bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure 2 from Hypophosphatemia Correction Reduces ICANS Incidence and Duration in CAR T-cell Therapy: A Pooled Clinical Trial Analysis
Authors: Tang Jack Pengfei , Lafeuille Penelope , Socolov Alexandru , Diamond Sheila S. , Aptekar Jacob , Moore Theodore B. , Nie Esther H. , Hanudel Mark R. , Nowicki Theodore S.
Published: October 2024

ICANS incidence and symptom duration in patients with various electrolyte derangements stratified by receipt of any repletion of the deficient electrolyte. ICANS incidence (top row, error bars represent 95% confidence interval (CI) in patients with (A) serum hypophosphatemia, (B) serum hypokalemia, (C) serum hypomagnesemia, and (D) serum hypocalcemia, stratified by receipt of any electrolyte products containing the deficient electrolyte, from time of CAR T-cell infusion (day 0) until either ICANS symptom onset or day +14. ICANS symptom duration (represented as mean ± SEM) in patients with (E) hypophosphatemia or (F) hypocalcemia stratified by receipt of any electrolyte products containing the deficient electrolyte, from time of CAR T-cell infusion (day 0) until either ICANS symptom onset or day +14. G, ICANS symptom duration in patients with serum hypocalcemia stratified by no repletion (n = 28), any calcium repletion (n = 21), calcium and phosphorus repletion (n = 19), and calcium repletion containing no phosphorus (n = 2). H, ICANS symptom duration in patients with hypokalemia (H) or hypomagnesemia (I) stratified by receipt of any electrolyte products containing the deficient electrolyte, from time of CAR T-cell infusion (day 0) until either ICANS symptom onset or day +14. *, P < 0.05; **, P < 0.01; Fisher exact test for ICANS incidence, unpaired t test for ICANS symptom duration.
Data from Hypophosphatemia Correction Reduces ICANS Incidence and Duration in CAR T-cell Therapy: A Pooled Clinical Trial Analysis
Authors: Tang Jack Pengfei , Lafeuille Penelope , Socolov Alexandru , Diamond Sheila S. , Aptekar Jacob , Moore Theodore B. , Nie Esther H. , Hanudel Mark R. , Nowicki Theodore S.
Published: October 2024

Abstract
A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell–associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020. In addition to clinical toxicities experienced by the patients, we also interrogated the impact of serum electrolyte data and repletion of corresponding electrolyte deficiencies with ICANS incidence, severity, and duration. Hypophosphatemia was a common occurrence in CAR T-cell recipients and the only electrolyte derangement associated with a significantly higher cumulative incidence of ICANS. Moreover, phosphorus repletion in patients with hypophosphatemia was associated with significantly decreased ICANS incidence and duration. Hypophosphatemia was uniquely associated with encephalopathy neurological adverse events, which also showed the strongest positive correlation with both ICANS and cytokine release syndrome severity. These findings suggest that serum phosphorus could be a reliable biomarker for ICANS, and expeditious, goal-directed phosphorus repletion in response to serum hypophosphatemia could be a safe, inexpensive, and widely available intervention for such patients.
Significance:
Herein we show that phosphorus repletion in patients with hypophosphatemia receiving anti-CD19 chimeric antigen receptor T-cell therapeutics was associated with significantly decreased immune effector cell–associated neurotoxicity syndrome (ICANS) incidence and symptom duration. Given the significant morbidity associated with ICANS and lack of targeted interventions, hypophosphatemia may serve as both a useful biomarker and an inexpensive intervention for ICANS.
Regulation of Skeletal Muscle Resistance Arteriolar Tone: Temporal Variability in Vascular Responses
Authors: Halvorson Brayden D. , Ward Aaron D. , Murrell Donna , Lacefield James C. , Wiseman Robert W. , Goldman Daniel , Frisbee Jefferson C.
Published: October 2024

Introduction: A full understanding of the integration of the mechanisms of vascular tone regulation requires an interrogation of the temporal behavior of arterioles across vasoactive challenges. Building on previous work, the purpose of the present study was to start to interrogate the temporal nature of arteriolar tone regulation with physiological stimuli. Methods: We determined the response rate of ex vivo proximal and in situ distal resistance arterioles when challenged by one-, two-, and three-parameter combinations of five major physiological stimuli (norepinephrine, intravascular pressure, oxygen, adenosine [metabolism], and intralumenal flow). Predictive machine learning models determined which factors were most influential in controlling the rate of arteriolar responses. Results: Results indicate that vascular response rate is dependent on the intensity of the stimulus used and can be severely hindered by altered environments, caused by application of secondary or tertiary stimuli. Advanced analytics suggest that adrenergic influences were dominant in predicting proximal arteriolar response rate compared to metabolic influences in distal arterioles. Conclusion: These data suggest that the vascular response rate to physiologic stimuli can be strongly influenced by the local environment. Translating how these effects impact vascular networks is imperative for understanding how the microcirculation appropriately perfuses tissue across conditions.
Mental Health Stigma and Mental Health Literacy in Russia: Their Prevalence and Associations with Somatic, Anxiety, and Depressive Symptoms
Authors: Zolotareva Alena , Maltsevab Natalia , Belousovac Svetlana , Smirnikova Olga
Published: October 2024

