Treatment-associated Adverse Events Research Articles

Short-course hypofractionated proton beam therapy, incorporating 18F-DOPA PET and contrast-enhanced MRI targeting, for patients aged 65 years and older with newly diagnosed glioblastoma: a single-arm phase 2 trial.

Older patients (aged ≥65 years) with glioblastoma have a worse prognosis than younger patients and a median overall survival of 6-9 months. 3,4-Dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-DOPA) PET sensitively and specifically identifies metabolically active glioblastoma for preferential targeting. Proton beam therapy potentially improves quality of life (QOL) by sparing more healthy brain tissue than photon radiotherapy. With improved targeting and the dosimetric advantages of proton beam therapy, we aimed to test whether hypofractionated proton beam therapy could improve survival and QOL in older patients with glioblastoma. In this single-arm phase 2 trial, we enrolled patients aged 65 years and older with an Eastern Cooperative Oncology Group performance status score of 0-2 and newly diagnosed WHO grade 4, malignant glioblastoma from two Mayo Clinic campuses (Phoenix, AZ, and Rochester, MN, USA). Radiotherapy target volumes were defined by 18F-DOPA PET and MRI regions of contrast enhancement. Patients were given dose-escalated hypofractionated proton beam therapy (35-40 Gy equivalents in five or ten treatments) plus oral concurrent temozolomide (75 mg/m2 daily on days 1-7 for the five-treatment regimen or on days 1-14 for the ten-treatment regimen), and 1 month after completing radiotherapy patients were given adjuvant temozolomide (150-200 mg/m2 on days 1-5 for six 28-day cycles). The primary endpoint was overall survival at 12 months after enrolment. The primary endpoint and safety were assessed in the intention-to-treat population (defined as all eligible patients who started radiotherapy). This study is registered with ClinicalTrials.gov, NCT03778294, and is now complete. Between May 22, 2019, and May 25, 2021, 43 patients were enrolled, of whom four did not receive treatment because of progression (n=2), death (n=1), or insurance denial (n=1), such that 39 patients received treatment (median age 70·2 years [IQR 67·4-74·3]; 11 [28%] of 39 patients were female, 28 [72%] were male, 37 [95%] were White, one [3%] was Black or African American, and one chose not to disclose their race). As of data cutoff (Jan 30, 2024), median follow-up was 25·4 months (IQR 22·1-29·7). 22 (56% [95% CI 39-72]) of 39 patients were alive at 12 months. Median overall survival was 13·1 months (95% CI 11·1-19·1). Grade 3 baseline-adjusted, treatment-associated adverse events were CNS necrosis (four [10%] of 39) and thrombocytopenia (one [3%]). No baseline-adjusted, treatment-associated grade 4 adverse events or deaths occurred. We observed improved overall survival compared with historical controls and a promising adverse event profile by using 18F-DOPA PET-guided, dose-escalated, hypofractionated proton beam therapy. These findings have resulted in the opening of a phase 2 study (NCT05781321) investigating this regimen versus standard-of-care treatment in adults of any age with newly diagnosed glioblastoma. Mayo Clinic Marley Endowment Funds and the Lawrence W and Marilyn W Matteson Fund in Cancer Research.

Metabolic, cardiac, and bone health testing in patients with prostate cancer on androgen-deprivation therapy: A population-based assessment of adherence to therapeutic monitoring guidelines.

Androgen-deprivation therapy (ADT) remains a cornerstone in treatment for patients with advanced prostate cancer. ADT is associated with several adverse effects, including osteoporosis, metabolic syndrome, and cardiovascular events, leading to guidelines recommending routine testing to monitor for these toxicities. There is a lack of data assessing adherence to these recommendations. The authors conducted a retrospective cohort study using administrative data from Ontario, Canada between 2008 and 2021. They identified all older men (aged 65 years and older) who received ADT for prostate cancer using comprehensive provincial health databases. The primary outcomes were the use of testing for lipids, dysglycemia (glucose), bone health serum, and bone density between 6 weeks before and 1 year after the initiation of ADT. In total, 29,097 patients were examined, of whom 52.8% were prescribed ADT by urologists, 37.9% were prescribed ADT by radiation oncologists, 2.8% were prescribed ADT by medical oncologists, and 2.4% were prescribed ADT by other physicians. Adherence to guidelines was low: only 21.3% of patients received a bone density scan, 41.2% underwent bone health-related serum tests, 51.3% completed a lipid profile, and 65.9% underwent dysglycemia testing within 1 year of diagnosis. Overall, only 11.9% of patients received all of the recommended investigations. Adherence to testing did not appear to improve over time (2008-2021) or with guideline publication. Patient (age) and physician (specialty) factors had important associations with adherence to testing. Most patients receiving ADT for prostate cancer do not receive recommended testing to monitor for treatment-related toxicity. Further study is required to address barriers to therapeutic monitoring of men on ADT and to reduce treatment-associated adverse events.

Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement.

