bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut microbiota in a mouse model of obesity and peripheral neuropathy associated with plasma and nerve lipidomics and nerve transcriptomics
Authors: Guo Kai , Figueroa-Romero Claudia , Noureldein Mohamed , Hinder Lucy M. , Sakowski Stacey A. , Rumora Amy E. , Petit Hayley , Savelieff Masha G. , Hur Junguk , Feldman Eva L.
Published: March 2023

Background

Peripheral neuropathy (PN) is a common complication in obesity, prediabetes, and type 2 diabetes, though its pathogenesis remains incompletely understood. In a murine high-fat diet (HFD) obesity model of PN, dietary reversal (HFD-R) to a low-fat standard diet (SD) restores nerve function and the nerve lipidome to normal. As the gut microbiome represents a potential link between dietary fat intake and nerve health, the current study assessed shifts in microbiome community structure by 16S rRNA profiling during the paradigm of dietary reversal (HFD-R) in various gut niches. Dietary fat content (HFD versus SD) was also correlated to gut flora and metabolic and PN phenotypes. Finally, PN-associated microbial taxa that correlated with the plasma and sciatic nerve lipidome and nerve transcriptome were used to identify lipid species and genes intimately related to PN phenotypes.

Results

Microbiome structure was altered in HFD relative to SD but rapidly reversed with HFD-R. Specific taxa variants correlating positively with metabolic health associated inversely with PN, while specific taxa negatively linked to metabolic health positively associated with PN. In HFD, PN-associated taxa variants, including Lactobacillus, Lachnoclostridium, and Anaerotruncus, also positively correlated with several lipid species, especially elevated plasma sphingomyelins and sciatic nerve triglycerides. Negative correlations were additionally present with other taxa variants. Moreover, relationships that emerged between specific PN-associated taxa variants and the sciatic nerve transcriptome were related to inflammation, lipid metabolism, and antioxidant defense pathways, which are all established in PN pathogenesis.

Conclusions

The current results indicate that microbiome structure is altered with HFD, and that certain taxa variants correlate with metabolic health and PN. Apparent links between PN-associated taxa and certain lipid species and nerve transcriptome-related pathways additionally provide insight into new targets for microbiota and the associated underlying mechanisms of action in PN. Thus, these findings strengthen the possibility of a gut-microbiome-peripheral nervous system signature in PN and support continuing studies focused on defining the connection between the gut microbiome and nerve health to inform mechanistic insight and therapeutic opportunities.
The role of midwives in supporting the development of the mother-infant relationship: a scoping review
Authors: Stoodley Cathy , McKellar Lois , Ziaian Tahereh , Steen Mary , Fereday Jennifer , Gwilt Ian
Published: March 2023

Background

The mother-infant relationship is complex and dynamic, informing the psychological development of the infant through bonding and attachment. Positive early interactions influence the quality of this relationship. Midwives are well placed to support the developing relationship between the mother and baby, yet there has been limited research exploring the role of the midwife in this context.

Aim

To explore interventions that have been provided by the midwife which support the development of the maternal-fetal or mother-infant relationship amongst a low-risk population from pregnancy, and up to six weeks postnatal. The review also sought to understand the types of interventions developed, format and delivery, outcomes measured and if cultural considerations had been incorporated.

Methods

A scoping review of the research literature was undertaken using the Joanna Briggs Institute framework. Five online databases were searched for relevant articles published in English from 2000 to 2021.

Findings

Sixteen articles met the inclusion criteria. Three themes emerged: (1) viewing the fetus as separate from the mother, (2) focused activities on the maternal-infant relationship and (3) targeted educational interventions.

Discussion

Providing focused activities and targeted education during the pre and postnatal periods support the development of the mother-infant relationship. Significantly, there was insufficient research that considered the influence of culture in supporting the mother-infant relationship.

Conclusion

Further research is required to develop interventions that include a diverse sample to ensure culturally appropriate activities can be integrated into care during pregnancy and/or the postnatal period provided by midwives.
Toward an intentional model aware of learner cognitive traits for pedagogical process guidance
Authors: Bayounes Walid , Saâdi Ines Bayoudh , Kinshuk
Published: March 2023

Previous research on adaptive learning successfully demonstrated that use of Intentional Model for Educational Processes Guidance has gained popularity in Intelligent Tutoring System. Within this context, the novelty of this version of Intentional Model of Pedagogical Process Guidance (IMPPG) is the effectiveness use of Cognitive Trait Model to be aware of different traits of learner. The proposed model leads to generate an individualized learning for each learner by selecting the most appropriate pedagogical process according to the actual preferences of the tutor and the cognitive traits of learner. In fact, this model couples the pedagogical intention with the pedagogical strategies and provides a multitude of paths between learner intentions. Based on the cognitive traits of the individual learners and the corresponding pedagogical method or the individual teaching style, the ITS adopts the proposed model to adaptively support the tutor to achieve his/he intention through the selected strategy. This model has been experimented and assessed with tutors and students learning spreadsheet management in a first-year studying in applied license’s degree in Business English and applied license’s degree in Education. The first results show that the intentions and the strategies selected by our model were relevant according to students’ needs and tutors’ preferences. In the initial tests, the process model has met what was expected, however, more studies with experiments must be carried out. The primary results are reported and discussed in the paper; several lessons learned from the experience and potential improvements are also included.
Humeral trochlear morphology does not influence coronoid fractures in elbow dislocation
Authors: Arrigoni Paolo , Archinà Martina , Luceri Francesco , Radici Mattia , Zaolino Carlo , Folco Gianluca , Foschini Chiara , Regazzoni Simona , Miano Paul Muriithi , Zagarella Andrea , Colozza Alessandra , Randelli Pietro
Published: March 2023

