bluuebunny/crossref_metadata_2025 huggingface dataset:
Peri-operative treatment patterns in real-world muscle-invasive bladder cancer patients undergoing radical cystectomy in the era of adjuvant immunotherapy.
Authors: Squires Patrick , Meng Ke , Hu Xiaohan , Turzhitsky Vladimir , Kao Yu-Han , Wermers Zara , Stuart Jennifer , Ramamurthy Chethan , Sweetnam Connor , Li Haojie , Mamtani Ronac
Published: February 2025

704

Background:
Muscle-invasive bladder cancer (MIBC) has traditionally been managed with radical cystectomy (RC) and pelvic lymph node dissection combined with neoadjuvant (NAD) and/or adjuvant (AD) chemotherapy in eligible patients. In late 2021, adjuvant nivolumab, was approved in the US among patients with certain high-risk of recurrence (HRR) features. Contemporary peri-operative treatment utilization patterns in MIBC patients post-RC is lacking. This study aimed to characterize demographics, clinical features, treatment patterns, and surgical outcomes, in a contemporary cohort of MIBC patients undergoing RC in the post-immunotherapy era.
Methods:
The US Syapse Learning Health Network Enriched Bladder Cancer Cohort, comprised of patients from community-based practices with cancer registry data supplemented and validated by chart review, was used to identify adults with clinically diagnosed MIBC (T2-T4aN0M0, T1-T4aN1M0) undergoing RC from February 19, 2021 (6-months prior to nivolumab approval) to December 31, 2023, with a minimum 6-month follow-up post-RC (except in cases of patient death). Patients with history of other primary cancer, non-bladder systemic antineoplastic therapies, prior partial cystectomy, NAD radiation, or clinical trial participation were excluded. Real-world HRR following resection was defined using a combination of NAD agent receipt and pathological staging (PS) from RC: received NAD cisplatin-based therapy and pT2-T4a or pN+; or, if patient did not receive NAD cisplatin-based therapy, pT3-4a or pN+. Pathological complete response (pCR) was defined as pT0N0.
Results:
Of 138 eligible patients, mean age was 66 years, and the majority were male (82%), white (83%), current/former smokers (68%), presented as de novo MIBC (97%), and had urothelial histology (91%). Overall, 49% (67/138) of patients received RC without NAD or AD treatment. Around 46% (64/138) received NAD chemotherapy; of these, one-third achieved pCR (20/61 NAD chemotherapy-treated patients with complete PS data post-RC). The most prevalent NAD regimens were cisplatin + gemcitabine (58%; 37/64) and methotrexate + vinblastine + doxorubicin + cisplatin (30%; 19/64). Only 14% (20/138) of all patients received AD treatment, with 10% (14/138) receiving AD nivolumab. Half of patients had HRR following resection (63/125 patients with complete PS data post-RC). Among the HRR subgroup, 22% (14/63) received AD treatment, with 19% (12/63) receiving nivolumab.
Conclusions:
In this contemporary cohort of MIBC patients undergoing RC, nearly half received NAD treatment (mainly gemcitabine and cisplatin) while there was limited use of AD treatment. Since FDA approval, AD nivolumab use was 10% among all RC-treated MIBC patients and less than a fifth among HRR patients (nivolumab eligible).
Use of urinary cell-free DNA methylation assay to identify tumor fraction for early detection and recurrence monitoring in urothelial carcinoma.
Authors: Zhao Huan , Dong Hang , Tang Haoran , Zhang Zhihui , Wei Na , Xu Jingjing , Du Pan , Jia Shidong , Xiao Ting , Guo Huiqin
Published: February 2025

844

Background:
Urothelial carcinoma (UC) remains one of the most common urologic cancers, presenting challenges in both initial diagnosis and follow-up due to the invasive nature of traditional diagnostic procedures. Urinary cell-free DNA (ucfDNA) analysis offers a non-invasive alternative, with DNA methylation patterns providing a promising avenue for identifying tumor-derived cfDNA. This study explores the utility of ucfDNA methylation-based tumor fraction (mTF) for early detection and monitoring recurrence in UC patients.
Methods:
A case-control study was conducted with 121 participants, analyzing ucfDNA from patients with pathologically confirmed malignant tumors and benign lesions. A panel of UC-specific methylation markers was developed to quantify tumor-derived ucfDNA in a tissue-agnostic manner. The methylation-based tumor fraction (mTF) was then correlated with reference circulating tumor DNA (ctDNA) levels and clinical urine cytology indicators.
Results:
Our analysis revealed a significantly higher mTF in UC patients compared to controls (Wilcoxon test, p-value = 3.3 x 10
-9
). Utilizing mTF as an independent biomarker for distinguishing malignant from benign cases achieved a positive predictive value (PPV) of 92% and a negative predictive value (NPV) of 90%. Moreover, relapse signals (mTF > 0.005) were detected in follow-up urine samples from all patients (7/7) who had undergone transurethral resection of bladder tumor (TURBT).
Conclusions:
The urinary cfDNA methylation-based tumor fraction presents a promising non-invasive biomarker for both early detection and recurrence monitoring of urothelial carcinoma. This approach could significantly improve patient management by providing a valuable tool for diagnosis and ongoing surveillance, underscoring the need for innovative diagnostic strategies in UC.
Use of urinary cell-free DNA fragmentomics in urothelial carcinoma diagnosis.
Authors: Zhao Huan , Gan Shuang , Dong Hang , Tang Haoran , Zhang Zhihui , Wei Na , Xu Jingjing , Du Pan , Jia Shidong , Xiao Ting , Guo Huiqin
Published: February 2025

