Long-term Therapeutic Effects Research Articles

Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia.

Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.

A real-world experience of venetoclax combined with hypomethylating agents vs. monotherapy hypomethylating agents in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia patients.

Current clinical research has reported the effectiveness and safety of venetoclax in combination with hypomethylating agents (VEN-HMA) in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Thus, this study aimed to examine the effectiveness and safety of VEN-HMA therapy in patients with MDS and CMML and compared its short-term and long-term therapeutic effects with HMA monotherapy. We analyzed data from our center, comprising 19 patients with MDS and CMML who received VEN-HMA therapy, compared to 32 patients treated with HMA monotherapy. The overall response rate (ORR) in the VEN-HMA group was 73.7%, compared to 59.4% in the HMA group. The survival analysis revealed that the median overall survival (mOS) time in the VEN-HMA group was 16 months, with a median progression-free survival (mPFS) time of 9 months, both of which were longer than those observed in the HMA group (p < 0.05). Key adverse events (AEs) included grade 3-4 neutropenia (89.5% in VEN-HMA group vs. 87.5% in HMA group), grade 3-4 thrombocytopenia (73.7% vs. 71.9%), and anemia (73.7% vs. 90.6%). Infection of grade 3 or higher occurred in 63.2% of patients in the VEN-HMA group and 65.6% of patients in the HMA group. Our study has confirmed the effectiveness and safety of the combined treatment of HMAs and venetoclax, which offers significant advantages to patients due to the relatively high and rapid response rates.

Comparison of Long-Term Outcomes of Surgical Treatment of Human Papillomavirus-Dependent Neoplastic Lesions in Patients With Chronic Immunosuppression After Allogenic Organ Transplantation and Patients With Primary or Acquired Immunodeficiency—A One-Center Experience

Immunodeficiency predisposes to severe manifestations of human papillomavirus (HPV) infection, including extensive, recalcitrant anogenital lesions and their progression towards carcinomas. This holds for primary and acquired immunodeficiencies, and post-transplant immunosuppressive therapy. About 50% to 90% of patients receiving chronic immunosuppression after allogenic transplantation develop HPV-associated lesions within 4 to 5 years, comprising 10% to 15% of patients presenting with (pre)cancerous HPV-dependent anogenital lesions. Immunodeficiency is one of the highest risk factors associated with severe clinical manifestations of HPV-associated cancers. The primary objective of this work is to compare the long-term therapeutic effectiveness of surgical intervention for HPV-dependent lesions in transplant recipients undergoing chronic immunosuppression and patients burdened with primary or acquired immunodeficiencies. Two groups of 30 patients (selected for most extensive presentations of HPV-dependent neoplastic anogenital lesions), who underwent surgical treatment of these lesions were followed up for 3 to 5 years. The first group comprised patients who qualified and underwent kidney or liver transplantation (10 for a rare disease indication) and are under chronic immunosuppressive regimens. The second group comprised patients burdened by primary or acquired immunodeficiency (15 each). The recurrence rate in the follow-up period was the primary compared parameter. The recurrence rate was higher in the second group, amounting to >15%. For the first group a <5% recurrence rate was observed for recipients without rare disease indications, compared to <15% for recipients with such indications. The importance of rapid surgical intervention and the need for postoperative monitoring for recurrence is highlighted. Chronic immunosuppression demonstrates high relative safety and efficacy in terms of HPV-dependent anogenital lesion recurrence.

Total eosinophil count as a biomarker for therapeutic effects of upadacitinib in atopic dermatitis over 48 weeks.