Background. Mental health stigma and mental health literacy can be potential targets of public education and health development. These areas are culturally specific and have so far been almost unexplored in Russia. Objective. This study aimed at examining mental health stigma and mental health literacy in Russia, their prevalence, and their associations with somatic, anxiety, and depressive symptoms. Design. The participants were 1,068 Russian adults. They completed the online questionnaire with measures assessing their mental health stigma (Perceived Devaluation and Discrimination Scale; Link et al., 2001); somatic symptoms (Somatic Symptom Scale-8; Gierk et al., 2014); anxiety symptoms (Generalized Anxiety Disorder-7; Spitzer et al., 2006); and depressive symptoms (Patient Health Questionnaire-9; Kroenke et al., 2001). To examine their mental health literacy, we used a series of questions exploring a person’s awareness of mental health and mental health problems. Results. Mental health stigma was found in 67% of the participants, who were less confident that most mental disorders can be prevented and more confident that mental disorders can be cured in most cases. Higher devaluation, discrimination, and mental health stigma were related to more severe somatic symptoms. Lower mental health literacy and higher devaluation, discrimination, and mental health stigma were associated with more severe anxiety and depressive symptoms. These associations were the same when adding covariates such as sex, age, partnership, parenthood, and educational background. Conclusion. This study highlighted the obvious need for measures to reduce mental health stigma and improve mental health literacy in Russian society. In general, these measures can contribute to the promotion of better mental health in Russia.
Career Orientations of Pre-Service Teachers: Exploring the Influence of Different Types of Universities
Authors: Valeeva Roza A. , Parfilova Gulfiia G. , Kremen Faina M. , Kremen Sergei A.
Published: October 2024

Background. More than half of future teachers in our country receive professional training in classical universities, which determines a great variability of motivational-professional and planned career trajectories. At the same time, the type of university (federal or regional) significantly influences the conditions for forming a professional teacher. This study identifies career orientations of students attending classical universities of different types in order to determine trends in career preferences according to choice of university type. Objective. This study aims to identify the peculiarities of career orientations of students studying at pedagogical bachelor degree programs of classical universities of different types (federal and regional), determining the interrelations of their indicators with socio-demographic and motivational-professional characteristics of the test subjects. Design. The study was conducted in the form of a comparison of career orientations of the first-year students in teacher education programs (83 students of Kazan Federal University and 89 students of Smolensk State University). The empirical methods used included the adapted Schein's career anchors tool and a questionnaire revealing socio-demographic and motivational-professional variables to identify factors related to career orientations. Results. The obtained results revealed common preferences for both universities in career orientations on the service, job stability and lifestyle integration scales, indicating stable trends in choosing the teaching profession. Students at both universities, who chose the teaching profession and plan to work in their specialty, demonstrate a readiness for professional development and overcoming difficulties. However, the university is an independent factor which determines differences according to the scales of entrepreneurship, autonomy and management. Students at a federal university are characterized by greater independence and initiative, but also more uncertainty in choosing a profession, in contrast to students at a regional university. Conclusion. Considering student career orientations according to their socio-demographic and motivational-professional characteristics, allows us to obtain an objective and comprehensive picture of the professional choices of students from different types of universities, leading to more effective delivery of their professional development.
How Spatial Differences in Climate Affect Agricultural Land Values in New Zealand
Authors: Pourzand Farnaz
Published: October 2024

This paper implements the “spatial first differences” (SFD) method to a Ricardian approach to analyze spatial differences in climate and evaluate their impact on farmland values in New Zealand. We use property valuation data from 1993 to 2018 across different agricultural land uses. Ricardian analyses harness cross-sectional variation in climate and farmland values to estimate the effect of climate on agriculture. However, Ricardian studies are vulnerable to omitted variables varying slowly or not varying over time. The idea of the SFD approach is to apply spatial analogous of the “first-differences” estimator for longitudinal analyses to control for omitted variables that vary differently than climate variables among neighboring units. The results suggest that a warmer or drier climate is associated with higher farmland values in New Zealand. These findings may be mediated by productivity differences, costly physical improvements, and climate amenity values. Besides contributing novel insights by applying the Ricardian approach to New Zealand data and overcoming challenges of unobserved heterogeneity with the SFD method, we conclude that, for a better understanding of the welfare implications of climate change, it is crucial to differentiate between the effects of costly improvements and amenity values, apart from the pure climate productivity effect.
Successful Percutaneous Rescue Treatment of Acute Carotid Stent Thrombosis Utilizing a Modified Embolic Protection Device
Authors: Di Giorgio Alessandro , Mazzapicchi Alessandro , Rochira Carla , Azzarelli Salvatore , Scardaci Francesco , Tomasello Davide Salvatore , Argentino Vincenzo , Amico Francesco
Published: October 2024

Acute Carotid Stent Thrombosis (ACST) is a rare complication of Carotid Artery Stenting (CAS) with a potentially fatal outcome. We report a case of ACST occurring five minutes after the end of a successful CAS procedure that was promptly treated by carotid stent-in-stent implantation using a new percutaneous strategy based on the creation of a modified embolic protection device. Following the procedure, we did not observe brain lesions suggestive of acute cerebral ischemic events at the CT scan performed at 48 hours, as well as no neurological deficits in the following days.
Attitudes toward implementation of electronic medical record and its associated factors among health professional workers in selected public hospitals in Addis Ababa, Ethiopia, 2023: A multi-center cross-sectional study
Authors: Mohammed Abdurehman Seid , Wudu Desalgn , Minda Zewdu , Diress Getachew Mekete
Published: October 2024

Background study

Electronic medical record (EMR) systems in healthcare delivery have the potential to transform healthcare in terms of saving costs, reducing medical errors, and improving data quality. This study aimed to assess the Attitudes toward implementing electronic medical records and associated factors among health professional workers in selected public hospitals in Addis Ababa.