Despite the extraordinary anti-tubercular activity of isoniazid (INH), the drug-induced hepatotoxicity and peripheral neuropathy pose a significant challenge to its wider clinical use. The primary cause of INH-induced hepatotoxicity is in vivo metabolism involving biotransformation on its terminal -NH2 group owing to its high nucleophilic nature. The human N-acetyltransferase-2 enzyme (NAT-2) exploits the reactivity of INH's terminal -NH2 functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH2 group also tends to react with vital endogenous molecules such as pyridoxine, leading to their deficiency, a major cause of peripheral neuropathy. The elevation of liver functional markers is observed in 10%-20% of subjects on INH treatment. INH-induced risk of fatal hepatitis is about 0.05%-1%. The incidence of peripheral neuropathy is 2%-6.5%. In this review, we discuss the genesis and historical development of INH, and different reported mechanisms of action of INH. This is followed by a brief review of various clinical trials in chronological order, highlighting treatment-associated adverse events and their occurrence rates, including details such as geographical location, number of subjects, dosing concentration, and regimen used in these clinical studies. Further, we elaborated on various known metabolic transformations highlighting the involvement of the terminal -NH2 group of INH and corresponding host enzymes, the structure of different metabolites/conjugates, and their association with hepatotoxicity or neuritis. Post this deliberation, we propose a hydrolysable chemical derivatives-based approach as a way forward to restrict this metabolism.

Ebronucimab in Chinese patients with hypercholesterolemia---A randomized double-blind placebo-controlled phase 3 trial to evaluate the efficacy and safety of ebronucimab

Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450 mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150 mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95 %CI) in LDL-C from baseline to week 12 of Ebronucimab 450 mg Q4W and Ebronucimab 150 mg Q2W groups versus the placebo group was −59.13 (-64.103, −54.153) (Adjusted p<0.0001) and −60.43 (-65.450, −55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9 %, 4.8 % and 3.5 %). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450 mg Q4W or 150 mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients.

Final Results from the First European Real-World Experience on Lusutrombopag Treatment in Cirrhotic Patients with Severe Thrombocytopenia: Insights from the REAl-World Lusutrombopag Treatment in ITalY Study.

Background and aims: Management of severe thrombocytopenia poses significant challenges in patients with chronic liver disease. Here, we aimed to evaluate the first real-world European post-marketing cohort of cirrhotic patients treated with lusutrombopag, a thrombopoietin receptor agonist, verifying the efficacy and safety of the drug. Methods: In the REAl-world Lusutrombopag treatment in ITalY (REALITY) study, we collected data from consecutive cirrhotic patients treated with lusutrombopag in 19 Italian hepatology centers, mostly joined to the "Club Epatologi Ospedalieri" (CLEO). Primary and secondary efficacy endpoints were the ability of lusutrombopag to avoid platelet transfusions and to raise the platelet count to ≥50,000/μL, respectively. Treatment-associated adverse events were also collected. Results: A total of 66 patients and 73 cycles of treatment were included in the study, since 5 patients received multiple doses of lusutrombopag over time for different invasive procedures. Fourteen patients (19%) had a history of portal vein thrombosis (PVT). Lusutrombopag determined a significant increase in platelet count [from 37,000 (33,000-44,000/μL) to 58,000 (49,000-82,000), p < 0.001]. The primary endpoint was met in 84% of patients and the secondary endpoint in 74% of patients. Baseline platelet count was the only independent factor associated with response in multivariate logistic regression analysis (OR for any 1000 uL of 1.13, CI95% 1.04-1.26, p 0.01), with a good discrimination power (AUROC: 0.78). Notably, a baseline platelet count ≤ 29,000/μL was identified as the threshold for identifying patients unlikely to respond to the drug (sensitivity of 91%). Finally, de novo PVT was observed in four patients (5%), none of whom had undergone repeated treatment, and no other safety or hemorrhagic events were recorded in the entire population analyzed. Conclusions: In this first European real-world series, lusutrombopag demonstrated efficacy and safety consistent with the results of registrational studies. According to our results, patients with baseline platelet counts ≤29,000/μL are unlikely to respond to the drug.

O-280 Vaginal microbiota transplant (VMT) without antibiotic pretreatment reveals changes in vaginal microbiota and immune profile in women with asymptomatic dysbiosis – a randomized, placebo-controlled trial