846

Background:
Traditional diagnostic procedures for urothelial carcinoma (UC) are often limited by patient burden and reduced sensitivity, impacting diagnostic accuracy. Liquid biopsy-based molecular detection, particularly through fragmentomics analysis, offers a promising supplement to clinical applications. Fragmentomics, which examines the unique fragmentation patterns of tumor DNA, can provide crucial insights into tumor origin and behavior. This study aims to leverage urinary cell-free DNA (ucfDNA) fragmentomics patterns to enhance the diagnostic capabilities for urothelial carcinoma.
Methods:
We conducted a case-control study to investigate cfDNA fragment size distributions in urine samples. The study included patients diagnosed with malignant UC (cases) and individuals with benign conditions (controls). High-throughput sequencing was used to identify distinct fragmentomics patterns, including variations in fragment size, end motifs, and genomic coverage at transcription factor binding sites. Diagnostic performance was evaluated using sensitivity, precision, and the area under the curve (AUC).
Results:
UC patients exhibited distinct fragmentation patterns, characterized by a shift towards shorter cfDNA fragments compared to controls. Analysis of fragment size and genomic coverage provided additional diagnostic insights when combined with methylation data, significantly improving early-stage UC detection. Fragmentomics combined with methylation markers achieved an AUC of 86.25%, with a sensitivity of 89.3% and a precision of 75.76%, demonstrating substantial improvements in diagnostic accuracy.
Conclusions:
Urinary cfDNA fragmentomics provides valuable complementary information to traditional molecular markers for detecting urothelial carcinoma. This innovative approach enhances diagnostic precision and shows potential for improving early detection strategies, with promising applications in non-invasive cancer screening and monitoring.
Determining an immunohistochemical profile to predict response to intravesical bacillus Calmette–Guérin (BCG) in patients with high-grade non-muscle invasive bladder cancer.
Authors: Lam Darren , Wei Gavin , Lawrence Mitchell G. , Choo Nicholas , Taylor Renea , Huntington Nicholas , Kumar Beena , Rorke Steuart , Nelva Piero , Keerthikumar Shivakumar , Harper Matthew , Donnellan Scott , Ranasinghe Weranja
Published: February 2025

847

Background:
Intravesical Bacillus Calmette–Guérin (BCG) remains the gold standard for the management of high-grade non-muscle invasive bladder cancer (NMIBC). However, up to 70% of patients fail BCG therapy. We aimed to define potential mechanisms for BCG resistance and develop an immunohistochemical (IHC) panel to help identify patients likely to respond to intravesical BCG.
Methods:
Patients with NMIBC undergoing induction intravesical BCG at a tertiary institution were identified. Twelve BCG-responders and 13 non-responders were matched for patient and tumour factors. RNA sequencing was performed with hierarchical clustering and Gene Set Enrichment Analysis to identify response resistance mechanisms. Immune cell subsets were measured using pre and post-BCG therapy for CD4, CD8, T-Bet, GATA-3 and PD-1 antibodies. GATA-3 and T-Bet stains were used as surrogates for Th-2 and Th-1 cells, respectively. T-tests were used to assess differences. An integrated IHC panel using CD4, CD8, T-Bet, GATA and PD1 was developed and correlated with BCG response using Receiver Operator Characteristic (ROC) curves.
Results:
On hierarchical clustering, BCG-responders and non-responders had distinct gene expression profiles pre- and post-BCG. Prior to exposure to BCG, non-responders had enrichment for a pro-inflammatory gene signature with a higher CD4:CD8 ratio (2.94 vs 1.71, p=0.0003) and a higher Th-2/Th-1 (GATA/T-Bet) ratio (5.95 vs 2.97, p=0.0026) compared to BCG-responders, on IHC. However, on exposure to BCG, non-responders had no changes to the CD4:CD8 or Th-2/Th-1 ratios but had a 78% increase in the PD-1 expression (MD 20.83/5hpf, p=0.016) with BCG, indicating T cell exhaustion. In contrast, upon exposure to BCG, responders had an increase in the Th-2/Th-1 ratio (mean difference 0.9323, p=0.0228) with enrichment of the natural killer cell pathway compared to non-responders (p<0.05). The area under the ROC curve using the integrated IHC panel to predict BCG response was 0.864 (95% CI: 0.663 to 1.000).
Conclusions:
BCG non-responders had a pro-inflammatory TME, which showed marked T cell exhaustion on exposure to BCG. In contrast, responders had a baseline TME with low CD4:CD8 and low Th-2/Th-1 ratios at baseline, which allowed activation of both humoral and adaptive responses to BCG. These immune changes can be utilised as an IHC panel to predict response to BCG therapy.
CD39 expression as a predictive biomarker for neoadjuvant treatment in muscle-invasive bladder cancer.
Authors: Buisan Oscar , Senserrich Jordi , Servian Pol , Sanchez Maria , Garcia Elisabet , Pagès Joan , Freixa Roger , Colomer Anna , Cervera Jordi , Areal Joan , Clotet Bonaventura , Bellmunt Joaquim , Cabrera Cecilia
Published: February 2025

850

Background:
Neoadjuvant therapy before radical cystectomy (RC) is the the standard treatment for muscle-invasive bladder cancer (MIBC). However, a significant number of patients do not respond to these therapies. Identifying biomarkers predictive of treatment response and developing novel therapeutic strategies are crucial to improving patient management and survival. This study aims to investigate non-invasive biomarkers that can predict response to neoadjuvant therapy in MIBC patients and explore their potential use in the design of new therapies.
Methods:
Immunophenotyping was performed on blood and bladder tissue samples from MIBC patients at pre-treatment (transurethral tumor resection (TUR); n=17; chemotherapy n=13 and immunotherapy n=4) and post-neoadjuvant treatment (RC, n=21; chemotherapy n=18 and immunotherapy n=3). Plasma soluble CD39 (sCD39) and adenosine levels were measured by ELISA and an enzymatic assay, respectively. Treatment response was evaluated at RC, and patients were classified as non responders (³ypT2³N1) or responders (<ypT2ypN0).
Results:
Non responder patients exhibited a significant higher percentage of CD39
+
cells in circulating total and different maturation CD4
+
T cells subsets, particularly at TUR, suggesting a potential role in treatment resistance. CD39
+
CD4
+
T cells showed elevated PD-1 expression, decreased levels of Granzyme-B and Perforin, and strong correlations with the regulatory T cell marker FoxP3 and the checkpoint inhibitor TIGIT. Intratumoral CD39
+
CD4
+
T cells were also more frequent in non responder patients, correlating positively with the expression of tumor checkpoint inhibitors TIGIT and ICOS and the regulatory marker FoxP3. In blood, CD39
+
CD4
+
T cell frequencies correlated with sCD39 levels, which in turn were associated with adenosine concentration in plasma.
Conclusions:
CD39 expression in CD4
+
T cells and its plasma levels emerge as promising biomarkers for predicting response to neoadjuvant treatment in MIBC. Targeting CD39 may offer a novel therapeutic strategy to overcome treatment resistance, potentially improving outcomes in MIBC patients.
Comprehensive bladder cancer molecular profiling and monitoring based on mutational, epigenomic, and expression data from real-world patients.
Authors: Tan Alan , Huang Yong , Bonora Giancarlo , Xiang Binggang , Dai Chao , Liu Fang , Zhu Ziqi , Jia Shidong , Du Pan
Published: February 2025