Method

An institution-based cross-sectional study was conducted on 422 health professionals in selected hospitals in Addis Ababa, Ethiopia, in 2023. The study participants were selected using a simple random sampling technique. A binary and multivariable logistic regression model was used to identify associated factors for electronic medical record implementation. A p-value < .05 was considered statistically significant.

Result

The overall electronic medical record implementation perceived as useful by health workers is 298 (73.6%), with an allocation of enough budget [AOR = 3.196 (1.49–6.735)] has no networking or problem with internet access [AOR = 1.794(1.089–2.954)]. Electronic medical record increases workload [AOR = 2.350 (1.302–4.243)], which was significantly associated with electronic medical record implementation.

Conclusion and Recommendation

According to this study, the overall perception of health professionals toward electronic medical record implementation was high. However, it would be better to build and establish strong internet connectivity and stable power supply or internet access without networking problems, allocate enough budget, and work in collaboration with hospitals and health bureaus to strengthen and support the electronic medical record in their facilities.
Thermosensing ability of TRPC5: current knowledge and unsettled questions
Authors: Ptakova Alexandra , Vlachova Viktorie
Published: October 2024

Our understanding of how the mammalian somatosensory system detects noxious cold is still limited. While the role of TRPM8 in signaling mild non-noxious coolness is reasonably understood, the molecular identity of channels transducing painful cold stimuli remains unresolved. TRPC5 was originally described to contribute to moderate cold responses of dorsal root ganglia neurons in vitro, but mice lacking TRPC5 exhibited no change in behavioral responses to cold temperature. The question of why a channel endowed with the ability to be activated by cooling contributes to the cold response only under certain conditions is currently being intensively studied. It seems increasingly likely that the physiological detection of cold temperatures involves multiple different channels and mechanisms that modulate the threshold and intensity of perception. In this review, we aim to outline how TRPC5 may contribute to these mechanisms and what molecular features are important for its role as a cold sensor.
Inhibition of malate dehydrogenase via nanoselenium coupling with nanocellulose composite in MCF-7 breast carcinoma cells
Authors: El-Sheekh Mostafa M. , Kenawy El-Refaie , Yousuf Wesam E. , Mohamed Tarek M.
Published: October 2024

Background

Cancer, a leading cause of mortality worldwide, continues to pose significant challenges in treatment and management. Conventional therapies often face limitations, including lack of selectivity, adverse effects, and the development of resistance mechanisms.

Methods

Therefore, this study aims to investigate nanocellulose, nanoselenium, and their nanocomposite which are previously synthesized and characterized. Molecular docking simulations were performed to assess binding affinity to malate dehydrogenase-1 (MDH-1), a key metabolic enzyme in cancer cells. Cytotoxicity was evaluated in A549 lung cancer cell line, the MCF-7 breast cancer cell line, and the WI-38 normal cell line. Mechanistic studies included assessment of MDH-1 activity and expression, intracellular reactive oxygen species (ROS) levels, and cell cycle analysis.

Results

Molecular docking simulations demonstrated a favorable binding affinity (136.98 kcal/mol) of cellulose and selenium as cofactor to the nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH) binding domain of human MDH-1. The nanocomposite exhibited a synergistic impact against cancer, causing a considerable decrease in the viability of MCF-7 cells compared to separate treatments with nanocellulose and nanoselenium. Moreover, it showed negligible toxicity towards normal cells. Biochemical studies demonstrated that nanocellulose, nanoselenium and the nanocomposite substantially reduced MDH-1 activity and messenger ribonucleic acid (mRNA) expression in MCF-7 cells. This was confirmed by flow cytometric analysis, which revealed that the nanocomposite could effectively reduce the intracellular ROS levels and induce potent cell cycle arrest in the G0/G1 phase, that inhibit MCF-7 cell proliferation.

Conclusions

In conclusion, our finding elucidated the promising therapeutic potential of nanocellulose, nanoselenium, and their nanocomposite as effective anticancer agents in breast cancer treatment, demanding further preclinical and clinical investigations to explain their mechanisms of action.
Associations between birthweight and preterm birth and the ages at menarche and menopause
Authors: Daniele Christian , Wacks Rachel E. , Farland Leslie V. , Manson JoAnn E. , Qi Lihong , Shadyab Aladdin H. , Wassertheil-Smoller Sylvia , Spracklen Cassandra N.
Published: October 2024

Background

Women who reach menarche and menopause at earlier ages have been shown to be at increased risk for numerous conditions including cardiovascular disease, cancer, depression, and obesity; however, risk factors for earlier ages of menarche and menopause are not fully understood. Therefore, we aimed to perform a retrospective investigation of the associations between a personal birthweight and/or being born preterm and the age of and menarche and menopause and related events in the Women’s Health Initiative, a large, racially and ethnically diverse cohort of postmenopausal women.