Atopic dermatitis (AD) is a chronic skin disease characterized by type 2-skewed immune responses, and significantly influenced by cytokines dependent on Janus kinases (JAKs). Upadacitinib, a JAK1 inhibitor, is effective for moderate-to-severe AD. This study aims to identify biomarkers that reflect long-term therapeutic effects of upadacitinib 15 mg or 30 mg. A retrospective study from August 2021 to July 2023 included 213 AD patients treated with upadacitinib 15 mg and 70 AD patients with 30 mg. We analyzed eczema area and severity index (EASI), peak pruritus-numerical rating scale (PP-NRS), serum immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), and total eosinophil count (TEC) at weeks 0, 4, 12, 24, 36, and 48 of treatment. Both treatments with upadacitinib 15 mg and 30 mg significantly reduced EASI and PP-NRS scores over week 4 to 48 compared to baseline. Upadacitinib 15 mg or 30 mg treatment significantly decreased TEC compared to baseline through week 4 to 36 or week 4 to 48, respectively. The percent reduction of TEC correlated with those of EASI and PP-NRS through week 4 to 48 of treatment with upadacitinib 15 mg, or through week 12 to 48 with 30 mg, respectively. After adjusting for % reductions of other laboratory markers, the significance of correlations was preserved at weeks 36 and 48 of 15 mg treatment, while at weeks 4 and 36 of 30 mg treatment. The % reduction of TEC correlated with those of EASI and PP-NRS during upadacitinib treatment, indicating its potential as a biomarker reflecting treatment responses to upadacitinib in AD patients. However, the variability of significant correlation during treatment indicates that further inspection is needed for its usefulness in monitoring responses to upadacitinib treatment for AD.

Comparison studies identify mesenchymal stromal cells with potent regenerative activity in osteoarthritis treatment

Osteoarthritis affects 15% of people over 65 years of age. It is characterized by articular cartilage degradation and inflammation, leading to joint pain and disability. Osteoarthritis is incurable and the patients may eventually need joint replacement. An emerging treatment is mesenchymal stromal cells (MSCs), with over two hundred clinical trials being registered. However, the outcomes of these trials have fallen short of the expectation, due to heterogeneity of MSCs and uncertain mechanisms of action. It is generally believed that MSCs exert their function mainly by secreting immunomodulatory and trophic factors. Here we used knee osteoarthritis mouse model to assess the therapeutic effects of MSCs isolated from the white adipose or dermal adipose tissue of Prrx1-Cre; R26tdTomato mice and Dermo1-Cre; R26tdTomato mice. We found that the Prrx1-lineage MSCs from the white adipose tissues showed the greatest in vitro differentiation potentials among the four MSC groups and single cell profiling showed that the Prrx1-lineage MSCs contained more stem cells than the Dermo1 counterpart. Only the Prrx1-lineage cells isolated from white adipose tissues showed long-term therapeutic effectiveness on early-stage osteoarthritis models. Mechanistically, Prrx1-lineage MSCs differentiated into Col2+ chondrocytes and replaced the damage cartilage, activated Col1 expressing in resident chondrocytes, and inhibited synovial inflammation. Transcriptome analysis showed that the articular chondrocytes derived from injected MSCs expressed immunomodulatory cytokines, trophic factors, and chondrocyte-specific genes. Our study identified a MSC population genetically marked by Prrx1 that has great multipotentiality and can differentiate into chondrocytes to replace the damaged cartilage.

CAR T therapy from haematological malignancies to aging-related diseases: An ever-expanding universe.

Short but impactful, the two-decade story of gene editing allowed a significant breakthrough in the treatment of haematological malignancies. However, despite different generations of chimeric antigen receptor T (CAR T), such a successful therapy has not yet been replicated in solid tumours and non-oncological diseases. This narrative review discusses how CAR T therapy still faces challenges in overcoming the complexity of the solid tumour microenvironment and the concerns that its long-term activity raises about potential unknown and unpredictable consequences in non-oncological diseases. In the most recent studies, the senolytic potential of CAR T is becoming an exciting field of research. Still, experimental but promising results indeed indicate the clearance of senescent cells as an effective strategy to improve exercise capacity and metabolic dysfunction in physiological ageing, with long-term therapeutic and preventive effects. However, an effective expansion of a CAR T population requires a lympho-depleting chemotherapy prior to infusion. While this procedure sounds reasonable for rescue therapy of oncological diseases, it poses genotoxic risks that may not be justified for non-malignant diseases. Those represent the leading gaps for applying CAR T therapy in non-oncological diseases. More is expected from current studies on the other classes of CAR cells now under investigation. Engineering NK cells and macrophages are candidates to improve cytotoxic and immunomodulating properties, potentially able to broaden application in solid tumours and non-oncological diseases. Finally, engineering autologous T cells in old individuals may generate biologically deteriorated CAR T clones with impaired function and unpredictable effects on cytokine release.