860

Background:
Bladder cancer poses considerable therapeutic challenges, particularly in the context of bladder preservation strategies that aim to balance maintaining quality of life with achieving optimal survival outcomes. Traditional treatments, such as radical cystectomy, often have profound impact on patient morbidity. However, recent advances in molecular profiling -- including mutational, epigenomic, and gene expression analyses -- offer promising avenues for personalized cancer treatment approaches. Despite these advances, comprehensive studies leveraging detailed analysis of molecular profiling and urine-based monitoring in bladder cancer are lacking.
Methods:
A cohort of 30 real-world patients with bladder and upper tract urothelial carcinoma (UTUC) of various subtypes were included in this study. Standard treatment modalities employed were neoadjuvant chemotherapy, trimodality therapy (TMT) for bladder preservation, and systemic chemotherapy or immunotherapy in the metastatic setting. PredicineCOMPLETE is an integrated assay that interrogates genomic alterations such as mutations, copy number variations (CNVs), and gene fusions – as well as DNA methylation and transcriptomic profiles. All samples had previously undergone the PredicineBEACON urine MRD test, which covers mutation/CNV/fusion analysis. We further performed whole-transcriptome sequencing (WTS) on baseline urine cell pellet (UCP) samples, and the PredicineEPIC DNA methylation assay on all the follow-up timepoint samples.
Results:
The PredicineCOMPLETE assay generated significantly more comprehensive data compared to mutational panels alone, providing a rich molecular landscape of each patient’s tumor biology. Comprehensive correlation analysis between DNA methylation and RNA expression were conducted. Strong correlation was observed for some bladder cancer biomarker genes such as TERT and TP53. An AI model was trained using patients’ treatment decision (bladder preservation versus surgery), clinical features, and the comprehensive molecular data obtained. The trained AI model accurately matches the physician’s choices over 90% of the validation cases.
Conclusions:
This study demonstrates that comprehensive molecular profiling using the PredicineCOMPLETE assay helps us understand the underlying disease biology. Combined with machine learning and AI modeling, it can effectively assist in treatment decision-making for bladder cancer patients. While these initial results are encouraging, the limited sample size necessitates further validation in larger, independent cohorts to confirm the model’s efficacy and generalizability.
Surveillance with plasma ctDNA in non-muscle invasive bladder cancer.
Authors: Kagathur Santosh , Haniff Shaniza , Christy Joshua Jonathan , Isaac Dan
Published: February 2025

864

Background:
Non-muscle invasive bladder cancer (NMIBC), constitutes 70% of all bladder cancer. Routine surveillance methods for detecting patients at risk of progression to muscle-invasive or metastatic disease are invasive and may delay intervention. Circulating tumor DNA (ctDNA) analysis presents a non-invasive alternative for monitoring minimal residual disease, potentially allowing for earlier detection of disease progression or recurrence. This study evaluates the role of plasma ctDNA in the early detection and monitoring of high-risk NMIBC.
Methods:
Eleven high-risk NMIBC patients were enrolled in this study. All patients underwent standard transurethral resection of bladder tumors (TURBT) before enrollment. Blood samples were collected prior to initiation of intravesical therapy and then every three months for two years (from January 12, 2022, to February 1, 2024). Plasma ctDNA was analyzed using Natera's Signatera, employing multiplex PCR and next-generation sequencing to detect tumor-specific mutations. Individual mutation profiles were established via whole-exome sequencing of tumor and matched normal tissue. Detection of ctDNA was compared with results from routine cystoscopy, urine cytology, and upper-tract imaging. Disease outcomes of interest included relapse, progression to muscle-invasive disease, and metastasis.
Results:
Of the eleven high-risk patients, one patient developed diffuse bilateral upper tract high-grade recurrence followed by metastatic disease that was preceded by positive ctDNA. Another patient was noted to have muscle-invasive disease again following the detection of ctDNA and subsequently underwent radical cystectomy. This patient eventually developed metastasis six months later. One patient elected to withdraw from the study. In our study, 20% of patients with high-grade papillary NMIBC had detectable ctDNA nine months post-diagnosis. Notably, both patients with positive ctDNA had normal findings on routine surveillance. However, they eventually progressed to stage IV urothelial carcinoma. In contrast, ctDNA was undetectable in the remaining eight patients, all of whom remained recurrent free to-date. These findings suggest ctDNA may serve as an early predictor of relapse and progression, with a number needed to test of 5 to prevent one delayed identification of disease progression.
Conclusions:
Plasma ctDNA analysis shows promise as a non-invasive tool for identifying NMIBC patients at risk of disease progression. Early ctDNA detection may enable more personalized treatment approaches, improving patient outcomes. Larger studies are warranted to confirm these findings and support the integration of ctDNA into standard NMIBC surveillance protocols.
Addition of darolutamide to first line treatment of metastatic castration-resistant prostate cancer (mCRPC): A randomized open label phase II trial (SAKK 08/23).
Authors: Vogl Ursula , Eckhardt Katrin , Gobat Katrin , Gillessen Silke , Cathomas Richard
Published: February 2025