Methods

At study entry, women reported their birthweight by category (< 6 lbs., 6–7 lbs. 15 oz, 8–9 lbs. 15 oz, or ≥ 10 lbs.) and preterm birth status (4 or more weeks premature). Ages at events related to menarche and menopause were also self-reported. Linear regression and logistic regression models were used to estimate unadjusted and adjusted effect estimates (β) and odds ratios (OR), respectively (n ≤ 86,857). Individuals born preterm were excluded from all birthweight analyses.

Results

After adjustments, individuals born weighing < 6lbs. were more likely to reach natural menopause at an earlier age (adjusted β=-0.361, SE = 0.09, P = < 0.001) and have a shorter reproductive window (adjusted β = -0.287, SE = 0.10, p < 0.004) compared to individuals weighing 6–7 lbs. 15 oz. Individuals born preterm were also more likely to reach natural menopause at an earlier age (adjusted β=-0.506, SE = 0.16, P = 0.001) and have a shorter reproductive window (adjusted β = -0.418, SE = 0.17, p < 0.006).

Conclusions

These findings raise concerns that, as more preterm and low birthweight individuals survive to adulthood, the prevalence of earlier-onset menarche and menopause may increase. Clinical counseling and interventions aimed at reducing the incidence of preterm and low birthweight births, as well as intensification of lifestyle modifications to reduce CVD risk among women with these early-life risk factors, should be prioritized.
Schistosoma japonicum infection-mediated downregulation of lncRNA Malat1 contributes to schistosomiasis hepatic fibrosis by the Malat1/miR-96/Smad7 pathway
Authors: Jiang Pengyue , Ye Shengyu , Fan Xiaobin , Tian Yini , Zhang Dongmei , Pan Weiqing
Published: October 2024

Background

Schistosoma japonicum infection causes hepatic fibrosis, a primary cause of morbidity and mortality associated with the disease, and effective treatments are still lacking. Long non-coding RNAs (lncRNAs) have been implicated in the pathogenic process of various tissue fibroses. However, the role of lncRNAs in schistosomiasis hepatic fibrosis (HF) is poorly understood. Understanding the role of lncRNAs in schistosomiasis HF will enhance knowledge of disease processes and aid in the discovery of therapeutic targets and diagnostic biomarkers.

Methods

Differentially expressed lncRNA profiles in primary hepatic stellate cells (HSCs) of mice infected with S. japonicum were identified using high-throughput lncRNA sequencing. Primary HSCs were isolated from infected mice using collagenase digestion and density-gradient centrifugation, cultured in DMEM with 10% fetal bovine serum. Dual-luciferase reporter assays, nuclear cytoplasm fractionation and RIP assays were employed to assess the relationship between Malat1 and miRNA-96. Malat1 lentivirus and ASO-Malat1 were constructed for forced expression and downregulated expression of Malat1. The Malat1-KO mouse was constructed by CRISPR/Cas9 technology. Pathological features of the liver were evaluated by hematoxylin-eosin (HE), Masson’s trichrome staining and immunohistochemistry (IHC). The expression levels of fibrosis-related genes were determined by quantitative real-time PCR (qRT-PCR) and Western blot.

Results

A total of 1561 differentially expressed lncRNAs were identified between infected and uninfected primary HSCs. Among the top altered lncRNAs, the downregulated Malat1 was observed in infected HSCs and verified by qPCR. Treatment of infected mice with praziquantel (PZQ) significantly increased the Malat1 expression. Elevated Malat1 expression in infected primary HSC reduced the expressions of profibrogenic genes, whereas Malat1 knockdown had the opposite effect. Moreover, Malat1 was found to interact with miR-96, a profibrotic miRNA, by targeting Smad7. Forced Malat1 expression reduced miR-96 levels in infected primary HSCs, attenuating fibrogenesis and showing negative correlation between Malat1 expression and the expression levels of miR-96 and profibrogenic genes α-SMA and Col1α1. Notably, in Malat1-KO mice, knockout of Malat1 aggravates schistosomiasis HF, while restored Malat1 expression in the infected HSCs reduced the expression of profibrogenic genes.

Conclusions

We demonstrate that lncRNA is involved in regulation of schistosomiasis HF. Elevated lncRNA Malat1 expression in infected HSCs reduces fibrosis via the Malat1/miR-96/Smad7 pathway, thus providing a novel therapeutic target for schistosomiasis HF. Furthermore, Malat1 expression is sensitive to PZQ treatment, thus offering a potential biomarker for assessing the response to chemotherapy.

Graphical abstract
Key challenges in prehospital and emergency care in Indonesia and Malaysia: a survey of frontline clinicians
Authors: Tokita Akio , Nunokawa Hanako , Liu Keibun , Iwamoto Yuta , Sonoo Tomohiro , Hara Konan , Nakajima Mikio , Fukaguchi Kiyomitsu , Takeda Takanori , Sanip Amirudin , Juzar Dafsah A. , Gurjeet Singh a/l Harvendhar Singh , Condro Lukito , Tobing Monalisa , Abu Hasan Muhammad Abdus-Syakur bin , Nik Abdul Rahman Nik Hisamuddin , Mahisa Orizanov , Aviesena Zairinal Ramdinal , Ramli Mohd Khairulizwan bin , Mohd Nor Mohd Afiq , Goto Tadahiro , Zakaria Mohd Idzwan bin
Published: October 2024

