bluuebunny/crossref_metadata_2025 huggingface dataset:
Residual biliary intraepithelial neoplasia without malignant transformation at resection margin for perihilar cholangiocarcinoma does not require expanded resection: a dual center retrospective study
Authors: Xu Zeliang , Fan Xiaoyi , Zhang Chengcheng , Li Yuancheng , Jiang Di , Hu Feng , Pan Bi , Huang Yixian , Zhang Leida , Lau Wan Yee , Liu Xingchao , Chen Zhiyu
Published: June 2024

Background

Additional resection for invasive cancer at perihilar cholangiocarcinoma (pCCA) resection margins has become a consensus. However, controversy still exists regarding whether additional resection is necessary for residual biliary intraepithelial neoplasia (BilIN).

Method

Consecutive patients with pCCA from two hospitals were enrolled. The incidence and pattern of resection margin BilIN were summarized. Prognosis between patients with negative margins (R0) and BilIN margins were analyzed. Cox regression with a forest plot was used to identify independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis was performed based on BilIN features and tumor characteristics.

Results

306 pCCA patients receiving curative resection were included. 255 had R0 margins and 51 had BilIN margins. There was no significant difference in OS (P = 0.264) or RFS (P = 0.149) between the two group. Specifically, 19 patients with BilIN at distal bile ducts and 32 at proximal bile ducts. 42 patients showed low-grade BilIN, and 9 showed high-grade. Further analysis revealed no significant difference in long-term survival between different locations (P = 0.354), or between different grades (P = 0.772). Portal vein invasion, poor differentiation and lymph node metastasis were considered independent risk factors for OS and RFS, while BilIN was not. Subgroup analysis showed no significant difference in long-term survival between the lymph node metastasis subgroup, or between the portal vein invasion subgroup.

Conclusion

For pCCA patients underwent curative resection, residual BilIN at resection margin is acceptable. Additional resection is not necessary for such patients to achieve absolute R0 margin.
Regulation of vascular endothelial integrity by mesenchymal stem cell extracellular vesicles after hemorrhagic shock and trauma
Authors: Barry Mark , Trivedi Alpa , Miyazawa Byron , Vivona Lindsay R. , Shimmin David , Pathipati Praneeti , Keane Callie , Cuschieri Joseph , Pati Shibani
Published: June 2024

Background

Patients with hemorrhagic shock and trauma (HS/T) are vulnerable to the endotheliopathy of trauma (EOT), characterized by vascular barrier dysfunction, inflammation, and coagulopathy. Cellular therapies such as mesenchymal stem cells (MSCs) and MSC extracellular vesicles (EVs) have been proposed as potential therapies targeting the EOT. In this study we investigated the effects of MSCs and MSC EVs on endothelial and epithelial barrier integrity in vitro and in vivo in a mouse model of HS/T. This study addresses the systemic effects of HS/T on multiorgan EOT.

Methods

In vitro, pulmonary endothelial cell (PEC) and Caco-2 intestinal epithelial cell monolayers were treated with control media, MSC conditioned media (CM), or MSC EVs in varying doses and subjected to a thrombin or hydrogen peroxide (H2O2) challenge, respectively. Monolayer permeability was evaluated with a cell impedance assay, and intercellular junction integrity was evaluated with immunofluorescent staining. In vivo, a mouse model of HS/T was used to evaluate the effects of lactated Ringer’s (LR), MSCs, and MSC EVs on endothelial and epithelial intercellular junctions in the lung and small intestine as well as on plasma inflammatory biomarkers.

Results

MSC EVs and MSC CM attenuated permeability and preserved intercellular junctions of the PEC monolayer in vitro, whereas only MSC CM was protective of the Caco-2 epithelial monolayer. In vivo, both MSC EVs and MSCs mitigated the loss of endothelial adherens junctions in the lung and small intestine, though only MSCs had a protective effect on epithelial tight junctions in the lung. Several plasma biomarkers including MMP8 and VEGF were elevated in LR- and EV-treated but not MSC-treated mice.

Conclusions

In conclusion, MSC EVs could be a potential cell-free therapy targeting endotheliopathy after HS/T via preservation of the vascular endothelial barrier in multiple organs early after injury. Further research is needed to better understand the immunomodulatory effects of these products following HS/T and to move toward translating these therapies into clinical studies.
Influenza virus infection exacerbates gene expression related to neurocognitive dysfunction in brains of old mice
Authors: Wu Wenxin , Alexander Jeremy S. , Booth J. Leland , Miller Craig A. , Metcalf Jordan P. , Drevets Douglas A.
Published: June 2024

Background

Age > 65 years is a key risk factor for poor outcomes after human influenza infection. Specifically, in addition to respiratory disease, non-neurotropic influenza A virus (IAV) causes neuro-cognitive complications, e.g. new onset depression and increases the risk of dementia after hospitalization. This study aimed to identify potential mechanisms of these effects by determining differences between young and old mice in brain gene expression in a mouse model of non-neurotropic IAV infection.

Methods

Young (12 weeks) and old (70 weeks) C57Bl/6J mice were inoculated intranasally with 200 PFU H1N1 A/PR/34/8 (PR8) or sterile PBS (mock). Gene expression in lung and brain was measured by qRT-PCR and normalized to β-actin. Findings were confirmed using the nCounter Mouse Neuroinflammation Array (NanoString) and analyzed with nSolver 4.0 and Ingenuity Pathway Analysis (IPA, Qiagen).

