCT model. Following seven i.p. administrations at 48 h intervals (33 mg/kg), both compounds exhibited increasing toxicity, manifested as cumulative body weight loss in treated mice. However, despite the aggressive CCT regimen, ESC showed low sensitivity to CPA. The ATE of CPA developed slowly, reaching a significant level only after four injections, and even after seven administrations, tumor inhibition (TI) did not exceed 30%. In contrast, ESC was significantly more sensitive to T1089 under the same CCT conditions. The ATE of T1089 exhibited a cumulative pattern but developed more rapidly and to a greater extent. A significant antitumor effect was observed after just two injections, with maximal efficacy (TI = 53%) achieved after four injections and sustained until the end of the observation period. A high ATE of T1089 was also observed in the B-16 melanoma CCT model. Following six i.p. administrations at 48 h intervals (28 mg/kg), T1089 treatment was associated with minimal toxicity. Despite this mild CCT regimen, melanoma exhibited high sensitivity to T1089. Maximal ATE (TI = 56%) was achieved after two injections, and subsequent administrations maintained a consistently high efficacy (TI = 52–55%) until the end of the study. In summary, preliminary findings demonstrate that T1089 possesses alkylating activity characteristic of bifunctional agents, accompanied by high in vitro cytotoxicity and in vivo ATEs in CCT models (at high doses). Given that the ICAD used as the basis for T1089 is a TLR agonist capable of stimulating antitumor immunity, T1089 can be considered a dual-action alkylating agent with combined antitumor effects. These results justify further investigation of T1089 in conventional and metronomic chemotherapy regimens, particularly in combination with immune checkpoint inhibitors and antitumor vaccines. Full article

Neuroblastoma (NB) is an aggressive pediatric cancer, with high-risk patients facing a five-year survival rate of ~50%. Standard therapies, including surgery, chemotherapy, radiation, and immunotherapy, are associated with significant long-term toxicities and frequent relapse. Histone deacetylase (HDAC) inhibitors have emerged as promising agents for cancer therapy, given their role in modulating gene expression and tumor phenotypes. This study evaluated M344 [4-(dimethylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide], an HDAC inhibitor, for its efficacy and mechanisms of action against NB. Analysis of clinical NB Gene Expression Omnibus data revealed advanced-stage tumors exhibit higher HDAC expression relative to early-stage samples. M344 treatment effectively increased histone acetylation, induced G0/G1 cell cycle arrest, and activated caspase-mediated cell death. Relative to vorinostat, an HDAC inhibitor in clinical use for lymphoma and clinical trials for NB, M344 displayed superior cytostatic, cytotoxic, and migration-inhibitory effects. In vivo, metronomic M344 dosing suppressed tumor growth and extended survival. Combination therapy with M344 and topotecan improved topotecan tolerability, while M344 co-administration with cyclophosphamide reduced tumor rebound post-therapy. In total, M344 demonstrated strong therapeutic potential for NB, offering improved tumor suppression, reduced off-target toxicities, and enhanced control of tumor growth post-therapy. These findings support further investigation of HDAC inhibitors, such as M344, for clinical application in NB treatment. Full article

We investigated synchronization behavior using an experimental setup consisting of two metronomes placed on a platform floating over water. By setting the metronomes to oscillate perpendicular to the line between them, we observed three distinct modes of movement: in-phase synchronization, anti-phase synchronization, and synchronization with a fixed phase difference. While this last mode resembles phase-locking, it is important to distinguish that phase-locking typically refers to an oscillator’s response to external pacing, whereas the fixed phase difference observed in our study emerges from the mutual interaction between two metronomes. The frequencies of oscillations, and the placement of the metronomes are also changed to check the reliability of the new phenomenon. Even if we changed the material of the platform to a heavier one or turned around one of the metronomes, synchronization with a fixed time delay still was still observed. Drawing on previous research, we developed mathematical equations to model the coupled metronomes and performed numerical simulations that successfully reproduced all three observed phenomena. The simulation results showed excellent agreement with our experimental observations. These findings contribute to our understanding of coupled oscillators and may have potential applications in various fields. Full article

