bluuebunny/crossref_metadata_2025 huggingface dataset:
A single-center, assessor-blinded, randomized controlled clinical trial to test the safety and efficacy of a novel brain-computer interface controlled functional electrical stimulation (BCI-FES) intervention for gait rehabilitation in the chronic stroke population
Authors: Biswas Piyashi , Dodakian Lucy , Wang Po T. , Johnson Christopher A. , See Jill , Chan Vicky , Chou Cathy , Lazouras Wendy , McKenzie Alison L. , Reinkensmeyer David J. , Nguyen Danh V. , Cramer Steven C. , Do An H. , Nenadic Zoran
Published: June 2024

Background

In the United States, there are over seven million stroke survivors, with many facing gait impairments due to foot drop. This restricts their community ambulation and hinders functional independence, leading to several long-term health complications. Despite the best available physical therapy, gait function is incompletely recovered, and this occurs mainly during the acute phase post-stroke. Therapeutic options are limited currently. Novel therapies based on neurobiological principles have the potential to lead to long-term functional improvements. The Brain-Computer Interface (BCI) controlled Functional Electrical Stimulation (FES) system is one such strategy. It is based on Hebbian principles and has shown promise in early feasibility studies. The current study describes the BCI-FES clinical trial, which examines the safety and efficacy of this system, compared to conventional physical therapy (PT), to improve gait velocity for those with chronic gait impairment post-stroke. The trial also aims to find other secondary factors that may impact or accompany these improvements and establish the potential of Hebbian-based rehabilitation therapies.

Methods

This Phase II clinical trial is a two-arm, randomized, controlled, longitudinal study with 66 stroke participants in the chronic (> 6 months) stage of gait impairment. The participants undergo either BCI-FES paired with PT or dose-matched PT sessions (three times weekly for four weeks). The primary outcome is gait velocity (10-meter walk test), and secondary outcomes include gait endurance, range of motion, strength, sensation, quality of life, and neurophysiological biomarkers. These measures are acquired longitudinally.

Discussion

BCI-FES holds promise for gait velocity improvements in stroke patients. This clinical trial will evaluate the safety and efficacy of BCI-FES therapy when compared to dose-matched conventional therapy. The success of this trial will inform the potential utility of a Phase III efficacy trial.

Trial registration

The trial was registered as ”BCI-FES Therapy for Stroke Rehabilitation” on February 19, 2020, at clinicaltrials.gov with the identifier NCT04279067.
Process approach as a cognitive biomarker related to gray matter volume in mild cognitive impairment and Alzheimer’s disease
Authors: Zhu Wenhao , Zhou Xia , Ren Mengmeng , Yin Wenwen , Tang Yating , Yin Jiabin , Sun Yue , Zhu Xiaoqun , Sun Zhongwu
Published: June 2024

Background

Process approach is valuable for memory assessment in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), yet its underlying mechanisms remain elusive. This study aims to synergize the process approach with brain structure analysis to explore both the discriminative capacity and potential mechanisms underlying the process approach.

Methods

37 subjects of MCI, 35 subjects of AD and 38 subjects of healthy control (HC) were included. The process approach in Auditory Verbal Learning Test (AVLT), including discriminability (A’), response bias (B"D), semantic clustering (LBCsem) and serial clustering (LBCser) was performed. The gray matter volume (GMV) was analyzed by voxel-based morphometry. Receiver operating characteristic (ROC) analysis and partial correlations were conducted to explore the value of the process approach and investigate the relationship between the process approach, traditional indices of AVLT and GMV.

Results

ROC analysis showed the value of A’, B"D and LBCser in differentiating MCI and AD. Combining AVLT-Immediately Recall (AVLT-IR) and LBCser showed a higher value in diagnosing MCI. Partial correlations revealed that in the MCI group, A’ and B"D were mainly positively associated with GMV of the hippocampus and temporal lobe.

Conclusion

This study indicated that the process approach is a promising cognitive biomarker to detect MCI and AD.
Cheek alveolar soft part sarcoma recurrence at the primary site during follow-up: a case report and review of the literature
Authors: An Wenyu , Xue Zhongxu , Zhuo Huifang , Wang Ning , Meng Lian , Jia Wei
Published: June 2024

Background

Alveolar soft part sarcoma (ASPS) occurs most often in the deep muscles or fascia of the extremities in adults, with only 3.4% of these tumours originating from the head, face and neck. To date, only 17 cases of buccal ASPS have been reported, including the case presented here. Only one case of ASPS recurrence at the primary site, similar to our case, has been reported thus far. Immune checkpoint inhibitors (ICPis)-associated diabetes, with an estimated incidence of 0.43%, is usually seen in older cancer patients and has not been reported in younger people or in patients with ASPS.

