bluuebunny/crossref_metadata_2025 huggingface dataset:
Automated radiosynthesis and preclinical evaluation of two new PSMA-617 derivatives radiolabelled via [18F]AlF2+ method
Authors: Iannone Marco Nicola , Valtorta Silvia , Stucchi Stefano , Altomonte Stefano , Turolla Elia Anna , Vino Elisa , Rainone Paolo , Zecca Valentina , Lo Dico Alessia , Maspero Marco , Figini Mariangela , Bellone Matteo , Ciceri Samuele , Colombo Diego , Chinello Clizia , Pagani Lisa , Moresco Rosa Maria , Todde Sergio , Ferraboschi Patrizia
Published: June 2024

Background

In the last decade the development of new PSMA-ligand based radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research. The most promising derivative in terms of interaction with the antigen and clinical properties has been found to be “PSMA-617”, and its lutetium-177 radiolabelled version has recently been approved by EU and USA regulatory agencies for therapeutic purposes. For the above reasons, the development of new derivatives of PSMA-617 radiolabelled with fluorine-18 may still be of great interest. This paper proposes the comparison of two different PSMA-617 derivatives functionalized with NODA and RESCA chelators, respectively, radiolabelled via [18F]AlF2+ complexation.

Results

The organic synthesis of two PSMA-617 derivatives and their radiolabelling via [18F]AlF2+ complexation resulted to proceed efficiently and successfully. Moreover, stability in solution and in plasma has been evaluated. The whole radiosynthesis procedure has been fully automated, and the final products have been obtained with radiochemical yield and purity potentially suitable for clinical studies. The biodistribution of the two derivatives was performed both in prostate cancer and glioma tumour models. Compared with the reference [18F]F-PSMA-1007 and [18F]F-PSMA-617-RESCA, [18F]F-PSMA-617-NODA derivative showed a higher uptake in both tumors, faster clearance in non-target organs, and lower uptake in salivary glands.

Conclusion

PSMA-617 NODA and RESCA derivatives were radiolabelled successfully via [18F]AlF2+ chelation, the former being more stable in solution and human plasma. Moreover, preclinical biodistribution studies showed that [18F]F-PSMA-617-NODA might be of potential interest for clinical applications.
Wayfinding in pairs: comparing the planning and navigation performance of dyads and individuals in a real-world environment
Authors: Bae Crystal , Montello Daniel , Hegarty Mary
Published: June 2024

Navigation is essential to life, and it is cognitively complex, drawing on abilities such as prospective and situated planning, spatial memory, location recognition, and real-time decision-making. In many cases, day-to-day navigation is embedded in a social context where cognition and behavior are shaped by others, but the great majority of existing research in spatial cognition has focused on individuals. The two studies we report here contribute to our understanding of social wayfinding, assessing the performance of paired and individual navigators on a real-world wayfinding task in which they were instructed to minimize time and distance traveled. In the first study, we recruited 30 pairs of friends (familiar dyads); in the second, we recruited 30 solo participants (individuals). We compare the two studies to the results of an earlier study of 30 pairs of strangers (unfamiliar dyads). We draw out differences in performance with respect to spatial, social, and cognitive considerations. Of the three conditions, solo participants were least successful in reaching the destination accurately on their initial attempt. Friends traveled more efficiently than either strangers or individuals. Working with a partner also appeared to lend confidence to wayfinders: dyads of either familiarity type were more persistent than individuals in the navigation task, even after encountering challenges or making incorrect attempts. Route selection was additionally impacted by route complexity and unfamiliarity with the study area. Navigators explicitly used ease of remembering as a planning criterion, and the resulting differences in route complexity likely influenced success during enacted navigation.
Protocol for the development of a tool to map systemic sclerosis pain sources, patterns, and management experiences: a Scleroderma Patient-centered Intervention Network patient-researcher partnership
Authors: Dal Santo Tiffany , Golberg Meira , Nassar Elsa-Lynn , Carrier Marie-Eve , Hu Sophie , Kwakkenbos Linda , Bartlett Susan J. , Fox Rina S. , Lee Yvonne C. , Varga John , Benedetti Andrea , Thombs Brett D. ,   the Scleroderma Patient-centered Intervention Network Pain Patient Advisory Team, Lapointe McKenzie Jo-Ann , Lawrie-Jones Amanda , Mieszczak Tracy , Petrozza Silvia , Sauve Maureen , Wixson Gayle
Published: June 2024

Introduction

Systemic sclerosis (SSc) is a rare, complex autoimmune rheumatic disease with multiple factors that contribute to pain. People with SSc emphasize the effect pain has on their quality of life, but no studies have systematically examined the frequency and relative importance of different SSc pain sources, patterns of pain from different sources, and pain management experiences. Our objectives are to (1) develop a tool, jointly with researchers, health care providers, and patients, to map sources of pain in SSc, determine patterns of pain from different sources, and understand pain management experiences; and (2) administer the final tool version to participants in the large multinational Scleroderma Patient-centered Intervention Network (SPIN) Cohort.

Methods

First, we will use validated pain assessment tools as templates to develop an initial version of our pain assessment tool, and we will obtain input from patient advisors to adapt it for SSc. The tool will include questions on pain sources, pain patterns, pain intensity, pain management techniques, and barriers to pain management in SSc. Second, we will conduct nominal group technique sessions with people living with SSc and health care providers who care for people with SSc to further refine the tool. Third, we will conduct individual usability testing sessions with SPIN Cohort participants. Once the tool has been finalized, we will administer it to individuals in the multinational SPIN Cohort, which currently includes over 1,300 active participants from 54 sites in 7 countries. We will perform unsupervised clustering using the KAy-Means for MIxed LArge data (KAMILA) method to identify participant subgroups with similar profiles of pain sources (present or absent) and to evaluate predictors of subgroup membership. We will use latent profile analysis to identify subgroups of participants with similar profiles based on pain intensity scores for each pain source and evaluate predictors.