TPS280

Background:
The implementation of androgen-receptor pathway inhibitors (ARPI) +/- docetaxel (doce) in addition to androgen deprivation therapy (ADT)in metastatic hormone sensitive prostate cancer (mHSPC) has limited the therapeutic options in the mCRPC setting. In the SAKK 08/16 trial, darolutamide (daro) maintenance demonstrated prolonged radiographic progression-free survival (rPFS) compared to placebo in patients (pts) with mCRPC who had received prior ARPI, and did not progress during taxane therapy. This benefit was more pronounced in pts with a response to the prior ARPI. Continuing enzalutamide in addition to doce versus a switch to doce alone after progression on enzalutamide in later line mCRPC has been demonstrated to prolong PFS in a phase 3 trial. The continued maximal androgen-receptor (AR) blockage in the mCRPC first-line setting in addition to a standard of care could potentially control persistent AR-pathway sensitive clones. Daro is an optimal drug for the use as ARPI maintenance because of its favourable safety profile and a low potential for drug-drug interactions.We hypothesize that the addition of daro to a first-line SOC in mCRPC in pts with a prior long response to ADT and ARPI in mHSPC improves rPFS.
Methods:
SAKK 08/23 is an international open-label randomized phase 2 trial enrolling pts with ECOG 0-2 having progressed to mCRPC with a response to prior ADT-ARPI combination for at least 18 months showing at least a 50% PSA response or partial remission according to RECIST. Pts must not have received treatment for mCRPC. Pretreatment with doce in mHSPC is allowed. Patients will be randomized 1:1 to receive physician’s choice standard of care (SOC: doce, cabazitaxel,
177
lutetium-PSMA, radium-223 or olaparib) or SOC with daro. Treatment with daro will be continued until progression according to PCWG3. Stratification factors include country and treatment with taxanes versus radium-223 versus
177
lutetium-PSMA vs olaparib. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to symptomatic/clinical progression, event-free survival, time to PSA progression by PCWG3, objective response rate according to RECIST, PSA response and PSA response duration. Without daro we expect a median rPFS of 6 months for taxanes, radium-223 and Olaparib and 8 months for
177
lutetium-PSMA. Assuming a three months increase in median rPFS with the addition of daro 121 events are needed (one-sided type I error of 10%, power of 80%) which leads to a sample size of 162 patients (including 10% dropout after one year). The trial will enroll pts in Switzerland and Spain. Accrual to the study is currently ongoing. Clinical trial information:
NCT06401980
.
A phase 2/3 multicenter trial evaluating safety and efficacy of a new mucoadhesive gemcitabine suspension for ablation of upper tract urothelial carcinoma.
Authors: St-Laurent Marie-Pier , Schmitt Veronika , Gleave Martin , Black Peter Colin
Published: February 2025

TPS889

Background:
Patients with large, multifocal, or frequently recurrent low-grade (LG) upper tract urothelial carcinoma (UTUC) often require nephroureterectomy to effectively manage their disease, despite the low oncologic risk of progression. There is a need for safer, more effective nephron-sparing treatments. Intraluminal therapies are underdeveloped and limited by the short dwell time of drugs in the collecting system. Intravesical gemcitabine has shown efficacy and minimal toxicity in treating bladder urothelial carcinoma, suggesting a similar potential for UTUC. The investigational drug (ST-02) is a novel mucoadhesive gemcitabine suspension designed for pyelocaliceal instillation. It changes from a liquid to a mucoadhesive gel in the collecting system once in contact with water, thereby facilitating prolonged exposure to gemcitabine. This trial aims to demonstrate that intraluminal administration of ST-02 can effectively and safely ablate LG UTUC.
Methods:
This is a prospective, multicenter, single-arm, open-label phase II/III clinical trial (NCT06124976) designed to enroll 70 patients with biopsy-confirmed LG UTUC. The study employs a two-stage design with early stopping rules, where the trial will be halted if there are 8 or fewer complete responses (CR) among the first 30 participants (phase II). Eligible patients must have tumors measuring 5-15 mm at treatment initiation. ST-02 will be instilled via retrograde or antegrade catheterization weekly for 6 weeks. The primary endpoint is the CR rate, assessed by ureteroscopic evaluation 6 weeks after the last instillation. Maintenance therapy with ST-02 will be offered to participants with ongoing CR at 3, 6, 9, 12, and 15 months. Secondary objectives include evaluating the durability of CR at 12 months, objective response rates based on tumor size, event-free survival, and safety. The trial includes a safety lead-in phase with pharmacokinetic evaluation in the first 10 patients. An independent Data Monitoring Committee will oversee safety and efficacy assessments. Clinical trial information:
NCT06124976
.
Inhibition of TSH receptor expression by a cyclotriazadisulfonamide as a potential treatment of Graves’ Hyperthyroidism
Authors: Krieger Christine C , Neumann Susanne , Sui Xiangliang , Templin Jay Scott , Kapri Topprasad , Demillo Violeta G , Olsen Ryan K , Intasiri Amarawan , Gershengorn Marvin C , Bell Thomas W
Published: February 2025

Graves’ hyperthyroidism (GH) is a condition in which autoantibodies chronically activate the thyrotropin (thyroid-stimulating hormone) receptor (TSHR). TSHR is one of the few G protein-coupled receptors (GPCRs) predicted to have a signal peptide, making it a potential target for cyclotriazadisulfonamide (CADA) compounds. We sought to determine whether a small-molecule drug that selectively induces nascent protein degradation could decrease TSHR expression in vitro and in vivo at therapeutically relevant levels. We tested several CADA compounds for their ability to reduce TSHR surface expression in HEK 293 cells overexpressing human TSHR (HEK-TSHR cells) using flow cytometry. Inhibition of downstream cAMP production and thyroglobulin (Tg) secretion were measured in HEK-TSHR and human thyrocytes respectively. Follow-up studies in VGD040-treated BALB/c mice assessed plasma levels of free T4 in response to TSH stimulation. Among a number of CADA analogues, VGD040 decreased TSHR at the surface of HEK-TSHR cells. VGD040 was found to be selective towards TSHR compared to similar glycoprotein hormone receptors. In human thyrocytes, reduction of TSHR surface-expression by VGD040 decreased cAMP production and Tg secretion. Most importantly, VGD040 decreased TH secretion in mice without apparent toxicity at the effective dose studied. VGD040 is an important new lead with potential for developing safe drug treatments for GH.
Analgesic Efficacy of Repeated Daily Injections Versus Continuous Adductor Canal Block After Total Knee Arthroplasty: An Open-Label, Randomized Clinical Trial
Authors: Kim Hansol , Yoo Seokha , Kwon Seokmin , Kim Youngwon , Bae Jinyoung , Kim Yoon Jung , Cho Youn Joung , Kim Jin-Tae , Lim Young-Jin
Published: February 2025