Abstract 5908: Angiosarcoma growth inhibition by targeting Doppel, a specific endothelial marker, with an antibody drug conjugate

Abstract Rare cancers are defined as cancers with an annual incidence rate lower than 15/100,000 by the National Cancer Institute. Despite what the terminology may suggest, rare cancers collectively are neither very rare, accounting for about a quarter of all cancers, nor less deadly than other forms of cancer. In fact, the comparative lack of research and case studies of rare cancers compared to other forms of cancer provides both an obstacle and a unique opportunity when it comes to drug development. While finding adequate animal models and cell lines to study the disease may be more difficult, the development of innovative treatment options for rare cancers is often incentivized by the Orphan Drug Act, accelerating approval from the FDA and acting as a gateway to approval for other indications. One such rare cancer is angiosarcoma, a rare cancer that originates from the endothelium. Angiosarcoma represents about 1% of total sarcomas and can develop anywhere in the body but occurs mainly in the breast, liver, or skin of the head and neck area. Angiosarcoma is characterized by a high metastasis rate of 16% to 44%, which results in a dismal prognosis, with overall survival ranging from 6 to 16 months. Considering the high reoccurrence rate and high metastatic potential of angiosarcoma, chemotherapeutic options seem to be the obvious choice. However, mainstream chemotherapies have failed to have long-term therapeutic effects. Another approach is the use of anti-angiogenic therapy, which proved effective but was unable to lead to a complete response. Herein, we describe a novel endothelial cell-targeting therapy option for the treatment of angiosarcoma. Previously, we have discovered Doppel, a 23 kDa GPI-anchored protein that is expressed specifically in the endothelium of tumor-associated blood vessels, except for the testis. Considering the fact that angiosarcoma is a rapidly growing tumor of endothelial origin, we hypothesized that Doppel might be a viable target for both the detection and treatment of angiosarcoma. We subsequently developed an antibody-drug conjugate to Doppel by conjugating a human antibody to MMAE using a unique linker, KGDEVD. When tested on xenografts of the angiosarcoma cell lines KU-CAS3 and KU-CAS5, the tumors responded extremely well to anti-Doppel ADC treatment. Most surprisingly, even tumors exceeding 1 cm^3 went into complete remission after 6 doses of the ADC. Thus, we delved deeper into the mechanism of action behind the ADC. ADC internalization was demonstrated using confocal microscopy. Apoptosis assays show that the ADC is capable of inducing apoptosis and caspase 3 expression in angiosarcoma cells, a crucial step in the activation of the KGDEVD linker. In-vitro toxicity assays of the ADC against KU-CAS3 show an IC50 value of 7.94 nM, much lower compared to normal endothelial cell lines. Citation Format: Byoungmo Kim, Ha Kyeong Lee, Youngro Byun, Yoon Gun Ko, Sang Yoon Kim. Angiosarcoma growth inhibition by targeting Doppel, a specific endothelial marker, with an antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5908.

Critical Points of Vitamin C Production and Long-Acting Pharmaceutical Preparations

Vitamin C offers numerous benefits, including its role in the immune system. This factor necessitates the intake of exogenous vitamin C since the human body cannot synthesize it endogenously. Long-acting drugs are known for providing long-term therapeutic effects. The halal and haram aspects of Islam are of great importance due to the potential doubt or syubhat between the two. There are different methods for producing vitamin C, such as Reichstein's method or classical two-step fermentation. In general, vitamin C synthesis involves biotransformation by microorganisms. One approach to creating long-acting preparations is coating them with gelatin. A product's halal or haram status is determined by its raw materials, additives, and manufacturing process. Vitamin C production typically involves fermentation using microorganisms, so a halal growth medium must be considered. Long-acting vitamin C preparations that use gelatin should also be evaluated regarding their halal status. If the gelatin comes from halal animals, the law depends on the production process. However, if the gelatin comes from haram animals, the law is haram.

Long-term treatment with Perampanel of Chinese patients with focal-onset seizures, especially in sleep-related epilepsy: a prospective real-world observational study.