Discussion

Once completed, our pain assessment tool will allow our team and other researchers to map sources of pain in SSc and to understand pain management experiences of people living with SSc. This knowledge will provide avenues for studies on the pathophysiology of pain in SSc and studies of interventions to improve pain management.
Improvement of insulin sensitivity by dietary fiber consumption during late pregnant sows is associated with gut microbiota regulation of tryptophan metabolism
Authors: Li Yang , He Jiaqi , Zhang Lijia , Liu Haoyu , Cao Meng , Lin Yan , Xu Shengyu , Che Lianqiang , Fang Zhengfeng , Feng Bin , Li Jian , Zhuo Yong , Wu De
Published: June 2024

Background

Dietary fiber (DF) consumption was reported to improve insulin sensitivity, change the tryptophan metabolism, and alter the gut microbiota. Herein, this study aimed to investigate the effects of DF consumption on insulin sensitivity, tryptophan metabolism, and gut microbiota composition in sows during late pregnancy, and explore the relationship between tryptophan metabolites and insulin sensitivity regulated by DF supplementation.

Results

Twelve sows were randomly assigned to two dietary treatment groups (six/group): the low-fiber (LF) group, which was fed a basal diet, and the high-fiber (HF) group, which was fed the basal diet supplemented with 22.60 g/kg inulin and 181.60 g/kg cellulose. During late pregnancy, meal test, glucose tolerance test, and insulin challenge test were used to investigate the insulin sensitivity of sows, using the percutaneous brachiocephalic vein catheterization technique. High DF consumption resulted in improved insulin sensitivity, especially during the second and third trimesters, and promoted serotonin production from tryptophan. Additionally, plasma serotonin concentration was positively correlated with the insulin sensitivity index during late pregnancy. Moreover, DF consumption elevated fecal short-chain fatty acid (SCFA) concentrations, altered fecal microbial diversity, and increased the abundances of Rikenellaceae_RC9_gut_group, Alloprevotella, Parabacteroides, Roseburia, and Sphaerochaeta, which were positively correlated to plasma serotonin concentration.

Conclusions

DF consumption improved insulin sensitivity during late pregnancy in sows, which improved microbial diversity in fecal samples and increased fecal SCFA concentrations, resulting in a positive correlation with plasma serotonin level.
Conservative femoral revision using short cementless stems with a tapered rectangular shape for selected Paprosky II–IV bone defects: an average seven-year follow-up
Authors: Li Yicheng , Zhang Xiaogang , Ji Baochao , Yushan Nuerailijiang , Wulamu Wuhuzi , Guo Xiaobin , Cao Li
Published: June 2024

Background

The use of long stems for severe femoral bone defects is suggested by many scholars, but it is associated with further bone loss, intraoperative fracture, increased surgical trauma, and complications. With better bone retention, simple and quick surgical procedures, and minimal complications, the short cementless stems with a tapered rectangular shape may be an alternative for femoral revision. This study aimed to evaluate the results of this type of stem in treating selected Paprosky II–IV bone defects.

Methods

This retrospective study included 73 patients (76 hips involved) who underwent conservative femoral revision using the short cementless stems with a tapered rectangular shape between January 2012 and December 2020. The preoperative femoral bone defects were identified as follows: 54 cases of type II, 11 cases of type IIIA, 7 cases of type IIIB, and 4 cases of type IV. Indications for revision included aseptic loosening (76.3%) and prosthetic joint infection (23.7%). Six cementless stems with a tapered rectangular shape from three companies were used in all patients. Among them, SLR-Plus, SL-Plus MIA, and Corail stems were employed in most patients (40.8%, 23.7%, and 17.1%, respectively). The average length of these stems measured 171.7 mm (SD 27 mm; 122–215 mm). Radiographic results, Harris hip scores (HHS), complications, and survivorship were analyzed. The follow-up lasted for 7 years on average (range 3–11 years).

Results

The subsidence was observed in three hips (3.9%), and all stems achieved stable bone ingrowth. Proximal femoral bone restoration in the residual osteolytic area was found in 67 hips (88.2%), constant defects in nine hips (11.8%), and increasing defects in 0 cases. There was no evidence of stem fractures and stem loosening in this series. The mean HHS significantly improved from 32 (range 15–50) preoperatively to 82 (range 68–94) at the last follow-up (t = − 36.297, P < 0.001). Five hips developed prosthesis-related complications, including three infection and two dislocation cases. The mean 5- and 10-year revision-free survivorships for any revision or removal of an implant and reoperation for any reason were 94.6% and 93.3%, respectively. Both mean 5- and 10-year revision-free survivorships for aseptic femoral loosening were 100%.

Conclusion

Conservative femoral revision using short cementless stems with a tapered rectangular shape can provide favorable radiographic outcomes, joint function, and mid-term survivorship with minimal complications. Of note, a sclerotic proximal femoral bone shell with continued and intact structure and enough support strength is the indication for using these stems.