Abstract Study question Investigate the safety of VMT and explore its effects on the vaginal microbiomes and local inflammation in healthy, asymptomatic volunteer women screened for vaginal dysbiosis Summary answer We demonstrate safety and engraftment of donor bacteria in 50% of recipients, and a distinct shift in local inflammatory markers following resolution of vaginal dysbiosis What is known already Dominance by a subset of vaginal Lactobacillus species is considered healthy. Dysbiosis characterized by high abundance of anaerobic species is observed in around one third of women, and affects fertility, pregnancy outcomes, risk of STIs and UTIs, and potentially cancer treatment. Current use of antibiotics is often insufficient with high recurrence rates and potentially antibiotic resistance. There is a clear need for alternatives and recently it was shown that VMT following antibiotic treatment resulted in long-lasting improvements in symptoms of bacterial vaginosis in four out of five patients, but RCTs without the use of antibiotics remain to be reported. Study design, size, duration We performed a randomized, placebo-controlled double-blinded trial in 34 recipients randomized in an active:placebo 3:1 ratio. Subjects in the active arm received VMTs from donor cervicovaginal secretions (CVS) while placebo participants received saline. All recipients were dosed on 3 consecutive days with active arm recipients receiving all 3 VMTs originating from the same donor. All recipients were followed for safety and efficacy assessments for 6 menstrual cycles after dosing. Participants/materials, setting, methods Donors: CVS was obtained from healthy subjects screened to be negative for a broad panel of infections and having lactobacilli-dominant vaginal microbiomes. RCT: Healthy, asymptomatic women aged 18 to 45 whose vaginal microbiome had combined lactobacilli relative abundance &amp;lt;10% and combined relative abundance of dysbiosis-associated bacteria &amp;gt;20% were included. VMTs were applied vaginally on three consecutive days. Follow-up visits were performed 1 week after the last VMT and then once every cycle for 6 cycles. Main results and the role of chance Here, we report the successful implementation of a donor program to obtain screened, frozen, and banked donor CVS to be used in the first VMT intervention RCT. In the ITT population, the primary efficacy analysis showed statistically significant increase from baseline in relative abundance of vaginal lactobacilli to follow-up timepoints 1 week and 3 cycles post intervention in the active arm, while no statistical significant change was observed in the placebo arm at any follow-up timepoint. Also, time-resolved metagenomic analysis showed that 50% of women treated with VMT displayed a shift of the vaginal microbiome toward the Lactobacillus-dominated donor CVS sample, confirmed with strain-level engraftment analysis. We observed no serious treatment-associated adverse events and the intervention was well tolerated. Further, the successful “twinning” of the recipient to match the donor microbiome post-VMT also led to a dramatic shift toward an anti-inflammatory environment based on transcriptomic analysis of CVS. Limitations, reasons for caution Recipients were asymptomatic and mainly Caucasian, which limits generalizability to other ethnicities and the symptomatic spectrum of vaginal dysbiosis. Due to COVID-19-related recruitment issues, the cohort size ended below the targeted number of n = 40. Future studies will aim to identify factors driving engraftment and its impact on clinical outcomes. Wider implications of the findings Vaginal microbial interventions including VMT have great potential as the first therapeutic intervention that provides effective and long-term vaginal microbiota restoration, positively impacting a wide variety of diseases and conditions affecting the female reproductive tract. Trial registration number NCT05114031

Characteristics, Treatment, and Outcomes of Invasive Group A Streptococcal Infections

Background: Group A Streptococcus (GAS; Streptococcus pyogenes) is an important human pathogen that can cause life-threatening invasive disease, ranging from skin/soft tissue infections to infective endocarditis. In the fall of 2022, the Center for Disease Control &amp; Prevention (CDC) issued an alert due to a global increase in invasive GAS infections, particularly among children and adults with co-morbidities. An increase in invasive disease was observed at our five-hospital healthcare system in Southeast Michigan. The objective of this study was to describe characteristics of patients with invasive GAS and characterize treatment and outcomes of disease. Methods: This was a retrospective cross-sectional study of patients from June 2013 to August 2023 with positive blood cultures for GAS. Patients were identified using a data query for positive blood cultures for GAS through Microsoft SQL Server. Patients with age &lt; 1 8 years, polymicrobial bacteremia, incomplete data, or who were enrolled in hospice and/or died within 48-hours of admission were excluded. Collected variables included: demographics, infection characteristics (syndrome, duration of bacteremia), microbiological characteristics (antimicrobial susceptibility testing; AST), antimicrobial treatment (empiric and final, antitoxin therapy), and clinical outcomes (length of hospital stay [LOS], treatment-associated adverse events, 30-day mortality and infection-related readmission). Results: 250 patients were included (Table 1). More than half were male with median age of 57.5 years. Diabetes mellitus (38%) and chronic kidney disease (23%) were common comorbidities [Table 1]. Persons experiencing homelessness and persons who use injection drugs accounted for 9% and 13% of the cases, respectively. The most common infective syndrome accompanying bacteremia was cellulitis (57%). The majority of patients received vancomycin for empiric therapy (81%) and penicillin (38%) or cephalosporin (36%) for final regimen [Table 2]. A total of 79 GAS isolates (32%) were clindamycin resistant. Clindamycin was included in the empiric regimen of 20 (8%) patients, the final regimen in 44 (18%) of patients, and as antitoxin adjunct therapy in 135 (54%) of patients. A third (33%) of patients received no antitoxin. The average duration of antitoxin therapy was 3.6 days and antimicrobial therapy 19.9 days. The mean LOS was 11.4 days (Table 3). Thirty nine (16%) patients had treatment failure and 8 (3%) experienced C. difficile infection within 30 days of antimicrobial treatment. Thirty-day mortality was 11%; of these, 9% had in-hospital mortality. Conclusions: Invasive GAS infection confers significant morbidity and mortality, and ongoing research is needed to determine the best treatment regimens in the era of increasing clindamycin resistance.

Preemptive dual therapy for children at risk for infantile-onset spinal muscular atrophy.

