Efficacy Of Therapy Research Articles

Patients' Perception of the Impact of Moderate to Severe Atopic Dermatitis on Their Sexual Well-Being: Comparison of Pre- and Posttreatment with Advanced Therapies.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly affects patients' quality of life (QoL). Limited data exists on the effects AD poses on sexual well-being. Objective: To evaluate the impact of moderate-to-severe atopic dermatitis (MtS-AD) on sexual well-being and assess the efficacy of advanced therapies, specifically abrocitinib and dupilumab, in improving sexual health. Methods: In this retrospective study, medical records and responses to an 8-item questionnaire assessing sexual well-being in patients with MtS-AD were reviewed at baseline and after 52 weeks of treatment with abrocitinib or dupilumab. Results: In total, 44 patients were included (mean age: 30.8, 43.2% female). Before treatment, 88.6% reported AD affected their sexual well-being, including feeling unattractive (79.5%), avoiding sexual activity (68.2%), feeling ashamed or embarrassed (68.2%), and experiencing rejection (56.8%). After 52 weeks of treatment with abrocitinib or dupilumab, these negative perceptions and behaviors significantly reduced. Conclusions: MtS-AD negatively impacts patients' sexual well-being; however, advanced therapies like abrocitinib and dupilumab can significantly improve the sexual lives of affected patients, highlighting the broader benefits of these treatments on QoL.

The impact of positive surgical margins after cystectomy on oncological outcomes: a nationwide study.

To evaluate whether surgical margin status, alongside existing postoperative risk indicators, improves the identification of bladder cancer patients who may benefit from adjuvant therapy following radical cystectomy (RC). In this nationwide cohort study, patients aged ≥18 years diagnosed with muscle-invasive bladder cancer(MIBC) without nodal or distant metastasis (cT2-4aN0/xM0) between November 2017 and December 2020 who underwent RC were selected from the Netherlands Cancer Registry. Detailed information on surgical margin status was obtained through linkage with the Dutch central pathology database, Palga. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. Multivariable Cox regression analysis was performed to assess the independent prognostic effect of positive surgical margins (carcinoma in situ (CIS)] only or invasive carcinoma) on PFS and OS. We identified 1445 MIBC patients treated by RC (53% open, 47% robot-assisted), of whom 135 (9.3%) had positive surgical margins (10.7% in the open and 7.7% in the robot-assisted cohort). In the entire cohort, OS was 79% and 60% at 12 and 48 months after RC, respectively. PFS was 70% and 61% at 12 and 24 months, respectively. Multivariable Cox regression showed worse PFS (hazard ratio (HR) 2.13, 95% confidence interval (CI) 1.67-2.72) and OS (HR 2.02, 95% CI 1.58-2.58) in patients with surgical margins with invasive carcinoma vs patients with negative margins. Patients with only CIS in the margins also appeared to have worse PFS (HR 1.60, 95% CI 1.00-2.58) but these results were not statistically significant. No difference was found for OS (HR 1.30, 95% CI 0.80-2.12). Positive margins should be considered a 'high risk feature, as they result in increased risk of disease progression and impaired survival outcomes. These findings support further investigation of the potential efficacy of adjuvant therapy (i.e., radiotherapy and systemic therapy) among patients with positive surgical margins.

Leveraging Mendelian randomization to inform drug discovery and development for ischemic stroke.

Discovery and development of efficacious and safe pharmacological therapies is fraught with challenges. As proteins constitute the majority of drug targets and are encoded by genes, naturally occurring genetic variation within populations can provide valuable insights to inform drug discovery and development efforts. The drug target Mendelian randomization (MR) paradigm leverages these principles to investigate the causal effects of drug targets in humans. This review examines the application of drug target MR in informing the efficacy and development of therapeutics for ischemic stroke prevention and treatment. We consider applications of MR for existing and novel treatment strategies, including targeting blood pressure, lipid metabolism, coagulation, inflammation and glycemic control. Several of these genetically supported targets are under evaluation in late-stage clinical trials. Methodological limitations of drug target MR are addressed, followed by an outline of future research directions. We anticipate that careful application of drug target MR will enhance the efficiency of drug development for ischemic stroke, consequently accelerating the delivery of effective medications to patients.