Graphical Abstract
Genetic analysis of BRPF1 exon deletion variant causing intellectual developmental disorder with dysmorphic facies and ptosis in a Chinese family
Authors: Liu Qian , Li Feifei , Wang Nana , Fan Zhengjun
Published: June 2024

Background

Intellectual developmental disorders with dysmorphic facies and ptosis (IDDDFP) are rare neurological conditions caused by variants in the BRPF1 gene. They primarily manifest as intellectual disabilities (ID) alongside distinctive facial features, particularly ptosis and blepharophimosis. This study aimed to investigate the molecular etiology and phenotype of the inaugural IDDDFP family documented in China.

Methods and results

Clinical data were collected and validated through trio-based whole-exome sequencing of DNA from the proband and her parents, complemented by quantitative polymerase chain reaction (qPCR). The proband, a 10-month-old girl, presented with focal seizures and developmental delays. Notably, she exhibited facial features similar to those of her mother and sister, including ptosis and blepharophimosis. Both the proband’s mother and sister also had mild ID. Genetic testing identified BRPF1 deletion variants in all affected individuals, resulting in exon 2–14 heterozygous deletion. The qPCR verification confirmed the wild-type BRPF1 in the proband’s father and eldest sister. A review of 46 documented patients with BRPF1 deficiency revealed that the primary clinical manifestations encompassed varying degrees of ID alongside special facial features, skeletal deformities, and ocular abnormalities. However, epilepsy was found to be rare in this syndrome. The syndrome has variable phenotypic features of neurodevelopmental disorders. Meanwhile, there seems to be a lack of correlation between phenotype and genotype.

Conclusion

Our findings broaden the genotypic and phenotypic spectrum of individuals with genetically pathogenic variants of BRPF1. Moreover, they underscore the significance of recognizing ptosis and blepharophimosis associated with ID or seizures as potential signs of BRPF1 variants.
The fig (
Ficus carica
L.): varietal evolution from Asia to Puglia region, southeastern Italy
Authors: Mazzeo Andrea , Magarelli Andrea , Ferrara Giuseppe
Published: June 2024

The fig represents one of the oldest and widespread species in the Mediterranean basin, and thanks to man-made selections, it is possible to survey numerous varieties currently used for both main crop and brebas production. The fig is often associated with the birth of horticulture in Mediterranean and Near Asia areas. Figs were probably carried to southern Italy by Phoenicians and successively by Greeks and played an important role in Roman society. Puglia was in the past the most important region in southern Italy to produce figs and especially brebas (first crop), thanks to the excellent qualitative aspects of some varieties such as ‘Petrelli’ (syn. “Fiorone di S. Giovanni,” “Fiorone di S. Antonio”) and ‘Domenico Tauro’ that are mainly cultivated in the provinces of Bari and Brindisi. Main crop production, on the other hand, has always been based on the ‘Dottato’ variety, which was mainly used for drying and is partly consumed fresh, but also processed into jams and marmalades. There are numerous ‘minor’ varieties, which allow Puglia to be among the regions in the world with the greatest fig biodiversity, a kind of living repository grown during the centuries and in the last years rediscovered. However, the consumption and trade are exclusively at the local level, due to limited resistance to handling and shipping of such fruit; only a limited amount is destined to export. The main fig varieties cultivated in Puglia allow a wide ripening calendar starting from the first 10 days of June for brebas (often at the end of May) and ending in late September–October with late ripening varieties. The purpose of this mini review is to highlight the high degree of biodiversity that exists in Puglia region since many centuries, and the importance that this ancient crop could have in modern fruit growing, as it was once a key player in market scenarios in many Mediterranean and Near Asia countries. The fig biodiversity could be used either for fresh and processed consumption or for breeding programs for new varieties with desired traits and qualities.
Inhibition of cysteine-serine-rich nuclear protein 1 ameliorates ischemia–reperfusion injury during liver transplantation in an MAPK-dependent manner
Authors: Wang Zhoucheng , Ge Wenwen , Zhong Xinyang , Tong Shizheng , Zheng Shusen , Xu Xiao , Wang Kai
Published: June 2024

Hepatic ischemia–reperfusion injury (HIRI) is a critical pathophysiological process during liver transplantation (LT). Multiple genes and signal pathways are dysregulated during HIRI. This study aims to identify genes as potential therapeutic targets for ameliorating HIRI. Datasets containing samples from the human donor liver (GSE151648) and mouse HIRI model (GSE117066) were analyzed to determine differentially expressed genes (DEGs). The selected DEGs were confirmed by real-time PCR and western blot in the hepatocyte hypoxia-reoxygenation (HR) model, mouse HIRI model, and human liver samples after transplantation. Genetic inhibition was used to further clarify the underlying mechanism of the gene in vitro and in vivo. Among the DEGs, CSRNP1 was significantly upregulated (|log FC|= 2.08, P < 0.001), and was positively correlated with the MAPK signal pathway (R = 0.67, P < 0.001). CSRNP1 inhibition by siRNA significantly suppressed apoptosis in the AML-12 cell line after HR (mean Annexin+ ratio = 60.62% vs 42.47%, P = 0.0019), but the protective effect was eliminated with an additional MAPK activator. Knocking down CSRNP1 gene expression by intravenous injection of AAV-shRNA markedly reduced liver injury in mouse HIRI model (ALT: AAV-NC vs AAV-shCsrnp1 = 26,673.5 ± 2761.2 vs 3839.7 ± 1432.8, P < 0.001; AST: AAV-NC vs AAV-shCsrnp1 = 8640.5 ± 1450.3 vs 1786.8 ± 518.3, P < 0.001). Liver-targeted delivery of siRNA by nanoparticles effectively inhibited intra-hepatic genetic expression of Csrnp1 and alleviated IRI by reducing tissue inflammation and hepatocyte apoptosis. Furthermore, CSRNP1 inhibition was associated with reduced activation of the MAPK pathway both in vitro and in vivo. In conclusion, our results demonstrated that CSRNP1 could be a potential therapeutic target to ameliorate HIRI in an MAPK-dependent manner.
Monitoring and enhancing spontaneous sustainability—a framework
Authors: Hassan Gehan I. , Ettouney Sayed M. , Abdel-Kader Nasamat M.
Published: June 2024