Purpose

Traumatic elbow dislocation is the second most frequent joint dislocation, even though the elbow is a congruent and stable joint. Individual variability in anatomical congruence of the elbow and how it relates to simple or complex instability has rarely been studied in the literature; we hypothesized that a greater articular coverage by the humeral trochlea would be more likely to result in complex dislocation. The aim of this study is to analyze trochlear morphology in simple (SED) and complex elbow dislocation (CED), to assess whether the degree of humeroulnar joint congruence influences the incidence of coronoid fractures in elbow dislocation. The secondary goal is to evaluate the association between trochlear morphology and coronoid fracture pattern.

Methods

All the elbow CT scans of the hospital server were retrospectively analyzed. 62 patients were enrolled and so divided in 2 groups: SED and CED with isolated coronoid fracture. Patients who were skeletally immature, presented with other concomitant elbow fractures, or who previously underwent elbow surgery were excluded. The CT scans were performed after closed reduction and prior to further treatment. Coronoid fracture pattern was classified on CT scan according to Regan‐Morrey and O’Driscoll classifications; “grade 0” was assigned to SED. Trochlear coverage was measured and expressed as three angles (anterior, posterior, and distal) and their width/depth ratios. Measurements were taken by four different readers and the assessment was repeated after 15 days.

Results

No statistically significant difference was found between humeral trochlear morphology of SED and CED patients. There was no association between morphometric measurements and coronoid fracture pattern. The results are strengthened by a good intra‐ and inter‐reader reproducibility of the CT analysis protocol.

Conclusions

Our study is the first to evaluate the impact of trochlear morphology on elbow instability. Considering the results, other variables may have a greater impact on coronoid bone damage, such as trauma energy or ligamentous hyperlaxity: in particular, we believe that the capsuloligamentous structures of the elbow might contribute in a preponderant way to articular stability. The CT analysis protocol gave excellent results: reproducible, accurate and easy to perform.

Level of evidence

III.
The emergence of an imported variant of dengue virus serotype 2 in the Jazan region, southwestern Saudi Arabia
Authors: Dafalla Ommer , Abdulhaq Ahmed A. , Almutairi Hatim , Noureldin Elsiddig , Ghzwani Jaber , Mashi Omar , Shrwani Khalid J. , Hobani Yahya , Sufyani Ohood , Ayed Reem , Alamri Abdullah , Al-Mekhlafi Hesham M. , Eisa Zaki M.
Published: March 2023

Background

Dengue virus (DENV) infection is a global economic and public health concern, particularly in tropical and subtropical countries where it is endemic. Saudi Arabia has seen an increase in DENV infections, especially in the western and southwestern regions. This study aims to investigate the genetic variants of DENV-2 that were circulating during a serious outbreak in Jazan region in 2019.

Methods

A total of 482 serum samples collected during 2019 from Jazan region were tested with reverse transcription-polymerase chain reaction (RT-PCR) to detect and classify DENV; positive samples underwent sequencing and bioinformatics analyses.

Results

Out of 294 positive samples, type-specific RT-PCR identified 58.8% as DENV-2 but could not identify 41.2%. Based on sequencing and bioinformatics analyses, the samples tested PCR positive in the first round but PCR negative in the second round were found to be imported genetic variant of DENV-2. The identified DENV-2 imported variant showed similarities to DENV-2 sequences reported in Malaysia, Singapore, Korea and China. The results revealed the imported genetic variant of DENV-2 was circulating in Jazan region that was highly prevalent and it was likely a major factor in this outbreak.

Conclusions

The emergence of imported DENV variants is a serious challenge for the dengue fever surveillance and control programmes in endemic areas. Therefore, further investigations and continuous surveillance of existing and new viral strains in the region are warranted.
Venoarterial-extra corporeal membrane oxygenation-assisted parathyroidectomy for hypercalcemic crisis due to parathyroid carcinoma complicated by severe circulatory and respiratory failure: a case report
Authors: Enomoto Yuria , Matsuda Yuko , Nagamine Yusuke , Goto Takahisa
Published: March 2023

Background

Hypercalcemia crisis is a rare but severe form of hypercalcemia complicated by multiple organ failure. Hypercalcemia crisis due to hyperparathyroidism is commonly caused by a parathyroid tumor, which often requires surgical resection. However, there are no clear recommendations on when the surgery should be performed.

Case presentation

A 64-year-old female patient developed hyperparathyroidism due to a parathyroid tumor and hypercalcemic crisis, which was complicated by severe circulatory and respiratory failure refractory to medical therapy, and an emergent surgery was planned to resect the parathyroid tumor. To prevent intraoperative circulatory and respiratory collapse, venoarterial-extra corporeal membrane oxygenation (VA-ECMO) was introduced, resulting in a safe operation and anesthetic management.