Rapid economic growth in Indonesia and Malaysia has widened the gap in emergency care supply and demand, intensifying challenges. Our study, from August to November 2022, assesses current diverse challenges in both countries' emergency care systems from frontline staff perspectives. The online survey involved emergency department (ED) personnel from 11 hospitals in Indonesia and Malaysia, drawing from an existing network. The survey collected data on respondents’ characteristics, factors affecting prehospital and ED care quality, missing clinical information, and factors influencing patients’ ED stay duration. With 83 respondents from Indonesia and 109 from Malaysia, the study identified common challenges. In both countries, inadequate clinical information from ambulances posed a primary challenge in prehospital care quality, while crowdedness during night shifts affected ED care quality. Frequent gaps in essential clinical information, such as family and medication history, were observed. Prolonged ED stays were associated with diagnostic studies and their turnaround time. This study offers insights into shared challenges in Indonesia and Malaysia's emergency care systems. Our findings stress recognizing common and country-specific challenges for enhanced emergency care quality in Southeast Asia, supporting tailored interventions.
Women’s entrepreneurial journey in developed and developing countries: a bibliometric review
Authors: Vuciterna Rina , Ruggeri Giordano , Mazzocchi Chiara , Manzella Sara , Corsi Stefano
Published: October 2024

This paper presents a comprehensive bibliometric review of the scientific literature on women’s entrepreneurship in agriculture across developed and developing countries. The paper delineates the evolving landscape, challenges, and opportunities that shape women’s entrepreneurship experiences in agriculture in the contexts of developed and developing countries. Through a detailed bibliometric analysis of 728 papers from 1992 to 2022, employing performance analysis and science mapping, our methodology distinguishes itself by quantifying contributions and mapping the thematic evolution within this domain. Our study reveals the significant contributions of women entrepreneurs to agricultural innovation, sustainability, and rural development while facing systemic biases, limited access to resources, and societal stereotypes that hinder their entrepreneurial path. The paper underscores the disparity in women’s entrepreneurship between developed and developing regions, with developed countries showcasing lower participation rates in agricultural entrepreneurship but a higher presence in decision-making roles within agribusinesses.

In contrast, developing countries display a higher engagement of women in entrepreneurship, driven by necessity and marked by significant contributions to food security and economic stability, though under challenging conditions. Notably, the paper highlights the underrepresentation of women’s agricultural endeavours in scholarly research, pointing to a gap in the documentation and understanding of their contributions. The study reveals emerging themes such as digital agriculture, climate resilience, sustainability, and innovation, pointing towards future research directions that could further empower women in agriculture. It calls for more inclusive research and policy-making to recognise and support women’s vital role in agriculture, advocating for a holistic approach to address women entrepreneurs’ challenges in different economic contexts. Through this analysis, the paper contributes to a deeper understanding of gender dynamics in agricultural entrepreneurship and suggests pathways for fostering more equitable and sustainable agricultural practices.
Experiences and support needs of psychiatrists under investigation
Authors: Kongara Swapna , Tamworth Millie , Gibbons Rachel
Published: October 2024

Aims and method

This study aimed to explore the experiences and support requirements of psychiatrists undergoing investigations within their mental health organisation. An anonymous online survey was distributed to all non-training psychiatrists registered as members of the Royal College of Psychiatrists.

Results

Of the 815 psychiatrists who responded to the survey, 287 (35%) had been investigated. The majority (76%) were unaware of the concerns before being notified, 36% lacked understanding and 62% experienced timeline deviations. Furthermore, 34% had concerns over conflicts of interest, with 52% perceiving the investigation as unfair, 62% were not informed of their rights. Many respondents reported feeling isolated and lacking support and experienced significant psychological distress, such as symptoms of post-traumatic stress disorder. Suggestions for improvement included better communication, transparency, impartiality, adherence to timelines, proactive support and oversight, and opportunities for learning and reparation post-investigation.

Clinical implications

Mental health service providers should recognise the multifaceted nature of complaints and provide comprehensive support and guidance to psychiatrists undergoing investigations.
Task-dependent functional connectivity changes in response to varying levels of social support
Authors: Burhanoglu Birce Begum , Uslu Ozgul , Ozkul Burcu , Oguz Kaya , Eroglu-Koc Seda , Kizilates-Evin Gozde , Candemir Cemre , Erdogan Yigit , Mull Defne Dakota , Kitis Omer , Gonul Ali Saffet
Published: October 2024

Background

Having social support improves one's health outcomes and self-esteem, and buffers the negative impact of stressors. Previous studies have explored the association between social support and brain activity, but evidence from task-dependent functional connectivity is still limited.

Aims

We aimed to explore how gradually decreasing levels of social support influence task-dependent functional connectivity across several major neural networks.

Method

We designed a social support task and recruited 72 young adults from real-life social groups. Of the four members in each group, one healthy participant (18 participants in total) completed the functional magnetic resonance imaging (fMRI) scan. The fMRI task included three phases with varying levels of social support: high-support phase, fair phase and low-support phase. Functional connectivity changes according to three phases were examined by generalised psychophysiological interaction analysis.

Results

The results of the analysis demonstrated that participants losing expected support showed increased connectivity among salience network, default mood network and frontoparietal network nodes during the fair phase compared with the high-support phase. During the low-support phase, participants showed increased connectivity among only salience network nodes compared with the high-support phase.