The paper presents and addresses the concept of “spontaneous sustainability”, the informal and unplanned sustainable development of communities, as the basis and framework to support the notion, drives, and agendas of “formal sustainability”. It follows the interdependence between the “spontaneous sustainability” of “distinct” communities and their “cultural” characteristics, including history, spatial continuity, values and behaviors, the associated physical settings, and tangible and intangible products, which enabled them to continue, survive, and develop. The research aims at formulating and validating a “framework” for monitoring and enhancing the “spontaneous sustainability” of “distinct” communities to enable, support and link it, to the broader frameworks of “sustainable development”. The proposed “framework” combines “sustainability” dimensions: environmental, economic, and socio-cultural; and the levels of community contexts, and spatial impact. The “framework” is formulated by integrating selected “urban sustainability” approaches, and systems, with later research that developed the key aspects, criteria, and indicators of those systems, together with research addressing “social and cultural sustainability”, and assessment aspects, criteria, and indicators. The “framework” is developed and validated through a limited questionnaire, involving local experts and specialists, academics, and practitioners, to point out limitations and potential, and to suggest the relative importance of its components, key aspects, and criteria. The validation supported the research propositions, the formulation, and development of the proposed “spontaneous sustainability framework” and emphasized its flexibility to include other approaches and agendas, and potential for further development and application in distinct local communities.
Maladaptive personality traits are associated with burnout risk in Italian anesthesiologists and intensivists: a secondary analysis from a cross-sectional study
Authors: Vittori Alessandro , Petrucci Emiliano , Cascella Marco , Bignami Elena Giovanna , Simonini Alessandro , Sollecchia Giacomo , Fiore Gilberto , Vergallo Alessandro , Marinangeli Franco , Pedone Roberto
Published: June 2024

Background

Burnout is a maladaptive response to chronic stress, particularly prevalent among clinicians. Anesthesiologists are at risk of burnout, but the role of maladaptive traits in their vulnerability to burnout remains understudied.

Methods

A secondary analysis was performed on data from the Italian Association of Hospital Anesthesiologists, Pain Medicine Specialists, Critical Care, and Emergency (AAROI-EMAC) physicians. The survey included demographic data, burnout assessment using the Maslach Burnout Inventory (MBI) and subscales (emotional exhaustion, MBI-EE; depersonalization, MBI-DP; personal accomplishment, MBI-PA), and evaluation of personality disorders (PDs) based on DSM-IV (Diagnostic and Statistical Manual of Mental Disorders Fourth Edition) criteria using the assessment of DSM-IV PDs (ADP-IV). We investigated the aggregated scores of maladaptive personality traits as predictor variables of burnout. Subsequently, the components of personality traits were individually assessed.

Results

Out of 310 respondents, 300 (96.77%) provided complete information. The maladaptive personality traits global score was associated with the MBI-EE and MBI-DP components. There was a significant negative correlation with the MBI-PA component. Significant positive correlations were found between the MBI-EE subscale and the paranoid (r = 0.42), borderline (r = 0.39), and dependent (r = 0.39) maladaptive personality traits. MBI-DP was significantly associated with the passive-aggressive (r = 0.35), borderline (r = 0.33), and avoidant (r = 0.32) traits. Moreover, MBI-PA was negatively associated with dependent (r =  − 0.26) and avoidant (r =  − 0.25) maladaptive personality features.

Conclusions

There is a significant association between different maladaptive personality traits and the risk of experiencing burnout among anesthesiologists. This underscores the importance of understanding and addressing personality traits in healthcare professionals to promote their well-being and prevent this serious emotional, mental, and physical exhaustion state.
Coverage and Socioeconomic Inequalities in Cervical Cancer Screening in Low- and Middle-Income Countries Between 2010 and 2019
Authors: Abila Derrick Bary , Wasukira Sulaiman B. , Ainembabazi Provia , Kiyingi Elizabeth Nakiyingi , Chemutai Beliza , Kyagulanyi Eddy , Varsani Jaimin , Shindodi Beatha , Kisuza Ruth Ketty , Niyonzima Nixon
Published: June 2024

PURPOSE

Cervical cancer screening is vital in addressing the global burden of cervical cancer. In this study, we describe the coverage and socioeconomic inequalities in the coverage of cervical cancer screening in low- and middle-income countries (LMICs).

METHODS

We analyzed data from the women's recode files of the Demographic and Health Surveys conducted in LMICs from 2010 to 2019 with variables on cervical cancer screening. We included women 21 years or older and determined the proportion of women who were screened for cervical cancer by age categories, wealth quintile, type of place of residence, level of education, and marital status. Socioeconomic inequality was measured using the concentration index (CIX) and the slope index of inequality (SII).

RESULTS

A total of 269,506 women from 20 surveys in 16 countries were included in the survey. Generally, there was a low coverage of screening, with lower rates among women age 21-24 years, living in rural areas, in the poorest wealth quintile, with no formal education, and who have never been in union with or lived with a man. The CIX and SII values for screening for cervical cancer were positive (pro-rich) for all the countries except Tajikistan in 2012 where they were negative (pro-poor).