Case presentation

A 24-year-old male patient presented with a slowly progressing right cheek mass with a clinical history of approximately 28 months. Sonographic imaging revealed a hypoechoic mass, which was considered a benign tumour. However, a pathological diagnosis of ASPS was made after excision of the mass. Five days later, functional right cervical lymph node dissection was performed. No other adjuvant therapy was administered after surgery. In a periodic follow-up of the patient six months later, blood-rich tumour growth was noted at the primary site, and Positron emission tomography-computedtomography (PET-CT) ruled out distant metastasis in other areas. The patient was referred to the Ninth People’s Hospital of Shanghai Jiaotong University. Due to the large extent of the mass, the patient received a combination of a Programmed Cell Death Ligand 1(PD-L1) inhibitor and a targeted drug. Unfortunately, the patient developed three episodes of severe diabetic ketoacidosis after the administration of the drugs. A confirmed diagnosis of ICPis-associated diabetes was confirmed. After the second operation, the postoperative pathological diagnosis was ASPS, and the margins were all negative. Therefore, we made a final clinical diagnosis of ASPS recurrence at the primary site. Currently in the follow-up, the patient is alive, has no distant metastases, and undergoes multiple imaging examinations every 3 months for the monitoring of their condition.

Conclusions

In analysing the characteristics of all previously reported cases of buccal ASPS, it was found that the clinical history ranged from 1 to 24 months, with a mean of approximately 3 to 9 months. Tumour recurrence at the primary site has been reported in only one patient with buccal ASPS, and the short-term recurrence in our patient may be related to the extraordinarily long 28-month history. ICPis-associated diabetes may be noted in young patients with rare tumours, and regular insulin level monitoring after use is necessary.
Therapeutic effects of Reiki on interventions for anxiety: a meta-analysis
Authors: Guo Xiulan , Long Yue , Qin Zhikai , Fan Yongtao
Published: June 2024

Purpose

This study aimed to assess the therapeutic efficacy of Reiki therapy in alleviating anxiety.

Methods

In adherence to academic standards, a thorough search was conducted across esteemed databases such as PubMed, Web of Science, Science Direct, and the Cochrane Library. The primary objective of this search was to pinpoint peer-reviewed articles published in English that satisfied specific criteria: (1) employing an experimental or quasi-experimental study design, (2) incorporating Reiki therapy as the independent variable, (3) encompassing diverse patient populations along with healthy individuals, and (4) assessing anxiety as the measured outcome.

Results

The study involved 824 participants, all of whom were aged 18 years or older. Reiki therapy was found to have a significant effect on anxiety intervention(SMD=-0.82, 95CI -1.29∼-0.36, P = 0.001). Subgroup analysis indicated that the types of subjects (chronically ill individuals and the general adult population) and the dosage/frequency of the intervention (≤ 3 sessions and 6–8 sessions) were significant factors influencing the variability in anxiety reduction.

Conclusion

Short-term Reiki therapy interventions of ≤ 3 sessions and 6–8 sessions have demonstrated effectiveness in reducing health and procedural anxiety in patients with chronic conditions such as gastrointestinal endoscopy inflammation, fibromyalgia, and depression, as well as in the general population. It is important to note that the efficacy of Reiki therapy in decreasing preoperative anxiety and death-related anxiety in preoperative patients and cancer patients is somewhat less consistent. These discrepancies may be attributed to individual pathophysiological states, psychological conditions, and treatment expectations.
Perception of diagnosis by family caregivers in severe brain injury patients in China
Authors: Yan Yifan , Li Meiqi , Annen Jitka , Huang Wangshan , Cai Tiantian , Wang Xueying , Hu Xiaohua , Laureys Steven , Di Haibo
Published: June 2024

Objectives

Surrogate decision-making by family caregivers for patients with severe brain injury is influenced by the availability and understanding of relevant information and expectations for future rehabilitation. We aimed to compare the consistency of family caregivers’ perceptions with clinical diagnoses and to inform their expectation of prognosis in the future.

Methods

The Coma Recovery Scale-Revised was used to assess the diagnosis of inpatients with severe brain injury between February 2019 and February 2020. A main family caregiver was included per patient. The family caregiver’s perception of the patient’s consciousness and expectations of future recovery were collected through questionnaires and compared consistently with the clinical diagnosis.

Results

The final sample included 101 main family caregivers of patients (57 UWS, unresponsive wakefulness syndrome, 37 MCS, minimally conscious state, 7 EMCS, emergence from MCS) with severe brain injury. Only 57 family caregivers correctly assessed the level of consciousness as indicated by the CRS-R, showing weak consistency (Kappa = 0.217, P = 0.002). Family caregivers’ demographic characteristics and CRS-R diagnosis influenced the consistency between perception and clinical diagnosis. Family caregivers who provided hands-on care to patients showed higher levels of consistent perception (AOR = 12.24, 95% CI = 2.06-73.00, P = 0.006). Compared to UWS, the family caregivers of MCS patients were more likely to have a correct perception (OR = 7.68, 95% CI = 1.34–44.06). Family caregivers had positive expectations for patients’ recovery in terms of both communication and returning to normal life.

Conclusion

Nearly half of family caregivers have inadequate understanding of their relative’s level of consciousness, and most of them report overly optimistic expectations that do not align with clinical diagnosis. Providing more medical information to family caregivers to support their surrogate decision-making process is essential.
The venom and telopodal defence systems of the centipede Lithobius forficatus are functionally convergent serial homologues
Authors: Schendel Vanessa , Müller Carsten H. G. , Kenning Matthes , Maxwell Michael , Jenner Ronald A. , Undheim Eivind A. B. , Sombke Andy
Published: June 2024

Background

Evolution of novelty is a central theme in evolutionary biology, yet studying the origins of traits with an apparently discontinuous origin remains a major challenge. Venom systems are a well-suited model for the study of this phenomenon because they capture several aspects of novelty across multiple levels of biological complexity. However, while there is some knowledge on the evolution of individual toxins, not much is known about the evolution of venom systems as a whole. One way of shedding light on the evolution of new traits is to investigate less specialised serial homologues, i.e. repeated traits in an organism that share a developmental origin. This approach can be particularly informative in animals with repetitive body segments, such as centipedes.