Background. Parkinson’s Disease (PD) is a neurological condition that can severely impair gait, often through changes to gait parameters including stride length, velocity, and variability. Therapeutic interventions such as Rhythmic Auditory Stimulation (RAS^®) target gait dysfunction in PD by using the regular beat of music or metronome clips to cue normalized walking patterns. Previous research has suggested that auditory cue properties (e.g., familiarity and groove) and individual factors (e.g., beat perception ability and susceptibility to dual-task interference) influence auditory cueing treatment efficacy in healthy young and older adults; however, optimization of rhythmic cueing across individuals with PD remains understudied. Methods. To address this, we explored the effects of familiarity, groove, beat perception ability, and synchronization instructions on gait in patients with PD during accelerated auditory cues. Individuals with idiopathic PD were randomized to walk freely or synchronized to music and metronome cues played 10% faster than their baseline walking cadence. Musical stimuli varied in self-reported familiarity and perceived groove and beat perception ability was assessed to classify participants as good or poor beat perceivers. Results. Overall, high-groove music and synchronized walking elicited faster gait patterns compared to low-groove music and free walking, respectively, as demonstrated by increased gait velocity and cadence. Familiarity and beat perception ability did not significantly affect gait in individuals with PD. Discussion. Altogether, our results indicate that high-groove music and synchronized walking lead to the greatest gait improvements during cueing, regardless of beat perception ability. Conclusion. Future studies and clinical interventions should consider stimulus type and synchronization instructions when implementing cueing therapies for gait dysfunction in PD in order to optimize treatment responses. Full article

This paper reports the first case in which a hyperlipidemic retriever (due to hypothyroidism) with a nasal tumor was successfully treated—achieving partial remission—and managed using a metronomic combination of chlorambucil (3.74 mg/m², SID) and prednisolone (0.28 mg/kg, SID) orally for 9 months at a general practice. A 35 kg spayed female golden retriever aged 8 years and 8 months with nosebleeds visited the Bundang New York Animal Hospital in July 2023 after being diagnosed with nasal carcinoma. A protocol of 4 weeks of chemotherapy followed by 1 week of rest was repeated in two cycles and continued metronomically for 9 months without pause after the two cycles. The nasal exudate was significantly reduced. The size of the nasal tumor was monitored using computed tomography (CT) imaging at a referral hospital. Since the first occurrence of epistaxis, 18 months have passed (as of January 2025) and the nasal exudate is barely visible, and the vital signs and weight of the dog remain stable. The size of the nasal tumor significantly decreased after 9 months of chemotherapy completion without moderate side effects, and all the blood work was normalized, including hypercholesteremia. This study demonstrates that, in hyperlipidemic cancer patients, a prednisolone/chlorambucil metronomic combination which is cost-effective can be an alternative to tyrosine kinase inhibitors such as sorafenib, even when excluding the price. Through a literature review, the author also investigates the effect of the hyperlipidemic state on cancer, focusing on carcinoma and vascular endothelial growth factor (VEGF), as well as the RAS-RAF-MEK pathway, which is a target for tyrosine kinase inhibitors, in order to reveal the molecular mechanism of chlorambucil metronomic chemotherapy. Also, the author investigates the molecular pathway of carcinoma development in human hyperlipidemia patients through single-cell RNA sequence analysis using open public data, and discusses the molecular action of chlorambucil. Full article

Cyclophosphamide (CPX) is an alkylating agent commonly used for various hematological and solid malignancies. In addition to its use as a cytotoxic agent to directly kill tumor cells, numerous immunomodulatory properties of CPX in the tumor microenvironment (TME) of several cancer types have also been documented. These properties include the selective depletion of immune-suppressive regulatory T cells (Tregs), triggering of immunogenic cell death (ICD) and enhanced antigen presentation, and release of type I interferons (IFNs). Moreover, preclinical models as well as human clinical trials have investigated the efficacy of the low-dose “metronomic” scheduling of CPX in combination with immunotherapies such as immune checkpoint inhibitors, dendritic cell tumor vaccines, and tumor antigen peptide vaccines. The metronomic dosing schedule involves administering a continuous (or frequent, such as daily) low dose of chemotherapy rather than using the canonical approach of administering the maximum tolerated dose. Despite the approval of immune checkpoint inhibitors for clinical usage against an increasing number of cancers, many malignancies simply do not respond to checkpoint inhibition, in part due to the heterogeneous intratumoral network of immune-suppressive cell populations. The immunomodulatory effects of cyclophosphamide have strong translational applicability and could serve to enhance and bolster anti-tumor immunity, potentially synergizing with immune checkpoint inhibitors and other existing immunotherapy agents. Full article