Conclusions

In patients with hypercalcemic crisis complicated by severe circulatory and respiratory failure, induction of prophylactic VA-ECMO was useful for safe anesthetic management. Surgical resection should be performed as soon as the diagnosis is made before VA-ECMO is required.
Recent advancements in identification and detection of saliva as forensic evidence: a review
Authors: Upadhyay Megha , Shrivastava Pankaj , Verma Kapil , Joshi Bhawana
Published: March 2023

Background

Saliva is the most common biological evidence found at any crime scene next to blood. It is a clear liquid which makes it immune to any possible evidence of alteration by the perpetrator. In forensics, saliva is used as biological evidence and is very helpful in determining various aspects of an individual such as sex, individuality, ABO blood groups, microbial signature, biomarkers, or habits like smoking.

Main body

Saliva shares a great resemblance with plasma as it encompasses similar organic or inorganic compound contents. In forensic casework, identifying any evidence is the primary goal to establish the groundwork for further investigation. Saliva may be found in the form of a pool or stained form, but its identification is challenging because of its transparency. It has been widely used as an informative tool in forensic situations like poisoning, hanging, or cases of drug abuse, etc. for more than two decades now. Over the years, many proposed ways or methods have been identified and described, which helped in the detection and identification of saliva as evidence.

Conclusion

This review article represents the significance of saliva as important forensic evidence, along with the different forms it may be encountered at the crime scene. The use of diverse collection and detection methods, over the past few decades, has been discussed. An attempt has been made to collect the available data, highlighting the merit and demerits of different identification techniques. The relevant data has been collected from all the published and reported literature (1987–2021).
Determinants of quality of life in Nigerian female patients with epilepsy on carbamazepine and levetiracetam monotherapy
Authors: Luqman Ogunjimi , Joseph Yaria , Akintomiwa Makanjuola , Akinyinka Alabi , Aderonke Aderinola , Bamidele Osalusi , David Oboh , Mojisola Olusola-Bello , Bolanle Falujo , Abdullahi Murtala , Olatunbosun Olawale , Fehintola Fatai , Adesola Ogunniyi
Published: March 2023

Background

The study is aimed to identify the predictors of Quality of Life (QOL) in women with epilepsy (WWE) on carbamazepine (CBM) and levetiracetam (LTM) monotherapy. 100 WWE were recruited (50 each on CBM and LTM), after clinical diagnosis of epilepsy supported by Electroencephalography (EEG) features and seizures classification by 2017 International League Against Epilepsy (ILAE) criteria, the Quality of Life Inventory Scale 31(QOLIE-31) and Zung Self-Rating Depression Scale (ZSRDS) were used to assess QOL and depression, respectively.

Result

Higher QOLIE-31 scores was seen in the LTM group across all domains except seizure worry (p = 0.051) compared to CBM group.Logistic regression showed that the use of CBM (p = 0.000), fast frequency on EEG (p = 0.005), longer duration of epilepsy (p = 0.017), presence of depression (p = 0.008) and lower level of education (p = 0.003) were predictors of QOL. Progesterone (p = 0.040), oestradiol (p = 0.011) and prolactin (p = 0.002) in follicular phase showed significant association with QOLIE-total score. In the luteal phase, luteinizing hormone–follicle stimulating hormone (LH–FSH) ratio (p = 0.009) and testosterone (p = 0.015), FSH (p = 0.015), prolactin (p = 0.000), showed significant association with QOL. None of the hormones independently predicts QOL.

Conclusion

LTM group appears to have better QOL than CBM group. Healthcare providers should focus on addressing these identified predictors which include medication effect, depression, Level of education, EEG background and duration of epilepsy with aim of improving QOL.
Could thalamic biochemical changes correlate to cognitive impairment in idiopathic generalized epilepsy?
Authors: Daker Lamiaa I. , Sayed Sayed S. , Abdelghaffar Mohamed , Hamed Amany Hamdy , Aboelnor Mahmoud I. , El-Khatib Mohamed El-Sayed
Published: March 2023

Background

The thalamus is crucial in the development of idiopathic generalized epilepsy (IGE), which could lead to cognitive dysfunctions, according to data from neuropsychology and advanced neuroimaging investigations. This research aimed to measure the metabolic changes in the thalamus and to assess if could be contributed to cognitive impairment in IGE patients. Thirty IGE patients and thirty healthy volunteers with matched ages, genders, and educational levels participated in this cross-sectional case–control research. The IGE patients and controls were evaluated neuropsychologically using Intelligence Quotient (IQ) to assess general cognitive ability, Digit span for attention, Wechsler memory scale (WMS) for verbal memory, cube drawing test for visuospatial memory, Trail making test for executive functions, and Controlled Oral Word Association test (COWAT) for verbal fluency and quantitative multi-voxel MR spectroscopy (MRS) measurements ofN-acetyl aspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, NAA/Cho and Cho/Cr ratios at 1.5 T scanner. The voxels were located over the right and left thalamus.