BACKGROUND:

Total knee arthroplasty is frequently associated with postoperative pain. Continuous adductor canal blocks are widely used for postoperative analgesia. However, the high dislocation rate of nerve block catheters often leads to ineffective pain control. This study aimed to compare the analgesic effectiveness of repeated daily injections of adductor canal block up to postoperative day (POD) 2 and continuous adductor canal block in patients who underwent total knee arthroplasty.

METHODS:

Seventy-six patients who underwent total knee arthroplasty under spinal anesthesia were randomized to receive repeated daily adductor canal blocks at the end of surgery and in the morning of POD1 and POD2 (n = 39) or continuous adductor canal block with a patient-controlled bolus (n = 37). All patients received perioperative multimodal analgesia. The primary outcome was the time-weighted average numeric rating scale pain score at rest, measured from the end of surgery to 14:00 on POD2. Pain scores over time were also compared using generalized estimating equations.

RESULTS:

There was no significant difference in the time-weighted average pain score at rest (from POD0 to POD2) between the repeated injection group (2.9 ± 1.9) and the continuous group (3.1 ± 2.1; mean difference 0.09, 95% confidence interval [CI], −0.81 to 0.99; P = .842). Repeated daily injections did not reduce pain at rest or pain during movement after adjusting for time. In the continuous group, the cumulative occurrence of nerve block catheter dislocation was 48.6% (18/37) on POD1 and 62.2% (23/37) on POD2, as assessed using ultrasonography.

CONCLUSIONS:

This study was unable to determine whether repeated daily injections or continuous adductor canal block provided superior analgesia in terms of the average pain score during the first 2 days after total knee arthroplasty. However, considering the high dislocation rate of nerve block catheters, reducing catheter dislodgement may improve the analgesic effectiveness of continuous adductor canal blocks.
The Safety and Effectiveness of Surgical Management of Brachial Plexus Tumors: A Retrospective Case Series
Authors: Al-Mistarehi Abdel-Hameed , Weber-Levine Carly , Jiang Kelly , Alfonzo Horowitz Melanie , Xia Yuanxuan , Fayez Feras , Mendelson Benjamin Z. , Albert Avi N. , Papali Pritika , Neerumalla Sushanth , Theodore Nicholas , Belzberg Allan J. , Lubelski Daniel
Published: February 2025

BACKGROUND AND OBJECTIVES:

Brachial plexus tumors represent a challenge for neurosurgeons because of complex anatomy, risks during surgery, and limited evidence-based guidance in managing these rare tumors. We aim to investigate the clinical characteristics, complications, and neurological outcomes of surgical resection of benign brachial plexus tumors.

METHODS:

We reviewed the medical records of patients diagnosed with benign brachial plexus tumors at (Johns Hopkins Medical Institutes) from July 2014 to April 2023. Of 123 screened patients, those who had surgical resection for benign brachial plexus tumors were identified.

RESULTS:

A total of 56 patients were included. Their mean (SD) age was 46.79 years (14.67), and 60.7% were women. The most common initial presentations were palpable mass (82.1%) and pain (66.1%). Sensory and motor deficits were reported in 27 (48.2%) and 12 patients (21.4%), respectively. Gross total resection was achieved in 53 patients (94.6%), and en bloc approach was performed in 39 patients (69.6%). Three patients developed postoperative complications, including hematoma, wound infection, and persistent sinus tachycardia, with no recorded deaths nor significant neurological deficits. With a mean follow-up of 38.08 (39.93) months after the surgery, 35 patients (94.6%) reported improvements in their preoperative pain, and 20 patients (54.1%) had total pain relief. Among those with preoperative neurological deficits, the recovery from sensory deficits was documented in 18 patients (66.7%), with better outcomes observed with preoperative dysesthesias rather than paresthesias, and the motor strength recovery rate was 83.3%. Two patients developed new sensory deficits, whereas no new motor deficits were reported. Tumor recurrence was reported in 1 patient (1.8%).

CONCLUSION:

Brachial plexus tumors can be cured surgically by gross total resection with favorable outcomes, minimal complications, and low incidence of recurrence.
A general RNA-templated RNA extension activity of E. coli RNA polymerase
Authors: Galls Drew , Mueller Andreas U , Greenwald Emily , Fire Andrew
Published: February 2025

Multi-subunit “DNA-dependent” RNA polymerases (RNAPs) have noncanonical RNA-directed RNA synthesis activity; this allows synthesis of complementary RNA from RNA templates. Such noncanonical RNAP activities are biologically significant, serving RNA pathogens such as hepatitis delta virus (HDV) and contributing to cellular gene regulation. Despite the broad biological implications of these processes, our understanding of the underlying RNAP mechanisms remains incomplete. Using E. coli RNAP, a multi-subunit RNAP, as a model, we describe here the general RNA-templated RNA extension activity of that enzyme. Our data argue that the 3' end of an added RNA template can fold back and pair with upstream bases in the template, creating an intramolecular primer-template duplex as short as 1-2 base pairs. The RNAP then extends this intramolecular duplex, incorporating nucleotides complementary to the template. RNA-templated RNA extension occurred in minutes and did not appear to be suppressed by the presence of a promoter-containing DNA template. Excepting oligonucleotides implicitly designed to prevent any possibility of 3' end self-priming, every RNA template we tested could be extended by the enzyme, highlighting the general nature of this reaction. These data define a general activity of a cellular RNAP. Unrestricted, this activity could contribute to emergence and replication of RNA-based agents such as HDV and viroids; if highly regulated, the activity could limit these same elements.
Numerical study on the kinematic response of piled foundations to a stationary or moving load
Authors: Ευθυμίου Γεωργία
Published: February 2025