Compare efficacy of gene therapy alone (monotherapy) or in combination with an SMN2 augmentation agent (dual therapy) for treatment of children at risk for spinal muscular atrophy type 1. Eighteen newborns with biallelic SMN1 deletions and two SMN2 copies were treated preemptively with monotherapy (n = 11) or dual therapy (n = 7) and followed for a median of 3 years. Primary outcomes were independent sitting and walking. Biomarkers were serial muscle ultrasonography (efficacy) and sensory action potentials (safety). Gene therapy was administered by 7-43 postnatal days; dual therapy with risdiplam (n = 6) or nusinersen (n = 1) was started by 15-39 days. Among 18 children enrolled, 17 sat, 15 walked, and 44% had motor delay (i.e., delay or failure to achieve prespecified milestones). Those on dual therapy sat but did not walk at an earlier age. 91% of muscle ultrasounds conducted within 60 postnatal days were normal but by 3-61 months, 94% showed echogenicity and/or fasciculation of at least one muscle group; these changes were indistinguishable between monotherapy and dual therapy cohorts. Five children with three SMN2 copies were treated with monotherapy in parallel: all sat and walked on time and had normal muscle sonograms at all time points. No child on dual therapy experienced treatment-associated adverse events. All 11 participants who completed sensory testing (including six on dual therapy) had intact sural sensory responses. Preemptive dual therapy is well tolerated and may provide modest benefit for children at risk for severe spinal muscular atrophy but does not prevent widespread degenerative changes.

Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation, with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth, but current evidence on dosing, candidacy and outcomes is limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. This single-center, open-label, pilot phase-1 safety and feasibility clinical trial included 25 pregnant individuals with a diagnosis of fetal SVP. Participants self-administered continuous MSO using medical-grade oxygen concentrators for up to 24 h per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation using echocardiography and late-gestation cardiovascular magnetic resonance imaging. Early outcomes were assessed, including perinatal growth and preoperative brain injury, and neurodevelopmental outcomes were assessed at 18 months using the Bayley Scales of Infant and Toddler Development 3rd edition, and compared with those of a contemporary fetal SVP cohort (n = 217) that received the normal standard of care (SOC). Among the 25 participants, the median maternal age at conception was 35 years, and fetal SVP diagnoses included 16 with right ventricle dominant, eight with left ventricle dominant and one with indeterminate ventricular morphology. Participants started the trial at approximately 29 + 2 weeks' gestation and self-administered MSO for a median of 16.1 h per day for 63 days, accumulating a median of 1029 h of oxygen intake from enrolment until delivery. The only treatment-associated adverse events were nasal complications that were resolved typically by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio or head-circumference-to-abdominal-circumference ratio Z-scores over gestation compared with SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over the study period compared with SOC (P = 0.02), this was probably due to initial baseline differences in placental resistance. At late-gestation cardiovascular magnetic resonance imaging, MSO was not associated with an increase in fetal cerebral oxygen delivery. Similarly, no differences were observed in neonatal outcomes, including preoperative brain weight Z-score and brain injury, mortality by 18 months of age and neurodevelopmental outcomes at 18 months of age. This pilot phase-1 clinical trial indicates that low-dose MSO therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with an increase in fetal cerebral oxygen delivery or improvements in early neurological or neurodevelopmental outcomes. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Abstract 3399: Prediction of cardiac adverse events (AE) in trastuzumab treated breast cancer patients (pts) via a comprehensive genomic and DNA methylation blood based assay

Abstract Background: ERBB2 (HER2) targeted therapy is an important therapeutic class used to treat HER2-positive breast cancer (BC) but has been associated with a risk of cardiotoxicity. Identifying pts likely to experience this AE could allow for early intervention and/or a change in treatment plan. Previous studies have demonstrated the ability to detect changes in methylation patterns of pts who had cardiotoxicity from anti-HER2 therapy. Here, we report a retrospective study assessing the feasibility of using the Guardant Infinity platform (genomic and epigenomic NGS analysis) to predict severe cardiac AE in pts treated with trastuzumab. Methods: Samples (n=46) from female pts with BC undergoing treatment with trastuzumab without prior record of heart failure and with a blood sampling &amp;lt;300 days prior to a documented heart failure event defined a positive case cohort. 70 blood samples were matched to the positive case cohort in all above attributes but without record of patient heart failure to comprise a negative cohort. The &amp;gt;20K differentially methylated regions on Guardant Infinity platform may be useful for detection of specific disease attributes such as treatment-associated AE. To explore this, mixture models were first trained using 880 BC samples unrelated to heart failure to distinguish methylation signals coming from tumor versus non-tumor cfDNA. The resulting normalized methylation signals represent the posterior probabilities of the region molecules to be derived from tumor cells. A subset of methylation regions were selected based on significance of association between heart failure status and normalized methylation signals in the positive and negative AE cohorts. A penalized logistic regression model was then trained on the normalized signals of the selected methylation regions to predict whether a patient would have future cardiac AE. Results: A 10-fold cross validation of the penalized logistic regression models trained on normalized methylation signals produced an area under the curve of 0.78 for predicting heart failure status, suggesting feasibility of using blood-based methylation signals to predict cardiac AE on this platform. The differentially methylated regions selected as model predictors show a clear separation in hypermethylation status between positive versus negative cohorts. Conclusion: Our results show the prediction of cardiac AE in BC pts undergoing trastuzumab treatment in advance of documented heart failure using a blood-based assay designed for simultaneous comprehensive genomic and epigenomic profiling. Given the relatively small sample size within this study, further refinement and validation of the classification models is warranted and ongoing. Citation Format: Sean Gordon, Catalin Barbacioru, Daniel Gaile, Denis Tolkunov, Nicole Zhang, Carin Espenschied, Jing Wang, Tara Dinman, Kimberly Banks, Amar Das, Han-Yu Chuang, Helmy Eltoukhy. Prediction of cardiac adverse events (AE) in trastuzumab treated breast cancer patients (pts) via a comprehensive genomic and DNA methylation blood based assay [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 3399.