Results

IAV PR8 did not invade the central nervous system. Young and old mice differed significantly in brain gene expression at baseline and during non-neurotropic IAV infection. Expression of brain Ifnl, Irf7, and Tnf mRNAs was upregulated over baseline control at 3 days post-infection (p.i.) only in young mice, but old mice expressed more Ifnl than young mice 7 days p.i. Gene arrays showed down-regulation of the Epigenetic Regulation, Insulin Signaling, and Neurons and Neurotransmission pathways in old mice 3 days p.i. while young mice demonstrated no change or induction of these pathways at the same time point. IPA revealed marked baseline differences between old and young mice. Gene expression related to Cognitive Impairment, Memory Deficits and Learning worsened in old mice relative to young mice during IAV infection. Aged mice demonstrate more severe changes in gene expression related to memory loss and cognitive dysfunction by IPA.

Conclusions

These data suggest the genes and pathways related to learning and cognitive performance that were worse at baseline in old mice were further worsened by IAV infection, similar to old patients. Early events in the brain triggered by IAV infection portend downstream neurocognitive pathology in old adults.
Children with ADHD and EEG abnormalities at baseline assessment, risk of epileptic seizures and maintenance on methylphenidate three years later
Authors: Socanski Dobrinko , Ogrim Geir , Duric Nezla
Published: June 2024

Purpose

This study aimed to assess the incidence of EEG abnormalities (EEG-ab) in children diagnosed with ADHD, investigate the risk of epileptic seizures (SZ) and maintenance on methylphenidate (MPH) over a three-year period.

Methods

A total of 517 ADHD children aged 6–14 years were included. Baseline assessments included the identification of EEG-ab, ADHD inattentive subtype (ADHD-I), comorbid epilepsy, the use of antiepileptic drugs (AEDs) and the use of MPH. At the 3-year follow-up, assessments included the presence of EEG-ab, maintenance on MPH, AED usage, SZ risk in cases with EEG-epileptiform abnormalities (EEG-epi-ab), compared with control ADHD cases without EEG-epi-ab matched for age and gender.

Results

EEG-ab were identified in 273 (52.8%) cases. No statistically significant differences were observed between the EEG-ab and EEG-non-ab groups in terms of age, gender, ADHD-I type or initial use of MPH. EEG non-epileptiform abnormalities (EEG-non-epi-ab) were found in 234 out of 478 (49%) cases without EEG-epi-ab. Notably, EEG-non-epi-ab occurred more frequently in the group of 39 cases with EEG-epi-ab (30/39 (76.9%) vs. 9/39, (21.3%), a subset selected for 3-year follow-up. At 3-year-follow-up no statistically significant difference was found in maintenance on MPH in ADHD cases with and without EEG-epi-ab. Nobody of ADHD cases without comorbid epilepsy or with comorbid epilepsy with achieved SZ freedom developed new SZ. Only 3 children with drug resistant epilepsy experienced SZs, without increase in SZ frequency. The disappearance rate of EEG-epi-ab was higher than that EEG-non-epi-ab (71.8% vs. 33.3%).

Conclusions

Children with and without EEG-ab exhibited similar patterns of MPH use (initial use, positive response, and maintenance on MPH). The presence of comorbid epilepsy and EEG-ab, with or without EEG-epi-ab, was not associated with an increased risk of SZ despite the use of MPH.
Bleeding in minimally invasive versus conventional aortic valve replacement
Authors: Bratt Sorosh , Dimberg Axel , Kastengren Mikael , Lilford Robert D. , Svenarud Peter , Sartipy Ulrik , Franco-Cereceda Anders , Dalén Magnus
Published: June 2024

Background

Observational studies have shown reduced perioperative bleeding in patients undergoing minimally invasive, compared with full sternotomy, aortic valve replacement. Data from randomized trials are conflicting.

Methods

This was a Swedish single center study where adult patients with aortic stenosis, 100 patients were randomly assigned in a 1:1 ratio to undergo either minimally invasive (ministernotomy) or full sternotomy aortic valve replacement. The primary outcome was severe or massive bleeding defined by the Universal Definition of Perioperative Bleeding in adult cardiac surgery (UDPB). Secondary outcomes included blood product transfusions, chest tube output, re-exploration for bleeding, and several other clinically relevant events.

Results

Out of 100 patients, three patients randomized to ministernotomy were intraoperatively converted to full sternotomy (none was bleeding-related). Three patients (6%) in the full sternotomy group and 3 patients (6%) in the ministernotomy group suffered severe or massive postoperative bleeding according to the UDPB definition (p = 1.00). Mean chest tube output during the first 12 postoperative hours was 350 (standard deviation (SD) 220) ml in the full sternotomy group and 270 (SD 190) ml in the ministernotomy group (p = 0.08). 28% of patients in the full sternotomy group and 36% of patients in the ministernotomy group received at least one packed red blood cells transfusion (p = 0.39). Two patients in each group (4%) underwent re-exploration for bleeding.

Conclusions

Minimally invasive aortic valve replacement did not result in less bleeding-related outcomes compared to full sternotomy.

Clinical Trial Registration

http://www.clinicaltrials.gov. Unique identifier: NCT02272621.
Influence of ABC stroke score on late recurrence of paroxysmal atrial fibrillation following radiofrequency catheter ablation
Authors: Gong Ke-Zeng , Xu Zhe , Zhuang Ting-Pei , Chen Xue-Hai , Chen Jian-Hua , Wang Wei-Wei , Xu Wen-Hua , Zhang Fei-Long
Published: June 2024

Background

In this study we investigated the impact of ABC stroke score on the recurrence of paroxysmal atrial fibrillation (PAF) following radiofrequency catheter ablation (RFCA).

Methods

A total of 132 patients with PAF who underwent RFCA from October 2018 to September 2019 were included in this study. During the first phase of this study the patients were categorized into two groups based on late recurrence of atrial fibrillation after RFCA. In the second phase, the patients were further divided into two groups based on whether their ABC stroke score was ≥ 6.5.