Background/Objectives: This study aimed to enhance the oral delivery and therapeutic synergy of atorvastatin (AT) and docetaxel (DT) through a metronomic schedule using a transporter-targeted nanoemulsion (NE), with the goal of improving antitumor efficacy and immune modulation. Methods: AT and DT were co-encapsulated in a NE system (AT/DT-NE#E) incorporating deoxycholic acid–DOTAP (D-TAP), biotin-conjugated phospholipid (Biotin-PE), and d-α-tocopherol polyethylene glycol succinate (TPGS) to exploit bile acid and multivitamin transport pathways and inhibit P-glycoprotein efflux. The optimized NE was characterized physicochemically and evaluated for permeability in artificial membranes and Caco-2/HT29-MTX-E12 monolayers. Pharmacokinetics, tumor suppression, and immune cell infiltration were assessed in vivo using rat and CT26.CL25 mouse models. Results: AT/DT-NE#E showed enhanced permeability of AT and DT by 45.7- and 43.1-fold, respectively, across intestinal cell models and improved oral bioavailability by 118% and 376% compared to free drugs. In vivo, oral metronomic AT/DT-NE#E reduced tumor volume by 65.2%, outperforming intravenous AT/DT. Combination with anti-PD1 therapy achieved a 942% increase in tumor suppression over the control, accompanied by marked increases in tumor-infiltrating CD45⁺, CD4⁺CD3⁺, and CD8⁺CD3⁺ T cells. Conclusions: Oral metronomic administration of AT/DT via a dual-transporter-targeted NE significantly improves drug absorption, tumor inhibition, and immune response. This strategy presents a safe and effective approach for colon cancer therapy, particularly when combined with immunotherapy. Full article

Hepatic sarcomas are rare and aggressive tumors in veterinary medicine, with limited reports in the literature. This case report describes a canine hepatic myofibroblastic sarcoma in a 5-year-old spayed female Dobermann. The dog presented with abdominal enlargement and was diagnosed with a large hepatic mass following comprehensive diagnostic evaluations, including blood tests, imaging, and histopathology. Histological and immunohistochemical analyses confirmed the tumor’s myofibroblastic origin, characterized by positivity for markers such as vimentin, glial fibrillary acidic protein (GFAP), nerve growth factor receptor (NGFR), alpha-smooth muscle actin (SMA), and muscular actin (HHF35). Treatment involved a combination of intense-dose chemotherapy using doxorubicin and a subsequent metronomic chemotherapy protocol, which resulted in prolonged survival of over 690 days at the time this manuscript was written. This case highlights the importance of extensive diagnostic and immunohistochemical profiling in the accurate classification of and treatment planning for hepatic sarcomas, and emphasizes the role of advanced veterinary diagnostics in improving patient outcomes. Future studies with larger sample sizes are needed to enhance understanding of the biological behavior and optimal therapeutic strategies for such rare tumors. Full article

Background: Gait disturbance in Parkinson’s Disease (PD) significantly impacts quality of life and is not completely mitigated by dopaminergic treatment. Auditory cueing has been shown to help improve certain aspects of gait, but its effects when matched to individuals’ preferred walking rate remain unexplored. Methods: Nine individuals with PD walked at their preferred rate across a GAITRite^® mat under three separate conditions: self-paced, metronome-cued, and music-cued. Spatiotemporal gait measures were collected and analyzed using repeated measures ANOVAs and post-hoc paired-samples t-tests. Results: A main effect of condition was revealed for step width (F = 3.533, p = 0.054, η_p² = 0.306), with reduced step width revealed during the music-cued condition. Post-hoc analysis revealed no significance (p > 0.063). Conclusions: The trend in step width data suggests a potential benefit of music cueing for enhancing gait stability in persons with PD. Results of this pilot study provide valuable framework for future research and the development of therapeutic interventions to enhance gait stability, reduce fall risk, and improve overall quality of life. Full article