CONCLUSION

The coverage of cervical cancer screening was low in LMICs with variations by the quintile of wealth (pro-rich) and type of place of residence (pro-urban). To achieve the desired impact of cervical cancer screening services in LMICs, the coverage of cervical cancer screening programs must include women irrespective of the type of place and wealth quintiles.
Stigma in Pediatric Cancer: An Exploratory Study of Osteosarcoma and Retinoblastoma in Guatemala, Jordan, and Zimbabwe
Authors: Graetz Dylan E. , Velasquez Thelma , Chitsike Inam , Halalsheh Hadeel , Cáceres-Serrano Ana , Fuentes Lucia , Chokwenda Nester , Matsikidze Edith , Ferrara Gia , Bilbeisi Tharwa , Williams Anneliese , Bhakta Nickhill , Jeha Sima , Rodriguez Galindo Carlos , Mack Jennifer W. , Santana Victor M.
Published: June 2024

PURPOSE

Stigma is an understudied barrier to health care acceptance in pediatric oncology. We sought to explore the stigma experience, including its impact on cancer treatment decision making, and identify strategies to mitigate stigma for patients with osteosarcoma and retinoblastoma in Guatemala, Jordan, and Zimbabwe.

METHODS

Participants included caregivers, adolescent patients (age 12-19 years), and health care clinicians. A semistructured interview guide based on The Health Stigma and Discrimination Framework (HSDF) was adapted for use at each site. Interviews were conducted in English, Spanish, Arabic, or Shona, audio-recorded, translated, and transcribed. Thematic analysis focused on stigma practices, experiences, outcomes, drivers, mitigators, and interventions.

RESULTS

We conducted 56 interviews (28 caregivers, 19 health care clinicians, nine patients; 20 in Guatemala, 21 in Jordan, 15 in Zimbabwe). Major themes were organized into categories used to adapt the HSDF to global pediatric cancer care. Themes were described similarly across all sites, ages, and diagnoses, with specific cultural nuances noted. Pediatric cancer stigma was depicted as an isolating and emotional experience beginning at diagnosis and including internalized and associative stigma. Stigma affected decision making and contributed to negative outcomes including delayed diagnosis, treatment abandonment, regret, and psychosocial fragility. Overcoming stigma led to positive outcomes including resilience, treatment adherence, pride, and advocacy. Identified stigma drivers and mitigators were linked to potential interventions.

CONCLUSION

Participants describe a shared stigma experience that transcends geography, cultural context, age, and diagnosis. Stigma manifestations have the potential to impact medical decision making and affect long-term psychological outcomes. Stigma assessment tools and interventions aimed at stigma mitigation including educational initiatives and support groups specific to pediatric cancer should be the focus of future research.
Randomized Placebo-Controlled Trial of Topical Capsaicin for Delayed Chemotherapy-Induced Nausea and Vomiting
Authors: Bright Heber Rew , Singh Ashish , Joel Anjana , Georgy Josh Thomas , John Ajoy Oommen , Rajkumar Pradeep , Jiji Hema , Stehno-Bittel Lisa , Samuel Prasanna , Chandy Sujith J.
Published: June 2024

PURPOSE

We examined the efficacy of topical capsaicin in reducing delayed chemotherapy-induced nausea and vomiting (CINV).

METHODS

Adults on highly emetogenic chemotherapy regimens applied 2 g of capsaicin ointment (0.075%) or matching placebo four times a day to the abdomen for 5 days in addition to standard antiemetic regimen in this blinded randomized controlled trial. Patients were monitored for nausea and vomiting in the immediate (day 1), delayed (days 2-5), and extended phases (days 2-15). Self-reported incidence and daily episodes of CINV were compared between the groups. Onset, severity, need for rescue antiemetics, cumulative vomiting episodes, and safety were also compared.

RESULTS

In total, 160 patients were enrolled. The final modified intention-to-treat population included 75 patients each in the capsaicin and placebo groups. Fewer patients experienced nausea (36.0% [n = 27] v 53.3% [n = 40]; P = .033) and vomiting (28.0% [n = 21] v 42.7% [n = 32]; P = .060) in the capsaicin arm during the delayed phase. During the extended phase, there was a significantly lower incidence of nausea (44% v 64.0%; P = .014) in the capsaicin arm. No difference in nausea (26.7% v 25.3%) or vomiting (22.7% v 18.7%) was evident in the immediate phase. The average daily episodes of nausea and vomiting were significantly fewer in the capsaicin arm during the delayed and extended phases. With capsaicin, no grade 3 nausea (9.3% v 0.0%; P = .007) was observed, and the time to first nausea and vomiting was significantly prolonged. There were no differences between the groups with respect to rescue antiemetics, unscheduled hospital visits, and adverse events.

CONCLUSION

Topical capsaicin reduced the incidence of nausea and the average number of vomiting episodes during delayed and extended phases without increasing adverse effects.
Deep immune profiling of intrahepatic cholangiocarcinoma with CODEX multiplexed imaging.
Authors: Shekhar Soumya , Sahai Vaibhav , Howe Kathryn , Zhu Qingfeng , Kondo Aya , Fedor Helen L. , Gunchick Valerie , Assarzadegan Naziheh , Azad Nilofer Saba , Yarchoan Mark , Baretti Marina
Published: June 2024