Thermoelectric Nanoheterojunction-Mediated Multiple Energy Conversion for Enhanced Cancer Therapy.

Electron-hole recombination and exogenous local hypoxia both impede the effectiveness of thermoelectric tumor catalytic therapy. Here, a thermoelectric heterojunction (Pt-TiO2-x/Ti3C2Tx-PEG) was developed to enhance charge carrier separation and alleviate tumor hypoxia. By incorporating titanium oxide with oxygen vacancies and platinum single atoms onto Ti3C2Tx MXene, we not only improve the charge separation efficiency but also prevent the recombination of positive and negative charges generated by the thermoelectric effect, leading to an increased production of reactive oxygen species (ROS). Furthermore, the Pt SAs exhibited excellent catalase-mimicking (CAT-mimicking) activity, catalyzing hydrogen peroxide to generate oxygen and alleviating the hypoxic tumor microenvironment. Titanium oxide with oxygen vacancies also serves as a sonosensitizer for sonodynamic therapy (SDT), enhancing ROS generation in collaboration with thermoelectric catalytic therapy. Moreover, the photothermal conversion efficiency of Pt-TiO2-x/Ti3C2Tx-PEG is augmented by Pt SAs with a surface plasmon resonance effect, further boosting CAT-mimicking activity and thermoelectric catalytic therapy efficacy. This tumor-specific thermoelectric heterojunction integrates thermoelectric therapy, SDT, and photothermal therapy, demonstrating excellent tumor suppression efficacy both in vitro and in vivo. Therefore, this study offers highly valuable and promising insights into utilizing photothermoelectric/ultrasound-mediated methods for cancer treatment.

Efficacy of adjunctive systemic or local antibiotic therapy in peri-implantitis: a systematic review and meta-analysis of randomized controlled clinical trials.

This systematic review and meta-analysis considered the results of randomized controlled clinical trials (RCTs) to evaluate the efficacy of systemic or local antibiotic therapy in peri-implantitis. Two independent authors screened publications from three electronic databases to include RCTs meeting all the inclusion and exclusion criteria. A meta-analysis was performed to evaluate the weighted mean differences in survival rate (SR) and changes in pocket probing depth (PPD), bone level (BL), and clinical attachment level (CAL). The study cohorts were defined as antibiotic and control groups with subgroups for analysis. Seven studies including 309 patients (390 implants) were considered. Within the limitations of this review, patients in the antibiotic groups exhibited significant improvements in PPD. Subgroup analysis indicated that the administration of systemic antibiotics or the use of antibiotics in non-surgical treatments did not result in a significant alteration in BL. It was established that the addition of antibiotics can ameliorate PPD and SR in the treatment of peri-implantitis, whether through surgical or non-surgical approaches, and also shows moderate performance regarding BL and CAL. Considering the lack of application of new technologies in the control group and the hardship of assessing the potential risks of antibiotics, careful clinical judgment is still necessary.

Antiangiogenic therapy exerts antitumor effects by altering the tumor microenvironment: bibliometric analysis

BackgroundAntiangiogenic therapy can alter the tumor microenvironment (TME) and thus exert anti-tumor effects, and has the potential to increase the efficacy of conventional therapy and immunotherapy. The aim of this study was to examine current research hotspots and collaborative networks on the relationship between previous antiangiogenic therapies and the TME through bibliometric analysis.MethodFrom the Web of Science Core Collection database, all publications from inception through December 2023 were downloaded. In-depth analysis was performed by Bibliometrix packages in R. Keywords and collaborative networks were analyzed using VOSviewers and Citespace.ResultWe obtained a total of 9027 publications. They come from 27 countries and were published in 1387 journals, with a total of 39,604 authors in the studied area. The number of publications increases dramatically from 2014 to 2023, accounting for 73.87% (6668/9027) of all publications. China and CANCERS have the highest number of publications on this topic and CANCER RESEACH is the most influential. In the last decade (2013- 2023), research has gradually shifted from studying the role of vascular endothelial growth factor in the TME to examining how antivascular therapy can contribute to the progression of cancer treatment. Furthermore, nanoparticle-based drug delivery systems and immunotherapy have been widely explored in the past five years. The findings of this study will help scientists to explore this promising field in depth by providing insight into the relationship between antiangiogenic therapy and the TME.ConclusionThe relationship between the antiangiogenic therapy and the TME has been developing rapidly, but cooperation between different institutions and countries is still limited. Researchers can use this study to identify hotspots and develop trends for related research, thereby facilitating the development and cooperative exchange in this field, as well as to suggest potential future research directions.