Results

The IGE patients showed worse cognitive performance in IQ, attention, executive function, and verbal and visuospatial memory domains compared to the controls. The IGE patients exhibited a significantly decrease NAA in the right thalamus (p = 0.004) and a lower NAA/Cr ratio in the left thalamus (p = 0.01). the mean thalamus NAA level exhibited a positive correlation with CDT (r = 0.45,p = P = 0.01), and WMS-R (r = 0.39,p = 0.03) and a negative correlation with trail-making A test (r = 0.42,P = 0.01).

Conclusions

it was concluded that IGE patients exhibited poor cognition which could be attributed to thalamic neurometabolic changes due to impaired thalamic cortical circuits.
Deep venous stenting in females
Authors: O’Sullivan Gerry , Smith Steven
Published: March 2023

Deep venous stenting has gained increasing prominence in recent years. This issue focuses on special considerations in female patients. The specific challenge relates to the fact that these patients are often much younger than those in whom arterial stents are placed. The stents have to perform adequately over potentially 60 years- and there is no data of that length available.
Construction and characterization of the infectious cDNA clone of the prevalent Chinese strain SC3 of soybean mosaic virus
Authors: Liu Hui , Zheng Huanfang , Xiang Wenyang , Song Yingpei , Li Bowen , Yin Jinlong , Liu Mengzhuo , Liu Xiaoxiang , Wang Liqun , Yang Shouping , Xu Kai , Zhi Haijian
Published: March 2023

The resistance of different soybean varieties to the Chinese isolate SC3 of soybean mosaic virus (SMV) was systematically studied. However, the resistance of different germplasm sources is still poorly understood. We constructed an infectious DNA clone of SMV-SC3 (pSC3) and modified it to allow the expression of yellow fluorescence protein (YFP)/ red fluorescence protein (RFP) during viral infection. By using the infection of pSC3-RFP, we can classify the resistance of different soybean cultivars to SMV-SC3 to the extreme resistance that restricts initial viral replication and the resistance that allows viral replication in the initially inoculated cells but restricts further movement. Also, we tracked the SMV-SC3 infection in susceptible cultivar Nannong 1138-2 (NN1138-2) and found that the seed transmission of SMV to the offspring plants can be tracked and recorded by imaging the virus-driven expression of YFP. Overall, we reveal new aspects of soybean resistance to SMV-SC3 and provide an essential tool to study the infection and transmission of SMV-SC3, which will help decipher the genes involved in SMV pathogenesis and host resistance.
The US President's Cancer Panel: A Model For Gathering Country-Level Input to Inform Cancer Control Policy and Program Initiatives
Authors: Paradis Lisa J. , Chao Ann , Rimer Barbara K. , Sandler Abby B. , Duncan Kalina , Cira Mishka Kohli , Hanisch Rachel
Published: March 2023

PURPOSE

The President's Cancer Panel (Panel) is a federal advisory committee charged with monitoring the US National Cancer Program and reporting directly to the US President. Since its creation a half century ago, the Panel has gathered input from individuals and organizations across the US cancer community and beyond and recommended actions to accelerate progress against cancer. The Panel is unique in its structure and function, and merits examination for its potential applicability in other settings worldwide.

METHODS

We present an overview of the general President's Cancer Panel model and describe the noteworthy and unique characteristics of the Panel that help achieve its charge. We also detail the specific processes, outputs, and achievements of the Panel appointed by President Barack Obama, which served between 2012 and 2018.

RESULTS

From 2012 to 2018, the Panel focused on three topics that addressed timely issues in cancer prevention and control: (1) HPV vaccination for cancer prevention, (2) connected health and cancer, and (3) value and affordability of cancer drug treatment. The Panel held 11 meetings with 165 participants who provided diverse perspectives on these issues. Four reports were delivered to the president, which were cited about 270 times in the literature. Over 20 collaborator activities, including commitments of funding, can be linked to the recommendations published in these reports.

CONCLUSION

The US President's Cancer Panel highlights the importance of independent advisory bodies within a national cancer control program and of national leadership support for the cancer community. The structure and function of the Panel could be applicable in other settings worldwide.
The prognostic value of ECOG performance status on overall survival among patients with metastatic prostate cancer: A systematic review of the literature and meta-analysis.
Authors: Assayag Jonathan , Kim Chai , Webster Jennifer , Chu Haitao
Published: March 2023