Result

The univariate analysis indicated that the risk factors for late recurrence of PAF included early recurrence, ABC stroke score, CHA2DS2-VASc score, and NT-proBNP (P < 0.05). Cox multivariate regression analysis revealed that ABC stroke score (P = 0.006) and early recurrence (P = 0.000) were independent predictors of late recurrence, and ABC stroke score ≥ 6.5 was a risk for predicting recurrence of PAF after RFCA with a sensitivity of 66.7% and specificity of 65.7%. After the completion of the 1:1 matching, the univariate Cox analysis indicated that an elevated score of ABC stroke (≥ 6.5) was an independent predictor of late recurrence of PAF (HR = 2.687, 95% CI: 1.036–6.971, P = 0.042). However, using an ABC stroke score cut off at 6.4 predicted the recurrence of atrial tachyarrhythmia with 85% sensitivity and 58.5% specificity.

Conclusion

An ABC stroke score ≥ 6.4 is a predictor for late recurrence of PAF after RFCA.
Small cell lung carcinoma presenting initially with recurrent pneumothoraces: a case report
Authors: Buchanan John , Shatila Mohamed , Menon Ashvini , Patel Akshay J.
Published: June 2024

Background

Pneumothorax is a non-physiological collection of air in the pleural space. Pneumothoraces can be broadly divided into Primary, Secondary, and Traumatic. Cancer of the lung is a known cause of secondary pneumothorax in both primary and metastatic lesions, however, pneumothorax as the presentation of lung cancer is exceedingly rare. Non-small cell lung carcinoma (NSCLC) has been reported in the literature to present with a pneumothorax, particularly in adeno/squamous cell carcinomas. It is almost completely unheard of for small cell lung carcinoma (SCLC) to present with a pneumothorax.

Case Presentation

We present the case of a 62-year-old male patient, presenting twice in two months with spontaneous pneumothorax. The initial management involved admission and chest drain insertion. The patient has a past medical history of COPD and a significant smoking history. On the second admission, he underwent a video-assisted thoracoscopic (VATS) bullectomy and talc pleurodesis. The pathology report of the resected specimen confirmed SCLC with extensive infiltration. No gross evidence of metastatic spread was present on CT. Due to the R1 resection and significant risk of recurrence, the management plan included four cycles of adjuvant chemotherapy with carboplatin and etoposide, and radiotherapy as a consideration upon completion.

Conclusions

Pneumothorax as the presentation of lung cancer imparts a very poor prognosis, however the reasons for this are largely unknown. Furthermore, the mechanisms underlying spontaneous pneumothorax in lung cancer are also not well understood.
Early outcomes of aortic valve replacement with Perceval PLUS sutureless valve: results of the prospective multicentric MANTRA study
Authors: Micovic Slobodan , Nobre Angelo , Choi Jae Woong , Solinas Marco , Shehada Sharaf-Eldin , Torella Michele , Baeza Cristian , Parrino Eugene , Pollari Francesco , Troise Giovanni , Kappert Utz , Mellert Friedrich , Je Hyung Gon , Argano Vincenzo , Lam Ka Yan , Rinaldi Mauro , Gutermann Herbert , Meuris Bart ,   the MANTRA Investigators
Published: June 2024

Background

The aim of this study is to report the preliminary real-word clinical and hemodynamic performance from the MANTRA study in patients undergoing aortic valve replacement with Perceval PLUS sutureless valve.

Methods

MANTRA is an ongoing “umbrella” prospective, multi-center, international post-market study to collect real-life safety and performance data on Corcym devices (Corcym S.r.l, Saluggia, Italy). Clinical and echocardiographic outcomes were collected preoperatively, at discharge and at each follow up. KCCQ-12 and EQ-5D-5L quality of life questionnaires were collected preoperatively and at 30-days.

Results

A total of 328 patients underwent aortic valve replacement with Perceval PLUS in 29 International institutions. Patients were enrolled from July 2021 to October 2023 and enrollment is still ongoing. Mean age was 71.9 ± 6.4 years, mean EuroSCORE II was 2.9 ± 3.9. Minimally invasive approach was performed in 44.2% (145/328) of patients; concomitant procedures were done in 40.8% (134/328) of cases. Thirty-day mortality was 1.8% (6/328) and no re-interventions were reported. Pacemaker implant was required in 4.0% (13/328) of the patients.

The assessment of the functional status demonstrated marked and stable improvement in NYHA class in most patients at 30-day follow-up, with significant increase of KCCQ-12 summary score (from 58.8 ± 23.0 to 71.8 ± 22.1, p < 0.0001) and EQ-5D-5L VAS score (from 64.5 ± 20.4 to 72.6 ± 17.5, p < 0.0001). Mean pressure gradient decreased from 46.2 ± 17.3 mmHg to 10.1 ± 4.7 mmHg at 30-day follow-up. Low or no incidence of moderate-to-severe paravalvular or central leak was reported.

Conclusions

Preliminary results demonstrate good clinical outcomes and significant improvement of Quality of Life at 30-days, excellent early hemodynamic performance within patient implanted with Perceval PLUS.

Trial Registration

The MANTRA study has been registered in ClinicalTrials.gov (NCT05002543, Initial release 26 July 2021).
Thirty-three-year follow-up of pseudoaneurysm of the mitral-aortic intervalvular fibrosa without surgical treatment: a case report and literature review
Authors: Mirhosseini Seyed Mohsen , Soltanipur Masood , Yarmohammadi Hossein , Rezaei Mahdi , Fattah Eisa , Bayat Fariba
Published: June 2024

Background

Pseudoaneurysm of the mitral-aortic intervalvular fibrosa (PMAIF) is a rare complication of infective endocarditis or aortic valve surgery. Surgical treatment is suggested, but the long-term follow-up of conservative management remains unclear.