Laser interstitial thermal therapy in the management of bottom-of-sulcus dysplasia-related epilepsy.

This study assessed the efficacy and safety of magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) versus open surgery (OS) for the treatment of patients with bottom-of-sulcus dysplasia (BOSD)-related epilepsy. Twenty-two patients underwent MRgLITT, while 39 underwent OS. Postoperative seizure-free rates were analyzed using Kaplan-Meier curves. The removal ratio, which represents the extent of damage, was calculated based on preoperative lesion volume and postoperative removal volume. Other outcomes, including adverse events, operative time, and hospital stay, were also compared. Kaplan-Meier curves indicated the seizure-free rates were comparable between the MRgLITT group (90.9%, 26.5 [23.0, 35.1] months) and OS group (89.7%, 25.2 [16.2, 34.6] months) at the final follow-up (p = 0.901, log-rank test). The removal ratio of MRgLITT (1.3 [1.1, 1.7]) was significantly lower (p = 0.007) than that of OS (5.8 [3.6, 8.5]). A comparison of postoperative neurological deficits, infection rates, and fever rates revealed no significant differences between MRgLITT and OS groups. The operative time (hours) of MRgLITT (3.0, [2.1, 4.9]) was significantly shorter (p = 0.007) than that of OS (3.5 [3.0, 4.5]). The hospital stay (days) after MRgLITT (6 [5.0, 7.5]) was significantly shorter (p < 0.001) than that of OS (11.0 [9.0, 13.5]). MRgLITT has advantages over OS, including comparable seizure control and adverse event profiles, along with reduced removal ratios, shorter operative time, and shorter hospital stays.

Efficacy and safety of combining anti-angiogenic therapy, radiotherapy, and PD-1 inhibitors in patients with driver gene-negative non-small cell lung cancer brain metastases: a retrospective study

BackgroundThe efficacy and safety of anti-angiogenic combination therapy in patients with driver gene-negative non-small cell lung cancer (NSCLC) with brain metastases (BM) are uncertain.MethodsEighty-eight records of driver gene-negative patients with NSCLC treated with craniocerebral radiotherapy (RT) and programmed death factor-1 (PD-1) inhibitors between May 2021 and May 2023 were collected. Based on whether anti-angiogenic therapy (AT) is combined or not, patients are categorized into the AT group and the non anti-angiogenic therapy (NAT) group. The NAT group patients received craniocerebral RT and PD-1 inhibitor and those in the AT group received craniocerebral RT and PD-1 inhibitor with ≥ 4 cycles of AT. Comparing the clinical efficacy and safety in these two patient cohorts was the main goal of the study.ResultsBy May 1, 2024, the iORR was 94.0% and 63.2% for AT and NAT group, respectively. The 1- and 2-year iLPFS for AT and NAT group were 93.6%, 80.9% and 69.7%, 36.4%, respectively. The 1- and 2-year iDPFS were 86.7%, 56.3% and 59.1%, 48.3%, respectively. The 1- and 2-year OS were 82.0%, 36.6% and 68.4%, 34.6%, respectively. Compared to the standard treatment (RT and PD-1 inhibitors), the addition of AT prolonged the median iLPFS (NR vs. 22.0 months, hazard ratio [HR] = 11.004, P < 0.001) and the median iDPFS (NR vs. 20.0 months, HR = 8.732, P = 0.003), but was not significant in the extension of the OS (21.0 vs. 19.0 months, HR = 1.601, P = 0.206). Multivariable analysis showed that combination therapy with AT is significantly associated with prolonged iLPFS (HR = 4.233, P = 0.002) and iDPFS (HR = 2.824, P = 0.007), whereas only GPA score is significantly associated with improved OS (HR = 0.589, P = 0.019). The incidence of hypertension in the AT group showed an increasing trend, and no significant increased risk of radiation-induced brain necrosis was found. No drug-related intracranial hemorrhage events occurred.ConclusionCombining AT, RT, and PD-1 inhibitors can substantially improve iLPFS and iDPFS for patients with driver gene-negative NSCLC with BM; however, it is not significantly associated with better OS.