124

Background: Eastern Cooperative Oncology Group Performance Status (ECOG PS) has been shown to be a strong predictor of mortality among patients with advanced cancer. However, in metastatic prostate cancer, there has been heterogeneity in the literature regarding the strength of association between different ECOG categories and overall survival (OS). Therefore, we conducted a systematic search and meta-analysis of studies reporting on the prognostic value of ECOG PS on OS within the metastatic prostate cancer population. Methods: We performed a systematic search of the literature within the Medline (PubMed) database from inception until March 21st 2022. Both trials and real-world data (RWD) studies were included. Using a random-effects model, a meta-analysis pooling ECOG categories on OS was performed separately for metastatic castrate resistant prostate cancer (mCRPC) and metastatic castrate sensitive prostate cancer (mCSPC) studies. We also stratified the analyses by prior use of chemotherapy and study type (RWD vs. Trial). Between-study heterogeneity was analyzed using the I2 statistic. Results: A total of 75 studies met the eligibility criteria, comprising of 32,298 patients. Nearly all studies (72 out of 75) were among patients with mCRPC, while the remaining three studies were among mCSPC patients. Overall, all ECOG PS categories were associated with OS, with the highest estimate observed among mCRPC patients with ECOG PS of ≥2 vs. <2 ([HR] = 2.10; 95% confidence interval [CI]: 1.87 to 2.37). In secondary analyses, among mCRPC patients with ECOG PS of ≥1 vs. <1, there was a significant difference according to study type (RWD: HR=1.98, 95% CI: 1.73 to 2.26 vs. trials HR=1.32, 95% CI: 1.13 to 1.54). There were no significant differences in the pooled HR of OS stratified by previous chemotherapy across all three ECOG PS categories. Conclusions: Overall, ECOG PS was a significant predictor of OS regardless of category, previous chemotherapy, and type of metastatic population, although differences were observed in RWD vs. trial populations. Additional studies are needed to quantify the association between ECOG PS and OS in the mCSPC population, as well as to better understand the role of ECOG PS on outcomes in RWD vs. trials of cancer treatments.
P-MCP treatment in non-metastatic biochemically relapsed prostate cancer (BRPC-M0): Final long-term results of a prospective phase II study.
Authors: Keizman Daniel , Frenkel Moshe A. , Peer Avivit , Kushnir Igal , Rosenbaum Eli , Sarid David Leonid , Leibovitch Ilan , Mano Roy , Yossepowitch Ofer , Margel David , Wolf Ido , Geva Ravit , Rouvinov Keren , Dresler Hadas , Eliaz Isaac
Published: March 2023

162

Background: 30% of patients with localized PC will have a biochemical relapse post local therapy. Their optimal treatment remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long-term benefit remains undefined, and it is toxic. Thus, evaluation of new nontoxic compounds in these patients is warranted. PectaSol-C modified citrus pectin (P-MCP) is an inhibitor of galectin-3 protein, which is involved in prostate cancer pathogenesis. We herein report the final long-term results of a multi-center phase 2 study of P-MCP treatment in BRPC-M0. Methods: Patients with BRPC-M0 were enrolled and treated with P-MCP, 4.8 grams X 3/day, for 6 months (first phase of trial). Patients without PSA progression and/or with improvement of PSA doubling time (PSADT), and with negative scans, were treated for an additional 12 months (second phase of trial). Results: 59 patients were initially enrolled. After initial 6 months of therapy, 46 patients (78%) without disease progression entered the second phase of additional 12 months therapy. Among them, 7 patients withdrew consent and chose to continue therapy out of pocket. Of the remaining 39 patients, after another year of therapy (total of 18 months), 85% (n=33) had an overall long-term response, with a decreased/stable PSA (62 %, n=24), and improvement of PSADT (90 %, n=35), and with negative scans. No patient had grade 3/4 toxicity. Conclusions: P-MCP may have a durable long-term efficacy in patients with BRPC-M0. Clinical trial information: NCT01681823 .
Phase 2 study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients (pts) with progressive metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Alonso Gordoa Teresa , Goodman Michael Moses , Vulsteke Christof , Roubaud Guilhem , Zhang Jingsong , Parikh Mamta , Piulats Josep M. , Azaro Analía , James Gareth D , Cavazzina Riccardo , Gangl Eric , Thompson Jeff , Pouliot Gayle Pageau , Kumar Rakesh , Sweeney Christopher
Published: March 2023

173

Background: Pts with mCRPC who progress on docetaxel and new hormonal agents (NHAs) have few therapeutic options. In the CARD study of cabazitaxel, 35.7% of pts had PSA responses and 36.5% of pts had tumor responses. While immune checkpoint inhibitors have limited single-agent activity in mCRPC, the combination of the adenosine 2A receptor antagonist, AZD4635, with durvalumab may improve response to chemotherapy. This study assessed AZD4635 in combination with durvalumab (Arm A) or with durvalumab + cabazitaxel (Arm B) in pts with mCRPC. We report interim analysis results from Arm B (Arm A to be reported elsewhere). Methods: Eligible pts had histologically confirmed mCRPC, disease progression ≤6 months prior to enrollment, and were previously treated with docetaxel and 1 NHA. Pts received AZD4635 75 mg PO QD + durvalumab 1500 mg IV Q3W + cabazitaxel Q3W (dosed per locally approved label) for up to 10 cycles. The primary endpoint was radiographic progression-free survival (rPFS), by RECIST v1.1 (soft tissue) or PCWG3 (bone). Secondary endpoints included safety, pharmacokinetics, confirmed PSA50 response, and objective response rate by RECIST v1.1. A futility analysis was planned based on PSA50 responses (confirmed + unconfirmed) after approximately 30 pts were treated. Results: As of August 10, 2021, 28 pts received AZD4635 + durvalumab + cabazitaxel, and 21 pts were still on treatment. Most common adverse events (AEs) possibly related to treatment were nausea (50.0%), diarrhea (46.4%), asthenia, and vomiting (each 28.6%). Treatment-related febrile neutropenia occurred in 7.1% pts. Twelve (42.9%) pts had a serious AE possibly related to treatment. One AE possibly related to treatment led to death (myositis). Exposures of cabazitaxel and/or durvalumab did not change when combined with AZD4635. Median rPFS was 4.4 months (95% CI: 4.2–not calculable) with low percent maturity. Of 28 PSA-evaluable pts, 8 (28.6%) had PSA50 responses (4 confirmed). There were 5 unconfirmed partial responses by RECIST v1.1. Conclusions: Although efficacy data are immature, enrollment was stopped for futility. Safety of the combination was consistent with the known safety profiles of the individual agents. Clinical trial information: NCT04089553 .
High-volume mCRPC is associated with decreased cancer specific survival in patients on second-generation hormone therapy in the post docetaxel setting.
Authors: Lehner Kelly , Ahmed Mohamed E. , Bole Raevti , Andrews Jack R. , Haloi Rimki , Bold Michael S. , Kendi Ayse T. , Karnes R. Jeffrey , Kwon Eugene D. , Bryce Alan Haruo
Published: March 2023