Η παρούσα αριθμητική μελέτη εστιάζει στο πρόβλημα της δυναμικής αλληλεπίδρασης θεμελιώσεων με πασσάλους υπό αρμονική διέγερση σε υψηλές συχνότητες που σχετίζονται με την πρακτική της αντιδονητικής προστασίας. Τα προγράμματα πεπερασμένων στοιχείων Plaxis (2D & 3D) και Abaqus χρησιμοποιούνται για αναλύσεις εν-χρόνω και κατά συχνότητα, αντίστοιχα. Σε πρώτο βήμα υπολογίζονται οι σύνθετες δυναμικές δυσκαμψίες ομάδων πασσάλων με πλάκα-κεφαλόδεσμο χωρίς / σε επαφή με το έδαφος (pile groups και piled rafts, αντίστοιχα), καθώς και εγκιβωτισμένων θεμελίων σε όλες τις διευθύνσεις ταλάντωσης, με στόχο την εμβάθυνση στην κατανόηση του προβλήματος της αδρανειακής φόρτισης. Έμφαση δίνεται στην κινηματική απόκριση μεμονωμένων πασσάλων και ομάδων πασσάλων σε κυματικό πεδίο που προέρχεται από ένα απομακρυσμένο σταθερό ή κινητό αρμονικό κατακόρυφο σημειακό φορτίο που δρα στην επιφάνεια του εδάφους. Η κινηματική αλληλεπίδραση ποσοτικοποιείται μέσω των συναρτήσεων μεταφοράς, οι οποίες είναι λόγοι της απόκρισης της θεμελίωσης προς εκείνη του ελεύθερου πεδίου. Ως κρίσμη στο πλαίσιο της συγκεκριμένης διέγερσης αξιολογείται η κατακόρυφη συνιστώσα της απόκρισης. Αποδεικνύεται ότι ένα σταθερό αρμονικό φορτίο είναι μια καλή προσέγγιση για ένα κινητό αρμονικό φορτίο σε περιπτώσεις όπου η ταχύτητα κίνησης του φορτίου είναι σχετικά χαμηλή συγκριτικά με την ταχύτητα των κυμάτων Rayleigh στο έδαφος – κάτι το οποίο είναι αρκετά συνηθισμένο στην πρακτική της μηχανικής. Αντίστοιχα, ένα στατικό φορτίο αποτελεί καλή προσέγγιση ενός κινητού φορτίου σταθερού μεγέθους. Επιπλέον, παρουσιάζονται αναλυτικές λύσεις για την απόκριση μεμονωμένων πασσάλων και ομάδων πασσάλων υπό διέγερση μέσω κυμάτων Rayleigh, οι οποίες μπορούν επίσης να χρησιμοποιηθούν στο εγγύς πεδίο. Η προσθήκη επιπλέον σειρών πασσάλων αντίθετα στη διεύθυνση της κυματικής διάδοσης εξετάζεται στο πλαίσιο της αντιδονητικής προστασίας. Πράγματι, για ένα σημαντικό εύρος συχνοτήτων, η περαιτέρω προσθήκη σειρών πασσάλων σε μια θεμελίωση με πασσάλους έχει ευνοϊκή επίδραση στη μείωση του επιπέδου των ταλαντώσεων που υπολογίζεται στην τελευταία σειρά των πασσάλων ή στο ελεύθερο πεδίο πίσω από τη θεμελίωση. Αυτό, ωστόσο, δεν ισχύει καθώς η συχνότητα διέγερσης αυξάνεται περαιτέρω, και η αλληλεπίδραση μεταξύ των πασσάλων γίνεται πολύπλοκη. Από την άλλη πλευρά, η επέκταση της πασσαλοθεμελίωσης με πρόσθετες στήλες πασσάλων παράλληλα στην κατεύθυνση διάδοσης του κύματος έχει θετική επίδραση στις υψηλές συχνότητες. Η ακρίβεια των αποτελεσμάτων επαληθεύεται με αναλυτικές λύσεις. Έμφαση δίνεται επίσης σε σημεία-κλειδιά της μοντελοποίησης με πεπερασμένα στοιχεία.
Σχολική επίδοση στη γλώσσα, στα μαθηματικά, στην αισθητική και φυσική αγωγή παιδιών πρωτοβάθμιας εκπαίδευσης τεκνοποιημένων με τεχνικές εξωσωματικής γονιμοποίησης
Authors: Αντωνιάδου Μαρία
Published: February 2025