The “Get Moving Trial”: A phase I/II RCT of home-based (P)rehabilitation ((P)REHAB) with ExerciseRx in muscle-invasive bladder cancer (MIBC)—Study protocol for a randomized controlled trial.

TPS706 Background: Patients with MIBC often have a high burden of frailty, sarcopenia, mobility impairment, and multimorbidity, each of which is associated with reduced treatment tolerability. Prehabilitation programs are designed to improve functional capability prior to treatment to mitigate functional decline and optimize outcomes. Barriers to widespread adoption include cost, time, intensity of in-person interventions, and overly restrictive inclusion criteria which would exclude most patients with MIBC. Here, we describe a randomized controlled trial to evaluate the feasibility, usability, and impact of a pragmatic (P)REHAB exercise intervention delivered via the ExerciseRx app in participants with MIBC undergoing neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). The primary objectives are to evaluate the (P)REHAB intervention vs. standard care (SC) to quantify the efficacy of the intervention to 1) improve or maintain physical function in patients with MIBC undergoing NAC followed by RC, and 2) globally characterize the impact of the (P)REHAB intervention with respect to patient-reported feasibility and acceptability, health-related quality of life, body-composition, frailty, treatment-associated and clinical outcomes. Methods: We will recruit and randomize 102 patients in a 1:1 ratio to the (P)REHAB or SC arms. The (P)REHAB arm will be prescribed a personalized, home exercise program (~20-minutes, 4x weekly) via the ExerciseRx app, during NAC, prior to RC and for 90-days post-RC as well as graded progression in step count. SC participants will receive printed guideline-based recommendations for physical activity during standard perioperative care. ExerciseRx comprises of 1) a provider dashboard integrated into the electronic health record for prescribing exercises and monitoring patient progress, and 2) a patient app, that administers exercise plans and tracks exercise repetitions using sensors in commodity smart devices. Step count in the (P)REHAB and SC arm will be tracked with Fitbit trackers. In the (P)REHAB arm, step count data from the Fitbit will be reviewable in the ExerciseRx provider dashboard and patient app. Eligibility criteria: English-speaking adults (&gt;18 years) with AJCC pT2-4 N0-1 M0 MIBC planning to undergo NAC followed by RC who are willing and able to participate in the trial. Primary outcome: Change in the Short Physical Performance Battery. Secondary outcomes: FitBit-assessed step count and sedentary time, ExerciseRx adherence and usability, patient-reported quality of life (EORTC-QLQ-C30, -BLM30), change in body composition (fat-mass, fat-free mass), frailty (Cancer and Aging Resilience Evaluation), treatment-associated adverse events between baseline and following NAC, and 3 months following RC. Trial enrollment will commence 10/2023. Clinical trial information: NCT06040762 .

Efficacy and safety of Lianhua Qingwen granule in the treatment of non-influenza viral pneumonia: a randomized, double-blind, placebo-controlled, multicenter clinical study.

To observe the effectiveness and safety of Lianhua Qingwen granule in the treatment of non-influenza viral pneumonia. This study was a multicenter, randomized, double-blind, placebo-controlled trial. Subjects who met the inclusion and exclusion criteria and were clinically diagnosed with viral pneumonia (negative for influenza virus) were randomly divided into the Lianhua Qingwen granule trial group and placebo control group. Patients in the trial group was given Lianhua Qingwen granule, 2 bags at a time, 3 times a day, and the controls were given placebo, with a treatment course of 7 days. Patients' clinical symptoms and signs, and treatment-associated adverse events were observed. Subjects should be included in the full analysis set (FAS) as long as they were all given the medication and had an effectiveness test performed after randomization. Subjects should be included in the Per Protocol Set (PPS),a subset of the total analysis set, which should contain those with strong compliance, no protocol violations, and complete baseline values for the primary indicators. A total of 169 subjects were enrolled in 12 subcenters, including 151 (76 in the trial group and 75 in the control group) in the FAS and 140 (68 in the trial group and 72 in the control group) in the PPS. After 7 days of treatment, the clinical symptom relief rates were 82.98% (FAS) and 87.12% (PPS) in the trial group, and 75.11% (FAS) and 76.02% (PPS) in the control group, respectively. The clinical symptom relief rates in the trial group were significantly higher than those in the control group (p < 0.001). Significant improvements in single symptoms of cough and expectoration in the trial group were observed compared with the control group (p < 0.05). There were no statistical differences in fever, sputum color change, chest pain, muscle pain, dyspnea, chills, and thirst between the two groups (p > 0.05). There were no significant differences in body weight, vital signs, blood routine, urine routine, stool routine, and blood biochemical indicators (CK, AST, ALT, Cr, and Bun) between the two groups before and after treatment (p > 0.05). During treatment, there were no significant differences in the incidence of adverse events and serious adverse events between the two groups (p > 0.05). Lianhua Qingwen granules improved the clinical symptoms of patients with non-influenza virus pneumonia, especially ameliorating cough and expectoration. Lianhua Qingwen granules were associated with good safety.