There is currently a lack of studies examining the long-term therapeutic effectiveness of the third-generation anti-sezure medication, perampanel (PER), for focal-onset seizures (FOS), particularly in Chinese patients with sleep-related epilepsy (SRE). Additionally, the appropriate dosage, plasma concentration, and the relationship between dose and plasma concentration of PER in Chinese patients are still uncertain. A prospective, single-center, 24-month observational study was conducted in patients diagnosed with FOS, with a focus on patients with SRE. Changes in seizure frequency from baseline, adverse events, and retention rates were analyzed at 12 and 24 months following the start of the treatment. Tolerability was evaluated based on adverse events and discontinuation profiles. PER plasma concentrations were used to assess dose-concentration-response relationships. A total of 175 patients were included (median age: 25 years; range: 4-72 years; 53. 1% males and 46.9% females), with the SRE population accounting for 49. 1% (n = 86). The patients diagnosed with SRE showed considerably higher response rates than those who did not have this diagnosis (p = 0.025, odds ratio = 3.8). Additionally, the SRE group adhered better to PER treatment (r = 0.0009). Patients with a shorter duration of epilepsy (median: 3 years; range:2-7 years) demonstrated a more favorable therapeutic response to PER (p = 0.032). Throughout the administration of maintenance doses, among the entire FOS population, the concentration of PER (C0) ranged between 101.5 and 917.4 ng/mL (median, 232.0 ng/mL), and the mean plasma concentration of PER in the responders was 292.8 ng/mL. We revealed a linear relationship between PER dose and plasma concentration, regardless of whether PER was used as monotherapy or add-on therapy. The retention rates were 77.7% and 65. 1% at 12 and 24 months, respectively. Drug-related adverse events occurred in 45.0% of the patients and were mostly manageable. PER effectively reduced seizure frequency in Chinese patients with FOS, particularly in those with SRE, over a 24-month period. The treatment was well-tolerated and had a clear linear dose-plasma concentration relationship.

Clinical and Radiological Outcomes After Combined ACL and MPFL Reconstruction Versus Isolated ACL Reconstruction for ACL Injury With Patellar Instability

Background: An anterior cruciate ligament (ACL) injury accompanied by patellar instability (PI) is a topic that has gained orthopaedic surgeons’ attention recently. Untreated PI is reportedly associated with worse clinical outcomes after isolated ACL reconstruction (ACLR) in patients after an ACL injury with PI. Nevertheless, the appropriate surgical approach and its long-term therapeutic effects in these patients remain unclear. Purpose: (1) To compare the clinical and radiological outcomes between isolated ACLR (iACLR) and combined ACLR and medial patellofemoral ligament reconstruction (cAMR) in patients after an ACL injury with PI and (2) to explore the correlations between these 2 procedures and clinical and radiological outcomes. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 106 patients diagnosed with an ACL injury accompanied by PI between January 2016 and April 2021 were analyzed in this study. There were 34 patients excluded because of missing postoperative radiological data. Among the remaining 72 patients, 34 patients underwent iACLR, while 38 patients underwent cAMR. Demographic characteristics, intraoperative findings, and patient-reported outcomes (Lysholm score, subjective International Knee Documentation Committee score, and Tegner activity score) were prospectively collected. Patellar alignment parameters and worsening patellofemoral osteoarthritis (PFOA) features (evaluated with the modified Whole-Organ Magnetic Resonance Imaging Score) were analyzed longitudinally on magnetic resonance imaging. The Kujala score was used to evaluate the functional recovery of the patellofemoral joint, and redislocations of the patella were prospectively recorded. Finally, multivariate logistic regression analysis was used to explore the correlations between these 2 procedures and clinical (not achieving the minimal detectable change [MDC] for the Lysholm score) and radiological (worsening PFOA features) outcomes. Results: The mean follow-up duration was 28.9 ± 6.2 and 27.1 ± 6.8 months for the iACLR and cAMR groups, respectively (P = .231). Significantly higher Lysholm scores (88.3 ± 9.9 vs 82.1 ± 11.1, respectively; P = .016) and subjective International Knee Documentation Committee scores (83.6 ± 11.9 vs 78.3 ± 10.2, respectively; P = .046) were detected in the cAMR group compared with the iACLR group postoperatively. The rates of return to preinjury sports were 20.6% and 44.7% in the iACLR and cAMR groups, respectively (difference, 24.1% [95% CI, 3.3%-45.0%]; P = .030). Moreover, the rates of worsening PFOA features were 44.1% and 18.4% in the iACLR and cAMR groups, respectively (difference, 25.7% [95% CI, 4.9%-46.4%]; P = .018). In addition, significantly higher Kujala scores (87.9 ± 11.3 vs 80.1 ± 12.0, respectively; P = .006), lower redislocation rates (0.0% vs 11.8%, respectively; difference, 11.8% [95% CI, 0.9%-22.6%]; P = .045), and significantly better patellar alignment were detected in the cAMR group compared with the iACLR group postoperatively. Furthermore, multivariate logistic regression analysis determined that iACLR and partial lateral meniscectomy were significantly correlated with not achieving the MDC for the Lysholm score and worsening PFOA features in our study population. Conclusion: In patients after an ACL injury with PI, cAMR yielded better clinical and radiological outcomes compared with iACLR, with better patellar stability and a lower proportion of worsening PFOA features. Furthermore, not achieving the MDC for the Lysholm score and worsening PFOA features were significantly correlated with iACLR and partial lateral meniscectomy. Our study suggests that cAMR may be a more appropriate procedure for patients after an ACL injury with PI, which warrants further high-level clinical evidence.