Results

Here, we investigate morphological and biochemical aspects of the defensive telopodal glandular organs borne on the posterior legs of venomous stone centipedes (Lithobiomorpha), using a multimethod approach, including behavioural observations, comparative morphology, proteomics, comparative transcriptomics and molecular phylogenetics. We show that the anterior venom system and posterior telopodal defence system are functionally convergent serial homologues, where one (telopodal defence) represents a model for the putative early evolutionary state of the other (venom). Venom glands and telopodal glandular organs appear to have evolved from the same type of epidermal gland (four-cell recto-canal type) and while the telopodal defensive secretion shares a great degree of compositional overlap with centipede venoms in general, these similarities arose predominantly through convergent recruitment of distantly related toxin-like components. Both systems are composed of elements predisposed to functional innovation across levels of biological complexity that range from proteins to glands, demonstrating clear parallels between molecular and morphological traits in the properties that facilitate the evolution of novelty.

Conclusions

The evolution of the lithobiomorph telopodal defence system provides indirect empirical support for the plausibility of the hypothesised evolutionary origin of the centipede venom system, which occurred through functional innovation and gradual specialisation of existing epidermal glands. Our results thus exemplify how continuous transformation and functional innovation can drive the apparent discontinuous emergence of novelties on higher levels of biological complexity.
Minimally invasive surgeries for spontaneous hypertensive intracerebral hemorrhage (MISICH): a multicenter randomized controlled trial
Authors: Xu Xinghua , Zhang Huaping , Zhang Jiashu , Luo Ming , Wang Qun , Zhao Yining , Gan Zhichao , Xu Bainan , Chen Xiaolei ,   the MISICH study team
Published: June 2024

Background

Intracerebral hemorrhage (ICH) is a common stroke type with high morbidity and mortality. There are mainly three surgical methods for treating ICH. Unfortunately, thus far, no specific surgical method has been proven to be the most effective. We carried out this study to investigate whether minimally invasive surgeries with endoscopic surgery or stereotactic aspiration (frameless navigated aspiration) will improve functional outcomes in patients with supratentorial ICH compared with small-bone flap craniotomy.

Methods

In this parallel-group multicenter randomized controlled trial conducted at 16 centers, patients with supratentorial hypertensive ICH were randomized to receive endoscopic surgery, stereotactic aspiration, or craniotomy at a 1:1:1 ratio from July 2016 to June 2022. The follow-up duration was 6 months. Patients were randomized to receive endoscopic evacuation, stereotactic aspiration, or small-bone flap craniotomy. The primary outcome was favorable functional outcome, defined as the proportion of patients who achieved a modified Rankin scale (mRS) score of 0–2 at the 6-month follow-up.

Results

A total of 733 patients were randomly allocated to three groups: 243 to the endoscopy group, 247 to the aspiration group, and 243 to the craniotomy group. Finally, 721 patients (239 in the endoscopy group, 246 in the aspiration group, and 236 in the craniotomy group) received treatment and were included in the intention-to-treat analysis. Primary efficacy analysis revealed that 73 of 219 (33.3%) in the endoscopy group, 72 of 220 (32.7%) in the aspiration group, and 47 of 212 (22.2%) in the craniotomy group achieved favorable functional outcome at the 6-month follow-up (P = .017). We got similar results in subgroup analysis of deep hemorrhages, while in lobar hemorrhages the prognostic outcome was similar among three groups. Old age, deep hematoma location, large hematoma volume, low preoperative GCS score, craniotomy, and intracranial infection were associated with greater odds of unfavorable outcomes. The mean hospitalization expenses were ¥92,420 in the endoscopy group, ¥77,351 in the aspiration group, and ¥100,947 in the craniotomy group (P = .000).

Conclusions

Compared with small bone flap craniotomy, endoscopic surgery and stereotactic aspiration improved the long-term outcome of hypertensive ICH, especially deep hemorrhages.

Trial Registration

ClinicalTrials.gov Identifier: NCT02811614.
Diabetes mellitus and serum organochlorine pesticides mixtures in Mexican women
Authors: Ugalde-Resano Rodrigo , Mérida-Ortega Ángel , Barajas Belén , López-Carrillo Lizbeth , Cebrián Mariano E.
Published: June 2024

Background

Very recently, it has been reported that exposure to different mixtures of organochlorine pesticides (OCP) is associated with the development of diabetes mellitus (DM). In Mexico, DM is a public health problem that might be related to the historical intense use of OCP. We aimed to evaluate, the association between DM and serum concentrations of OCP mixtures, and identify the main contributors within them.

Methods

We conducted a secondary cross-sectional analysis on the control group from a breast cancer population-based case-control study conducted from 2007 to 2011 in Northern Mexico. We identified 214 self-reported diabetic women and 694 non-diabetics. We obtained direct information about sociodemographic, lifestyle and reproductive characteristics. We determined 24 OCP and metabolites in serum by gas chromatography using an electron capture micro detector. We used Weighted Quantile Sum regression to assess the association of DM and exposure to multiple OCP, and the contribution of each compound within the mixture.