Efficacy and safety of prazequantel for the treatment of Schistosoma mansoni infection across different transmission settings in Amhara Regional State, northwest Ethiopia.

Schistosoma mansoni and S. haematobium infections have been public health problems in Ethiopia, S. mansoni being more prevalent. To reduce the burden of schistosomiasis, a national school-based prazequantel (PZQ) mass drug administration (MDA) program has been implemented since November 2015. Nevertheless, S. mansoni infection is still a major public health problem throughout the country. Reduced efficacy of PZQ is reported by a few studies in Ethiopia, but adequate data in different geographical settings is lacking. Hence, this study aimed to assess the efficacy and safety of PZQ for the treatment of S. mansoni infection across different transmission settings in Amhara Regional State, northwest Ethiopia. A school-based single-arm prospective cohort study was conducted from February to June, 2023 among 130 S. mansoni-infected school-aged children (SAC). Forty-two, 37, and 51 S. mansoni-infected SAC were recruited from purposely selected schools located in low, moderate, and high transmission districts, respectively. School-aged children who were tested positive both by Kato Katz (KK) using stool samples and by the point of care circulating cathodic antigen (POC-CCA) test using urine samples at baseline were treated with a standard dose of PZQ and followed for 21 days for the occurrence of adverse events. After three weeks post-treatment, stool and urine samples were re-tested using KK and POC-CCA. Then the cure rate (CR), egg reduction rate (ERR), and treatment-associated adverse events were determined. The data were analyzed using SPSS version 21. Out of the total 130 study participants, 110 completed the follow-up. The CR and ERR of PZQ treatment were 88.2% (95%CI: 82.7-93.6) and 93.5% (95%CI: 85.4-98.5), respectively, by KK. The CR of PZQ based on the POC-CCA test was 70.9% (95%CI: 62.7-79.1) and 75.5% (95%CI: 67.3-83.6) depending on whether the interpretation of 'trace' results was made as positive or negative, respectively. After treatment on the 21st day, 78 and 83 participants tested negative both by KK and POC-CCA, with respective interpretations of 'trace' POC-CCA test results as positive or negative. The CR in low, moderate and high transmission settings was 91.7%, 91.2% and 82.5%, respectively (p = 0.377) when evaluated by KK. The CR among SAC with a light infection at baseline (95.7%) by KK was higher than that of moderate (81.5%) and heavy (64.3%) infections (χ2 = 12.53, p = 0.002). Twenty-six (23.6%) participants manifested at least one adverse event. Eleven (10.0%), eight (7.3%), six (5.5%), and three (2.7%) participants complained about abdominal pain, nausea, headache, and anorexia, respectively. All adverse events were mild, needing no intervention. Occurrence of adverse events was slightly higher in high endemic areas (32.5%) than moderate (23.5%) and low endemic areas (p = 0.279). A single dose of 40 mg/kg PZQ was efficacious and safe for the treatment of S. mansoni infection when it was evaluated by the KK test, but a lower efficacy was recorded when it was evaluated by the POC-CCA test. However, the POC-CCA test's specificity, clearance time of CCA from urine after treatment, and interpretation of weakly reactive (trace) test results need further research.

Real-world study of hepatic artery infusion chemotherapy combined with anti-PD-1 immunotherapy for hepatocellular carcinoma patients with portal vein tumor thrombus.

Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) present a poor prognosis. Current systemic therapies offer limited benefits. Hepatic artery infusion chemotherapy (HAIC) is a local regional treatment for advanced HCC, particularly in selected patients such as patients with PVTT or high intrahepatic tumor burden. The purpose of this study is to retrospectively evaluate the efficacy and safety of HAIC combined with anti-PD-1 immunotherapy for HCC patients with PVTT, and explore factors related to survival prognosis, providing clues for treatment decisions for HCC patients. This is a single-center retrospective study conducted over 2 years on consecutive PVTT patients receiving HAIC combined anti-PD-1 antibodies. The primary endpoint was overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors affecting OS. Treatment-associated adverse events were evaluated as well. A total of 119 patients were analyzed. The median OS and PFS were 14.9 months and 6.9 months. A total of 31.1% of grade 3-4 adverse events were reported, with elevated transaminase and total bilirubin being the most common. The independent variables correlated with survival include treatment-related alpha-fetoprotein (AFP) response, the presence of extrahepatic organ metastasis, absolute value of platelet (PLT), neutrophil-to-lymphocyte ratio, and combined usage of tyrosine kinase inhibitors (TKIs). In HCC patients with PVTT, combination therapy with HAIC and anti-PD-1 antibodies might be a promising therapy. The efficacy and safety of this combination protocol on patients with HCC complicated by PVTT warrants further investigation prospectively, especially in combination with TKIs.