Case presentation

A 33-year follow-up of a patient who developed PMAIF six years after aortic valve replacement is reported. The patient presented to our center with dyspnea, and the echocardiography revealed an ejection fraction of 20% and a PMAIF measuring 7 × 10 mm. Despite being advised to undergo surgery, the patient declined due to fear of surgical outcomes. Consequently, conservative treatment with close observation but without surgery was initiated. During the 33-year follow-up period, the patient did not experience any adverse health effects.

Conclusion

Surgical intervention should be considered whenever the PMAIF is diagnosed. However, in any case that the surgery was not applicable, conservative management might lead to long-term survival, based on this and similar case reports in the literature.
Thymic Rosai-Dorfmann disease: a case report
Authors: Liu Gaohua , Jing Min , Wang Juan
Published: June 2024

Background

Rosai-Dorfman disease (RDD), known as sinus histiocytosis with massive lymphadenopathy, commonly involves lymph nodes in the neck or mediastinum, although extranodal involvement is observed in approximately 40% of RDD patients. RDD involving only the thymus has rarely been reported. Here, we report a case of RDD originating in the thymus. The lesion was surgically removed, and a cure was finally achieved. There was no recurrence after telephone follow-up for 3 years.

Case presentation

A 52-year-old male was accidentally found to have a 7 × 6 cm anterior mediastinum lump by chest computed tomography (CT). The mediastinal lesion was resected by surgery, and postoperative pathology revealed RDD originating from the thymus. Regular telephone follow-up after surgery lasted 3 years and showed that the patient remained in good condition without any relevant symptoms.

Conclusions

RDD originating in the thymus cannot be characterized from CT images and is easily misdiagnosed as a traditional mediastinal tumor. This is mainly because there is so little disease in this area that physicians are not aware of it. We report this case with the hope that clinicians will have a better understanding of this disease. According to our follow-up results, surgery is an effective means of treatment.
Trends in hospitalizations of children with respiratory syncytial virus aged less than 1 year in Italy, from 2015 to 2019
Authors: Cutrera Renato , d’Angela Daniela , Orso Massimiliano , Guadagni Liliana , Vittucci Anna Chiara , Bertoldi Ilaria , Polistena Barbara , Spandonaro Federico , Carrieri Ciro , Montuori Eva Agostina , Iantomasi Raffaella , Orfeo Luigi
Published: June 2024

Background

Respiratory syncytial virus (RSV) affects 60–80% of children below 1 year and it’s the first cause of acute bronchiolitis. The aim of this study was to assess the trend and characteristics of hospitalizations for RSV infections in Italy.

Methods

This is a retrospective study based on the Italian Hospital Discharge Record (HDR) database. We analysed HDRs from June 2015 to May 2019, considering two groups of infants: Group 1 had a confirmed diagnosis of RSV; Group 2 had a diagnosis of acute bronchiolitis not RSV-coded.

Results

There were 67,746 overall hospitalizations (40.1% Group 1, and 59.9% Group 2). Hospitalization rate increased for Group 1 from 125 to 178 per 10,000 infants (+ 42.4%), and for Group 2 from 210 to 234 per 10,000 (+ 11.4%). The mean hospitalization length was 6.3 days in Group 1, longer than Group 2 (+ 1.0 day). A further analysis revealed that infants with heart disease or born premature had longer mean hospital stay compared to infants without risk factors (10.7 days versus 6.1 days, p < 0.0001; 34.0 days versus 6.1 days, p < 0.0001, respectively). Group 1 required more critical care (oxygen therapy and/or mechanical ventilation) than Group 2. We found that, in proportion to hospital admissions in pediatric and general hospitals, RSV was more frequently diagnosed in the first ones. The mean hospitalization cost increased for Group 1 (from € 2,483 to € 2,617) and Group 2 (from € 2,007 to € 2,180).

Conclusions

Our results confirmed that RSV pulmonary disease in infants is seasonal and often requires hospitalization. Our study suggested that RSV is responsible for an increasing hospitalization rate and related costs during the study period.
The effect of exercise rehabilitation with exergames combined with ice therapy in the treatment of obese patients with gout: protocol for a clinical trial
Authors: Cao Manting , Yusof Hazwani Ahmad , Chen Jianer , Jalil Mohd Faizal , Rahim Siti Khairizan , Abdullah Mohamad Zulfadhli
Published: June 2024

Background

Gout remains a leading cause of inflammatory arthritis worldwide, and the main risk factor for gout is persistent hyperuricemia. The clinical management of gout is mostly drug-based, and other treatment options are often ignored. This research proposal will explore whether exergames combined with ice therapy can help patients with gout to lose weight, relieve pain, improve the range of movement, improve quality of life, decrease uric acid level, decrease kinesiophobia and improve mental health of patients with gout.

Methods

This experiment will use a two-arm randomized controlled design. The study setting is at the Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia (USM). Obese patients with gout (N = 30) will be randomly assigned to the control group (receive an exergames intervention) and intervention group (receive an exergames intervention combined with ice therapy). The outcomes measurement will be conducted before (baseline) and after intervention (4 weeks). Then, it will be followed up at 12 weeks.

Discussion

To our knowledge, no study has investigated the effect of exergames and ice therapy among gout patients. This study is expected to demonstrate that exercise rehabilitation facilitated by exergames with ice therapy is more effective in gout management compared to a conventional rehabilitation intervention.