Clinical Outcome of Intravenous Alteplase Treatment in Patients With Acute Mild Cerebral Infarction

ABSTRACTBackgroundThe efficacy of intravenous alteplase therapy for acute cerebral infarction is well established, regardless of the ischemic stroke subtype. However, its effectiveness in patients with mild cerebral infarction remains controversial, raising concerns about the significance of the treatment.AimTo retrospectively evaluate the efficacy of intravenous alteplase in patients with mild cerebral infarction and other factors affecting the outcome.MethodsA total of 527 patients received intravenous alteplase (0.6 mg/kg) at our hospital between October 2012 and March 2023. Of these, 118 patients with mild cerebral infarction (National Institutes of Health Stroke Scale [NIHSS] ≤ 5) who were treated with intravenous alteplase without mechanical thrombectomy were retrospectively evaluated for treatment efficacy and the factors affecting the efficacy.ResultsThe modified Rankin scale (mRS) outcome at 90 days was good (mRS: 0–1) in 85 (72%) patients and poor (mRS: 2–5) in 33 (28%) patients. Branch atheromatous disease (BAD) and proximal anterior circulation large vessel occlusion (proximal LVO: internal carotid artery and M1 segment of middle cerebral artery) were observed more frequently in the poor outcome group than in the good outcome group. Multivariate analysis, adjusted for age and sex, identified BAD and proximal LVO as factors associated with poor outcomes after intravenous alteplase treatment for mild cerebral infarction. Symptomatic intracranial hemorrhage was observed in one patient with BAD.ConclusionMost patients with mild cerebral infarction who were treated with intravenous alteplase alone had good outcomes. BAD and proximal LVO were other factors influencing poor outcomes.

Safety and therapeutic potential of allogeneic adipose-derived stem cell spray transplantation in ischemic cardiomyopathy: a phase I clinical trial

BackgroundIschemic cardiomyopathy, characterized by coronary artery atherosclerosis, impairs the myocardial tissue. Coronary artery bypass grafting (CABG) is commonly used to revascularize affected areas and improve patient survival rates; however, it can fail to enhance cardiac function. Impaired capillary blood flow may obstruct functional recovery, prompting interest in treatments, such as angiogenic factor administration. Adipose-derived stem cells (ADSCs), which are known for immune evasion, have shown the potential to construct capillary networks and improve myocardial function. This clinical trial aimed to evaluate the safety and efficacy of ADSC spray therapy combined with CABG.MethodsThis single-center, randomized, double-blind study involved patients with ischemic cardiomyopathy who were scheduled for CABG and who had a left ventricular ejection fraction ≤ 40%. The participants were randomized to receive CABG as well as ADSC spray therapy or placebo. The primary endpoints were safety, changes in late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) volumes, and feasibility. The secondary endpoints included left ventricular function, exercise tolerance, and heart failure symptoms.ResultsSeven patients were enrolled; of them, six were randomized to receive ADSC therapy (n = 3) or placebo (n = 3). The procedure was successfully completed with minimal adverse events. One patient in the ADSC group developed pleural effusion that was resolved with drainage. The LGE-MRI volumes decreased in the ADSC group but remained unchanged in the placebo group. Improvements in left ventricular function and exercise tolerance were noted in the ADSC group, with heart failure symptoms improving to New York Heart Association class I. In contrast, the placebo group showed no significant changes, with one patient experiencing worsening symptoms.ConclusionsADSC spray therapy combined with CABG demonstrated safety and efficacy at enhancing cardiac function. ADSC likely contributes to capillary network reconstruction, thereby augmenting the benefits of CABG. Future phase II and III trials are warranted to confirm its therapeutic efficacy and long-term outcomes. This novel approach represents a significant advancement in the treatment of ischemic cardiomyopathy and offers a viable strategy for improving myocardial function and patient prognosis.Trial registration This study was registered with the Japan Registry of Clinical Trials (jRCT2053190103) and ClinicalTrials.gov (NCT04695522)Graphical

Review of Current and Upcoming Second-Line Treatments for Primary Biliary Cholangitis.