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

Evaluation of embedded modular branched stent graft in treating aortic arch aneurysm using imaging-based computational flow analysis

Embedded modular branched stent graft (EMBSG) was a new option for aortic arch aneurysm. However, the therapeutic effect of this innovative stenting technique has not been fully assessed. Computational fluid dynamics and three-dimensional structural analyses were performed on three patients (Patient I, Patient II and Patient III) with aortic arch aneurysm, both before and after EMBSG implantation. Patient-specific alterations from preoperative to postoperative were analyzed via morphological and functional metrics. Patient I and Patient II showed notable curvature changes and area reduction after intervention procedure. Three patients showed an increase in flow velocity after EMBSG implantation, while the pressure drop from ascending aorta to the aortic arch was remarkable in Patient I and Patient II with the value of 7.09 ​mmHg, and 10.95 ​mmHg, respectively. Patient I and Patient II also showed elevated time-averaged wall shear stress (TAWSS) in the stenting region, while Patient III showed a trivial change in TAWSS after intervention procedure. Three patients showed low relative residence time after EMBSG insertion. The short-term results of EMBSG in treating aortic arch aneurysm were promising. Hemodynamic parameters have the potential to assist in the outcome evaluation and might be used to guide the stent graft design and wise selection, thereby improving the long-term therapeutic effect in managing complex vascular disease.

Tandem peptide lipid CRISPR-Cas9 complex combating APP and APOE4 gene abnormality in Alzheimer's disease

Alzheimer's attacks 24 million global population and dominates 60-80% of existing cases of dementia. It causes the accumulation of beta-amyloid (Aβ) plaques in the hippocampus and entorhinal cortex, resulting in decreased mass from the brain. Recent studies have shown that the manifestation of this disease is due to an overaccumulation of abnormal Aβ protein due to abnormalities in the APP and APOE4 genes. Point mutations in the APP gene will create the toxic form of Aβ protein, namely Aβ42, and the toxic APOE4 gene will accelerate the onset of Aβ42 deposition and pro-inflammatory activity that exacerbates the degenerative process of the brain. Gene editing as a potential definitive therapy was recently a concern by researchers. CRISPR-Cas9 repairs the APP gene and substitutes the APOE4 gene with APOE3 by modifying the gene's DNA sequence. Nano complex CRISPR-Cas9 tandem peptide lipid is a model for clinicians to target brain nerve cells. In vivo research on an Alzheimer's mouse model proved the potential of nano-complex-based peptides as carriers of CRISPR-Cas9 in brain nerve cells. This engineering technology offers satisfactory results with high precision, minimal side effects, and a relatively low price for long-term therapeutic effects and even a lifetime.

Long-term effects of adenotonsillectomy in children with attention deficit hyperactivity disorder.