Trial registration

Chinese Clinical Trial Registry (ChiCTR2300070029). Registered on 31 March 2023.
Outcome improvement for anaemia and iron deficiency in ERAS hip and knee arthroplasty: a descriptive analysis
Authors: Jørgensen Christoffer Calov , Kehlet Henrik ,   The Center for Fast-track Hip, Knee Replacement Collaborative Group, Hansen Torben B. , Gromov Kirill , Jakobsen Thomas , Varnum Claus , Overgaard Soren , Rathsach Mikkel , Lindberg-Larsen Martin , Bieder Manuel Josef
Published: June 2024

Background and purpose

Preoperative anaemia including iron deficiency anaemia (IDA) is a well-established perioperative risk factor. However, most studies on iron therapy to treat IDA have been negative and few have been conducted within an enhanced recovery after surgery (ERAS) protocol. Furthermore, patients with IDA often have comorbidities not necessarily influenced by iron, but potentially influencing traditional study endpoints such as length of stay (LOS), morbidity, etc. The aim of this paper is to discuss patient-related challenges when planning outcome studies on the potential benefits of iron therapy in patients with IDA, based upon a large detailed prospective database in ERAS total hip (THA) and knee arthroplasty (TKA).

Methods

A prospective observational cohort study in ERAS THA and TKA from 2022 to 2023. Detailed complete follow-up through questionnaires and electronic medical records.

Results

Of 3655 included patients, 276 (7.6%) had IDA defined as a haemoglobin (Hb) of < 13.0 g/dL and transferrin saturation of 0.20, while 3379 had a Hb of ≥ 13.0. Patients with IDA were a median 5 years older than non-anaemics, with an increased fraction living alone (38.4% vs. 28.8%), using walking aids (54.3% vs 26.4%) and receiving home care (16.2% vs 4.7%). Fewer IDA patients were working (12.7% vs. 29.6%) and a median number of prescribed drugs was higher (10 vs. 6).

Median LOS was 1 day in both IDA and non-anaemic patients, but a LOS of > 2 days occurred in 11.6% of patients with IDA vs. 4.3% in non-anaemics. The proportion with 30- or 90-day readmissions was 6.5% vs. 4.1% and. 13.4% vs6.0%, in patients with IDA and non-anaemics, respectively. However, potentially anaemia or iron deficiency-related causes of LOS > 2 days or 90-day readmissions were only 5.4% and 2.2% in patients with IDA and 1.9% and 1.0% in non-anaemics.

Conclusion

Conventional randomised trials with single or composite “hard” endpoints are at risk of being inconclusive or underpowered due to a considerable burden of other patient-related risk factors and with postoperative complications which may not be modifiable by correction of IDA per se. We will propose to gain further insights from detailed observational and mechanistic studies prior to initiating extensive randomised studies.
Exploring the interplay of emotional intelligence, psychological resilience, perceived stress, and life satisfaction: A cross-sectional study in the Turkish context
Authors: Kartol Aslı , Üztemur Servet , Griffiths Mark D. , Şahin Derya
Published: June 2024

Background

Emotional intelligence and life satisfaction are essential components for good psychological well-being. Studies examining the elements contributing to emotional intelligence and its relationships with different psychological constructs are likely to positively contribute to mental health. Therefore, the present study examined the mediating roles of perceived stress and psychological resilience in the relationship between emotional intelligence and life satisfaction.

Methods

The study sample comprised 780 university students (62.3% females) studying at universities in different regions of Türkiye. An online survey included the Emotional Intelligence Scale, Satisfaction with Life Scale, Psychological Resilience Scale, and Perceived Stress Scale. A multifactorial complex predictive correlational design was used.

Results

The results showed that emotional intelligence was (i) positively correlated with life satisfaction and psychological resilience, and (ii) negatively correlated with perceived stress. In the final model, perceived stress and psychological resilience played a mediating role in the relationship between emotional intelligence and life satisfaction. The findings suggest that higher emotional intelligence may lower perceived stress and appears to have a positive effect in relation to life satisfaction and psychological resilience.

Conclusion

Individuals working in the field of mental health need to help individuals increase their level of EI, which may help reduce the level of perceived stress and increase psychological resilience and life satisfaction.
Autocrine insulin-like growth factor 2 signaling as a potential target in the associated development of pulmonary emphysema and cancer in smokers
Authors: Boo Hye-Jin , Min Hye-Young , Lim Heung-Bin , Lee Euni , Lee Ho-Young
Published: June 2024

Background

Tobacco smoking causes pulmonary inflammation, resulting in emphysema, an independent risk factor for lung cancer. Induction of insulin-like growth factor 2 (IGF2) in response to lung injury by tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and polycyclic aromatic hydrocarbon benzo[a]pyrene in combination (NB), is critical for the proliferation of alveolar type 2 cells (AT2s) for lung repair. However, persistent IGF2 overexpression during NB-induced severe injury results in hyperproliferation of AT2s without coordinated AT2-to-AT1 differentiation, disrupting alveolar repair, which leads to the concurrent development of emphysema and lung cancer. The current study aims to verify the role of IGF2 signaling in the associated development of emphysema and cancer and develop effective pharmaceuticals for the diseases using animal models that recapitulate the characteristics of these chronic diseases.

Methods

The pathogenesis of pulmonary emphysema and cancer was analyzed by lung function testing, histological evaluation, in situ zymography, dihydroethidium staining, and immunofluorescence and immunohistochemistry analyses utilizing mouse models of emphysema and cancer established by moderate exposure to NB for up to seven months.

Results

Moderate NB exposure induced IGF2 expression in AT2s during the development of pulmonary emphysema and lung cancer in mice. Using AT2-specific insulin receptor knockout mice, we verified the causative role of sustained IGF2 signaling activation in AT2s in emphysema development. IGF2-targeting strategies, including voltage-dependent calcium channel blocker (CCB) and a neutralizing antibody, significantly suppressed the NB-induced development of emphysema and lung cancer. A publicly available database revealed an inverse correlation between the use of calcium channel blockers and a COPD diagnosis.