4117

Background: Intrahepatic cholangiocarcinoma (iCCA) is subclassified by the presence or absence of potentially actionable molecular alterations, of which IDH1 mutations and FGFR2 fusions and rearrangements are most frequently observed. Little is known about the relationship between molecular features of iCCAs and the tumor immune microenvironment (TME). Methods: We performed a high-parameter immune phenotyping of the TME of FGFR2 fusion/rearrangement positive (FGFR2+), IDH1 mutation positive (IDH1+), and FGFR2/IDH1 wild type iCCA samples at the single-cell level using CO-Detection by indEXing (CODEX). Neighborhood analysis was based on a k-nearest-neighbors approach followed by k-means clustering to identify the spatial location of each cell type and their proximity to one another. Simplified spatial networks specific to molecular subtypes were generated based on the shortest Euclidean distances from any given cell to all other cell types. Results: A total of 24 tumors were examined (n=7 FGFR2+, n=9 IDH1+, n=8 other). Compared to other molecular subtypes, FGFR2+ tumors had an immune-desert phenotype characterized by a reduced abundance of CD8+ T cells (p < 0.05), CD117+ mast cells (p < 0.05), and CD68+/CD163+ macrophages (p < 0.05) but with an increased number of CD11b+/CD15+ granulocytes (p < 0.05). IDH1+ tumors were characterized by a decreased amount of CD11b+/CD15+ granulocytes (p < 0.05) when compared to other subtypes. In terms of spatial analysis, CD4+ T cells were located further from tumor cells in FGFR2+ iCCA compared to IDH1+ iCCA (p < 0.05) and other molecular subtypes (p=0.05). In contrast, CD11b+/CD15+ granulocytes were located closer to tumor cells in FGFR2+ tumors (p < 0.05). Additionally, closer neighbor proximity between CD4+ T cells and CD11b+/CD15+ granulocytes was observed in FGFR2+ tumors compared to both IDH1+ tumors (p < 0.05) and other tumor subtypes (p = 0.05), indicating a stronger lymphoid–myeloid neighboring relationship in the TME of FGFR2+ iCCA. Conclusions: FGFR2+ and IDH1+ iCCAs have distinct immunophenotypes, providing initial evidence that molecular alterations may inform the selection of patients for immunotherapy. Both the quantity of immune cells as well as the spatial relationships between immune cells may influence iCCA prognosis and response to therapy. Tailoring immunotherapeutic approaches to specific molecular subsets may improve outcomes across the divergent molecularly defined iCCA subtypes.
Utilization of tumor-informed circulating tumor DNA in detecting minimal residual disease and guiding adjuvant therapy in liver cancer.
Authors: Guo De-Zhen , Zhang Shi-Yu , Gu Zhu-Jun , Zhou Shuang-Tao , Jin Da-Wei , Yang Shuang , Fan Jia , Zhou Jian , Yang Xin-Rong
Published: June 2024

4125

Background: Hepatocellular carcinoma (HCC), a prevalent malignancy and a leading cause of cancer-related mortality, often exhibits a grim prognosis due to recurrence post-surgical treatment. Minimal residual disease (MRD) is deemed a crucial factor contributing to early relapse following radical surgery. Previous studies have indicated that circulating tumor DNA (ctDNA) may serve as a promising biomarker for evaluating MRD in various cancers. However, its applicability in liver cancer remains unclear. Methods: We prospective included 136 patients during 2019 to 2021 who underwent curative-intention surgery for HCC in Zhongshan hospital. Plasma samples (n=625) were collected prior to surgery, 1-month post-surgery, and during subsequent surveillance. Patient-specific somatic mutations were identified through whole-exome sequencing of tumor tissue. For each patient, 16 patient-specific somatic mutations were selected and employed to assess ctDNA through ultra-deep sequencing of plasma DNA. Results: The median follow-up period was 24 months. At the last follow-up, 45 (33.1%) patients relapsed. The preoperative ctDNA concentration was elevated in patients who experienced tumor relapse after surgical treatment compared to those didn’t relapse (median: 125 vs.8.4 mean tumor molecules/mL, P<0.001). Most of patients (80.9%) demonstrated a significant decrease in ctDNA concentration to negative levels after curative surgery. Those maintaining a positive postoperative ctDNA status faced a higher recurrence risk (HR=11.5, P<0.001). Throughout longitudinal follow-up, positive longitudinal ctDNA (positive in any point) was significantly associated with a higher recurrence risk (HR=69.3, P<0.001). The area under the curve of longitudinal ctDNA for predicting recurrence was 0.956, boasting a sensitivity of 93.3% and specificity of 97.8%. The median interval from the first positive longitudinal ctDNA to clinical recurrence confirmed by imaging test was 4 months. The predictive performance of longitudinal ctDNA for recurrence surpassed that of alpha-fetoprotein (0.956 vs. 0.680, P<0.001). Patients with positive longitudinal ctDNA experienced benefits from adjuvant therapy (HR=0.4, P=0.019). Moreover, a decrease or stability of ctDNA after adjuvant therapy indicated treatment response and delayed clinical relapse (HR=0.3, P=0.00012). Conclusions: Tumor-informed ctDNA proves to be a reliable indicator for MRD detection after surgical treatment for HCC, enabling the prediction and anticipation of recurrence before clinical manifestation. It plays a crucial role in guiding the application of adjuvant therapy and assessing treatment efficacy, thereby facilitating postoperative management and enhancing the precision of medical interventions.
Bone metastases and skeletal related events in patients with gastrointestinal neuroendocrine tumors.
Authors: Bruges Paula , Schonman Ian , Zahurak Marianna , Laheru Daniel A. , He Jin , Johnston Fabian McCartney , Greer Jonathan , Solnes Lilja , De Jesus-Acosta Ana
Published: June 2024