Η υπογονιμότητα, η μειωμένη ικανότητα φυσικής σύλληψης και τεκνοποίησης, αφορά στο 3,5% έως 16,7% του παγκόσμιου πληθυσμού αναπαραγωγικής ηλικίας. Τα ζευγάρια που αντιμετωπίζουν προβλήματα υπογονιμότητας καταφεύγουν συχνά σε τεχνικές ιατρικώς υποβοηθούμενης αναπαραγωγής (ΙΥΑ). Από την έναρξη της εφαρμογής των μεθόδων ΙΥΑ εκφράστηκαν ανησυχίες, από τη διεθνή επιστημονική κοινότητα, για τη σωματική υγεία των γεννηθέντων παιδιών και τη γνωστική, κινητική και ψυχοσυναισθηματική τους ανάπτυξη. Στη διεθνή βιβλιογραφία υπάρχει ασυνέπεια μεταξύ των ευρημάτων που αφορούν στη σχέση μεταξύ των μεθόδων ΙΥΑ και των μεταβλητών σωματικά υγεία, γνωστική, κινητική και ψυχοσυναισθηματική ανάπτυξη. Η παρούσα διατριβή, σχεδιάστηκε με σκοπό τη διερεύνηση της σχολικής επίδοσης παιδιών Πρωτοβάθμιας Εκπαίδευσης, τεκνοποιημένων με τεχνολογίες ΙΥΑ. Το δείγμα της έρευνας αποτέλεσαν 638 παιδιά (ηλικίας 6 έως 12 ετών), 330 αγόρια και 308 κορίτσια, που φοιτούσαν στην Α΄ τάξη έως την Στ΄ τάξη σε δημόσια Δημοτικά Σχολεία της Περιφέρειας Κεντρικής Μακεδονίας. Τα παιδιά ταξινομήθηκαν σε δύο ομάδες με κριτήριο την αναφορά των γονέων τους: φυσικής σύλληψης και εξωσωματικής γονιμοποίησης. Η σχολική τους επίδοση αξιολογήθηκε από τους/τις διδάσκοντες/ουσες εκπαιδευτικούς σε πέντε μαθήματα του προγράμματος σπουδών (Γλώσσα, Μαθηματικά, Εικαστικά, Μουσική, Φυσική Αγωγή) με ειδικό «εργαλείο» που δημιουργήθηκε για τον σκοπό της μελέτης. Πραγματοποιήθηκε ανάλυση δεδομένων μεταξύ των δύο ομάδων και εντός κάθε ομάδας. Βρέθηκαν σημαντικές διαφορές μεταξύ α) κοριτσιών και αγοριών και των δύο ομάδων, αφού τα κορίτσια σημείωσαν σημαντικά καλύτερες επιδόσεις στη μέση σχολική επίδοση, στα Εικαστικά, στη Μουσική και στη Φυσική Αγωγή, β) κοριτσιών και αγοριών εξωσωματικής γονιμοποίησης στη Γλώσσα, με τα κορίτσια να υπερέχουν και γ) δίδυμων και τρίδυμων, με υψηλότερες επιδόσεις των δίδυμων παιδιών και των δύο φύλων έναντι των τρίδυμων, με εξαίρεση τα Εικαστικά. Τα ευρήματα της εργασίας συζητούνται σε θεωρητικό κι εφαρμοσμένο επίπεδο. Το θεωρητικό περιλαμβάνει βιολογικές και ψυχολογικές ερμηνείες και το εφαρμοσμένο εκπαιδευτικές πρακτικές και διδακτικές στρατηγικές στο πλαίσιο της Πρωτοβάθμιας Εκπαίδευσης. Τέλος, σχολιάζονται εκτενώς οι κοινωνικές και πολιτικές προεκτάσεις της εκπαιδευτικής αξιολόγησης των παιδιών τεκνοποιημένων με τεχνικές ΙΥΑ.
Regional Cardiac Needs - Africa: How to Heal the Global South
Authors: Yankah Charles
Published: February 2025

Background: The current population of Africa of 1.4 billion will double by 2050. Similarly the pediatric (43%: 387,6 million, < 15 yrs old) as the student age (< 25 years) population (60% : 884 millIion) will double. About 1- 4% of babies are born with congenital heart disease and 1-30% are susceptible to develop preventable rheumatic heart disease caused by streptococcal throat infection associated with rheumatic fever. Only 2% (0.5-3.4%) of children with heart diseases have access to heart surgery. Open heart surgery per million population in sub-Saharan Africa is 5/million as compared to 116/ million in South America, WHO recommends 400 OHS/million which is currently impossible in Africa even the 40 OHS/million suggested by PASCaTS remains unmet.
Case Report: Surface Contamination and Chickenpox: A Report of a Rare Transmission
Authors: Bereda Gudisa
Published: February 2025

Chickenpox is an extremely contagious disease; caused by the varicella-zoster virus primary infection. The most common symptom of chickenpox is a vesicular rash that appears on the scalp, back, and front of the neck, face, and scapulae and then disseminates distally to the limbs. A 27-year-old adult Black African male health care worker presented with severe headache, intermittent weakness and inability to walk, intermittent nausea, fever, nocturnal polydipsia, shortness of breath, itching, pruritus (intensely pruritic erythematous macules), lesions with pus on the skin, sleep disturbances, and nightmares for two days. In this case report, the patient face, neck and scapulae were the most infected areas of the body and the rest of the body except the legs, hands, genital areas and buttocks, were also highly infected. Acyclovir 800 mg orally, five times a day, was given for ten days to treat chickenpox infection because acyclovir inhibits varicella zoster virus replication. It is typically unable to eradicate varicella-zoster virus from the latent state in neurons.
A Comprehensive Review of Systemic Sclerosis: Diagnosis, Clinical Features and Management Strategies
Authors: Borowiec Agnieszka , Borowiec Kinga , Kwaśniewska Paulina , Biernikiewicz Julia , Biernikiewicz Milena , Wilewska Anna , Pomirski Bartosz , Pomirska Agata , Alabrudziński Konstanty , Kałachurska Miszela
Published: February 2025

Introduction
Systemic sclerosis (SSc) is a rare autoimmune disease characterized by fibrosis of the skin and internal organs, along with vasculopathy. It is associated with significant morbidity and mortality, particularly due to pulmonary and renal complications. Early diagnosis is challenging, but crucial, as severe internal organ involvement can occur within three years of disease onset. SSc is categorized into subsets, such as diffuse and limited cutaneous forms with varying degrees of skin and organ involvement. Specific autoantibodies are critical for diagnosing and predicting disease severity and understanding these serological profiles aids in personalized treatment decisions. Management focuses on addressing specific manifestations like Raynaud’s phenomenon, skin fibrosis, pulmonary involvement, and gastrointestinal issues with treatment strategies tailored to the disease’s stage and organ involvement. Despite advances in treatment, SSc remains a challenging disease requiring ongoing vigilance for early detection and intervention.
Purpose
The purpose of this article is to provide a comprehensive overview of systemic sclerosis, focusing on its diagnostic criteria, clinical features and management strategies. It aimsto highlight the importance of early detection, particularly in the context of skin and organ involvement and the role of serological markers in guiding diagnosis and treatment. Ultimately, the goal is to improve awareness and understanding of SSc among healthcare professionals, particularly dermatologists, to enhance early diagnosis and optimize patient outcomes.
Materials and Methods
Our review is based on an analysis of material collected in 'Pubmed', 'Google Scholar' and other scientific articles using the keywords: systemic sclerosis, antinuclear antibodies, Raynaud’s phenomenon, pulmonary arterial hypertension.
Citrulline: A Multifunctional Compound for Health, Performance, and Therapeutic Applications
Authors: Mycyk Marcin , Cioch Michał Jakub , Kaczmarska Urszula , Woźniak Aleksandra , Nowak Julia , Hermanowicz Kamil , Doman Katarzyna , Najdek Agnieszka , Oleksy Daria , Komada Dawid
Published: February 2025

