bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours
Authors: Geurts Birgit S. , Battaglia Thomas W. , van Berge Henegouwen J. Maxime , Zeverijn Laurien J. , de Wit Gijs F. , Hoes Louisa R. , van der Wijngaart Hanneke , van der Noort Vincent , Roepman Paul , de Leng Wendy W. J. , Jansen Anne M. L. , Opdam Frans L. , de Jonge Maja J. A. , Cirkel Geert A. , Labots Mariette , Hoeben Ann , Kerver Emile D. , Bins Adriaan D. , Erdkamp Frans G.L. , van Rooijen Johan M. , Houtsma Danny , Hendriks Mathijs P. , de Groot Jan-Willem B. , Verheul Henk M. W. , Gelderblom Hans , Voest Emile E. 
Published: March 2023

Abstract
Background
In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile.

Patients and methods
Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses.

Results
Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB.

Conclusion
Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings.

Trial registration

Clinical trial registration: NCT02925234. First registration date: 05/10/2016.
Intracranial efficacy and safety of furmonertinib 160 mg with or without anti-angiogenic agent in advanced NSCLC patients with BM/LM as salvage therapy
Authors: Xu Ziyi , Hao Xuezhi , Wang Qi , Yang Ke , Li Junling , Xing Puyuan 
Published: March 2023

Abstract
Objectives
Central nervous system (CNS) metastases including brain metastases (BM) and leptomeningeal metastases (LM) are frequent in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), and are correlated with poor outcomes. In this study, we evaluated the efficacy of single-agent furmonertinib 160 mg or combining with anti-angiogenic agent in NSCLC patients who had developed BM/LM progression from previous tyrosine kinase inhibior (TKI) treatment.

Methods
EGFR-mutated NSCLC patients who developed BM (the BM cohort) or LM progression (the LM cohort) were included, having received furmonertinib 160 mg daily as second-line or later treatment, with or without anti-angiogenic agents. The intracranial efficacy was evaluated by intracranial progression-free survival (iPFS).

Results
Totally 12 patients in the BM cohort and 16 patients in the LM cohort were included. Almost one half of patients in the BM cohort and a majority in the LM cohort had a poor physical status, with a Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥2. The administration of single-agent furmonertinib or combination treatment achieved a median iPFS of 3.6 months (95%CI 1.435–5.705) in the BM cohort, and 4.3 months (95%CI 2.094–6.486) in the LM cohort. Subgroup and univariate analysis has shown that a good ECOG-PS correlated with a favorable efficacy of furmonertinib in the BM cohort (median iPFS = 2.1 with ECOG-PS ≥ 2 vs. 14.6 months with ECOG-PS < 2, P < 0.05). Overall, any grade of adverse events (AEs) occured in 46.4% of patients (13/28). Among them, 14.3% of patients (4 of 28) had grade 3 or higher AEs, and were all under control, led to no dose reductions or suspension.

Conclusion
Single-agent furmonertinib 160 mg or in combination of anti-angiogenic agent is an optional salvage therapy for advanced NSCLC patients who developed BM/LM progression from prior EGFR-TKI treatment, with a promising efficacy and an acceptable safety profile, and is worth of further exploration.
Phase II clinical trial of sequential treatment with systemic chemotherapy and intraperitoneal paclitaxel for gastric and gastroesophageal junction peritoneal carcinomatosis - STOPGAP trial
Authors: Senthil Maheswari , Dayyani Farshid 
Published: March 2023

Abstract
Background
Studies from Asia indicate that normothermic intraperitoneal chemotherapy (NIPEC) may confer survival benefit in patients with gastric peritoneal carcinomatosis (PC). However, data regarding this approach is lacking in western population. The current STOPGAP trial is intended to assess 1-year progression-free survival benefit of sequential systemic chemotherapy and paclitaxel NIPEC in patients with gastric/ gastroesophageal junction (GEJ) adenocarcinoma PC.

Methods
This is a prospective, single center, single arm, phase II investigator-initiated clinical trial. Patients with histologically proven gastric/GEJ (Siewert 3) adenocarcinoma with positive peritoneal cytology or PC will be eligible to participate after three months of standard of care systemic chemotherapy and with no evidence of visceral metastasis on restaging scans. The primary treatment is iterative paclitaxel NIPEC with systemic paclitaxel and 5-fluorouracil, which will be administered on days1 and 8 and repeated every three weeks for 4 cycles. Patients will undergo diagnostic laparoscopy both before and after NIPEC to assess peritoneal cancer index (PCI). Patients with PCI less than or equal to 10 in whom complete cytoreduction (CRS) is feasible may opt to undergo CRS with heated intraperitoneal chemotherapy (HIPEC). The primary endpoint is 1-year progression free survival and secondary endpoints are overall survival and patient reported quality of life outcomes measured by EuroQol- 5 dimensions-5 level (EuroQol-5D-5L) questionnaire.