Results

We found a positive adjusted association between DM and an OCP mixture (OR: 2.63, 95%CI: 1.85, 3.74), whose primary contribution arose from p, p’-DDE (mean weight 23.3%), HCB (mean weight 17.3%), trans nonachlor (mean weight 15.4%), o, p’-DDE (mean weight 7.3%), heptachlor epoxide (mean weight 5.9%), oxychlordane (mean weight 4.7%), and heptachlor (mean weight 4.5%). In addition, these OCP along with p, p’-DDT and cis chlordane, were of concern and remained associated when excluding hypertensive women from the analysis (OR 2.55; 95% CI 1.56, 4.18).

Conclusions

Our results indicate, for the first time in a Latin-American population, that the concomitant exposure to multiple OCP is associated with DM. Further research is needed since the composition of OCP mixtures may vary according to regional pesticides use patterns.
Upconversion nanoparticles doped optical lens: let’s see the near-infrared light
Authors: Hu Yulin , Xu Baoqi , Li Wei , Liang Lin , Fei Fan , Lin Quankui
Published: June 2024

The human cannot detect light with a wavelength exceeding 700 nm, primarily due to limitations in the physiological structure of the human eye. However, in certain specific scenarios, the ability to detect near-infrared (NIR) light proves to be extremely valuable. To attain this desired capability, NIR up conversion nanoparticles (UCNPs) were prepared and doped in the optical lens materials, aiming to obtain a NIR light “visible” optical lens. It is demonstrated that the doping of UCNPs in the optical lens materials does not significantly impact on their mechanical properties, optical properties, surface properties and it exhibits excellent biocompatibility in cell and animal experiments. More importantly, the UCNPs doping can convert NIR light into visible light within the material effectively and stably. The eyes can “see” the NIR light after wearing such UCNPs doped optical lens. Such NIR light visible optical lens could have great potential in actual applications.

Graphical Abstract
Legal aspects of privacy-enhancing technologies in genome-wide association studies and their impact on performance and feasibility
Authors: Brauneck Alissa , Schmalhorst Louisa , Weiss Stefan , Baumbach Linda , Völker Uwe , Ellinghaus David , Baumbach Jan , Buchholtz Gabriele
Published: June 2024

Genomic data holds huge potential for medical progress but requires strict safety measures due to its sensitive nature to comply with data protection laws. This conflict is especially pronounced in genome-wide association studies (GWAS) which rely on vast amounts of genomic data to improve medical diagnoses. To ensure both their benefits and sufficient data security, we propose a federated approach in combination with privacy-enhancing technologies utilising the findings from a systematic review on federated learning and legal regulations in general and applying these to GWAS.
An exploration of the self-similarity of traditional settlements: the case of Xiaoliangjiang Village in Jingxing, Hebei, China
Authors: Peng Peng , Zhou Xiangyun , Wu Shaopu , Zhang Yuechen , Zhao Jiajie , Zhao Limin , Wu Jinyu , Rong Yan
Published: June 2024

In order to retain the characteristics and style of traditional settlements and respect their layout and structure, it is necessary to carry out original planning and expansion of traditional settlements. This model of planning and expansion aims to protect the unique character of the settlement, maintain its original historical and cultural value, and integrate with the surrounding environment. Early research on the space complexity of settlements was dominated by qualitative analysis, and the depth of quantitative research on the spatial form of traditional settlements was insufficient. This article takes Xiaoliangjiang Village in Jingxing County, Shijiazhuang City, Hebei Province, which entered the fifth batch of the list of Chinese traditional villages list, as the research object. The spatial relationship of the settlement was obtained through field surveys and drone oblique photography, and the spatial morphological elements of Xiaoliangjiang Village were analyzed and extracted. Based on three quantitative theories of spatial form, namely topology theory, fractal theory, and space syntax, the self-similarity of settlements is analyzed from the perspectives of buildings, streets, and spaces. The research uses Matlab and DepthMap software to quantitatively analyze the spatial form of Xiaoliangjiang Village and obtains data. Through the analysis of data, it was found that Xiaoliangjiang Village has self-similarity at three levels: buildings, roads and settlement spaces. The buildings iteratively generate various forms of architectural courtyards through the basic “L”-shaped pattern. The spatial structures at all levels of roads and settlement space in Xiaoliangjiang Village are relatively similar, in line with the bottom-up traditional settlement evolutionary law. By studying settlement self-similarity, people can better understand the formation mechanism of traditional settlement space structure and its evolution law. At the same time, it enriches the research perspective of traditional settlements and provides technical support for analyzing the self-similarity of traditional settlements and settlement protection planning.
Noradrenaline infusion prevents anesthesia-induced hypotension in severe aortic stenosis patients undergoing transcatheter aortic valve replacement: a retrospective observational study
Authors: Onishi Kenta , Yoshida Masashi , Ito Hisakatsu , Kawakami Masaaki , Takazawa Tomonori
Published: June 2024

Background

Patients with severe aortic valve stenosis (AS) are particularly prone to developing hypotension during general anesthesia induction, which increases postoperative morbidity and mortality. Although the preventive effect of a single vasopressor dose on anesthesia-induced hypotension has been reported, the effects of continuous vasopressor infusion are unknown. This study aimed to assess the effect of noradrenaline (NAd) infusion on hemodynamic stability during general anesthesia induction in severe AS patients undergoing transcatheter aortic valve replacement (TAVR).