Conclusions

The results indicate that the loss of support was perceived as a threat signal and induced widespread increased functional connectivity within brain networks. The observation of significant functional connectivity changes between fair and high-support phases suggests that even a small loss of social support from close ones leads to major changes in brain function.
Clinicopathologic Characteristics Influencing Overall Survival of Patients With Early- Versus Average-Onset Colorectal Cancer at a Tertiary Care Center in Indonesia
Authors: Hutajulu Susanna Hilda , Howdon Daniel , Putra Yasjudan Rastrama , Susanti Susanti , Heriyanto Didik Setyo , Yoshuantari Naomi , Handaya Adeodatus Yuda , Utomo Bambang Purwanto , Dwidanarti Sri Retna , Kurnianda Johan , Sudoyo Aru Wisaksono , Ilyas Mohammad , Allsop Matthew John
Published: October 2024

PURPOSE

There has been a global increase in early-onset colorectal cancer (EOCRC), yet there has been very limited exploration of its impact in Indonesia. This study aimed to determine the clinicopathologic characteristics and the overall survival (OS) of EOCRC compared with those of average-onset colorectal cancer (AOCRC).

METHODS

Medical records were retrospectively reviewed from all patients presenting with colorectal cancer (CRC) at Dr Sardjito General Hospital (Yogyakarta, Indonesia) between 2016 and 2019. Sociodemographic, clinicopathologic, and treatment variables were extracted.
t
Tests were used to compare characteristics of EOCRC and AOCRC patient groups. The Cox proportional hazards regression model was used to analyze age and other potential prognostic factors.

RESULTS

The total population (N = 1,276) comprised EOCRC (n = 149; 11.7%) and AOCRC (n = 1,127; 88.3%) patients. EOCRC patients were more likely to have a higher education level, be single, have out-of-pocket insurance, be underweight, and have signet ring histology (all
P
values <.05), compared with AOCRC patients. EOCRC and AOCRC groups had a comparable estimated 5-year OS of 34.2% and 36.9%, respectively. In multivariable analyses, performance status (Eastern Cooperative Oncology Group), hemoglobin level, cancer stage, and treatment intention were independent prognostic factors for OS (all
P
values <.05).

CONCLUSION

To our knowledge, this first major study of EOCRC in Indonesia highlights its role in the overall burden of CRC and its connection with social determinants of health. Patients with EOCRC are more commonly underweight and generally have a higher proportion of signet ring histology than AOCRC, yet OS in both groups is similar. Future research is required to identify risk factors to inform the content and focus of public health education activities, alongside delineating the biology and causes of early and average onset of the disease.
Phase 3 randomized study comparing docetaxel-platinum with docetaxel-platinum-5 fluorouracil as neoadjuvant chemotherapy in technically unresectable oral cancer.
Authors: Singh Ajaykumar , Patil Vijay Maruti , Noronha Vanita , Menon Nandini Sharrel , Chaturvedi Pankaj , Mathrudev Vijayalakshmi , Bhattacharjee Atanu , Chopade Sunil Ramdhan , Srinivas Sujay , Roy Somnath , Mondal Tanmoy , D'souza Hollis , Chaukar Devendra A , Pai P. S. , Nair Sudhir Vasudevan , Thiagarajan Shivakumar , Laskar Sarbani , Nawale Kavita Prakash , Dhumal Sachin Babanrao , Prabhash Kumar
Published: October 2024

6013

Background:
Neoadjuvant chemotherapy (NACT) with DCF (Docetaxel, Cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer (LAOC) and has a survival advantage over the CF (Cisplatin and 5FU) regimen. DC regimen (Docetaxel, Cisplatin) had shown promising results in small series, with a lower rate of adverse events but has never been compared with DCF.
Methods:
This was a phase 3 open-label superiority randomized study. Adult patients with very LAOC (technically unresectable), ECOG PS 0-2 and adequate organ function were eligible. They were randomly assigned in a 1:1 fashion to either DCF or DC regimen. After the administration of 2 cycles, these patients were evaluated in the multidisciplinary clinic. Based on the response, further treatment either surgery followed by adjuvant or radical chemoradiation or palliative therapy was planned. The primary endpoint was overall survival (OS). The key secondary endpoint was adverse events.
Results:
495 patients were randomized in this study, 250 patients in arm A and 245 in arm B. At a median follow-up of 39.5 months. The 2-year OS was 29.1% in the DCF and 23.5% in the DC arm respectively (HR=0.81; 95%CI 0.66-0.99, P-value= 0.043). Grade 3 or above adverse events were higher in the DCF arm - oral mucositis (10.6% versus 1.2%), diarrhea (13.6% versus 9.6%), febrile neutropenia (23.2% versus 2.6%), hyponatremia (40.8% versus 20.8%), and hypokalemia (17.9% versus 1.6%).
Conclusions:
NACT with DCF has a survival benefit over DC in oral cancers but it comes at the cost of an increment in acute adverse events.
Clinical trial information: CTRI/2016/04/006804.
Liquid Biopsy for Minimal Residual Disease Detection in Head and Neck Squamous Cell Carcinoma (LIONESS): A personalized cell-free tumor DNA analysis for patients with HNSCC.
Authors: Flach Susanne , Howarth Karen , Hackinger Sophie , Pipinikas Christodoulos , Ellis Pete , McLay Kirsten , Marsico Giovanni , Walz Christoph , Reichel Christoph A. , Gires Olivier , Canis Martin , Baumeister Philipp
Published: October 2024