4126

Background: The clinical implications and management of bone metastases in patients (pts) with gastrointestinal neuroendocrine tumors (GI-NETs) is poorly characterized. In this study we investigated the frequency of bone metastases and skeletal-related events (SRE) in pts with GI-NETs. Methods: Retrospective review of ptswith GI-NETs seen at our institution between 2010-2022. We collected clinicopathologic data including tumor primary site, tumor differentiation, grade using Ki-67 labeling index (G1, G2, or G3), time of diagnosis of metastatic GI-NET, and development of bone metastases (synchronous or metachronous). Diagnosis of metastatic bone disease was assessed by contrast imaging (CT, MRI) and/or functional imaging studies (FDG or DOTATATE PET). SRE were defined as bone pain, spinal cord compression, pathological fracture or tumor-related hypercalcemia. Bone directed therapy was defined as use of bisphosphonates, radiation therapy, and surgical intervention. Results: We identified a total of 865 pts with metastatic GI-NETs. Of these, 122 pts (14%) had evidence of bone metastases. In pts with bone metastases, median age was 60 y/o and 72 pts (59%) were male. Primary tumor sites included pancreas (n=52, 47%), small bowel (n=50, 45%), rectum (n=4, 4%), colon (n=3, 3%), and gallbladder (n=1, 1%). Tumors were G1 (n=31, 28%), G2 (n=51, 47%), G3 (n=27, 25%). The majority of pts had well-differentiated tumors (n=103, 84%). Imaging for initial diagnosis of bone metastasis included PET (n=65, 53%), MRI (n=29, 24%), and CT (n=28, 23%). Synchronous metastases occurred in 34 pts (28%). Metachronous bone metastasis occurred in 88 pts (72%) with a median time to developing bone metastasis of 38 months. SRE occurred in 46 pts (38%), with 36 pts (30%) experiencing bone pain, 5 pts (4%) experiencing pathological fracture, 5 pts (4%) experiencing spinal cord compression, and 2 pts (2%) experiencing hypercalcemia. Thirty-six pts (30%) received bone-directed therapy, including bisphosphonates (n=25, 20%), radiation (n=19, 16%), or surgical intervention (n=4, 3%). Median overall survival (OS) was 83.3 months. Factors associated with increased probability of SRE included younger age, non-white race, low tumor grade, synchronous presentation, and poorly differentiated tumor. Risk factors for decreased OS included male gender, intermediate or high-grade disease, and spinal cord involvement. Bisphosphonate therapy was the most frequently used bone-directed treatment (n=25, 20%). Conclusions: Bone metastases occurred in 14% of pts with GI-NETs and SRE occurred in 38% of these pts. SRE were more likely to occur in pts with synchronous metastatic bone disease, intermediate/high grade tumors or poorly differentiated tumors. Further studies evaluating interventions to decrease SRE and impact in quality of life in pts with GI-NETs are warranted.
Types of thromboembolic events and their outcomes among patients with active colorectal cancer: A nationwide propensity matched analysis.
Authors: Farooq Faryal , Kumar Manoj , Afzal Muhammad Sohaib , Sultan Muhammad , Nasir Bilal , Byreddi Laxman Yashwant , Devarkonda Vishal , Ali Shafaqat , Atluri Sundeep
Published: June 2024

e15530

Background: Venous thromboembolic events (VTE) are a major cause of morbidity & mortality in patients with active cancer. We aim to investigate the outcome and incidence of acute DVT and PE in colorectal cancer compared to all other malignancies. Methods: The National Readmission Database (2016-2020) was queried to identify all-cause admissions for patients with active colorectal cancer (CRC). A Propensity Score Matching (PSM) model, matched such patients with cases having any type of other malignancies. Pearson’s x2 test was applied to the PSM-2 matched cohorts to compare outcomes. Results: Among 2.9 million all-cause hospitalizations of CRC patients, about 3.9% suffered a VTE. The majority had acute DVT (1.9%), followed by acute PE (1.3%), followed by DVT with PE (0.7%). After propensity-matching & multivariate analysis, patients with CRC have a lower incidence of acute DVT (2.7% vs 2.8%, aOR: 0.92), acute PE (1.8% vs 2%, aOR: 0.84) & DVT with PE (0.96% vs 1.02%, aOR: 0.90) [p < 0.001] as compared to other malignancies. Among different VTEs, the mortality was highest for acute PE (aOR: 2.66), followed by DVT with PE (aOR: 2.28) & DVT (aOR: 1.89) [p < 0.001]. Resource utilization is also higher in CRC-related hospitalizations complicated by VTE, with patients suffering a DVT having the highest LOS (9 vs 5 days) & total cost of hospitalization ($25,910 vs $17,964) [p < 0.001] followed by DVT with PE and PE respectively. CRC patients had higher readmission rates for DVT as compared to PE at 30 days (18.2% vs 17%, p: 0.029) and subsequently at 90-day intervals. Conclusions: CRC-related hospitalizations had lower rates of DVT and PE compared to other active malignancies. The mortality was highest for PE in this cohort, while healthcare-related burden and readmission rates were higher for DVT.
The treatment outcomes of patients with BRAFV600E–mutated metastatic colorectal cancer (mCRC): The Polish retrospective cohort study.
Authors: Zok Jolanta , Bieńkowski Michał , Radecka Barbara , Kuchar Agata , Borowiec Szymon , Streb Joanna , Jurczyk Michał , Jakieła-Drąg Anna , Gelej Marek , Zając Patryk , Ploch-Glapińska Małgorzata , Duchnowska Renata
Published: June 2024