Methods

This single-center, retrospective study included severe AS patients who underwent elective TAVR. Patients in the NAd group received a continuous prophylactic NAd infusion of 0.1 μg/kg/min from the time of anesthesia induction. The control group received inotropes and vasopressors as indicated by the occurrence of hypotension. The primary outcome was the lowest mean blood pressure (MBP) before the start of surgery.

Results

The study included 68 patients in the NAd group and 113 in the control group. The lowest MBP before the start of surgery was significantly higher in the NAd group than in the control group (63 ± 15 vs 47 ± 13 mmHg, P < 0.01). MBP immediately before intubation was also significantly higher in the NAd group (75 ± 17 vs 57 ± 16 mmHg, P < 0.01). Differences in postoperative complications between the groups were negligible.

Conclusion

Continuous administration of NAd at 0.1 μg/kg/min in patients with severe AS might prevent hypotension during general anesthesia induction for TAVR.
Cancer Trials Ecosystem in India—Ready for Prime Time?
Authors: Mankan Arun K. , Shankar Abhishek , Limaye Sewanti , Ajaikumar B.S. , Nachane Prajakta , Singh Navneet , Dawkhar Shekhar , Batra Ullas , Bhosekar Amol , Ganguly Sandip , Gawli Pramod , Debnath Khokan , Padalalu Vivek , Reddy Prasanth , Sundaramoorthy Shanthi , Naveen K.K. , Bondarde Shailesh , Kumar Praveen , Davis Sanish , Ramkissoon Shakti H. , Chacko Raju Titus , Vidal Laura , Chico Isagani , Hegedus Andrew , Gupta Sudeep , Saini Kamal S.
Published: June 2024

Executing global clinical trials for cancer is a long, expensive, and complex undertaking. While selecting countries global studies, sponsors must consider several aspects including patient pool, quality of trained investigators, competing trials, availability of infrastructure, and financial investment versus returns. With a large, often treatment-naïve, and diverse patient pool, relatively low cost, good quality health care facilities in urban areas, and a robust and well-trained workforce, India offers several advantages for conducting oncology clinical trials. However, there remains challenges, including a shifting regulatory environment in recent decades. With the implementation of the New Drugs and Clinical Trial Rules in 2019, India's regulatory atmosphere seems to have stabilized. In this article, we present a review of the evolving clinical trial landscape in India, highlight the current regulatory scenario, and discuss the advantages and challenges of selecting India as a potential location for conducting global oncology clinical trials.
Impact of ATRX loss on survival and immune microenvironment in multiple sarcoma subtypes.
Authors: Denu Ryan Austin , Lazcano Segura Rossana , Farooqi Ahsan Saleem , Ingram Davis , Wani Khalida M. , Cai Yiming , Torres Keila E , Keung Emily Zhi-Yun , Roland Christina Lynn , Somaiah Neeta , Ying Haoqiang , Huse Jason T. , Rai Kunal , Conley Anthony Paul , Patel Shreyaskumar , Wang Wei-Lien , Lazar Alexander J. , Nassif Haddad Elise F
Published: June 2024

11511

Background: Sarcomas are heterogeneous mesenchymal malignancies often with few treatment options and poor outcomes. ATRX is commonly altered in sarcoma, with loss-of-function (LOF) mutations observed in up to 35% of cases. ATRX plays roles in DNA damage response, telomere maintenance, and epigenetic regulation. However, the impact of ATRX loss on sarcoma biology and the potential of ATRX mutation to serve as a prognostic biomarker in sarcoma are under investigation. Methods: The predominant alteration seen in ATRX in sarcoma is LOF mutation, thus tumor specimens were scored for presence or absence of ATRX staining by immunohistochemistry (IHC) in clinically-annotated tissue microarrays (TMAs) including 95 patients with uterine leiomyosarcoma (ULMS), 127 with soft tissue leiomyosarcoma (STLMS), 82 with undifferentiated pleomorphic sarcoma (UPS), and 84 with well-differentiated/dedifferentiated liposarcoma (WD/DDLPS). We also performed IHC staining using a panel of immune cell markers and checkpoints on the ULMS TMA, including CD8, CD20, CD68, PDL1, CTLA4, CD47, and CD163, among others. Kaplan-Meier analysis with log rank tests were used to assess the impact of ATRX loss on overall survival (OS), disease-specific survival (DSS), and progression free survival (PFS). Cox proportional hazards modeling was used to determine whether ATRX loss is an independent predictor of survival. T tests, ANOVA, and Chi squared tests were used to test for association between ATRX loss and immune markers in the ULMS TMA. Results: ATRX loss was seen in 14.1% of STLMS (n = 18), 52.6% of ULMS (n = 50), 36.6% of UPS (n = 30), and 8.3% of WD/DDLPS (n = 7). In univariate analysis, ATRX loss was associated with significantly worse OS (HR 0.50, 95% CI 0.31-0.80, p = 0.004) and PFS (HR 0.51, 95% CI 0.33-0.81, p = 0.004) in ULMS, worse DSS in UPS (HR 0.46, 95% CI 0.23-0.95, p = 0.03), and worse PFS in WD/DDLPS (HR 0.13, 95% CI 0.02-0.73, p = 0.02). In multivariate analyses, ATRX loss was also associated with worse OS and PFS in ULMS and worse DSS in UPS. In ULMS, ATRX loss was associated with increased density of CD8+ T cells (p = 0.01), PDL1 expression (p = 0.03), CTLA4 expression (p = 0.049), IDO-positive tumor cells (p = 0.01), and CD163-positive cells (p = 0.003). Conclusions: ATRX loss is associated with worse outcomes in ULMS, UPS, and WD/DDLPS. ATRX loss is also associated with a distinct immune microenvironment in ULMS characterized by T cell exhaustion and immunosuppressive M2 macrophages. Future work will focus on understanding the molecular underpinnings of these associations and potential ways to exploit these findings therapeutically.
Anti-angiogenic TKIs in patients with advanced Ewing sarcoma: A systematic review and single-arm meta-analysis.
Authors: Castro Caio , Belluco Ana Paula , Michelon Isabella , Dacoregio Maria Inez , N. Priantti Jonathan , Vilbert Maysa , Koch Hein Erica C. , Cavalcante Ludimila
Published: June 2024