6017

Background:
Despite improvements in multimodal treatment options for patients with head and neck squamous cell carcinoma (HNSCC), survival has only improved modestly over the past decades as patients frequently develop recurrences. Detection of cell-free circulating tumor DNA (ctDNA) post-operatively and during clinical follow-up has the potential to identify patients with molecular residual disease (MRD) or who are at an increased risk of relapse, and who may therefore benefit from personalized treatment strategies.
Methods:
We conducted LIONESS, a single-center prospective cohort study to investigate ctDNA in patients with HNSCC who received primary surgical treatment with curative intent. 58 patients have been recruited as of January 2022, with disease stage I (15.5%), II (13.8%), III (36.2%) and IV (34.5%). Whole exome sequencing was performed on FFPE tissue. RaDaR, a highly sensitive personalized assay using deep sequencing of tumor-specific variants, was used to analyze serial pre- and post-operative plasma samples for evidence of molecular residual disease and recurrence. In addition, pre-operative saliva samples were collected for detection of tumor DNA in saliva.
Results:
236 longitudinal plasma samples from 35 patients have been analyzed so far, using personalized panels designed targeting a median 48 (20-60) somatic variants. Preliminary data shows 94.28% ctDNA detection in baseline samples taken prior to surgery. In post-surgery samples, ctDNA could be detected at levels as low as 0.0005% variant allele fraction (eVAF). Survival analysis showed a significant difference (p-value = 7e-7) in recurrence rates between patients who tested ctDNA+ during follow-up (8/11, 72.7%) and those who were negative for ctDNA (0/24, 0%). In all eight cases with clinical recurrence, ctDNA was detected prior to progression, with lead times ranging from 56 to 265 days. Patients were followed for clinical recurrence with a median follow-up of 9.5 months to date, but longer follow-up is necessary for patients who may be at increased risk of recurrence. Work is ongoing for analysis of the full cohort of plasma and saliva samples, which will be presented at the congress.
Conclusions:
In this prospective observational study, detection of residual disease using ctDNA was associated with poorer progression-free survival and much earlier detection of disease prior to clinical relapse. The implementation of a highly sensitive ctDNA assay such as RaDaR into clinical practice has the potential to tailor personalized treatment strategies for molecular residual disease and recurrence in patients with HNSCC. In future, ctDNA analysis with subsequent ctDNA-guided treatment may reduce morbidity for HNSCC patients.
Predicting emergency department use and unplanned hospitalization in patients with head and neck cancer: Development and validation of a machine learning algorithm.
Authors: Noel Christopher W , Sutradhar Rinku , Gotlib Conn Lesley , Forner David , Chan Wing , Fu Rui , Hallet Julie , Coburn Natalie , Eskander Antoine
Published: October 2024

6021

Background:
We recently demonstrated that patient reported symptom burden is strongly associated with emergency department use and unplanned hospitalization (ED/Hosp) in head and neck cancer (Noel et. al 2021 J. Clin Oncol - DOI: 10.1200/JCO.20.01845). We hypothesized that symptom scores could be used to build a tool that would accurately risk stratify patients.
Methods:
This was a population-based study of patients diagnosed with head and neck cancer between 2007 and 2018. All outpatient clinical encounters were identified. Edmonton Symptom Assessment Scores (ESAS) and clinical and demographic factors were abstracted. Training and test cohorts were randomly generated in a 4:1 ratio. Various machine learning algorithms were explored including: (1) logistic regression, (2) random forest, (3) gradient boosting machines (4) k-nearest neighbors and an (5) artificial neural network. Our main outcome was any 14-day ED/Hosp event following symptom assessment. The performance of each risk model was assessed on the test cohort using the area under the receiver operator characteristic (AUROC) curve and calibration plots. Shapley values were used to identify the variables with greatest contribution to the model.
Results:
The training cohort consisted of 9,409 patients undergoing 59,089 symptom assessments (80%). The remaining 2,352 patients and 14,193 symptom assessments were set aside as the test cohort (20%). Several models had high predictive accuracy, particularly the gradient boosting machine algorithm (validation AUROC 0.80 [95%CI 0.78-0.81]). A Youden-based cut-off corresponded to a validation sensitivity of 0.77 and specificity of 0.66. A second model built only with symptom severity data had an AUROC of 0.72 [95%CI 0.70-0.74].
Conclusions:
Machine learning approaches can be used to predict ED/Hosp in head and neck cancer patients. This tool can risk stratify patients and may help direct targeted intervention.
Comprehensive immune landscape and molecular characteristics of clinical responses to chemotherapy, antiangiogenic agents, and PD-1 inhibitors in recurrent or metastatic nasopharyngeal carcinoma.
Authors: Chen Mingyuan , Rui You , Zou Xiong , Meng-Xia Zhang , Zhang Weijing , Ding Xi , Wang Xiao
Published: October 2024