Periocular Merkel Cell Carcinoma - an overview of clinical aspects and current therapeutic options

Merkel cell carcinoma (MCC) is a rare but highly aggressive and rapidly expanding malignant skin tumor. It affects the periocular region in approximately 10% of cases. The current treatment recommendation for resectable non-metastatic MCC comprises total surgical excision; however, lymph node or distant metastases are often already present by the time of the diagnosis. Since an immune checkpoint inhibitor therapy with avelumab was first approved for MCC in 2016, there has been considerable improvement in mean survival compared to cytostatic therapy; at the same time, there has been a reduction in serious treatment-associated adverse events. Other immune checkpoint inhibitors are currently still in clinical trials, with very promising initial results. Because of the complexity of the diagnosis, treatment, and prognosis, it is essential that MCC patients receive interdisciplinary care in a specialized center including consultation with a tumor review board.

Efficacy and safety of praziquantel treatment against Schistosoma mansoni infection among pre-school age children in southern Ethiopia

BackgroundPreventive chemotherapy with a single dose of praziquantel given to an all-at-risk population through mass drug administration is the cornerstone intervention to control and eliminate schistosomiasis as a public health problem. This intervention mainly targets school age children, and pre-school age children (pre-SAC) are excluded from receiving preventive chemotherapy, partly due to scarcity of data on praziquantel treatment outcomes.MethodsWe conducted active efficacy and safety surveillance of praziquantel treatment among 240 Schistosoma mansoni-infected pre-SAC who received a single dose of praziquantel (40 mg/kg) in southern Ethiopia. The study outcomes were egg reduction rates (ERR) and cure rates (CRs) four weeks after treatment using the Kato–Katz technique and treatment-associated adverse events (AEs) that occurred within 8 days post-treatment.ResultsThe overall ERR was 93.3% (WHO reference threshold ≥ 90%), while the CR was 85.2% (95% CI = 80.0–89.5%). Baseline S. mansoni infection intensity was significantly associated with CRs, 100% among light infected than moderate (83.4%) or heavy (29.4%) infected children. An increase of 100 in baseline S. mansoni egg count per gram of stool resulted in a 26% (95% CI: 17%, 34%) reduction in the odds of cure. The incidence of experiencing at least one type of AE was 23.1% (95% CI: 18.0%, 29.0%). Stomachache, diarrhea, and nausea were the most common AEs. AEs were mild-to-moderate grade and transient. Pre-treatment moderate (ARR = 3.2, 95% CI: 1.69, 6.14) or heavy infection intensity (ARR = 6.5, 95% CI: 3.62, 11.52) was a significant predictor of AEs (p < 0.001). Sex, age, or soil-transmitted helminth coinfections were not significant predictors of CR or AEs.ConclusionsSingle-dose praziquantel is tolerable and effective against S. mansoni infection among pre-SAC, and associated AEs are mostly mild-to-moderate and transient. However, the reduced CR in heavily infected and AEs in one-fourth of S. mansoni-infected pre-SAC underscores the need for safety and efficacy monitoring, especially in moderate-to-high infection settings. Integrating pre-SACs in the national deworming programs is recommended to accelerate the elimination of schistosomiasis as a public health problem.

Frequency and Risk Factor Analysis for Metronidazole-Associated Neurologic Adverse Events.

Little is known about the risk factors and frequency of metronidazole-associated neurological adverse events. To investigate the risk factors and frequency of metronidazole-associated neurological adverse events. This retrospective study contained two parts. First, we investigated metronidazole treatment-associated neurologic adverse events by performing a population-based cohort study using the Korea Adverse Event Reporting System (KAERS) database from January 2011 to December 2020. Second, we conducted a matched case-control study based on a retrospective cohort of patients treated with metronidazole between January 2006 and July 2021 at a tertiary hospital in South Korea. The data analysis was performed from August 2021 to April 2022. In the case-control study, case patients were defined as those diagnosed with metronidazole-associated encephalopathy or peripheral neuropathy during the study period with causal assessment based on the clinical diagnoses and findings from associated tests. In a ratio of 1:3, case patients were compared to a control group of patients prescribed metronidazole without neurologic adverse events matched for age and cumulative dose of metronidazole. Frequency and risk factors for metronidazole-associated neurological adverse events. Overall, 2,309 cases of neurologic adverse events were reported to the KAERS from 2011 to 2020, and the number of reported neurological adverse events showed an increasing trend. Further, 92,838 patients were prescribed metronidazole during the study period at the Severance Hospital; 54 patients were diagnosed with metronidazole-associated encephalopathy or peripheral neuropathy, 40 with central and 28 with peripheral nervous system adverse events. Liver cirrhosis, chronic kidney disease, intravenous administration, and lower body weight were identified as risk factors for these adverse events. The number of reported metronidazole-associated neurological adverse events are increasing. Prolonged metronidazole treatment in patients with the aforementioned factors requires careful examination for neurological adverse events.