11531

Background: The treatment of patients with localized Ewing Sarcoma (ES) is well established; however, strategies for relapsed disease remain uncertain. Encouraging outcomes have surfaced from early-phase trials assessing tyrosine kinase inhibitors (TKIs) with anti-angiogenic properties in this population. Hence, we conducted a systematic review and meta-analysis to synthesize current data on efficacy and safety of TKIs in patients with ES. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases for clinical trials and cohort studies assessing anti-angiogenic TKIs in the treatment of advanced ES patients who had received at least one previous line of therapy. Main outcomes were objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), and safety. Heterogeneity was assessed using I2 statistics. All analyses were conducted using R software (v.4.2.2), employing random effects models. Results: We included 10 studies: four phase II clinical trials and six retrospective cohort studies, comprising 191 patients. The following TKIs were evaluated: cabozantinib, regorafenib, apatinib, anlotinib and sorafenib. Median age in each study varied from 15 to 33 years, and 48.6% of patients had received ≥2 previous lines of therapy. In a pooled analysis of all ES patients treated with TKIs, the ORR was 30.1% (95%IC 16.3-43.8; I2=83.14%) and DCR was 66.8% (95%IC 59.4-73.5; I2=3.97%). In a comparative analysis stratified by drug, anlotinib was associated with an increased ORR (p<0.01) and no difference was seen in DCR among TKIs assessed (p=0.26). Seven studies evaluated TKIs in monotherapy, while the others included patients treated with TKIs + chemotherapy (CT); TKI+CT displayed higher ORR (p=0.04) and DCR (p=0.05), in a subgroup analysis by treatment strategies. The median PFS varied from 3.5 to 16.0 between drugs, and the overall median PFS was 4.4 months (95%CI 3.4-10). Dose reduction and interruption of treatment due to toxicity were reported in 39.6% and 6% of patients, respectively. Most common grade 3 or 4 adverse events were leukopenia (24.5%), anemia (8.8%), hypertension (5.6%), and diarrhea (4.3%). Conclusions: Anti-angiogenic TKIs are well tolerated and have shown anti-tumoral activity and clinical benefit in the treatment of patients with advanced Ewing sarcoma. Prospective randomized trials with adequate control groups are warranted to further evaluate the benefits of these agents. [Table: see text]
Novel models for the functional characterization of SDHA germline variants to predict cancer risk.
Authors: Kent Jason , Heinrich Michael C.
Published: June 2024

11532

Background: SDHA mutations are the most common cause of SDH-deficient GIST. More than 80% of SDHA-mutant GIST are associated with heterozygous germline mutations. Enhanced cancer surveillance of individuals carrying a known pathogenic germline SDHA mutation has the potential to detect early-stage tumors, allowing for curative surgery. However, of the > 1000 SDHA missense variants listed in ClinVar, > 95% are VUS. We must improve our ability to interpret the significance of SDHA variants before genetic sequencing can be utilized to its fullest potential for assessing cancer risk. Methods: We generated a novel clonal SDHA knock out (SDHAKO) human cell line with complete loss of SDHA expression and enzymatic activity. We next generated a clonal cell line harboring one copy of a landing pad cassette, allowing for site-specific integration of transfected expression cassettes mediated by Bxb1 recombinase. We validated that wild-type SDHA cDNA restored SDHA expression and enzymatic activity to levels equivalent to the parental HAP1 cells. We then selected 17 known benign variants (B,LB) and 21 known cancer missense variants (P, LP). In addition, we selected six missense variants associated with primary mitochondrial disease rather than cancer. Lastly, we selected 22 missense VUS. We created a mutant cell line in our KO landing pad cell line for each SDHA variant, as well as a control nonsense variant (SDHAR31X). Cell lines were analyzed for normalized SDH activity measurements (SDHAWT activity score = 1) Results: As expected, benign variants were collectively WT-like, with a mean Activity Score of 0.917. However, there was substantial variability amongst individual variants, with SDHAY55H having the lowest score at 0.215. Although known PMD variants (mean Activity Score = 0.358) were associated with lower functionality than that of benign variants, the extent of SDH dysfunction corresponding to cancer variants (mean Activity Score = 0.007) was substantially lower. Notably, all but one cancer variant could be described as functionally amorphic, as their Activity Scores were not significantly different from that of a control null variant, SDHAR31X, whose mean Activity Score was 0.004. We used the Activity Scores of these clinical control variants to establish thresholds to classify "cancer-like" or "benign-like" variants, which meet ACMG/AMP criteria for PS3_strong and BS_3 strong evidence according to an OddsPath calculation. We biochemically profiled 22 cell lines expressing a SDHA VUS. Using functional data and ACMG criteria, 3 variants could be reclassified as "Likely Benign", 14 could be reclassified as "Likely Pathogenic", and 5 remained a VUS (77% successfully reclassified). Conclusions: Functional characterization of SDHA germline missense variants has the potential to identify individuals who will benefit from genetic counseling and enhanced cancer screening procedures.
Molecular characterization of long-term and short-term survivors of metastatic uterine leiomyosarcoma.
Authors: Sia Tiffany Y. , Brown David N , Miller Kathryn M , Leitao Mario M. , Abu-Rustum Nadeem , Chiang Sarah , Weigelt Britta , Hensley Martee Leigh
Published: June 2024