Conclusions

Our work confirms sustained IGF2 signaling activation in AT2s couples impaired lung repair to the concurrent development of emphysema and cancer in mice. Additionally, CCB and IGF2-specific neutralizing antibodies are effective pharmaceuticals for the two diseases.
The in situ stress prediction of a fractured shale reservoir based on amplitude variation with angle and azimuth inversion: A case study from Southwest China
Authors: Huang Guangtan , Wei Shuying , Yang Chunhe , Guo Yintong
Published: June 2024

In situ stress estimation of a shale reservoir is critical for the design of shale hydraulic fracturing and wellbore stability analysis. Fractured shales have orthogonal anisotropy (OA) because of the presence of vertical fractures and lamination. However, the existing in situ stress estimation method mainly focuses on transversely isotropic media. To accommodate orthogonally anisotropic media, an in situ stress estimation method is developed by using amplitude variation with angle and azimuth inversion and linear-slip theory. First, an orthogonal anisotropic medium is introduced to characterize the fractured shale by using a linear-slip model, and then we formulate a reflection coefficient approximation for OA media to perform the seismic inversion. Next, a fracture weakness inversion strategy that incorporates the vertically transverse isotropic background is developed to obtain the stiffness matrix of the media. Finally, the in situ stresses of the OA medium are formulated by using a stress-strain relationship. Inversion tests and a real data application indicate that our method is effective.
Germline Mutational Landscape and Novel Targetable RAD51D Variant in Chinese Patients With Ovarian Cancer
Authors: Feng Zheng , Chen Siyu , An Na , Xiu Zhihui , Ju Xingzhu , Chen Xiaojun , Bi Rui , Wang Jie , Zhu Shida , Wu Xiaohua , Wen Hao
Published: June 2024

PURPOSE

Genetic variants of ovarian cancer (OV) show ethnic differences, but data from the Chinese population are still insufficient. Here, we elucidate the inheritance landscape in Chinese patients with OV and examine the functional implications of a Chinese-enriched RAD51D variant.

METHODS

Between 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of BRCA1/2, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched RAD51D variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays.

RESULTS

Overall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 accounted for 16.09% and 5.36%, respectively, with one patient having both variants. In addition, 32 (8.58%) patients carried other HRR gene variants, whereas three (0.8%) patients had MMR gene variants. The RAD51D variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the RAD51D K91fs variant (c.270_271dup, p.Lys91Ilefs*13) and demonstrated satisfactory platinum response and favorable prognosis. This variant confers enhanced sensitivity to poly (ADP-ribose) polymerase inhibitors in OV cells. However, the effects on platinum sensitivity were inconsistent across different cell lines. Against the background of the TP53 variant, RAD51D K91fs variant showed increased sensitivity to cisplatin.

CONCLUSION

Our study revealed the inheritance landscape of OV and identified an enriched RAD51D variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.
Impact of colorectal liver metastases (CRLM) in patients with metastatic colorectal cancer (mCRC) receiving trifluridine/tipiracil (FTD/TPI) with or without bevacizumab (BEV) in the phase 3 SUNLIGHT trial.
Authors: Tabernero Josep , Prager Gerald W. , Taieb Julien , Calleja Elizabeth Martine , Liu Mei , Amellal Nadia , Fakih Marwan
Published: June 2024

3584

Background: Many patients with CRC develop CRLM during their disease, which are associated with poor prognosis. In the phase 3 SUNLIGHT trial, the addition of BEV to FTD/TPI significantly improved overall survival (OS) compared with FTD/TPI alone in patients with refractory mCRC, irrespective of mutational status, tumor sidedness, and other factors associated with poor prognosis. Here, we assessed the impact of baseline CRLM on efficacy outcomes among patients treated in SUNLIGHT. Methods: In this post hoc analysis, OS, progression-free survival (PFS), and disease control rate (DCR) were assessed in patients with and without CRLM. Differences in survival between FTD/TPI + BEV and FTD/TPI alone were assessed in each subgroup. The Kaplan-Meier method and log-rank test were used to compare differences in OS and PFS; DCRs were compared using Fisher's exact tests. The hazard ratios (HRs) for OS and PFS were estimated using a Cox proportional hazards model. Results: Of the 492 patients enrolled in SUNLIGHT, 382 (77.6%) had CLRM, comprising 194 randomized to FTD/TPI + BEV and 188 randomized to FTD/TPI alone. Among patients randomized to FTD/TPI + BEV (n=246), median OS (95% confidence interval [CI]) was 10.4 (8.6, 11.0) months and not estimable (NE) (11.1–NE) for patients with and without CRLM, respectively (HR: 1.88; P=0.005). For patients randomized to FTD/TPI alone (n=246), median OS (95% CI) was 6.5 (5.9, 8.0) months and 10.9 (9.0, 13.8) months for patients with and without CRLM, respectively (HR: 1.75; P=0.002). Similar trends were observed for PFS and DCR. When comparing treatment effects across arms, FTD/TPI + BEV resulted in longer OS and PFS compared with FTD/TPI alone in patients with and without CRLM. In patients with CRLM, the HRs for OS and PFS were 0.61 (95% CI: 0.48, 0.77; P<0.001) and 0.44 (95% CI: 0.35, 0.55; P<0.001), respectively. In patients without CRLM, the HRs for OS and PFS were 0.60 (95% CI: 0.35, 1.0; P=0.052) and 0.38 (95% CI: 0.24, 0.58; P<0.001), respectively. The DCR was also higher in patients treated with FTD/TPI + BEV compared with FTD/TPI alone (68.6% vs 38.3% in patients with CRLM and 73.1% vs 53.5% in patients without CRLM). Conclusions: The results of this analysis show that patients treated with the combination of FTD/TPI + BEV had numerically longer OS and PFS and a higher DCR than those treated with FTD/TPI alone, irrespective of whether or not patients had CRLM at baseline. Owing to the imbalance in numbers of patients with and without CRLM, the data need to be interpreted with caution. Clinical trial information: NCT04737187 .
Real-world ctDNA testing patterns, associated biomarkers and sites of metastasis in early stage colorectal cancer.
Authors: Fidyk Erin , Kalesinskas Laurynas , Krismer Konstantin , Blarre Auriane , Bouzit Lilia , Ritten John James , Gao Jessica , Marinescu Anca , Kelly Jonathan , Harrison Katherine , Cohen Aaron B.
Published: June 2024