Discussion
If the sequential approach of systemic chemotherapy followed by paclitaxel NIPEC proves beneficial, then this approach could be used in larger, muti-institutional randomized clinical trial of gastric PC.

Trial Registration
The trial was registered on 21/02/2021, under clinical trials.gov; Identifier: NCT04762953.
Raltitrexed enhanced antitumor effect of anlotinib in human esophageal squamous carcinoma cells on proliferation, invasiveness, and apoptosis
Authors: Zhen Hongchao , Tian Jizheng , Li Guangxin , Zhao Pengfei , Zhang Ying , Che Juanjuan , Cao Bangwei 
Published: March 2023

Abstract
Background
Anlotinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) which has exhibited encouraging clinical activity in advanced non-small cell lung cancer (NSCLC) and soft tissue sarcoma. Raltitrexed is well known to be effective in the treatment of colorectal cancer in China. The present study aims to investigate the combinatory antitumor effect of anlotinib and raltitrexed on human esophageal squamous carcinoma cells and further explore the molecular mechanisms in vitro.

Methods
Human esophageal squamous cell lines KYSE-30 and TE-1 were treated with anlotinib or raltitrexed, or both, then cell proliferation was measured by MTS and colony formation assay; cell migration and invasion were detected by wound-healing and transwell assays; cell apoptosis rate was studied by flow cytometry and the transcription of apoptosis-associated proteins were monitored by quantitative polymerase chain reaction (qPCR) analysis. Finally, western blot was performed to check phosphorylation of apoptotic proteins after treatment.

Results
Treatment with raltitrexed and anlotinib showed enhanced inhibitory effects on cell proliferation, migration and invasiveness compared with raltitrexed or anlotinib monotherapy. Meanwhile, raltitrexed combined with anlotinib strongly increased cell apoptosis percentage. Moreover, the combined treatment down-regulated mRNA level of the anti-apoptotic protein Bcl-2 and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9), while up-regulated pro-apoptotic Bax and caspase-3 transcription. Western blotting showed that the combination of raltitrexed and anlotinib could inhibit the expression of phosphorylated Akt (p-Akt), Erk (p-Erk) and MMP-9.

Conclusions
This study indicated that raltitrexed enhanced the antitumor effects of anlotinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, providing a novel treatment option for patients with esophageal squamous cell carcinoma (ESCC).
Diagnosis and management of ADHD: a pediatric perspective on practice and challenges in Switzerland
Authors: Zysset A. , Robin D. , Albermann K. , Dratva J. , Hotz S. , Wieber F. , von Rhein M. 
Published: March 2023

AbstractBackgroundAttention deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in childhood. In Switzerland, the complex diagnosis and treatment are being carried out by adolescent−/child psychiatrists, and pediatricians. Guidelines recommend a multimodal therapy for patients with ADHD. However, it has been questioned whether health professionals follow this approach or favor drug therapy. This study aims to provide insights into the practice of pediatricians in Switzerland regarding diagnosis and treatment of ADHD and their perceptions of these processes.MethodAn online survey (self-report) about current practices of diagnosis and management as well as challenges regarding ADHD was distributed to office-based pediatricians in Switzerland. One hundred fifty-one pediatricians participated. Results show that therapy options were almost always discussed with parents and older children. Exchange with parents (81%) and level of child’s suffering (97%) were central when selecting therapy options.ResultsTherapies about which pediatricians informed most often were: pharmacological therapy, psychotherapy, and multimodal therapy. Challenges voiced were the subjectivity of diagnostic criteria and dependence on third parties, low availability of psychotherapy, and a rather negative public attitude towards ADHD. Needs that were expressed were further education for all professionals, support for coordination with specialists and schools as well as improvement of information on ADHD.ConclusionsPediatricians do consider a multimodal approach when treating ADHD and take the families` and children’s opinions into account. Improvements of the availability of child and youth psychotherapy, the strengthening of the interprofessional cooperation with therapists and schools, and efforts to increase public knowledge about ADHD are proposed.
Probable enterotoxin-associated toxic shock syndrome caused by Staphylococcus epidermidis
Authors: Pomputius William F. , Kilgore Samuel H. , Schlievert Patrick M. 
Published: March 2023

Abstract
Background
We describe a case of a toxic shock-like syndrome in a child, which was associated with Staphylococcus epidermidis instead of Staphylococcus aureus or Streptococcus pyogenes, the usual causes of toxic shock syndrome.