11542

Background: While some metastatic uterine leiomyosarcomas (uLMS) are clinically aggressive, others have a more indolent disease pace, suggesting biologic heterogeneity. Our objective was to determine whether the molecular characteristics of metastatic uLMS tumors differed between long-term survivors (LS) and short-term survivors (SS). Methods: Patients with metastatic uLMS between 1/1/2000 – 11/31/2020 who received care at our institution and had tumor tissue available were included. uLMSs were subjected to a targeted DNA next-generation sequencing panel of up to 505 cancer-related genes. Metastatic overall survival (mOS) was calculated from the date of diagnosis of metastatic disease until the date of death or last follow-up. LS was defined as mOS >2 years and SS as mOS <2 years. Appropriate statistical tests were used. Results: Our cohort included 17 LS and 10 SS (Table). uLMSs from LS harbored TP53 alterations in 58% of cases compared to 90% of SS (P<0.001). Rate of RB1 alterations in LS was 76% compared to 50% in SS (P<0.001). Rates of somatic genetic alterations affecting ATRX(11% LS vs. 20% SS) and BRCA2(47% LS vs. 50% SS) were similar between groups (P>0.05 for both). Most BRCA2alterations (92%) were homozygous deletions. Levels of chromosomal instability as quantified by the fraction of genome altered was similar between groups (median 27.3% in LS versus 22.9% in SS, p=0.26). Tumor mutational burden was low in both groups. Conclusions: While uLMS from LS and SS have similar levels of chromosomal instability and tumor mutational burden, uLMS in LS have lower rates of TP53 alterations compared to SS patients, as well as compared to previously reported rates in uLMS. Rates of RB1alterations were higher in LS compared to SS. Interestingly, the rate of BRCA2alterations in both LS and SS is higher than previously reported and provides rationale for next-generation sequencing in patients with metastatic uLMS. Further studies in larger cohorts to validate these findings are warranted. [Table: see text]
Analysis of the time to progression in patients who underwent metastasectomy plus isolated lung chemoperfusion for disease recurrence after metastasectomy alone.
Authors: Levchenko Evgeny , Mikhnin Aleksandr , Senchik Konstantin , Mamontov Oleg , Ergnyan Stepan , Levchenko Nikita , Yurin Roman , Khandogin Nikolay , Nyukhlov Evgeny , Imyanitov Evgeny
Published: June 2024

11568

Background: The combination of pulmonary metastasectomy (ME) with isolated lung chemoperfusion (ILuP) has shown promising results, however, a direct comparison of the clinical outcomes obtained by ME plus ILuP versus ME alone is complicated. The heterogeneity of patients in terms of cancer types, number of metastases and composition of prior systemic therapy adds to the difficulties of this analysis. Methods: Patients who initially received ME alone, and then ME plus normothermic ILuP after the disease relapse, were considered. The aim of the study was to compare the time to pulmonary disease progression (TTP) after the first and second interventions (TTP1 and TTP2, respectively) in the same subjects. Results: Of 225 patients who underwent ME plus ILuP in 2007 - 2020, we selected 48 patients who received this treatment due to pulmonary disease progression after ME alone. There were 16 patients with soft tissue sarcoma, 8 patients with osteosarcoma, 14 colorectal cancer cases and 10 patients with other tumor types. The mean number of metastases was 2.94 before ME alone and 4.33 before ME plus ILuP. Cisplatin was used in 30 patients at a mean dose of 191.8 mg, and melphalan was utilized in 18 subjects at a mean dose of 44.1 mg. The median follow-up was 31.1 months. The median TTP1 was 6.9 months, and the median TTP2 was 19.0 months (p <0.0001). TTP2/TTP1 ratio equal or above 1.5 was observed in 34 out of 48 patients (71%). Conclusions: This is the first study comparing the results of ILuP plus ME versus ME alone in the same patients. The data obtained strongly support the feasibility of adding isolated lung chemoperfusion to surgery in patients amenable to excision of lung metastases.
Walking dose required to achieve a clinically meaningful reduction in cancer-related fatigue among patients with breast cancer receiving chemotherapy: A URCC NCORP nationwide prospective cohort study.
Authors: Mattick Lindsey Jean , Lin Po-Ju , Mustian Karen Michelle , Peppone Luke Joseph , Gada Umang , Samuel Stephen Rajan , Clark Viktor , Yilmaz Sule , McGuire Jeremy , Conlin Alison Katherine , Weiselberg Lora Rose , Mitchell Jerry W. , Janelsins Michelle Christine
Published: June 2024