e15535

Background: BRAF V600E mutation is found in approximately 6-11% of metastatic colorectal cancer patients (mCRC). According to the international guidelines in BRAFV600E mutated mCRC, the triplet chemotherapy FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan) with bevacizumab and encorafenib plus cetuximab should be considered in 1st and 2nd line treatment setting, respectively. Methods: This retrospective and multicenter study evaluates clinical practices in BRAFV600Emutated mCRC patients treated between 2011 and 2023 in Poland. All patients were tested for BRAF and RAS mutations before starting the 1st line treatment, using PCR from archival paraffin-embedded tumor tissue. Results: One hundred twenty-six patients (median age 68 years (range 45-85), 55% female and 45% male) from five oncology centers were included. The majority of patients had a right-sided primary tumor 69 (55%). The 1st line of chemotherapy received 100 patients (79,4%). The majority of patients received doublet chemotherapy: FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin), FOLFIRI (folinic acid, 5-fluorouracil, irinotecan), XELOX (capecitabine, oxaliplatin), FOLFIRI and bevacizumab: 30 (30%), 47 (47%), 5 (5%), 3 (3%), respectively. Only three patients (3%) received FOLFOXIRI, and one patient with bevacizumab. The median duration of 1st line treatment for the overall population was 5.26 months (95% CI 2 days - 18.9 months). Subsequently, 50 (50%), 20 (20%), 6 (6%), and 1 (1%), patients received 2nd, 3rd, 4th, and 5th line therapy, respectively. The most frequently used 2nd chemotherapy regimens were FOLFOX ( n = 8; 16%), FOLFOX plus bevacizumab ( n = 13; 26%), FOLFIRI ( n = 13; 26%), and FOLFIRI plus aflibercept ( n = 7; 14%). During the median follow-up period of 38.5 months (range 32.0 – N/A), 96 (79.3%) patients died. Median OS from mCRC diagnosis was 13.7 months (95% CI: 11.3-17.6). Conclusions: This study highlights the unmet need for effective treatment strategies for patients with BRAFV600E mutated mCRC in Poland.
Androgen Receptor Splice Variant 7 in Asian Patients With Metastatic Castration-Resistant Prostate Cancer
Authors: Ang Daniel , Chan Johan , Ong Whee Sze , Tan Hui Shan , Ng Quan Sing , Yuen John , Chen Kenneth , Tay Kae Jack , Wong Siew Wei , Saad Marniza , Nagata Masayoshi , Horie Shigeo , Chansriwong Phichai , Ng Chi-Fai , Wong Alvin , Chua Melvin L.K. , Toh Chee Keong , Tan Min-Han , Lim Tony , Bhagat Ali Asgar S. , Kanesvaran Ravindran
Published: June 2024

PURPOSE

Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated with poor outcomes. On progression to castrate resistance, ARV-7 positivity has been identified in global populations at an incidence of 17.8%-28.8%. Here, we characterize the incidence of ARV-7 positivity in Asian patients with mCRPC in a prospective fashion and evaluate its implications on treatment outcomes.

METHODS

Patients with mCRPC from multiple centers in Southeast and East Asia were enrolled in a prospective manner before initiation of androgen receptor signaling inhibitors or docetaxel. ARV-7 status was evaluated at baseline with three commercially available assays: AdnaTest Prostate Cancer platform, Clearbridge method, and IBN method. Clinical outcomes at progression were assessed. The primary end point of this study was prevalence of ARV-7 positivity; secondary end points were incidence of ARV-7 positivity, prostate specific antigen (PSA) response rate, PSA progression-free survival (PFS), and overall survival (OS).

RESULTS

A total of 102 patients with a median age of 72 years at enrollment participated. Overall, an incidence of ARV-7 positivity of between 14.3% and 33.7% in Asian patients with mCRPC was demonstrated depending on the assay used. Patients found to have ARV-7 positivity at enrollment had a numerically worse PSA PFS compared with ARV-7 negative patients.

CONCLUSION

In this study, the incidence of ARV-7 positivity in Asian patients with mCRPC was shown to be similar to the global population. Patients with ARV-7 positivity appear to have more aggressive disease with numerically worse PSA PFS and OS. Further prospective studies are needed to fully characterize the relationship that ARV-7 positivity has on prognosis of Asian patients with mCRPC.
The Serenade Topic, the Serenade Construction, and the Creation of Amorous Sweetness in Ottocento Opera
Authors: Boyle Matthew L. C.
Published: June 2024

The critical reception of early nineteenth-century Italian opera has long focused on its supposed cloying sweetness. This sweetness, often framed as amorous, shaped the discourse and affective experiences of primo ottocento opera. Stendhal, for instance, likened Gioachino Rossini's music to lusciously ripe fruit and to sexual arousal. Adolf Bernhard Marx found a concert of Mercadante arias to leave the bitter “aftertaste of lots of sugar.” And August Wilhelm Ambros compared Rossini's melodies to gazing into the eyes of a Titian nude. This article proposes that amorous sweetness was associated with the vocal serenade, a genre evocative of sweet melodies and the ardent love of courtship. The musical elements that articulated serenade topics, what Stephen Rumph calls figurae, saturated slow movements of early nineteenth-century Italian opera. These included pizzicato strings, sustained winds, parallel thirds, and modulations to mediant keys. Although these figurae may appear in conjunction with diegetic serenades or topical serenade passages, they also frequently appeared independent of dramatically appropriate amorous situations. This article proposes that a common configuration of serenade figurae acted as a stock orchestral texture. This convention is modeled as a musical construction: the serenade construction. It paired musical structures with the semantic meanings of the serenade. In its evocation of serenading, the serenade construction preserved scripted listening strategies for attending to vocal melodies and their associated affective responses. It consequently regulated the perception of vocal timbre and perceived melodicity.