Treatment for primary biliary cholangitis (PBC) was defined by its singular relationship with ursodeoxycholic acid (UDCA) for decades. However, nearly 40% of patients fail to achieve adequate biochemical response with UDCA, necessitating second-line therapies. The aim of our review was to assess the efficacy and safety of second-line therapies for PBC from phase three trials. We conducted a systematic review of PubMed, Medline, and ClinicalTrials.gov for published phase three trial data of second-line PBC therapies. Four phase three clinical trial evaluating obeticholic acid, bezafibrate, seladelpar, and elafibranor, were identified. All trials but one defined the treatment endpoints of an alkaline phosphatase (ALP) less than 1.67 times the upper limit of normal (ULN), a 15% decrease of ALP from baseline, and normal total bilirubin (TB) after 12months. All therapies demonstrated statistically significant achievement of primary endpoints relative to placebo. Reduction in ALP from baseline ranged from 113 to 133.9 U/L (-34.6% to -50%) across all trials. Primary endpoint treatment differences relative to placebo ranged between 31 and 47%. ALP normalization rates were described for three treatments and varied between 15 and 67% in treatment cohorts,compared to 0% to 2% of placebo cohorts. Only elafibranor and seladelpar demonstrated significant reduction in total 5D itch scale scores. Discontinuation rates across studies ranged from 1 to 14% due to adverse effects. All reviewed therapies met their respective study endpoints. Effective second-line therapies area available and continue to receive long-term evaluation in patients with PBC.

A real-world study: third-line treatment options for metastatic colorectal cancer

BackgroundNumerous third-line treatment options exist for colorectal cancer. This study aims to assess the efficacy and safety of third-line therapies, including TKIs (fruquintinib, regorafenib) combined with PD-1 inhibitors, and trifluridine/tipiracil combined with bevacizumab, in patients with refractory microsatellite stable metastatic colorectal cancer who have progressed or are intolerant following standard first- and second-line treatments.Materials and methodsThis retrospective analysis collected data from patients with microsatellite stable advanced colorectal adenocarcinoma, diagnosed through histopathology and treated at Henan Provincial Cancer Hospital from May 2019 to April 2023. We compared the efficacy and safety of fruquintinib combined with PD-1 inhibitors, regorafenib combined with PD-1 inhibitors, and trifluridine/tipiracil combined with bevacizumab.ResultsAmong 60 eligible patients with refractory microsatellite stable metastatic colorectal adenocarcinoma, 29 (48.3%) received fruquintinib combined with PD-1 inhibitors, 15 (25%) received regorafenib combined with PD-1 inhibitors, and 16 (26.7%) received trifluridine/tipiracil combined with bevacizumab. The average follow-up period was 12.6 months (ranging from 2.3 to 37.6 months). After third-line treatment, the overall objective response rate (ORR) was 8.6%, and the disease control rate (DCR) was 78.6%. The median overall survival (OS) for the regorafenib, fruquintinib, and trifluridine/tipiracil groups was 19.2 months, 14.0 months, and 16.2 months, respectively, with no statistically significant differences observed. However, there were statistically significant differences in progression-free survival (PFS); the median PFS for the regorafenib group was 6.3 months, for the fruquintinib group was 4.2 months, and for the trifluridine/tipiracil group was 5.4 months. Pairwise comparisons indicated that the PFS for the regorafenib group was similar to that for the trifluridine/tipiracil group, both of which were superior to the fruquintinib group. Cox univariate regression analysis revealed that the presence of liver and peritoneal metastases was associated with PFS in third-line treatment.ConclusionIn the third-line treatment of colorectal cancer, regorafenib combined with PD-1 inhibitors and trifluridine/tipiracil combined with bevacizumab showed superiority over fruquintinib combined with PD-1 inhibitors in terms of PFS, but no statistically significant difference in OS was noted among the three groups.