12008

Background: Exercise is recommended by ASCO as a treatment for cancer-related fatigue (CRF) - one of the most pervasive toxicities patients with breast cancer experience. Current oncology guidelines recommend aerobic exercise (e.g., walking) at a weekly dose of 150 minutes of moderate intensity or 75 minutes of vigorous intensity. While these recommendations exist and are effective for treating CRF, patients with breast cancer struggle to achieve these levels of exercise, especially at a vigorous intensity during chemotherapy. The purpose of this study was to determine the doses of low and moderate intensity walking required to elicit a clinically meaningful reduction in CRF. Methods: As part of a nationwide prospective cohort study, 580 female breast cancer patients (stage I-IIIC; receiving chemotherapy) were recruited from 19 University of Rochester Cancer Center NCI Community Oncology Research Program (URCC NCORP) Research Base locations. CRF (Multidimensional Fatigue Symptom Inventory) and exercise dose (i.e., walking via ACLS Physical Activity Measure) were measured at pre-chemotherapy, 1-month post-chemotherapy, and 6-months post-chemotherapy. Exercise dose was measured in METs (energy expenditure normalized for body weight and time; 1 MET = 1 kcal/kg/hr) and converted into walking time (minutes) and intensity (mph). A low-intensity walking pace is < 2.5mph (< 3 METs), and a moderate-intensity walking pace is 2.6-4.5mph (3.1-6 METs). Results: Pre-chemotherapy, patients with breast cancer averaged walking 40-60 minutes/week at a low intensity or 20-38 minutes/week at a moderate intensity (median: 2.0 MET hrs/wk). Linear mixed modeling demonstrated a higher amount of walking significantly predicts lower CRF at all three time points (β: -0.26, SE: 0.08; p < 0.001). Logistic regression identified that patients who increase their walking by 111-162 minutes at a low-intensity pace or 54-108 minutes at a moderate-intensity pace (i.e., 1 SD) are 43% more likely to experience a clinically meaningful reduction in CRF (- 4.5 MFSI total) from pre-chemotherapy to 1-month post-chemotherapy (SD: 5.4 MET hrs/wk; OR: 1.43, 95% CI: 1.19-1.72; p < 0.001). Conclusions: Over the course of chemotherapy, patients with breast cancer who can increase their walking at a low intensity pace (< 2.5 mph) up to 151-222 min/wk or at a moderate intensity pace (2.6-4.5 mph) up to 74-146 min/wk are 43% more likely to have clinically meaningful lower levels of CRF post-chemotherapy.
Effect of nurse-led multi-disciplinary treatment on patients with head and neck tumors: A randomized controlled trial.
Authors: Wang Jingjing , Cai Lei , Pei Yiyan , Li Juejin , Wei Zhigong , Li Ruidan , Su Yonglin , Hu Xiaolin , Peng Xingchen
Published: June 2024

12013

Background: Patients undergoing radiotherapy (RT) for head and neck tumors are prone to experiencing nutritional and psychological issues as a result of adverse events to the treatment, which may ultimately lead to radiotherapy interruption (RTI). We conducted a prospective, randomized controlled trial to assess the effect of nurse-led multi-disciplinary treatment (MDT) interventions, incorporating psychological and nutritional interventions, on RTI rates and quality of life (QoL) among patients undergoing RT for head and neck tumors. Methods: Patients with head and neck cancer undergoing RT at West China Hospital, Sichuan University were enrolled. Eligible patients were randomly assigned in a 1:1 ratio to receive either the standard oncology care (standard group) or the nurse-led, whole-course MDT care (MDT group). The MDT care included nutritional and psychological interventions provided by a team of a radiotherapist, an oncology specialty nurse, a dietitian, a psychotherapist and a rehabilitation therapist. The primary end point was RTI rate in the per-protocol set (PPS). Patients’ QoL was assessed using the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires. Nutritional status was assessed using NRS 2002 and PG-SGA, and psychological status was assessed using DT, PHQ-9 and HADS. Results: A total of 233 patients were enrolled in the study. At the final follow-up, 112 patients in the standard group and 114 patients in the MDT group completed all follow-up assessments. The RTI rate in the MDT group was significantly lower than that in the standard group (MDT vs. standard: 11.4% vs. 25.9%, P= 0.005). Differences in QoL among patients favored MDT care over standard care, particularly in emotional function, GHS, fatigue, and insomnia. Baseline patients’ nutritional and psychological status were similar between two groups. From mid-RT to 6 months after RT, the nutritional and psychological status of patients in the MDT group improved at certain follow-up points compared with the control group. The rehospitalization rate in the MDT group was significantly lower than that of control group (MDT vs. standard: 7.9% vs. 18.8%, P= 0.016). Conclusions: Nurse-led MDT interventions effectively reduces RTI, improves nutritional status of patients, and alleviates their psychological burden, making it a worthy approach for dissemination in developing countries. Clinical trial information: NCT05828004 .