3610

Background: There is a growing body of evidence to support the prognostic and predictive relevance of ctDNA in patients (pts) with early stage colorectal cancer (CRC). Relatively little is known about the real-world (rw) utilization of tumor-informed, personalized ctDNA assays in this population. We described the uptake of ctDNA testing over time as well as how results correlate with other biomarkers and the development of specific sites of metastasis (SOM). Methods: Pts with stage I-III CRC diagnosed after 1/1/2018 and a commercial ctDNA test in the early stage setting were selected using machine learning models from the Flatiron Health nationwide EHR-derived, de-identified database with a data cutoff of 10/31/23. Pts were considered ctDNA positive (ctDNA+) if they had at least one positive test. Odds ratios (OR) were calculated using logistic regression, adjusting for age, race, stage, practice type, insurance, and adjuvant treatment. Median time to metastasis (mets) for the ctDNA+ cohort (indexed to first positive test) was estimated using the Kaplan Meier estimator. Differences in minimal residual disease (MRD) in MTM/mL were compared using a Wilcox rank-sum test using maximum MRD. Results: In a cohort of 78,046 pts with stage I-III disease, 17,209 ctDNA tests were performed in 5,005 pts (median 3 per pt) with the majority in stage III pts (54.2%). 11% of pts (1652 / 14803) diagnosed between 1/1/21 and 4/1/22 received ctDNA testing compared to 14% of pts (1610 / 11412) diagnosed between 4/1/22 and 4/1/23. Among tested pts, 1,729 (34.5%) had at least one positive test. Pts with ctDNA+ tests were more likely to have tumor mutations in TP53 (OR: 1.69 [95% CI: 1.37, 2.08]) and KRAS (OR: 1.78 [95% CI: 1.10, 1.72]) than pts with ctDNA- tests. No differences were found in NRAS, BRAF or HER2. Progression to metastatic disease was observed in 365 (21.1%) pts with ctDNA+ tests vs 93 (2.8%) pts with ctDNA- tests (OR: 8.84 [95% CI: 6.95, 11.26]). The median time from first ctDNA+ to mets was 24.2 [95% CI: 21.7, NR] months. In those who developed mets, pts with ctDNA+ tests were significantly more likely to have liver mets compared to pts with ctDNA- tests (OR: 1.89 [95% CI: 1.12, 3.19]). Pts with liver mets had higher levels of MRD compared to non-liver SOM. (p <0.001). Conclusions: This is the largest study to date of early stage CRC ctDNA testing in routine practice. Results suggest that pairing ctDNA and NGS testing has the potential to predict risk for liver mets and other pt outcomes. Future work is needed to translate these findings into clinically actionable insights and treatment strategies. [Table: see text]
Overall survival results from the phase 2 NIVOFGFR2 study of first-line nivolumab plus CAPOX in patients with FGFR2-positive, PD-L1-positive metastatic gastric cancer.
Authors: Tsimafeyeu Ilya , Musayeva Gunel , Samira Mahmudova , Otkhozoria Nana , Abbasov Bahadur , Kahharov Alisher
Published: June 2024

4042

Background: The interim analysis of the NIVOFGFR2 phase 2 study showed a 1-year PFS rate of 30.4% in patients with FGFR2-positive, PD-L1-positive metastatic gastric cancer treated with the combination of nivolumab and CAPOX in the first-line setting (GI ASCO 2024). Here, we present data on overall survival (OS) and second-line PFS (PFS2). Methods: In this single-arm, multi-center, phase 2 study, eligible patients had metastatic untreated HER2-negative gastric adenocarcinoma, and their PD-L1 expression (CPS≥5; DAKO 28-8) and FGFR2 status (moderate (2+) and strong (3+) membranous staining in more than 1% of tumor cells; Abсam EPR24075-418) were centrally confirmed by IHC. Patients were treated with nivolumab 360 mg in combination with capecitabine and oxaliplatin every 3 weeks till disease progression or unacceptable toxicity. Following progression, the planned treatment regimen included ramucirumab at a dose of 8 mg/kg with paclitaxel. The primary endpoint was the 1-year PFS rate and secondary endpoints included median PFS, PFS2, OS, objective response rate (ORR), and the Grade ≥3 adverse events (AEs) rate. Results: Twenty-three patients were enrolled (median age 61 years, men 74%, Caucasian 91%, ECOG PS 1-2 78%, organs with ≥2 metastases 78%; CPS (5-9) 22%, (≥10) 78%, previous surgery 61%, adjuvant/neoadjuvant therapy 17%, time to metastatic disease <1 year 48%). Two (8.7%) patients remain on first-line therapy, 19 (82.6%) have received second-line ramucirumab and paclitaxel, and 10 (43.5%) have received 3 or more lines of therapy. The median follow-up for OS was 17.3 months, with 7 patients still alive. We present the updated efficacy and toxicity results (Table). Conclusions: Despite the modest efficacy of nivolumab with CAPOX in the first-line setting, a favorable median OS was observed, possibly attributable to the incorporation of ramucirumab with paclitaxel in the second-line treatment of FGFR2-positive, PD-L1-positive metastatic gastric cancer. Clinical trial information: NCT05859477 . [Table: see text]
Impact of CTNNB1 alterations on outcomes in patients with hepatocellular carcinoma (HCC).
Authors: Pai Jonathan , Baca Yasmine , Ganguly Rituparna , Akce Mehmet , Algaze Sandra , Chow Lydia D. , Misirian Ani , Hanna Diana L. , Lenz Heinz-Josef , Marshall John , Iqbal Syma , Shroff Rachna T. , Borad Mitesh J. , El-Khoueiry Anthony B.
Published: June 2024