6028

Background:
The role of a triple combination of gemcitabine (chemotherapy) plus apatinib (anti-VEGF) and toripalimab (anti-PD-1) (GAT) in recurrent/metastatic nasopharyngeal carcinoma is unclear.
Methods:
Between August 2019 and April 2020, 54 patients with recurrent or metastatic NPC were screened, of whom 41 eligible patients were enrolled and received study treatment. Patients were treated with gemcitabine (1000 mg/m
2
) on days 1 and 8 once every 3 weeks for a maximum of 6 cycles plus toripalimab (240 mg) on day 1 once every 3 weeks and apatinib (orally administered at 250 mg) once a day until disease progression, death, dose-limiting toxicities, or at the patient’s request to stop. The primary endpoint was the safety. The secondary endpoints included the objective response rate (ORR) and progression-free survival (PFS).
Results:
By the data cutoff date, the median follow-up time was 13.4 months. G3-4 hematologic, gastrointestinal and kidney toxicities were observed in no more than 3 (3/41, 7.3%) patients, while G3-4 nasopharyngeal wall necrosis was observed in 9 (9/41, 21.9%) patients. High-risk factors for nasopharyngeal necrosis, included repeated radiotherapy and an interval of less than 12 months from the last radiotherapy. Among all 41 patients, the ORR was 90.2% (95% CI: 76.9%-97.2%). The median PFS was 13.93 months (95% CI: NR-NR), and the 12-month PFS rate was 72.0% (95% CI: 57.1%-86.9%). A substantial increase of CD28+ and ICOS+ CD4+/CD8+ T cells and a decrease of PD1+ CD4+/CD8+ T cells were observed in the peripheral blood after the GAT treatment. 11q13.3 amplification and MRGPRF high expression in tumors correlated with poor PFS from the triple combination therapy. NPCs with 11q13.3 amplification was characterized by high epithelial mesenchymal transition (EMT) and immune suppressive transcriptional signatures. Furthermore, serial circulating tumor DNA (ctDNA) sequencing could predict PFS outcomes to combination therapy.
Conclusions:
The triple combination of GAT exhibits a promising antitumor activity and manageable toxicities in patients with recurrent/metastatic NPC. Patients with repeated radiotherapy and an interval of less than 12 months from the last radiotherapy should be carefully selected for antiangiogenic therapies. An integrated genomic and transcriptional analyses may aid to identify the beneficial patient populations in response to this novel combination therapy.
Clinical trial information: NCT04073784.
Efficacy and safety of camrelizumab combined with apatinib in previously treated recurrent or metastatic nasopharyngeal carcinoma: A phase II clinical trial.
Authors: Tang Lin-Quan , Jia Guo-Dong , Lv xiao-Fei , Xie Siyi , Chen Yu , Li Ji-Bin , Li Xiao Yun , Zhu Manyi , Liu Sai Lan , Liu LiTing , Sun Xue-Song , Guo Shanshan , Luo Dong-Hua , Chen Qiu-Yan , Mai Hai-Qiang
Published: October 2024

6042

Background:
The synergistic antitumour effect immune checkpoint inhibitors combined with antiangiogenic targeted therapy in refractory RM-NPC patients remains unknown. This phase 2 trial assessed the efficacy and safety of camrelizumab (an anti-programmed death 1 [PD-1] inhibitor) plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) after at least first-line therapy in refractory RM-NPC patients.
Methods:
We did a phase 2 single-armed study to evaluate the activity of camrelizumab plus apatinib in platinum-resistant (cohort 1) and PD-1 inhibitor resistant (cohort 2) NPC. Eligibility required measurable disease (RECIST 1·1), Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, age of 18-75 years, and disease progression on platinum but PD-1 inhibitor-naive (cohort 1) or disease progression on PD-1 inhibitor (cohort 2) after at least first-line therapy. Patients in cohort 1 received 200 mg intravenous camrelizumab every 3 weeks plus 250 mg oral apatinib daily. Patients in cohort 2 received apatinib monotherapy in the first two weeks to modify the immune-resistant microenvironment, and were then administered camrelizumab plus apatinib until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). This study was registered with ClinicalTrials.gov (NCT04547088, NCT04548271).
Results:
From August 20, 2020 to September 6, 2021, 72 patients were enrolled into the trial: 40 patients were enrolled in cohort 1 and 32 in cohort 2. Median follow-up was 13.1 months (IQR 10.0-15.2 months) for cohort 1 and 9.0 (5.9-10.7) months for cohort 2. Among the 40 evaluable patients in cohort 1, an objective response was achieved by 26 (65%; 95% CI, 49.6-80.4). A total of 16 (40%) patients had tumor progression, and the median PFS was not reached. Among the 32 evaluable patients in cohort 2, an objective response was achieved by 11 (34.4%; 95% CI, 17.0-51.8). A total of 22 (69%) patients had tumor progression, and the median PFS was 6.0 months (95% CI, 4.4 to 7.6). Grade ≥ 3 treatment-related adverse events (TRAE) were reported in 34 (47.2%) of 72 patients, with the most common TRAE being hypertension (18.1%), an increase of serum transaminase (13.9%) and hand and foot syndrome (12.5%). No treatment-related deaths occurred.
Conclusions:
In patients with platinum-resistant or PD-1 inhibitor resistant RM-NPC, camrelizumab plus apatinib achieved promising outcomes. Further studies of the camrelizumab plus apatinib treatment regimen are warranted in a phase 3 trial.
Clinical trial information: NCT04547088, NCT04548271.