Advanced Strategies of CAR-T Cell Therapy in Solid Tumors and Hematological Malignancies.

Chimeric antigen receptor T-cells, known as CAR-T cells, represent a promising breakthrough in the realm of adoptive cell therapy. These T-cells are genetically engineered to carry chimeric antigen receptors that specifically target tumors. They have achieved notable success in the treatment of blood-related cancers, breathing new life into this field of medical research. However, numerous obstacles limit chimeric antigen receptors T-cell therapy's efficacy, such as it cannot survive in the body long. It is prone to fatigue and exhaustion, leading to difficult tumor elimination and repeated recurrence, affecting solid tumors and hematological malignancies. The challenges posed by solid tumors, especially in the context of the complex solid-tumor microenvironment, require specific strategies. This review outlines recent advancements in improving chimeric antigen receptors T-cell therapy by focusing on the chimeric antigen receptors protein, modifying T-cells, and optimizing the interaction between T-cells and other components within the tumor microenvironment. This article aims to provide an extensive summary of the latest discoveries regarding CAR-T cell therapy, encompassing its application across various types of human cancers. Moreover, it will delve into the obstacles that have emerged in recent times, offering insights into the challenges faced by this innovative approach. Finally, it highlights novel therapeutic options in treating hematological and solid malignancies with chimeric antigen receptors T-cell therapies.

Endovascular treatment for carotid stenosis developing after neck radiotherapy

Aims: One of the causes of carotid stenosis is radiation therapy to the neck area. Cervical irradiation is frequently used in the treatment of head and neck cancers. However; the ionizing effect of radiation causes arteritis, which can lead to acceleration of fibrosis or atherosclerosis, thrombosis, stenosis, or occlusion. Carotid stenosis due to radiation is relatively rare. Accordingly, in this study, our aim was to assess the feasibility, safety and preliminary efficacy of endovascular therapy for carotid stenosis developing after neck radiotherapy. Methods: This study was a retrospective review of a prospectively maintained database of a consecutive unselected group of symptomatic and asymptomatic patients with carotid artery stenosis developing after neck radiotherapy. Data was collected from 2017 to 2023. A total of 17 patients who developed carotid stenosis due to neck radiotherapy were included in the study. Neck irradiation was applied in 76.5% of cases due to laryngeal cancer. All statistical analysis was performed using R version 4.2.1 (The R Foundation for Statistical Computing, Vienna, Austria; https://www.r-project.org). Univariate analysis was performed using ?2 and Wilcoxon tests. Cumulative survival estimates were assessed using the life-table method. Results: One patient had a technical failure due to a difficult aortic arch. Because of the degree of stenosis (40?) was not serious in conventional angiography of 2 patients, medical follow-up was decided. 3 patients were admitted to the emergency department due to acute ischemic stroke. Endarterectomy was performed in 4 patients due to the complex structure of the aortic arch and carotid arteries for carotid artery stending. The number of patients with stenosis in the right carotid was 10, while the number of patients with stenosis in the left carotid was 7. No restenosis was observed in patients with stent placement in follow-up carotid Doppler and CT angiography performed 3 months later. Additionally, no new neurodeficit was observed in the neurological examinations 3 months later. Conclusion: This retrospective study demonstrates that endovascular treatment for carotid stenosis developing after neck radiotherapy is safe, effective and reliable.

The Efficacy of Brainspotting and Sand Therapy to Reduce Anxiety Symptoms in Children Aged 8-9

This study explored the use of Brainspotting (BSP) in combination with Sand Therapy (ST) for use with 8–to 9-year-old children with anxiety symptoms in a school-based setting. Using the Spence Children's Anxiety Scales (SCAS), The Behavior and Feelings Survey (BFS), and the Top Problems Assessment (TPA), the research project measured anxiety as reported by parents/caregivers and students, internalizing, externalizing, and total concerns as reported by parents/caregivers, teachers, and students, and finally individually identified unique concerns as reported by parents/caregivers, teachers, and students. The researcher collected data from student participants (11) who experienced six sessions of BSP and ST. The quantitative data collected identified project signifiers for future researchers. Outcomes reflected statistical significance of a reduction in anxiety scores for parents in the subscale of generalized anxiety and a significant reduction of scores in children in the subscales of generalized anxiety and separation anxiety. Parents and teachers indicated significantly lower scores in internalizing and total concerns identified across time intervals. All three groups of reporters indicated a significant reduction of top problems identified across time intervals. Outcomes demonstrate the promise of the integrated practice of BSP and ST while laying a framework for future research of this method.