192

Background: In the setting of disease progression of metastatic castrate resistant prostate cancer (mCRPC) on docetaxel, abiraterone acetate (AA) and enzalutamide are two commonly used second line therapies with data demonstrating survival benefits. Less is known about patient specific factors that contribute to success with these therapies. The objective of this study is to improve patient selection for post-docetaxel second generation hormone therapy (AA or enzalutamide) by evaluating whether overall metastatic burden is associated with treatment response in this setting. Methods: By retrospective chart review, patients with mCRPC treated with AA or enzalutamide following docetaxel failure (defined as PSA rise and radiographic progression) were identified. Patients were categorized into low volume and high volume metastatic disease based on the number of pre-treatment metastatic lesions; where low volume disease describes patients with ≤ 5 metastatic lesions (e.g. oligometastatic disease), and high volume disease represents patients with > 5 individual lesions. The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Median follow-up time was 29.5 months. Results: 75 patients were identified and included in our analysis: 39 with high volume metastatic disease, and 36 with low volume metastatic disease. Baseline characteristics of age and pre-treatment ECOG were not statistically different between these groups. Pre-treatment high-volume disease burden was significantly associated with increased risk of radiographic disease progression (HR 4.21, 95%CI 1.97-8.99, p < 0.0001) and cancer specific mortality (HR 5.84, 95% CI 1.58-21.53, p = 0.0026) during treatment with second generation androgen deprivation therapy. Conclusions: High volume metastatic disease burden is associated with significantly increased cancer specific mortality and decreased progression free survival for patients on second line therapy with AA or enzalutamide following docetaxel treatment failure.
Titration as an effective strategy to reduce apalutamide induced skin rash: A multi-institutional real-world experience.
Authors: Yu Zhixian , Yu Kaiyuan , Lv Shihui , Wen Huihuang , Fang Weijie
Published: March 2023

197

Background: With increasing use of novel androgen receptor inhibitors to treat prostate cancer (PCa), better safety management has been spotlighted. Apalutamide (APA) is suggested for metastatic hormone-sensitive prostate cancer (mHSPC) and high-risk non-metastatic castrate-resistant prostate cancer (NM-CRPC). However, around 25% of patients will experience skin rash. This analysis aims to investigate whether dose titration might be effective to reduce the incidence of skin rash for apalutamide-treated patients. Methods: A retrospective analysis of 73 PCa patients received APA plus androgen deprivation therapy at 3 centers in Wenzhou, China by Aug 2022 was done. Titration was defined as starting APA from a low daily dose of 120mg or 180mg and gradually increase to 240mg. The study group was dose titration patients and compare group was patients received initial 240mg qd. 1 center used 1-week dose escalation (120mg qd in week 1, 180mg qd in week 2, 240mg qd in week 3 and after) strategy and the rest 2 centers used personalized plan (starting dose of 120 or 180mg qd, the physican decide when to increase the dose). Incidence of skin rash, Grade 3 skin rash, dose modification and termination were compared. We also compared the PSA response of two groups at 1,3 and 6 months. Results: 31 and 42 patients in study and control groups were enrolled. Median age was 75.36 years (56.0-90.0), with 1.67 m height (1.50-1.80) and 69.0 kg weight (47.5-92.0). 51% was mHSPC, 90% had Gleason score ≥ 8, 66% have a high tumor volume per CHAARTED. Incidence of skin rash was significantly lower in the study vs control (6.45% vs 26.19%, p=0.029). No patient in study vs 3 (7.5%) patients in control experienced Grade 3 rash. 2 (7.69%) and 9 (22.50%) patients in study and control had dose modification and 3 (7.5%) patients in control group terminated APA due to adverse events. PSA response was slightly lower in study group in month 1 (median PSA decline, study vs control, 85.80% vs 93.85%, p = 0.117) and was consistent in month 3 (95.17% vs 98.71, p=0.152) and month 6 (98.61% vs 99.19%, p=0.530). For selection of titration strategy, incidence of skin rash between 1-week strategy and personalized strategy was consistent (5.88% vs 7.14%, p=0.887). 1-week strategy has significantly better PSA decline at month 1 (median PSA decline, 1-week vs personalized 97.00% vs 75.54%, p=0.019) and performs slightly better in month 3 (99.29% vs 87.74%, p=0.087) vs personalized strategy, in which patients’ dose started to increase between week 2-8. Conclusions: Our results demonstrated that titration might be an effective strategy to reduce incidence of skin rash for PCa patients receiving apalutamide, with little interference to patient efficacy in PSA decline. For time frame to increase dose, 1-week plan might be a better selection. Future prospective studies are needed for validation.
Tumor transcriptomic profile in patients (pts) with advanced prostate cancer (PCa) with cribriform and signet ring-like histologies.
Authors: Seasor Tori , Balatico Michael , Chigarira Beverly , Sahu Kamal Kant Kant , Kim Jong Taek , Matynia Anna P , Barry Marc , Albertson Daniel Joseph , Mahlow Jon , Swami Umang , Agarwal Neeraj , Sirohi Deepika
Published: March 2023