PD-1 Inhibitors combined with paclitaxel (Albumin-bound) and cisplatin for larynx preservation in locally advanced laryngeal and hypopharyngeal squamous cell carcinoma: a retrospective study.

laryngeal and hypopharyngeal squamous cell carcinoma (SCC) is a common head and neck cancer with significant impact on quality of life due to its crucial roles in vocalization, airway protection, and swallowing. This retrospective study aims to evaluate the efficacy and larynx organ preservation of neoadjuvant treatment with PD-1 inhibitors in combination with paclitaxel (Albumin-bound) and cisplatin for locally advanced laryngeal and hypopharyngeal SCC. Medical records of consecutive patients diagnosed with histologically or cytologically confirmed locally advanced SCC of the larynx and hypopharynx, who received PD-1 inhibitor therapy at a single tertiary care center, were reviewed from January 1, 2019, to December 15, 2022. The patients were treated with a combination of PD-1 inhibitors, paclitaxel (Albumin-bound) 260mg/m2, and cisplatin 60mg/m2 (TP) as their first-line therapy. Survival outcomes, laryngectomy-free survival (LFS) rates and response rates were assessed. The study cohort comprised 156 patients, predominantly male, with a median age of 60.4 years. The estimated one-year overall survival (OS) rate was 94.1%, two-year OS rate was 82.5%, one-year progression-free survival (PFS) rate was 80.4%, and two-year PFS rate was 66.3%. The one-year LFS was 86.4%, and the two-year LFS rate was 73.0%. The overall response rate after TP + PD-1 inhibitors therapy was 88.5%. Common treatment-associated adverse events included rash, thyroid function abnormalities, myelosuppression, and colitis. Neoadjuvant therapy with PD-1 inhibitors in combination with paclitaxel (Albumin-bound) and cisplatin showed promising efficacy and tolerability for larynx preservation in locally advanced laryngeal and hypopharyngeal SCC. The high response rates and favorable survival outcomes suggest this approach as a potential treatment option. Prospective randomized controlled trials are needed to further validate these findings and establish the role of immunotherapy in larynx preservation.

Efficacy and safety of ultra-short wave diathermy on COVID-19 pneumonia: a pioneering study.

The ultra-short wave diathermy (USWD) is widely used to ameliorate inflammation of bacterial pneumonia, however, for COVID-19 pneumonia, USWD still needs to be verified. This study aimed to investigate the efficacy and safety of USWD in COVID-19 pneumonia patients. This was a single-center, evaluator-blinded, randomized controlled trial. Moderate and severe COVID-19 patients were recruited between 18 February and 20 April 2020. Participants were randomly allocated to receive USWD + standard medical treatment (USWD group) or standard medical treatment alone (control group). The negative conversion rate of SARS-CoV-2 and Systemic Inflammatory Response Scale (SIRS) on days 7, 14, 21, and 28 were assessed as primary outcomes. Secondary outcomes included time to clinical recovery, the 7-point ordinal scale, and adverse events. Fifty patients were randomized (USWD, 25; control, 25), which included 22 males (44.0%) and 28 females (56.0%) with a mean (SD) age of 53 ± 10.69. The rates of SARS-CoV-2 negative conversion on day 7 (p = 0.066), day 14 (p = 0.239), day 21 (p = 0.269), and day 28 (p = 0.490) were insignificant. However, systemic inflammation by SIRS was ameliorated with significance on day 7 (p = 0.030), day 14 (p = 0.002), day 21 (p = 0.003), and day 28 (p = 0.011). Time to clinical recovery (USWD 36.84 ± 9.93 vs. control 43.56 ± 12.15, p = 0.037) was significantly shortened with a between-group difference of 6.72 ± 3.14 days. 7-point ordinal scale on days 21 and 28 showed significance (p = 0.002, 0.003), whereas the difference on days 7 and 14 was insignificant (p = 0.524, 0.108). In addition, artificial intelligence-assisted CT analysis showed a greater decrease in the infection volume in the USWD group, without significant between-group differences. No treatment-associated adverse events or worsening of pulmonary fibrosis were observed in either group. Among patients with moderate and severe COVID-19 pneumonia, USWD added to standard medical treatment could ameliorate systemic inflammation and shorten the duration of hospitalization without causing any adverse effects.Clinical Trial Registration: chictr.org.cn, identifier ChiCTR2000029972.

Evaluating salvage electroconvulsive therapy for the treatment of prolonged super refractory status epilepticus: A case series

Background and ObjectivesClinicians have treated super refractory status epilepticus (SRSE) with electroconvulsive therapy (ECT); however, data supporting the practice are scant and lack rigorous evaluation of continuous electroencephalogram (cEEG) changes related to therapy. This study aims to describe a series of patients with SRSE treated at our institution with ECT and characterize cEEG changes using a blinded review process. MethodsWe performed a single-center retrospective study of consecutive patients admitted for SRSE and treated with ECT from January 2014 to December 2022. Our primary outcome was the resolution of SRSE. Secondary outcomes included changes in ictal-interictal EEG patterns, anesthetic burden, treatment-associated adverse events, and changes in clinical examination. cEEG was reviewed pre- and post-ECT by blinded epileptologists. ResultsTen patients underwent treatment with ECT across 11 admissions (8 female, median age 57 years). At the time of ECT initiation, nine patients had ongoing SRSE while two had highly ictal patterns and persistent encephalopathy following anesthetic wean, consistent with late-stage SRSE. Super-refractory status epilepticus resolution occurred with a median time to cessation of 4 days (interquartile range [IQR]: 3–9 days) following ECT initiation. Background continuity improved in five patients and periodic discharge frequency decreased in six. There was a decrease in anesthetic use following the completion of ECT and an improvement in neurological exams. There were no associated adverse events. DiscussionIn our cohort, ECT was associated with improvement of ictal-interictal patterns on EEG, and resolution of SRSE, and was not associated with serious adverse events. Further controlled studies are needed.