Simultaneous targeting and suppression of heat shock protein 60 to overcome heat resistance and induce mitochondrial death of tumor cells in photothermal immunotherapy

As the most aggressive and metastatic subtype of breast cancer, clinical demands of triple negative breast cancer (TNBC) have far not been met. Heat shock protein 60 (HSP60) is over expressed in tumor cells and impair the efficacy of photothermal therapy. In this work, a conjugate composed of self-designed peptide targeting HSP60 and gold nanorods was constructed, referred to as AuNR-P17. Results showed that AuNR-P17 was able to simultaneously down regulate the level of HSP60 and locate in the mitochondria where HSP60 is enriched in the tumor cells of TNBC, which also impeded the interaction between HSP60 and integrin α3, thereby reducing the tumor cells' heat tolerance and metastatic capabilities. At the same time, AuNR-P17 induced remarkable mitochondrial apoptosis when exposed to the laser irradiation of 808 nm. The dual functions of AuNR-P17 led to the decrement of BCL-2 and the activation of p53 and cleaved caspase-3. The danger associated molecular patterns (DAMPs) generated from the mitochondrial apoptosis elicited strong and long-term specific immune responses against TNBC in vivo and ultimately inhibited the tumor metastasis and recurrence with significantly prolonged survival (>100 days) on TNBC mice. In conclusion, this study demonstrated HSP60 a promising potential therapeutic target for triple negative breast cancer and exhibited powerful capacity of AuNR-P17 in photothermal immune therapy.

Long Term Outcome Among HCV-Infected People Who Use Drugs (PWUD) Successfully Treated for HCV Infection with Glecaprevir/Pibrentasvir (G/P)

BackgroundSeveral clinical trials, including the recently published GRAND PLAN study from Vancouver Infectious Diseases Center (VIDC), have demonstrated the efficacy of HCV therapy among active drug users, including those facing significant addiction-related and social challenges. In GRAND PLAN, we documented SVR12 in 108/117 (92.3%) individuals (108/111 (mITT) or 97.3% of those reaching the SVR12 timepoint) receiving an 8-week course of Glecaprevir/Pibrentasvir (G/P), with almost all using fentanyl and over half being unstably housed. Data on the maintenance of this favorable outcome in the long term in such a population with a significant risk of reinfection are limited. We hypothesized that the offer of ongoing multidisciplinary care (including addiction care) after SVR12 was achieved would reduce the likelihood of loss to follow up, HCV reinfection or death and consolidate the gains achieved by initial engagement in care to diagnose and treat HCV infection. MethodsThe inception cohort for this analysis was the 108 individuals achieving a cure of HCV infection within the GRAND PLAN study. All were offered the opportunity to continue to receive care at VIDC. This is a multidisciplinary model of care to address medical, mental health, social and addiction-related concerns on an ongoing basis. This included, if necessary, opiate agonist and safer supply therapy, usually provided by the pharmacy adjacent to our inner-city campus. Among those choosing to be retained in care, the endpoint of this analysis was loss to follow up, mortality and HCV reinfection and their correlates. Reinfection was ascertained by repeat HCV RNA testing every 6 months, more frequently if clinically indicated. ResultsOf the 108 individuals making up the inception cohort for this analysis, all chose to remain in care at VIDC. We note median age 47 (22-75) years, 28% female, 21.3% identifying as indigenous, the majority with mild fibrosis (90.8% F0-F2), slightly more than half with unstable housing. It is of note that we recorded a 20% decrease in fentanyl users among those who were cured compared to the baseline evaluation of the overall study cohort (73.5% vs 94.9%, p < 0.000001). Among the cured individuals, 104 (96.3%) remained alive, while 4 individuals died of opioid overdoses. Out of the 104 patients, 99 (95.2%) remained HCV-free, while 5 (4.8%) were re-infected. All five have recently initiated repeat HCV therapy at VIDC, 2 of whom are already documented to be cured. ConclusionAmong a population of vulnerable inner-city residents cured of HCV infection within a multidisciplinary program of care at VIDC, all accepted the offer to remain in long-term follow up, with a statistically significant reduction in fentanyl use over time. In the setting of an ongoing opioid crisis where 3 deaths/day are recorded in the neighborhood where the study population resides, we documented 4 deaths. Reinfections occurred at a very modest rate, with maintenance in care allowing prompt re-treatment, with a cure already being documented in 2/5 cases, with the other 3 individuals remaining on HCV therapy at VIDC.