Adenotonsillectomy (AT) improves short-term symptoms of attention deficit hyperactivity disorder (ADHD) in children; however, its long-term effects remain unclear. We aimed to verify the therapeutic long-term effects of AT in children with ADHD. This retrospective control study included children ages < 18 years who were diagnosed with ADHD and receiving ADHD medications. Participants were divided into groups depending on whether AT was performed (AT [+] or AT [-] groups) and matched 1:1 for age, sex, and year and month of diagnosis using randomized nonreplacement selection. Among patients with ADHD (n = 171,112), 3,615 underwent AT. In both groups, the number of drugs taken gradually increased before and decreased after the AT date (ATD). There was no difference in the number of drugs used before (P = .88) and after ATD (P = .06). Before ATD, the average number of outpatient visits (nOV) did not change in both groups (AT [+]: P = .12; AT [-]: P = .71). After ATD, the average number of outpatient visits decreased only in the AT (+) group (P = .001). However, there was no difference in the average number of outpatient visits between the two groups before (P = .47) and after ATD (P = .17). Before ATD, methylphenidate doses between the groups were not different (P = .06); however, a significant increase was noted after ATD in the AT (+) group (P < .001). AT does not result in significant long-term therapeutic effects in terms of medication use and health care utilization in children with ADHD. Lee J, Choi A, Kim S, Kim K. Long-term effects of adenotonsillectomy in children with attention deficit hyperactivity disorder. J Clin Sleep Med. 2024;20(5):727-733.

Systemic immune-inflammation index predicts the clinical outcomes in patients with acute uncomplicated type-B aortic dissection undergoing optimal medical therapy

BackgroundOptimal medical therapy (OMT) for uncomplicated type B aortic dissection (uTBAD) provides excellent short-term outcomes during follow up; however, its long-term therapeutic effectiveness is unsatisfactory. This study evaluated the predictive value of systemic immune-inflammation index (SII) for adverse events among patients with acute uTBAD undergoing OMT.MethodsWe performed a retrospective analysis of a prospectively maintained database between 2013 and 2020. The primary end point in this study was composite outcomes including aortic intervention, all-cause mortality, retrograde type A aortic dissection (rTAAD) and aortic diameter growth > 5 mm. The patients were divided into high and low SII groups according to the optimal cut-off value of SII as determined using the receiver operating characteristic curve. Cox proportional hazards models were constructed to estimate the hazards ratios and identify the predictors of composite outcomes.ResultsA total of 124 patients with acute uTBAD who underwent OMT were enrolled. One patient died during hospitalisation. At the end of a mean follow-up duration of 51 ± 23 months, 53 (43.1%) patients experienced composite outcomes, 15 patients (12.2%) died, 31 (25.2%) underwent aortic intervention, 21 (17.1%) exhibited diameter growth of > 5 mm, and 2 developed rTAAD. The patients were divided into low SII group (n = 78, 62.9%) and high SII group (n = 46, 37.1%) as per the optimal cut-off SII value of 1449. The incidence of composite outcomes in high SII group was significantly higher than that in low SII (28 [60.9%] vs. 26[33.3%], p < 0.01). Patients with high SII demonstrated significantly higher mortality rate than those with a low SII (11 [23.9%] vs. 5 [6.4%], respectively; p < 0.01). In addition, the high SII group had significantly higher rate of aortic-related reinterventions than the low SII group (16 [34.8%] vs. 15 [19.2%], p = 0.03). Multivariable Cox analyses showed that a high SII score was independently associated with composite outcomes rate (hazard ratio, 2.15; 95% confidence interval, 1.22–3.78; p < 0.01).ConclusionsThe long-term therapeutic effectiveness of OMT alone in patients with acute uTBAD is unsatisfactory. An SII > 1449 at the time of diagnosis is an independent predictor of OMT failure.

Spinal Neuromodulation for Peripheral Arterial Disease of Lower Extremities: A Ten-Year Retrospective Analysis.