Case presentation
The patient was an 8-year-old boy who developed a toxic shock syndrome-like illness, including fever, hypotension, and rash. The Staphylococcus epidermidis isolate was cultured from urine, but this organism was unavailable for toxin testing. Multiple blood cultures were negative. Instead, a highly novel assay was used on acute plasma from the patient which demonstrated the presence of the genes for superantigens, staphylococcal enterotoxins A, C, D, and E. Superantigens are the known causes of toxic shock syndrome.

Conclusions
Our study suggests strongly that Staphylococcus epidermidis was causing the TSS symptoms through the known Staphylococcus aureus superantigens. It is unknown how many other such patients exist; this should be explored. Of great importance is that PCR performed directly on blood plasma in the absence of microbial isolation could be used to demonstrate superantigen genes.
(Cost-)effectiveness of a personalized multidisciplinary eHealth intervention for knee arthroplasty patients to enhance return to activities of daily life, work and sports – rationale and protocol of the multicentre ACTIVE randomized controlled trial
Authors: Straat A. Carlien , Maarleveld Jantine M. , Smit Denise J. M. , Visch Lara , Hulsegge Gerben , Huirne Judith A. F. , van Dongen J. M. , van Geenen Rutger C. , Kerkhoffs Gino M. M. J. , Anema Johannes R. , Coenen Pieter , Kuijer P. Paul F. M. 
Published: March 2023

Abstract
Background
With the worldwide rising obesity epidemic and the aging population, it is essential to deliver (cost-)effective care that results in enhanced societal participation among knee arthroplasty patients. The purpose of this study is to describe the development, content, and protocol of our (cost-)effectiveness study that assesses a perioperative integrated care program, including a personalized eHealth app, for knee arthroplasty patients aimed to enhance societal participation post-surgery compared to care as usual.

Methods
The intervention will be tested in a multicentre randomized controlled trial with eleven participating Dutch medical centers (i.e., hospitals and clinics). Working patients on the waiting-list for a total- or unicompartmental knee arthroplasty with the intention to return to work after surgery will be included. After pre-stratification on medical centre with or without eHealth as usual care, operation procedure (total- or unicompartmental knee arthroplasty) and recovery expectations regarding return to work, randomization will take place at the patient-level. A minimum of 138 patients will be included in both the intervention and control group, 276 in total. The control group will receive usual care. On top of care as usual, patients in the intervention group will receive an intervention consisting of three components: 1) a personalized eHealth intervention called ikHerstel (‘I Recover’) including an activity tracker, 2) goal setting using goal attainment scaling to improve rehabilitation and 3) a referral to a case-manager. Our main outcome is quality of life, based on patient-reported physical functioning (using PROMIS-PF). (Cost-)effectiveness will be assessed from a healthcare and societal perspective. Data collection has been started in 2020 and is expected to finish in 2024.

Discussion
Improving societal participation for knee arthroplasty is relevant for patients, health care providers, employers and society. This multicentre randomized controlled trial will evaluate the (cost-)effectiveness of a personalized integrated care program for knee arthroplasty patients, consisting of effective intervention components based on previous studies, compared to care as usual.

Trial registration
Trialsearch.who.int; reference no. NL8525, reference date version 1: 14–04-2020.
Comparison between primary repair and augmented repair with gastrocnemius turn-down flap for acute Achilles tendon rupture: a retrospective study with minimum 2-year follow-up
Authors: Yang Shuai , Shi Weili , Yan Wenqiang , Ao Yingfang , Guo Qinwei , Yang Yuping 
Published: March 2023

Abstract
Background
To explore and compare the clinical outcomes in patients undergoing primary repair versus augmented repair with a gastrocnemius turn-down flap for acute Achilles tendon rupture.

Methods
From 2012 to 2018, the clinical data of 113 patients with acute Achilles tendon rupture who were treated with primary repair or augmented repair with a gastrocnemius turn-down flap by the same surgeon were retrospectively reviewed. The patients’ preoperative and postoperative scores on the visual analog scale (VAS), American Orthopaedic Foot and Ankle Society Ankle⁃Hindfoot (AOFAS) score, the Victorian Institute of Sport Assessment⁃Achilles (VISA-A), the Achilles tendon total rupture score (ATRS), and the Tegner Activity Scale were examined and compared. The postoperative calf circumference was measured. A Biodex isokinetic dynamometer was used to evaluate the plantarflexion strength on both sides. The time to return to life and exercise as well as the strength deficits in both groups were recorded. Finally, the correlation analyses between patient characteristics and treatment details with clinical outcomes were conducted.