4106

Background: The WNT/beta catenin (CTNNB1) pathway plays an integral role in the development of HCC. CTNNB1 has been implicated in HCC progression, metastasis, and drug resistance. We examined associations between CTNNB1 mutations and mRNA expression and clinical outcomes in a real-world cohort of patients with HCC. Methods: 1652 HCC tumors were tested at Caris Life Sciences (Phoenix, AZ) and analyzed with Whole Transcriptome Sequencing (WTS; Illumina Novaseq), Whole Exome Sequencing (NovaSeq,WES) and NextGen DNA sequencing (NextSeq, 592 genes). mRNA expression (transcripts per million) was further stratified into top (Q4) and bottom quartiles (Q1). Kaplan Meier estimates were calculated for overall survival (OS) in the molecularly defined cohorts and estimated from time of tissue collection to last contact. Significance was determined to be p <0.05. Chi-square and Mann-Whitney tests determined molecular differences between subgroups and adjusted for multiple comparisons (q<0.05). Results: Pathogenic CTNNB1 mutations were present in 32% of HCC and mutation status was not associated with CTNNB1 expression level. Pts whose tumors had lower CTNNB1 expression had significantly improved OS, 17.9 vs 12.4 months, Q1 vs Q4, HR 0.72, CI: 0.58-0.89 p=0.002. This association remained significant in patients who received first-line IO (Q1 vs Q4: OS 16.7 vs 10.6 mo, HR 0.54, CI: 0.32-0.94, p=0.025) or TKI (Q1 vs Q4: OS 27.1 vs 17.6 mo, HR 0.60, CI: 0.38-0.94, p=0.025). Low CTNNB1-expressing tumors (Q1) had more frequent ARID1A mutations (15% vs 8%); less frequent TP53 mutations (31% vs 42%); lower VEGFA, EPHB4, EPHA2, HIF1A, TGFB1/2/3 expression, lower MAPK activation and lower T-cell inflamed scores vs Q4 tumors (all q < 0.05). All tumors were MSS. CTNNB1 mutation status (MT vs WT) did not impact survival (OS 17.6 vs 15.3 mo, CTNNB1-MT vs CTNNB1-WT, HR 1.05, CI: 0.91-1.20, p=0.55). Similarly, CTNNB1 mutation status (MT vs WT) did not impact OS in pts treated with IO (19.8 vs 19.6 mo, HR 0.99, p=0.94) or TKI (23.0 vs 22.0 mo, HR 0.86, p=0.33). Conclusions: CTNNB1 mRNA expression, but not CTNNB1 mutation status, is associated with survival in HCC. Patients whose tumors had lower CTNNB1 expression appeared to derive more benefit from immune checkpoint inhibitors and TKI therapy in first line. CTNNB1 expression is associated with DNA repair, immune, neuronal and angiogenic pathways which may pave the way for potential therapeutic opportunities. Further studies are needed to prospectively evaluate CTNNB1 as a biomarker for treatment selection in HCC.
A study on classifying tumor neoantigens to enhance the accuracy of liquid biopsy in CRC cancer.
Authors: Guo Fenghua , Liao Wenting , Li Jun , Chen Yaru
Published: June 2024

e15507

Background: Personalized neoantigen vaccines are a promising therapeutic approach in colorectal cancer (CRC). These vaccines are designed based on the identification of specific gene mutations, aiming to evoke an immune response. However, a major challenge arises from the need to distinguish true mutated sites from numerous false positives, particularly in samples of liquid biopsy, where detection rates may be relatively low. To address this issue, we have developed a robust pipeline to enhance the precision and efficiency of detecting target gene mutations, which is crucial during the neoantigen design process. Methods: In this study, an extensive analysis was conducted using tissue and blood samples from a cohort of 859 CRC patients. We identified mutations in the top third most frequently mutated genes (APC, TP53, and KRAS). To design antigenic sequences, the mutations at these gene sites were concatenated with 14 amino acids from both up and down flanking regions. Subsequently, we utilized a similarity scoring algorithm (pairwise2.align from Biopython) to assess the mutation correlation between oncogenes (APC and KRAS) and the suppressor gene TP53. Results: This study observed that mutations within a specific gene tend to generate distinct patterns of new antigens. The majority of APC mutations (90.04%) in the vicinity of the mutation sites led to premature stop codons. Regarding KRAS, the mutation sites with the highest frequency were in the vicinity of the c.35 and c.182 positions, sharing identical neoantigens with NRAS. In contrast, TP53 mutations appeared to be more influenced by other mutations. Neoantigens derived from TP53 were identified, and it was observed that 82.27% of the sequences exhibited more than 40% similarity with other mutations in the same sample.This may be indicative of a co-occurrence mechanism. Conclusions: The classification of neoantigens appears to be similar to the classification of oncogenes and tumor suppressor genes, which may contribute to adjust the minimum detection threshold of liquid biopsy from the perspective of neoantigens. [Table: see text]