259

Background: Histological subtypes of Pca are generally associated with worse clinical outcomes. Here in, we hypothesize that histological subtypes of PCa, e.g., cribriform, and signet ring-like, may have distinct genomic characteristics that may unravel new therapeutic targets. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: Pathology slides of advanced PCa (with cribriform and signet ring-like histology, and non-cribriform/signet ring-like histology as control) with transcriptomic data available. Only Gleason grade 4 or 5 were included to ensure homogeneity in population. Histology was independently reviewed by two genitourinary pathologists. RNA-sequencing of treatment naive primary prostate tissue was performed by a CLIA certified lab. DeSeq2 analysis was implemented in Bioconductor Software to analyze differentially expressed genes in patients with cribriform versus non-cribriform and signet ring-like versus non-signet ring-like histology. DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) in order to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Statistical significance level was predetermined at 0.05. Results: 34 patients were included: cribriform histology n=17, signet ring-like n=4, control non-cribriform/signet ring-like PCa n=13 (control were matched for age, PSA and disease volume). Compared to control, upregulated pathways in cribriform histology included adipogenesis, fatty acid and xenobiotic metabolism, while the down regulated pathways included mitotic spindle, G2M checkpoint and E2F targets. In signet ring-like histology, inflammatory response pathways were upregulated; DNA repair, MYC targets and androgen response pathways were downregulated. Conclusions: Cribriform, and signet ring-like histologic subtypes were noted to have distinct genomic expression profile. These data may need further validation and will guide further drug development.
Is transrectal ultrasound or magnetic resonance imaging better at estimating prostatic volume for patients with prostate cancer?
Authors: Sandberg Maxwell , Whitman Wyatt , Rong Anita , Davis Ronald , Hemal Ashok , Tsivian Matvey
Published: March 2023

314

Background: Determining the correct size (volume) of the prostate is imperative for patients with prostate cancer. Prostate size can affect many parameters in patient care such as cores in a biopsy taken and available treatment options. Traditionally, most patients underwent transrectal ultrasound (TRUS) during prostate biopsy to estimate prostatic volume. While TRUS is still used to estimate prostate volume, more recently prostate Magnetic Resonance Imaging (MRI) has also come into favor. Current literature indicates MRI is more accurate than TRUS for prostate size, but few studies exist, and whether differences in the two are clinically significant remains uncertain. The purpose of this study was to compare prostate volumes from TRUS and MRI to gross specimens after prostatectomy. Methods: Patients who underwent radical prostatectomy for prostate cancer between 2017–2022 were identified. TRUS and MRI measurements closest to the date of surgery were obtained. These were compared to gross prostate specimens after surgery, which was considered the gold standard. All TRUS volumes were recorded by a urologist during prostate biopsy using the ellipsoid formula (L*W*H*(π/6)). MRI measurements were done by a radiologist also using the ellipsoid formula. The weight and dimensions of gross specimens were measured by a pathologist. Ellipsoid formula was then used to calculate final volume measurements in gross specimens. Paired samples t-test was used to compare averages of TRUS and MRI to the gross specimen. Results: 83 patients were included in the study with an average age at prostatectomy of 65.47 years. TRUS volume significantly differed from gross specimen volume by an average of –4.56 mL (p=0.017) and gross specimen weight by -14.31 g (p <0.001). MRI volume was not significantly different from gross specimen volume, by an average of –0.56 mL (p=0.771) and was significantly different from prostate weight by –10.32 g (p <0.001). When compared to one another, TRUS and MRI significantly differed on average by –4 mL (p=0.033). Conclusions: MRI is more accurate than TRUS to estimate prostate volume. Both MRI and TRUS underestimate prostate weight. Urologists should be aware of potential inaccuracies when assessing preoperative prostate volume with TRUS, and recognize MRI is the best predictor of size. While imperfect, TRUS is still relatively accurate measuring prostate volume, and given its ease of availability and cost, we feel it is a useful modality to determine prostate size. [Table: see text]
US real-world first-line (1L) treatment patterns and outcomes for patients with metastatic urothelial carcinoma (mUC) following maintenance avelumab approval.
Authors: Li Haojie , Herms Lisa , Leong Traci , Conkling Paul R. , Franco Sonia , Singhal Puneet , Mamtani Ronac , Bupathi Manojkumar
Published: March 2023