Introduction:L-citrulline, a non-proteinogenic amino acid, is predominantly synthesized in the enterocytes of the small intestine, with smaller amounts produced in the kidneys, which plays a critical role in the detoxification of ammonia in the urea cycle, and serves as a precursor for nitric oxide (NO). Recent studies have highlighted citrulline's potential benefits in diverse physiological and pathological contexts, ranging from enhancing physical performance and muscle recovery to supporting cardiovascular health, mitigating endothelial dysfunction, and acting as a therapeutic agent in various health conditions. 
Aim of study:The study aims to provide a comprehensive summary of current knowledge on the biochemical characteristics, physiological functions, and therapeutic potential of citrulline. Materials and methods:A comprehensive scientific literature review was conducted using the PubMed database, focusing on studies published up to 2024, reporting experimental, clinical, or in vivo data related to citrulline's synthesis, biological functions, and therapeutic applications.Conclusion:Emerging evidence highlights citrulline's potential in treating various health conditions, such as erectile dysfunction, neurodegenerative diseases, and intestinal barrier dysfunction, as well as its protective effects in hepatic failure, wound healing, and oxidative stress-related damage. These findings suggest that citrulline may serve as a multifaceted therapeutic agent, meriting further research to optimize its clinical use.
Obesity-related endocrine disorders
Authors: Kiełczewska Aleksandra , Kiełczewska Anna , Szcześniak Grzegorz
Published: February 2025

Introduction and Purpose: Several endocrine disorders, including diabetes, insulinoma, Cushing syndrome, hypothyroidism, polycystic ovarian syndrome, and growth hormone deficiency, are associated with obesity. The mechanisms underlying the development of obesity vary according to the abnormalities of endocrine function. This review examines the hormonal disturbances linked to obesity, extending beyond just diabetes. It explores the prevalence, clinical features, screening, diagnosis, and management of these related conditions.
Materials and Methods: A comprehensive survey of articles published in scientific journals was conducted via PubMed and Google Scholar online research platforms. Articles were searched by entering keywords in the appropriate configuration:  “obesity,” “hypothyroidism”, “hypercortisolism”, “hypogonadism” and “PCOS”.
Description of current knowledge: Prediabetes and diabetes are the most frequently encountered endocrine conditions by physicians and endocrinologists. Other common endocrine disorders seen in specialty clinics include hypothyroidism, Cushing's syndrome, androgen excess in women, and hypogonadism in men.
Summary: With our expanding knowledge of obesity, it is vital to acknowledge the influential role of fat cells in hormone synthesis. Physicians caring for obese patients should adopt a meticulous approach, screening for hormonal imbalances beyond just diabetes, to ensure comprehensive patient management.
Hypervitaminosis D in the pediatric population
Authors: Pawłowski Bartosz , Maliszewska Bernadeta , Łaba Łukasz , Łuczyński Dominik , Tokarzewska Agata , Żybowska-Męczyńska Monika , Kłusek Magdalena , Klimas Filip , Rusiński Kacper , Sienkiewicz Michał
Published: February 2025

Vitamin D is a fat-soluble vitamin that plays a huge role in the metabolism of bones and teeth, which is especially important among pediatric patients. Its deficiency in the developmental period is associated with a decrease in bone mass, bone mineralization disorders, as well as the development of rickets. In addition, vitamin D has an immunomodulatory effect, and its reduced level correlates with a higher incidence of certain autoimmune diseases and cancer. However, it is worth noting that nowadays, in the era of high availability of over-the-counter (OTC) drugs and dietary supplements, not only hypovitaminosis D can be dangerous and pose a significant clinical problem. More and more parents decide to administer exogenous vitamin D preparations, often without prior consultation with a doctor to determine the optimal dose or duration of supplementation. Unfortunately, it happens that over-the-counter supplements contain a higher dose of vitamin D than the manufacturer suggests. This is very often due to inadequate control of supplement production. Restrictions similar to those in the case of drug production should be sought. It should be remembered that the human body, thanks to exposure to sunlight, under the influence of UV radiation, is able to synthesize endogenous vitamin D on its own. Another source of vitamin D is many foods such as fatty fish, eggs, mushrooms or dairy products, which should be in the diet of every person, especially a child. Therefore, it becomes necessary to define uniform recommendations for doctors and parents regarding vitamin D supplementation in children, as well as to educate the public about possible toxic effects resulting from excessive supply.
The Impact of a Vegetarian Diet on the Cardiovascular System
Authors: Grądalski Łukasz , Niemirka Szymon , Dębicki Filip , Janiak Aleksandra , Kopaczyńska Adrianna , Szafrańska Katarzyna , Dominiczak Kinga
Published: February 2025

The vegetarian diet is gaining increasing popularity worldwide, particularly in developed countries. This phenomenon is driven by various factors, such as concern for animal welfare, growing social awareness about health, and the role of nutrition in maintaining it. Cardiovascular diseases have been the leading cause of death globally for many years, with many risk factors - including diet - being potentially modifiable causes. A vegetarian diet can support the treatment and prevention of cardiovascular diseases. According to the latest available knowledge, it has a particularly beneficial effect on lowering blood pressure, reducing the risk of developing coronary artery disease, and preventing metabolic syndrome. However, exclusively following this diet requires the inclusion of nutritional supplements to address potential deficiencies, preventing the development of other health issues.