This long-term retrospective study evaluated the survival and amputation outcome of subjects who received neuromodulation therapy for the management of peripheral arterial disease (PAD). The study reviews the health data of a single cohort of 51 patients who received spinal neuromodulation (spinal cord stimulation [SCS] or dorsal root ganglion stimulation [DRG-S]) for PAD from 2007 to 2022 in a single German center. Survival rate and major amputation rate were determined. Pain, quality of life, walking distance, and opioid usage were assessed before implantation (baseline), one, six, and 12 months (M) after implantation, and then annually (during a follow-up visit). Implant-related complications also were documented. In total, 51 patients (37 men [mean age 68.9± 10.2 years], 14 women [mean age (68.7± 14.6 years]) underwent SCS (n= 49) or DRG-S (n= 2) implantation owing to persistent ischemic pain. The follow-up mean years± SD is 4.04± 2.73. At baseline, patients were classified as Rutherford's category 3 (n= 23), category 4 (n= 15) or category 5 (n= 9). At 24 M, 42 of 47 patients did not require a major amputation after the implant. All the patients reported nearly complete pain relief from pain at rest. A total of 75% of patients were able to walk >200 m, and 87% of patients who used opioids at baseline were off this medication at 24 M. Overall, 93% of patients reported an improvement in their overall health assessment. These improved outcomes were sustained through years three to 10 for patients who have reported outcomes. Our single-center data support the efficacy of spinal neuromodulation for improvements in limb salvage, pain relief, mobility, and quality of life. The data also show that neuromodulative therapy has a long-term therapeutic effect in patients with chronic limb pain with Rutherford category 3, 4, and 5 PAD.

Onabotulinum toxin a treatment for posttraumatic trigeminal neuropathic pain: case series and literature review

This case series aimed to assess the treatment outcomes of onabotulinum toxin A (BTX-A) in patients with refractory posttraumatic trigeminal neuropathic pain (PTNP) and to conduct a narrative review of the evidence for BTX-A in PTNP. Thirteen patients were treated with BTX-A infiltrations. Patient demographic and pain characteristics, BTX-A administration, and treatment outcomes were retrospectively analyzed. Papers retrieved after a literature search of articles on PTNP treatment using BTX-A were reviewed. Six patients reported an improvement in pain 3 months after the initial BTX-A injection, with 4 patients reporting a 50% reduction. Two patients achieved an 80% reduction in pain score over 3 years of BTX-A therapy. Three patients reported temporary ipsilateral facial muscle weakness. The literature review revealed five case reports on the use of BTX-A in PTNP patients that reported similar effectiveness to the present cohort study. BTX-A may be a potential treatment modality for refractory PTNP, thus reducing the need for polypharmacy. Multiple intraoral BTX-A injections administered over the painful sites are well tolerated, safe and easily practiced. High-quality studies are required to evaluate the long-term therapeutic efficacy and side effects of BTX-A therapy.

Short-term and long-term efficacy in robot-assisted treatment for mid and low rectal cancer: a systematic review and meta-analysis

ObjectiveThis study aims to conduct a meta-analysis to evaluate the short-term and long-term therapeutic effects of robot-assisted laparoscopic treatment in patients with mid and low rectal cancer.MethodsA comprehensive search strategy was employed to retrieve relevant literature from PubMed, NCBI, Medline, and Springer databases, spanning the database inception until August 2023. The focus of this systematic review was on controlled studies that compared the treatment outcomes of robot-assisted (Rob) and conventional laparoscopy (Lap) in the context of mid and low rectal cancer. Data extraction and literature review were meticulously conducted by two independent researchers (HMW and RKG). The synthesized data underwent rigorous analysis utilizing RevMan 5.4 software, adhering to established methodological standards in systematic reviews. The primary outcomes encompass perioperative outcomes and oncological outcomes. Secondary outcomes include long-term outcomes.ResultA total of 11 studies involving 2239 patients with mid and low rectal cancer were included (3 RCTs and 8 NRCTs); the Rob group consisted of 1111 cases, while the Lap group included 1128 cases. The Rob group exhibited less intraoperative bleeding (MD = −40.01, 95% CI: −57.61 to −22.42, P < 0.00001), a lower conversion rate to open surgery (OR = 0.27, 95% CI: 0.09 to 0.82, P = 0.02), a higher number of harvested lymph nodes (MD = 1.97, 95% CI: 0.77 to 3.18, P = 0.001), and a lower CRM positive rate (OR = 0.46, 95% CI: 0.23 to 0.95, P = 0.04). Additionally, the Rob group had lower postoperative morbidity rate (OR = 0.66, 95% CI: 0.53 to 0.82, P < 0.0001) and a lower occurrence rate of complications with Clavien–Dindo grade ≥ 3 (OR = 0.60, 95% CI: 0.39 to 0.90, P = 0.02). Further subgroup analysis revealed a lower anastomotic leakage rate (OR = 0.66, 95% CI: 0.45 to 0.97, P = 0.04). No significant differences were observed between the two groups in the analysis of operation time (P = 0.42), occurrence rates of protective stoma (P = 0.81), PRM (P = 0.92), and DRM (P = 0.23), time to flatus (P = 0.18), time to liquid diet (P = 0.65), total hospital stay (P = 0.35), 3-year overall survival rate (P = 0.67), and 3-year disease-free survival rate (P = 0.42).ConclusionRobot-assisted laparoscopic treatment for mid and low rectal cancer yields favorable outcomes, demonstrating both efficacy and safety. In comparison to conventional laparoscopy, patients experience reduced intraoperative bleeding and a lower incidence of complications. Notably, the method achieves comparable short-term and long-term treatment results to those of conventional laparoscopic surgery, thus justifying its consideration for widespread clinical application.