483

Background: The introduction of the immune checkpoint inhibitors (ICI) pembrolizumab and atezolizumab has dramatically changed the 1L mUC treatment paradigm. These agents are currently recommended by the National Comprehensive Cancer Network for platinum-ineligible patients (irrespective of programmed death-ligand 1 (PD-L1) status) and, in the case of atezolizumab, for cisplatin-ineligible patients whose tumors express PD-L1. More recently, avelumab, received approval as the first ICI for the maintenance treatment of patients who have not progressed on 1L platinum-containing chemotherapy. In this study, we described real-world 1L treatment patterns and outcomes for mUC patients following avelumab maintenance approval. Methods: We used electronic medical record data from The US Oncology Network, which includes 1,400 affiliated physicians operating in over 500 sites of care across states and treats approximately 1.2 million cancer patients annually. mUC patients diagnosed between 30 April 2020 (i.e., ~3 months before avelumab maintenance approval) and 30 June 2021 were included, with follow-up until 31 December 2021, last patient record or death, whichever occurred first. Chart review was conducted to verify mUC diagnosis, baseline characteristics, treatment patterns, and clinical outcomes. Avelumab maintenance was defined as receiving avelumab after 1L platinum-containing chemotherapy, with no documented progressive disease prior to avelumab start or as maintenance therapy indicated by physician notes. Results: A total of 249 eligible mUC patients initiated 1L treatment. Of these, 132 (53%) received ICI monotherapy, 99 (40%) received platinum-containing chemotherapy, and 18 (7%) received other treatments. Almost one-third (n=32) of those who received 1L platinum-containing chemotherapy received avelumab maintenance therapy. ICI monotherapy use increased with age, ranging from 36% among <65-year-olds to 67% among ≥75-year-olds. During a median follow-up of 14.5 months, 68 (27%) patients received second-line treatment. Median (95% confidence interval) overall survival (OS) for 1L ICI monotherapy and 1L platinum-containing chemotherapy was 10.9 (7.2, 13.0) and 16.8 (13.5, not reached) months, respectively. Conclusions: During the 18-month period following maintenance avelumab approval, in this US community oncology setting, ICI monotherapy was the most utilized 1L treatment for mUC patients, especially among older patients. The uptake of maintenance avelumab was modest. Longer follow-up is needed to further characterize OS, especially for those who received platinum therapy followed by avelumab maintenance.
Understanding drivers of treatment preferences in locally advanced or metastatic urothelial carcinoma: A qualitative interview study with patients, caregivers, and physicians.
Authors: Apolo Andrea B. , Simon Nicholas I. , Farrar Mallory , Grewal Simrun , Hepp Zsolt , Mucha Lisa , Michaels-Igbokwe Christine , Heidenreich Sebastian , Cutts Katelyn , Gore John L.
Published: March 2023

492

Background: The development and selection of treatments for locally advanced or metastatic urothelial carcinoma (la/mUC) have historically focused on clinical outcomes while stakeholder preferences are often considered less frequently. To facilitate the consideration of various perspectives, this study explored factors that may influence preferences of patients, caregivers, and physicians around aspects of la/mUC treatments. Methods: Interview guides elicited perspectives on disease impact (symptoms, health-related quality of life [HRQOL], survival), therapy goals and unmet needs and were conducted with patients with la/mUC, their caregivers, and medical oncologists in the US. Qualitative semi-structured data were collected on symptoms, treatment expectations, and hypothetical treatments that required trade-offs between overall survival (OS), progression-free survival (PFS), cancer pain, and the risk of severe adverse events (SAEs). Participant’s willingness to accept AEs was also explored. Results: Thirty participants, including: 10 patients (mean age 58 years; 60% female, ineligible for cisplatin: 50%), 10 caregivers (mean age 50 years; 70% female), and 10 physicians (mean 17 years treating la/mUC; 30% female) were interviewed. The most frequently reported symptom at diagnosis was pain (patients 90%, caregivers 90%) and blood in urine (physicians 100%). All three groups reported emotional impacts with depression/sadness the most common. Patients (n=7) and caregivers (n=7) relied on physicians for decision-making but felt that alternative treatments were not discussed (patients: n=5; caregivers: n=3). All groups were willing to accept some level of risk of experiencing an AE, but the accepted risk of SAEs varied (patients: 0-50% risk of SAEs; caregivers: 5-100%; physicians: 3-30%). Physicians focused treatment discussions on AEs (n=8), and overall response rate (ORR; n=6), and rarely discussed survival (n=3). All three groups described PFS and treatment response as very or most relevant to them. In the hypothetical choice tasks, all would make trade-offs between OS, PFS, pain reduction and risk of SAEs; consistent with an approach that weighs benefits and risks in treatment selection. Conclusions: Patients likely may benefit from shared, informed decision-making to identify the most appropriate treatment option for them based on clinical outcomes, AEs, HRQOL, and pain control. All groups were willing to make benefit-risk trade-offs but preferences were heterogeneous. While this study included a relatively small number of patients, planned research informed by these results will expand and further identify which treatment attributes are most important to patients.