Phase I trial and preclinical data of ACT using neoantigen-reactive TIL for patients with advanced epithelial and ICB-resistant solid cancers

Background and PurposeACT of ex vivo expanded TIL can mediate objective tumor regression in 28-49% of metastatic melanoma patients. However, the efficacy of TIL therapy in most epithelial cancers remains limited. We present the design of a phase I clinical study that aims to assess the safety and efficacy of NEXTGEN-TIL, a TIL product selected based on ex vivo neoantigen recognition, in patients with advanced epithelial tumors and ICB-resistant solid tumors. MethodsPreREP TIL cultures expanded in high dose IL-2 (HD-IL-2) from patients with metastatic solid tumors were screened for recognition of autologous TCL and/or neoantigens. 6 GMP validations of preREP TIL expansion were performed and TIL cultures from these 6 intermediate products were selected to perform the clinical scale GMP validation of the REP. ResultsTIL expanded in 82% of patient-derived tumor biopsies across different cancer types and these contained tumor- and neoantigen-reactive T cells. During GMP-validations, a variable number of TILs expanded, constituting the intermediate products (preREP). Three finished products (REP) were manufactured which reached cell doses ranging from 4.3e9 to 1.1e11 and met the established specifications. The NEXTGEN-TIL clinical trial entails a first expansion of TIL from tumor fragments in HD-IL-2 followed by TIL screening for neoantigen-recognition and REP of selected neoantigen-reactive TIL cultures. Treatment involves a classical non-myeloablative lymphodepleting chemotherapy followed by NEXTGEN-TIL product administration together with HD-IL-2. ConclusionsNEXTGEN-TIL consists of selected neoantigen-reactive TIL and aims to potentially improve efficacy in patients with epithelial and ICB-resistant tumors, with a safety profile like traditional TIL.

Safety and efficacy of a novel mini-pool intravenous immunoglobulin therapy in children with primary immunodeficiency.

Intravenous polyvalent immunoglobulins (IVIG) for prophylaxis in patients with primary immunodeficiency disorders (PIDs) exposes them to life-threatening infections and debilitating diseases. To improve access to IVIG in lower middle-income countries, the WHO recommends a stepwise approach for the local production of purified and virus-inactivated plasma immunoglobulins by national blood transfusion services using new technologies and medical devices. One new technology relies on single-use sterile medical devices for the purification of plasma immunoglobulin G (IgG), as well as lipid-enveloped virus inactivation from mini-pools of recovered plasma separated from whole blood (mini-pool IVIG [MP-IVIG]). This study aimed to compare the safety and efficacy of MP-IVIG to standard IVIG (STD-IVIG). In this prospective crossover clinical study, we investigated the safety and efficacy of MP-IVIG for STD-IVIG preparations as a replacement therapy in a cohort of 21 paediatric patients with PID. Both MP-IVIG and STD-IVIG were effective in reducing the frequency of severe bacterial infections and hospital admissions in patients with PID. Mild side effects have been observed in seven patients (6.2%) with PID who received MP-IVIG and five patients (5.3%) who received STD-IVIG. No moderate or severe side effects or haemolytic transfusion reactions were reported. The mortality rates were also comparable and were not related to the study products. MP-IVIG presented no safety issues and was as effective as STD-IVIG in IgG replacement in patients with PID. Due to the small numbers, the results have to be addressed with caution.

Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study

Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n=16, nusinersen: n=154, both: n=2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).