Regulatory effects and clinical application of panax-based compound formula on chronic diseases

Hypertension, diabetes, and hyperlipidemia are common chronic diseases today and can lead to severe complications. Panax-based compound formula, as a comprehensive traditional Chinese medicine formulation, incorporates various components such as Panax, exerting multiple pharmacological effects, including nourishing the kidney qi, strengthening the heart, vasodilation, and increasing blood flow. Through the study of multiple cases, including patients with hypotension, heart disease, diabetes, hyperlipidemia, as well as early and long-term hypertension, preliminary evidence has been provided, indicating the potential positive effects of this compound in different types of hypertensive and diabetic patients. It demonstrates clear antiarrhythmic effects and effectively reduces blood pressure, improves heart failure, and alleviates hyperlipidemia. However, further research and clinical trials are required to verify its long-term therapeutic effects and safety. It is crucial to develop personalized treatment plans when using this compound formula.

Abstract 13272: Acute Effects of Enhanced External Counterpulsation in Adults With Fontan Circulation

Background: Patients who have undergone Fontan palliation for single ventricle CHD exhibit reduced cardiac output. Aims: To study the safety and acute hemodynamic effects of enhanced external counterpulsation (EECP) in a cohort of Fontan patients. Methods: Pilot study of adult Fontan patients recruited through the ambulatory clinic at a single, large-volume ACHD center. Patients underwent TTE and measurement of pulmonary blood flow (PBF), a surrogate for cardiac output, followed by 1 hour of EECP divided into 20-minute stages (80 mmHg, 160 mmHg, 240 mmHg). TTE and PBF measurement were repeated at each stage and 15-30 minutes after completion of EECP. Patients were monitored for symptoms throughout the visit. A repeated measures linear-mixed-model (robust to non-normality) was used to estimate the mean at each time point and to test for differences across time points. Results: There were 23 patients enrolled (52% male, 91% cis-gender, 74% White). Mean age at enrollment and at Fontan completion was 33.0 ± 7.8 years and 5.1 ± 4.1 years, respectively. Six patients (26%) had a pacemaker. Twenty-two (96%) completed a full hour of EECP. Pressure was reduced in the third stage for 3 patients due to discomfort. No patients reported chest pain or increased dyspnea during EECP. PBF was increased at each stage of EECP compared to baseline and returned to baseline post-EECP (Fig. 1). There was a small qualitative improvement in ventricular systolic function in the second and third stages of EECP compared to baseline (160 mmHg: p=0.048; 240 mmHg: p=0.024). O 2 saturation was increased at each stage of EECP compared to baseline (baseline: 93.0%, 80 mmHg: 94.3% [p=0.008], 160 mmHg: 94.6% [p=&lt;0.001], 240 mmHg: 94.6% [p=&lt;0.001]). Mean arterial pressure and heart rate did not change. Conclusions: EECP is well-tolerated in adult Fontan patients and acutely improves PBF at pressures as low as 80 mmHg. Further study is warranted to explore long-term therapeutic effects of EECP in these patients.