Results
In total, 68 patients were included and completed the follow-up. The 42 and 26 patients who were treated with primary repair and augmented repair were assigned to group A and B, respectively. No serious postoperative complications were reported. No significant between-group differences in any outcomes were observed. It was found that female sex was correlated with poorer VISA-A score (P = 0.009), complete seal of paratenon was correlated with higher AOFAS score (P = 0.031), and short leg cast was correlated with higher ATRS score (P = 0.006).

Conclusions
Augmented repair with a gastrocnemius turn-down flap provided no advantage over primary repair for the treatment of acute Achilles tendon rupture. After surgical treatment, females tended to had poorer outcomes, while complete seal of paratenon and short leg cast contributed to better results.

Level of evidence
Cohort study; Level of evidence, 3.
Characteristics and outcomes of patients who did not respond to a national spine surgery registry
Authors: Kaur Simran , Alhaug Ole Kristian , Dolatowski Filip C. , Solberg Tore K. , Lønne Greger 
Published: March 2023

Abstract
Background
Loss to follow-up may bias outcome assessments in medical registries. This cohort study aimed to analyze and compare patients who failed to respond with those that responded to the Norwegian Registry for Spine Surgery (NORspine).

Methods
We analyzed a cohort of 474 consecutive patients operated for lumbar spinal stenosis at four public hospitals in Norway during a two-year period. These patients reported sociodemographic data, preoperative symptoms, and Oswestry Disability Index (ODI), numerical rating scales (NRS) for back and leg pain to NORspine at baseline and 12 months postoperatively. We contacted all patients who did not respond to NORspine after 12 months. Those who responded were termed responsive non-respondents and compared to 12 months respondents.

Results
One hundred forty (30%) did not respond to NORspine 12 months after surgery and 123 were available for additional follow-up. Sixty-four of the 123 non-respondents (52%) responded to a cross-sectional survey done at a median of 50 (36–64) months after surgery. At baseline, non-respondents were younger 63 (SD 11.7) vs. 68 (SD 9.9) years (mean difference (95% CI) 4.7 years (2.6 to 6.7); p =  < 0.001) and more frequently smokers 41 (30%) vs. 70 (21%) RR (95%CI) = 1.40 (1.01 to 1.95); p = 0.044. There were no other relevant differences in other sociodemographic variables or preoperative symptoms. We found no differences in the effect of surgery on non-respondents vs. respondents (ODI (SD) = 28.2 (19.9) vs. 25.2 (18.9), MD (95%CI) = 3.0 ( -2.1 to 8.1); p = 0.250).

Conclusion
We found that 30% of patients did not respond to NORspine at 12 months after spine surgery. Non-respondents were somewhat younger and smoked more frequently than respondents; however, there were no differences in patient-reported outcome measures. Our findings suggest that attrition bias in NORspine was random and due to non-modifiable factors.
Locked intramedullary nailing of open fractures in resource-poor settings: a prospective observational study of challenges and functional outcomes in 101 fractures at Ogbomoso, Nigeria
Authors: Adesope Adesina Stephen , Olusayo Amole Isaac , Owolabi James Idowu , Oyewusi Oluwafemi Oyewole , Goodness Adefokun Imri , Uwale Eyesan Samuel 
Published: March 2023

Abstract
Background
Trauma is now one of the fastest growing epidemics globally but low and middle-income countries (LMICs) are more severely affected in terms of cost, disability and death. The high-energy trauma of road traffic accidents and violence often produces open fractures which can be difficult to manage in resource-poor settings. Adequate stabilization, such as provided by locked nails, has been found to ensure better outcome for open fractures. There is dearth of published studies on the use of locked intramedullary nail in the treatment of open fractures in Nigeria.

Methods
This is a prospective observational study of all the 101 open fractures of the humerus, femur and tibia treated over a period of 92 months with Surgical Implant Generation Network (SIGN) nail. Fracture severity was classified according to the modified Gustilo-Anderson system. The intervals between fracture and antibiotics administration, débridement and definitive fixation, as well as surgery duration and method of fracture reduction were noted. Outcomes measured at follow-up included infection, ongoing radiographic healing, knee flexion/shoulder abduction beyond ninety degrees (KF/SA > 900), full weight bearing (FWB), painless squatting (PS&S)/shoulder abduction-external rotation (SAER).

Results
Most of the patients fall between ages 20 and 49 years; 75.5% of them were males. There were more Gustilo-Anderson type IIIA fractures than other types but nine type IIIB tibia fractures were also nailed. The overall infection rate was 15%, contributed mostly by the type IIIB fractures. By the 12th post-operative week, at least 79% had ongoing radiographic healing and had achieved all of KF/SA > 900, FWB, and PS&S/SAER.

Conclusion
The SIGN nail’s solid construct reduces the risk of infection and allows earlier use of the limb, making it particularly suitable in LIMCs where socioeconomic functioning often requires an unhindered use of the limbs.